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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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CC-90010


str1

CC-90010

C21 H21 N O4 S, 383.46

CAS 1706738-98-8

1(2H)-Isoquinolinone, 4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methyl-

  • 4-[2-(Cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methyl-1(2H)-isoquinolinone
  • 4-[2-(Cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one
  • 4-[2-(Cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

Quanticel Pharmaceuticals Inc, Michael John BennettJuan Manuel BetancortAmogh BoloorStephen W. KaldorJeffrey Alan StaffordJames Marvin Veal

Image result for QUANTICEL

Celgene  (now a wholly owned subsidiary of  Bristol-Myers Squibb ) , following its acquisition of  Quanticel , is developing CC-90010, an oral inhibitor of BET (bromodomain and extraterminal) proteins, for the potential treatment of solid tumors and non-Hodgkin’s lymphoma.  In August 2019, a phase I trial for diffuse astrocytoma, grade III anaplastic astrocytoma and recurrent glioblastoma was planned

PATENT

WO2018075796 claiming solid composition comprising a bromodomain inhibitor, preferably 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one in crystalline form A.

PATENT

WO2015058160 (compound 89, page 103).

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=9B64008287A0D105A68DDF31141C7419.wapp1nA?docId=WO2015058160&tab=PCTDESCRIPTION

Example 89: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one

[00344] A suspension of 4-bromo-2-methylisoquinolin-l-one (100 mg, 0.42 mmol), bis(pinacolato)diboron (214 mg, 0.84 mmol), Pd(dppf)Cl2 (31 mg, 0.04 mmol) and potassium acetate (104 mg, 1.05 mmol) in dioxane (2 mL) under nitrogen was warmed up to 90 °C for 135 minutes. It was then cooled down to room temperature and diluted with ethyl acetate (8 mL). The mixture was washed with aqueous saturated solution of NaHC03 (8 mL) and brine (8 mL). The organic phase was separated, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purifed by normal phase column chromatography (10-90% EtOAc/Hexanes) to give the title compound (44 mg, 37%). 1H NMR (CDC13, 400 MHz) δ 8.43 (d, J = 7.9 Hz, 1 H), 8.40 (dd, J = 8.2 Hz, 0.9 Hz, 1 H), 7.68 (s, 1 H), 7.65 (ddd, J = 8.2, 8.2, 1.1 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 3.63 (s, 3H), 1.38 (s, 12H). LCMS (M+H)+ 286. Step 2: 4-[2-(cyclopropylmethox -5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

[00345] The title compound was prepared in a manner similar to Example 18, step 3, substituting 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methylisoquinolin-l(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one for N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (DMSO-d6, 400 MHz) δ 0.09 (m, 2 H), 0.29 (m, 1H), 0.35 (m, 1H),

0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s, 3H), 3.95 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.37 (d, J =

8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8,

2.4 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H). LCMS (M+H)+ 384.

[00346] Alternatively, 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one can be prepared as described below.

Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one

[00347] A mixture of 4-bromo-2-methylisoquinolin-l-one (8.0 g, 33.6 mmol),

bis(pinacolato)diboron (17.1 g, 67.2 mmol), KOAc (6.6 g, 67.2 mmol), Pd2(dba)3 (3.1 g, 3.36 mmol) and X-Phos (1.6 g, 3.36 mmol) in anhydrous dioxane (200 mL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (PE : EA = 15 : 1) to give the title compound (6.0 g, 62 %) as a solid.

Step 2: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

[00348] The title compound from Step 1 (5.0 g, 17.5 mmol), 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene (6.4 g, 21 mmol), K3PO4 (9.3 g, 43.9 mmol) and Pd(dppf)Cl2 (1.4 g, 1.75 mmol) in a dioxane/water (100 mL / 10 mL) mixture were stirred at 60 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA : DCM = 1 : 4).

Appropriate fractions were combined and concentrated under reduce pressure. The resultant solid was recrystallized from DCM / MTBE (1 : 1, 50 mL) to give the title compound (4.0 g, 60 %) as a white solid. 1H NMR: (CDC13, 400 MHz) δ 8.51 (dd, Ji = 8.0 Hz, J2 = 0.8 Hz, 1 H), 7.98 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.53 (m, 2 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.10 (m, 2 H), 3.88 (m, 2 H), 3.66 (s, 3 H), 3.09 (s, 3 H), 1.02-0.98 (m, 1 H), 0.44-0.38 (m, 2 H), 0.11-0.09 (m, 2 H). LCMS: 384.1 (M+H)+

Patent

WO-2020023438

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020023438&tab=PCTDESCRIPTION&_cid=P10-K6HCMJ-20465-1

A process for preparing bromodomain inhibitor, particularly 4-[2(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one (having HPLC purity of 99%; compound 1; (hereafter referred to as C-90010)) and its hydrates, solvates, prodrugs and salts comprising the reaction of a substituted 4-(methylsulfonyl)phenol compound with a quinoline derivative, followed by purification is claimed. Also claimed are novel intermediates of CC-90010 and their processes for preparation. Further claimed are novel crystalline form of CC-90010. CC-90010 is known and disclosed to be a bromodomain containing protein inhibitor, useful for treating cancer.

Scheme 10: Synthesis of Compound 1

[0090] Acetonitrile (1.6L) was charged to a mixture of Compound 2 (156.7g, 460 mmol), Compound 3 (lOOg, 420 mmol) and potassium phosphate tribasic (223g, l.OSmol). Agitation

was begun and water (400mL) charged to the batch. The system was vacuum purged three times with nitrogen and charged with Pd(PPh3)2Cl2 (2.9g, 4 mmol) and the system vacuum purged three times with nitrogen. The batch was heated to about 65 to about 75 °C (or any temperature in between and including these two values) and contents stirred for at least about 16 hours until reaction was complete by HPLC analysis. The batch was cooled to about 60 to about 70 °C (or any temperature in between and including these two values), agitation halted and the mixture allowed to settle. The bottom aqueous layer was removed. Water (150mL) and acetonitrile (700mL) were charged at about 60 to about 70°C (or any temperature in between and including these two values). Ecosorb C-941 (15g) and Celite (lOg) were charged to the reaction vessel at about 60 to about 70°C (or any temperature in between and including these two values). After lh, the mixture was filtered to remove solids. The solids were washed twice each with 18% water in acetonitrile (500 mL) at about 60 to about 70°C (or any temperature in between and including these two values). The filtrates were combined and concentrated under atmospheric pressure to a final volume of 1.5L. The batch was cooled to about 60 to about 65°C (or any temperature in between and including these two values) and seeded with Compound 1 (1 g). After lh, water (500 mL) was charged over at least 1 hour at about 60 to about 65°C (or any temperature in between and including these two values). The slurry was cooled to about 15 to about 25°C (or any temperature in between and including these two values) over 4 hours. The product was collected by suction filtration. The wet cake was washed with 45% water in acetonitrile (500mL) twice. The product was dried under vacuum at about 40°C with nitrogen purge. Yield: 139g of 1.

[0091] The above procedure for coupling Compound 3 and Compound 2 to produce

Compound 1 may be modified in any of the ways that follow. Reaction solvents: Different reaction solvents from acetonitrile can be used, including tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, and isopropanol. Boronic ester: Different boronic esters from Compound 2 can be used, including pinacolato ester compound 7, and the free boronic acid of Compound 2. Examples of boronic esters can be found in Lennox et al., Chem. Soc. Rev., 43: 412 (2014). Carbon treatment: Different carbon treatments from Ecosorb C-941 could be used. Different amounts of carbon, from 0.01 to 0.5X weight can be used. The carbon can be eliminated. Different amounts of Celite, from 0.01 to 0.5X weight can be used.

Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used.

The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCk(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy3 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5);

Pd(PPh3)2Cb (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

VI. Purification of Compound 1 fCC-900101 bv crystallization from formic acid and water

[0092] Described herein are methods of purifying Compound 1 by crystallization from formic acid and water. Also described are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1 and two metastable forms, Form 4

The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCh(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy3 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5);

Pd(PPh3)2Cl2 (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

VI. Purification of Compound 1 (CC-90010! bv crystallization from formic acid and water

[0092] Described herein are methods of purifying Compound 1 by crystallization from formic acid and water. Also described are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1 and two metastable forms, Form 4

33 -a

and Form 5. Supporting data (XRPD, DSC, photomicroscopy) for all three forms is provided in the examples below.

[0093] The stmcture of Compound 1 (CC-90010) is shown below:

Example 1: Synthesis of Compound 1

[0217] Synthesis of compound 1 was accomplished according to Scheme 1 below. Referring to Scheme 1, synthesis commenced with bromination of starting material 4-(methylsulfonyl)phenol 4, to produce compound 5. Compound 5 was O-alkylated with (bromomethyl)cyclopropane to produce compound 6. Boronate Compound 2 was then formed by borylation of Compound 6 with Pd catalyst and bis(pinacolato)diboron to produce transient Compound 7, which was subsequenctly treated with diethanolamine (DBA) to afford cross-coupling partner Compound 2. Cross-coupling partner Compound 3 was formed in one pot starting from commercially available Compound 8. Compound 8 was N-methylated and brominated to afford Compound 3. Compounds 2 and 3 were cross-coupled (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995)) to afford the target compound 1.

Scheme 1: Synthesis of compound 1

1.1: Bromination of 4

[0218] The bromination of Compound 4 to produce Compound 5 itself is simple, however stopping at the mono-brominated Compound 5 was challenging. The bis-brominated Compound 5-a (see Scheme 2 below) is a particularly pernicious impurity as it couples downstream to form a di ffi cult-to-purge impurity.

Scheme 2: Bromination of Compound 4

[0219] The key to high purity with reasonable yield was to exploit the solubility differences of the starting material Compound 4 (46 mg/ml at 20 °C) and the product Compound 5 (8 mg/ml) in CH2CI2. These solubility differences are summarized in Table 3 below.

[0220] This solubility difference is exploited by performing the reaction at a high

concentration to drive Compound 5 out of solution once formed, thereby minimizing its ability to react further with the brominating reagent to form Compound 5-a diBr. The reaction is seeded with Compound 5 to initiate its crystallization.

[0221] In Fig. 22 (Conversion of Compound 4 to Compound 5: Effect of Sulfuric Acid) it can be seen that in the absence of acid the initial reaction to Compound 5 is rapid, however the conversion plateaus at about 30% Compound 5. The main side product was found to be the impurity Compound 5-a diBr (see Fig. 23: Conversion of Compound 5 and Compound 5-a diBr: No H2SO4). Addition of increasing amounts of sulfuric acid leads to a higher conversion to desired Compound 5.

[0222] Fig. 24 (Compound 4 to Compound 5 Reaction Profile: Portion-wise Addition of NBS, Seeding) depicts further reaction control. The portion-wise addition ofNBS after addition of catalytic sulfuric acid minimizes the temperature rise, and the addition of Compound 5 after an initial NBS charge promotes the reactive crystallization of Compound 5. After about 6 to 7 hours of reaction it can be seen that the major product is Compound 5, with only a small (<5%) of the di-brominated impurity formed. In contrast, in a reaction where Compound 4 and all of the NBS were charged followed by the addition of 4 volumes of methylene chloride, a rapid exotherm resulted and undesired Compound 5-a diBr was found to be the major product.

[0223] Thus, the reaction was run under a high concentration in CH2CI2 with a portion-wise solid addition of NBS (to control both availability of the electrophile and the exotherm). An end of reaction slurry sample typically showed not more than 5% of the starting material Compound 4 remaining. After filtration the crude cake was washed with cold CH2CI2 and the OkCk-washed filter cake contained not more than 0.5% by weight dibrominated Compound 5-a. It also contained a large amount of HPLC-silent succinimide.

[0224] The following procedure was carried out: Compound 4 (25g, 145mmol) followed by CH2CI2 (lOOmL) were added to a reaction vessel and agitated. The batch was adjusted to 17 °C to 23 °C. Sulfuric acid was charged (2.7mL, Slmmol) to the batch maintaining 17 °C to 23°C. The batch was stirred at 17 °C to 23 °C for 10 minutes to 20 minutes. The first portion of A-bromosuccimide (NBS) was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23°C and stirred for at least 30 min. The second portion of NBS was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23°C and stirred for at least 30 min. The batch was seeded with

Compound 5 (0.02wt) and stirred for ca. 30 min at 17 °C to 23 °C to induce crystallization.

[0225] The third portion of NBS was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23 °C and stirred for at least 30 min. NBS (6.5g, 36.5 mmol) was charged to the batch at 17 °C to 23 °C and stirred for at least 30 min. Additional CH2CI2 was charged (50mL) to the batch while maintaining 17 °C to 23 °C to aid in agitation and transfer for filtration. The batch was stirred at 17 °C to 23 °C until complete by HPLC analysis (~20 – 40 h). The product was collected by suction filtration. The filter cake was slurry washed with CH2CI2 (3 x 50mL) at 17 °C to 23 °C (target 20 °C). The filter cake was slurry washed with purified water (3.0vol) at 65 °C to 75 °C for 2 to 3 hours. Then, the filter cake was slurry washed with purified water (3 x 1.0 vol, 3 x 1.0 wt) at 17 °C to 23°C. The wet cake was dried under vacuum with nitrogen bleed at 60 °C. Yield: 27g 5 (74% molar) >97% by weight. ¾ NMR (500 MHz, de-DMSO) 8.01 (1H, d, 4J = 2.1 Hz, RO-Ar meta- H ), 7.76 (1H, dd, J = 8.6 and 4J = 2.1 Hz, RO-Ar meta-H ), 7.14 (1H, d, J = 8.6 Hz, RO-Ar ortho- H), 3.38 (1H, br s, OH), 3.20 (3H, s,

CHJ); MS (ES-) calc. 249/251; found 249/251. Melting point (MP): (DSC) 188 °C.

[0226] The above procedure allowed for the following modifications. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as acetonitrile, tetrahydrofuran, or 2- methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from about 2X vol to about 20 X vol (with respect to Compound 4). Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Different amounts of the brominating reagent can be used, from about 0.8 equiv to about 1.9 equiv. Bromination reagent addition: The brominating reagent can be added all at once, portion wise in about 2 to about 20 portions, or continuously. The addition times can vary from about 0 to about 72 hours. Temperature: Reaction temperatures from about 0 °C to about 40 °C could be used. Acids: Different acids can be envisioned, including benzenesulfonic acid, para-toluenesulfonic acid, triflic acid, hydrobromic acid, and trifluoroacetic acid. Isolation: Instead of directly filtering the product and washing with methylene chloride and water, at the end of reaction an organic solvent capable of dissolving Compound 5 could be charged, followed by an aqueous workup to remove succinimide, and addition of an antisolvent or solvent exchange to an appropriate solvent to crystallize Compound 4. Drying: A temperature range of about 10 to about 60 °C could be used for drying.

[0227] An alternative process to Compound 5 has also been developed. This process is advantageous in that it does not use a chlorinated solvent, and provides additional controls over the formation of the Compound 5-a dibromo impurity. See Oberhauser, T. J Org. Chem 1997, 62, 4504-4506. The process is as follows. Compound 4 (10 g, 58 mmol) and acetonitrile (100 ml) were charged to the reactor and agitated. The batch was cooled to -20 °C. Triflic acid (CF3SO3H or TfOH, 5.5 mL, 62 mmol) was charged while maintaining a batch temperature of -10 to -25 °C. N-bromosuccinimide was charged (NBS, 11.4 g, 64 mmol), stirred at -10 to -25 °C for 30 minutes, then warmed to 20 °C over 3 to 4 hours. Agitation was continued at 15 °C to 25 °C until reaction completion. If the reaction conversion plateaued before completion, the reaction was cooled to -5 to -15 °C, and additional NBS was added, the amount based off of unreacted starting material, followed by warming to 15 °C to 25 °C and reacting until complete.

[0228] After reaction completion, the batch was warmed to 40 °C to 50 °C and concentrated under reduced pressure to 40 mL. The batch was cooled to -5 °C to -15 °C and the resulting product solids were filtered off. The solids were slurry washed three times, each with 20 mL water, for at least 15 minutes. The final cake was dried at 50 °C to 60 °C under reduced pressure to furnish 10 g of 5 containing less than 0.1% MeCN, 0.07% water, and 0.1% triflic acid (TfOH) by weight.

[0229] Alternatives to the above procedure employing MeCN and TfOH are as follows. Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination Reagent Stoichiometry: Different amounts of the brominating reagent can be used, from about 0.8 equiv to about 2 equiv. Drying: A temperature range of about 10 °C to about 60 °C could be used for drying.

[0230] The impurity 5-a is was prepared and characterized as follows. 10 g of Compound 4 and sulfuric acid (35 mol%) were dissolved in MeOH (10 vol). The mixture was set to stir at 20 °C to 25 °C for 5-10 min and 2.0 equivalents of NBS were charged in one portion. The resulting yellow mixture was stirred for three days at 20-25 °C. The batch was concentrated under reduced pressure and the resulting solid was slurried in water at 95-100 °C for 3 hours. After a second overnight slurry in CH2CI2 at room temperature, the batch was filtered and dried to give a white solid 5-a (15.0 g, 78%). ¾ NMR (500 MHz, de-DMSO), 8.05 (2H, s, ArH), 3.40 (1H, br s, HO-Ar), 3.28 (3H, s, CH3); MS (ES) calc. 327/329/331; found

327/329/331; MP (DSC): 226 °C (onset 221 °C, 102 J/g); lit. 224-226 °C.

1.2: O-alkylation of 5 to produce 6

[0231] Compound 6 was prepared according to Scheme 7 below.

Scheme 7: O-alkylation of 5 to produce 6

[0232] Compound 5 (100 g, 398 mmol) and methyl ethyl ketone (MEK, 700 mL) were charged to the reaction vessel and agitated. Potassium carbonate (K2CO3, 325 mesh 82.56 g, 597 mmol) was then charged to the stirred reaction vessel at 15 °C to 25 °C.

Bromomethylcyclopropane (64.4 mL, 664 mmol) was charged to the reaction vessel over at least 1 hour, maintaining the temperature between 15 °C to 25 °C. MEK (200 mL) was added into the reactor and the reactor heated to 65 to 75 °C. The contents of the reaction vessel were stirred at 65 to 75°C for approximately 10 hours until reaction was complete by HPLC analysis. Water (3.0 vol, 3.0wt) was charged to the vessel maintaining the temperature at 65 to 75 °C. The batch was stirred at 65 to 75 °C. The phases were allowed to separate at 65°C to 75 °C and the lower aqueous phase was removed. Water (300 mL) was charged to the vessel maintaining the temperature at 65 °C to 75 °C. The batch was agitated for at least 10 minutes at 65 to 75 °C. The phases were allowed to separate at 65 °C to 75 °C and the lower aqueous phase was removed. The water wash was repeated once. The temperature was adjusted to 40 to 50°C. The mixture was concentrated to car. 500 mL under reduced pressure. The mixture was distilled under reduced pressure at up to 50 °C with MEK until the water content was <1.0% w/w. n-heptane (500mL) was charged to the vessel maintaining the temperature at 40 to 50 °C. The mixture was continuously distilled under vacuum with n-heptane (300mL), maintaining a 1L volume in the reaction vessel. Compound 6 seeds (0.0 lwt) were added at 40 to 50 °C. The mixture was continuously distilled under reduced pressure at up to 50 °C with n-heptane (300mL) while maintaining 1L volume in the reactor. The batch was cooled to 15 to 25 °C and aged for 2 hours. The product was collected by suction filtration. The filter cake was washed with a solution of 10% MEK in n-heptane (5vol) at 15 to 25°C. The filter cake was dried under reduced pressure at up to 40 °C under vacuum with nitrogen flow to afford 95g of 6. 1H NMR (500 MHz, de-DMSO) 8.07 (1H, d, 4J = 2.2 Hz, ArH), 7.86 (1H, d, J = 8.7 Hz, meta-ArH), 7.29 (1H, d, J = 8.8 Hz, ortho-AiK),

4.04 (2H, d, J = 6.9 Hz, OCH2CH), 3.21 (3H, s, CH3), 1.31-1.24 (1H, m, OCH), 0.62- 0.58 (2H, m, 2 x CHCHaHb), 0.40-0.37 (2H, m, 2 x CHC¾Hb); MS (ES+) calc. 305/307; found 305/307; MP: (DSC) 93 °C.

[0233] The following modifications of the above reaction, synthesis of 6 from 5, may be employed as well. Solvent: Different solvents could be used, for example acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, or 2-methyl tetrahydrofuran. Reaction volume: Reaction volumes of 3 to 30 volumes with respect to 3 could be used. Base: Different inorganic bases, such as cesium carbonate or phosphate bases (sodium, potassium, or cesium) could be used. Also, organic bases, such as trimethylamine or diisopropyldiimide could be used. Base particle size: Different particle sizes of potassium carbonate from 325 mesh could be used. Reaction temperature: A lower temperature, such

as 50 °C could be used. A higher temperature, such as about 100 °C could be used. Any temperature above the boiling point of the solvent could be run in a pressure vessel.

Isolation: Different solvent ratios of MEK to n-heptane could be used. Different amounts of residual water can be left. Different amounts of seeds, from 0 to 50% could be used.

Seeding could take place later in the process and/or at a lower temperature. An un-seeded crystallization can be employed. A different isolation temperature, from 0 °C to 50 °C could be used. A different wash could be used, for example a different ratio of MEK to n-heptane. A different antisolvent from n-heptane could be used, such as hexane, pentane, or methyl tert-butyl ether. Alternatively, the batch could be solvent exchanged into a solvent where Compound 3 has a solubility of less than 100 mg/ml and isolated from this system. Drying: A temperature range of 10 to 60 °C could be used for drying.

[0234] Compound 10, shown below may also be formed as a result of O-alkylation of unreacted 4 present in product 5, or alternatively from or via a palladium mediated proteodesbromination or proteodesborylation in subsequent chemistry discussed in Example 1.3 below.

[0235] Preparation of methylsulfonylphenyl(cyclopropylmethyl) ether 10: Compound 4 (0.86 g, 5.0 mmol) and K2CO3 (1.04 g, 7.5 mmol) were slurried in acetone (17 mL, 20 vols). Cyclopropylmethyl bromide (0.73 mL, 7.5 mmol) was added in several small portions over ~1 minute and the reaction mixture heated to 50 °C for 48 hours, then cooled to 25 °C. Water (5.0 mL) was added with stirring and the acetone was evaporated on a rotary evaporator from which a fine white solid formed which was filtered off and returned to a vessel as a damp paste. A 1 : 1 mixture of MeOH/ water (8 mL) was added and heated to 40 °C with stirring. After 1 hour, the white solid was filtered off. Some residual solid was washed out with fresh water that was also rinsed through the cake, which was then isolated and left to air dry over the two days to give a dense white solid 10 (1.00 g, 88%). ¾ NMR (500 MHz, CDCb) 7.85

(2H, d, J = 8.8 Hz, RO-Ar ortho-H), 7.00 (2H, d, J = 8.8 Hz, RO-Ar meta- H), 3.87 (2H, d, J = 7.0 Hz, OCH2CH), 3.02 (3H, s, CHs), 1.34-1.23 (1H, m, OCH2CH), 0.72-0.60 (2H, m, 2 x CHCHflHb), 0.42-0.31 (2H, m, 2 x CHCH^.

1.3: Synthesis and Isolation Coupling Partner Boronic Ester 2

[0236] The final bond forming step to Compound 1 is a Suzuki-Miyaura coupling between Compounds 2 and 3, as shown in Scheme 3 below (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995)). Early studies demonstrated that the boronic ester of the isoquinolinone Compound 3-a had poor physical attributes and solid phase stability (Kaila, N. et al., J. Med Chem., 57: 1299-1322 (2014)). The pinacolatoboronate of the O-alkyl phenol, Compound 7, had acceptable solid phase stability and could be isolated via crystallization.

Scheme 3: Suzuki-Miyaura coupling between 2 and 3

[0237] Process robustness studies for the isolation of Compound 7, however, indicated that Compound 7 has poor solution stability, decomposing primarily to the proteodeborylated compound 10, as shown in Scheme 4 below. This was particularly problematic as the isolation process involved a solvent exchange from 2-MeTHF (2-methyl tetrahydrofuran) to iPrOAc (isopropyl acetate), which is not a fast unit operation on scale.

Scheme 4: Modification of 7

[0238] A search for a more stable boronic ester was undertaken. Early attempts targeted making N-methyliminodiacetic acid (MID A) boronate Compound 2-a (E. Gilis and M. Burke,“Multi step Synthesis of Complex Boronic Acids from Simple MIDA Boronates,” J Am. Chem. Soc., 750(43): 14084-14085 (2008)), however, all attempts resulted in product decomposition. Applicant then turned to a relatively obscure boronate formed by the addition of diethanolamine to Compound 7 (Bonin et al., Tetrahedron Lett., 52: 1132-1135 (2011)). Addition of diethanolamine to a solution of Compound 7 led to rapid ester formation and concomitant crystallization of Compound 2.

[0239] The discovery of boronic ester Compound 2 allowed for a simple, fast, high-yielding, high-purity process comprising the following procedure. Tetrahydrofuran (THF, 1500mL) was charged to a flask containing Compound 6 (100g, 328 mmol), bis(pinacolato)diboron (90.7g, 357 mmol) and cesium acetate (CsOAc, 158g, 822 mmol). The system was vacuum purged three times with nitrogen. Pd(PPh3)2Cl2 (13.8g, 20 mmol) was charged to the reaction and the system was vacuum purged three times with nitrogen. The reaction was then heated to 55 to 65°C.

[0240] The batch was stirred for approximately 8 hours until reaction was complete by HPLC analysis. The batch was cooled to 15 to 25 °C (target 20 °C ) and charged with silica gel (20g) and Ecosorb C-941 (20g). After lh, the mixture was filtered to remove solid. The residual solids were washed twice, each with THF (300mL). The filtrate and washes were combined. In a separate vessel, diethanolamine (34.5mL, 360 mmol) was dissolved in THF (250 mL). The diethanolamine solution in THF (25mL) was then charged to the batch. After 10 minutes, the batch was seeded with 2 (1 g) and aged for 1 to 2 hours. The remaining of the diethanolamine solution in THF was charged to the batch over at least 2 hours and the slurry was stirred for at least 2 hours. The product 2 was collected by suction filtration. The wet cake was washed thrice with THF (200mL). The material was dried under vacuum at 40 °C with nitrogen purge yielding 94.6g of 2.

[0241] The reaction to synthesize Compound 2 from Compound 6 described above may be modified as follows. Solvent: Different solvents from THF could be used, such as 1,4 dioxane or 2-methyltetrahydrofuran. Reaction volume: The reaction volume can be varied from 4 to 50 volumes with respect to compound 2. Catalyst and base: Different palladium catalyst and bases can be used for the borylation. Examples can be found in Chow et al., RSC Adv., 3 : 12518-12539 (2013). Borylation reaction temperature: Reaction temperatures from room temperature (20 °C) to solvent reflux can be used. Carbon/ Silica treatment:

The treatment can be performed without silica gel. The process can be performed without a carbon treatment. Different carbon sources from Ecosorb C-941 can be used. Different amounts of silica, from 0.01X to IX weight equivalents, can be used. Different amounts of Ecosorb C-941, from 0.01X to IX weight equivalents, can be used. Crystallization: A different addition rate of diethanolamine can be used. Different amounts of diethanolamine, from 1.0 to 3.0 molar equivalents can be used. A different cake wash with more or less THF can be used. Different amount of seeds from 0.0001X wt to 50X wt can be used.

Alternatively, the process can be unseeded. Drying: A temperature range of 10 °C to 60 °C could be used for drying.

[0242] The subsequent Suzuki-Miyaura coupling between Compounds 2 and 3 also proceeded well, providing over 20 kg of crude compound 1 with an average molar yield of 80% and LCAP of 99.7%.

1.4: Synthesis of Coupling Partner 3

[0243] Cross-coupling partner 3 was prepared by two different processes corresponding to Schemes 8 and 9 shown below.

Scheme 8: Process A for preparation of 3

[0244] According to Process A, Compound 9 (100g, 628 mmol) was dissolved in acetonitrile (450 mL) at room temperature. In a separate vessel, N-bromosuccinimide (NBS, 112g, 628 mmol) was suspended in acetonitrile (1 L). Compound 9 in acetonitrile was charged to the NBS slurry over at least 45 minutes. The contents of the reaction vessel were warmed to 45 °C to 55 °C and the batch stirred until the reaction was complete by HPLC analysis. The batch was cooled to 35 °C to 45 °C and ensured dissolution. Norit SX plus carbon (lOg) was charged to the mixture and the reaction mixture adjusted to 55 °C to 60 °C. The mixture was stirred at 55 °C to 60 °C for about lh and the mixture filtered at 55 °C to 60 °C to remove solids. The solids were washed with acetonitrile (500mL) at 55 °C to 60 °C. The volume of the combined filtrate was reduced to 900 mL by distilling off acetonitrile under reduced pressure. The batch with Compound 3 (lg) and stirred at 35 °C to 45 °C for at least 60 minutes. The contents of the reaction vessel were cooled to 15 °C to 25 °C over at least 1 hour. Water (2000 mL) was charged to the reaction vessel over at least 90 minutes and the slurry aged for at least 60 minutes. The product was collected by suction filtration. The cake was washed with a premixed 5% solution of acetonitrile in water (300mL). The wet cake was dried under vacuum at 40 °C with nitrogen purge. Yield: 120g of 3.

[0245] The above procedure, Process A for this synthesis of 3, may be practiced with alternative reagents and conditions as follows. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as methylene chloride, chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as tetrahydrofuran, or 2-methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from 2X vol to 40 X vol (with respect to Compound 9). Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent Stoichiometry: Different amounts of the brominating reagent can be used, from 0.8 equiv to 2 equiv. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 °C to 60 °C could be used for drying.

Scheme 9: Process B for preparation of 3

[0246] According to Process B, Compound 3 can be formed starting from 8 via non-isolated compound 9 as follows. Compound 8 (80 g, 55 mmol), cesium carbonate (CS2CO3, 215 g, 66 mmol), and acetonitrile (800 mL) were charged to the reactor. The temperature was adjusted from 15 to 25 °C and iodomethane charged to the reactor (Mel, 86 g, 0.61 mol) while maintaining a batch temperature below 25 °C. The batch was heated to 40 °C and agitated for 10 hours to form Compound 9. The batch was cooled to 25 °C, filtered into a fresh reactor to remove solids, and the solids washed twice with acetonitrile. The combined organic layers were concentrated via atmospheric distillation to about 320 mL.

[0247] In a separate reactor N-bromosuccinimide (NBS, 98.1 g, 0.55 mol) was charged to acetonitrile (800 mL) and agitated. The batch containing Compound 9 was transferred to the NBS solution while maintaining a batch temperature of 15 to 25 °C. The batch was heated to 45 to 55 °C and agitated for at least 4 hours to allow for reaction completion to Compound 3. Upon reaction completion, Norit SX Plus activated carbon (8 g) was charged, and agitated at 45 to 55 °C for one hour. The batch was filtered into a fresh vessel, the Norit SX plus cake was washed with 400 ml of 45 to 55 °C acetonitrile. The acetonitrile layers were combined, cooled to 35 to 45 °C, and distilled under reduced pressure to 720 mL. The batch was adjusted to a temperature of 40 °C, charged with Compound 3 seeds (0.8 g), agitated for one hour, cooled to 15 to 25 °C over at least on hour, then charged with water (1600 mL) over at least two hours. The mixture was agitated for an additional one to two hours, filtered, the cake washed with a premixed 5% solution of acetonitrile in water (240 mL). The wet cake was dried under vacuum at 40°C with nitrogen purge. Yield: 52 g of 3.

[0248] Process B to synthesize Compound 3, described above, may be modified as follows. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as methylene chloride, chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as tetrahydrofuran, or 2-methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from 2X vol to 40 X vol (with respect to Compound 8).

Alkylating reagent: Alternative methylating reagents to methyl iodide can be used such as dimethylsulfate. Alkylating reagent stoichiometry: 1 to 10 molar equivalents of methyl iodide may be used. Base: Different inorganic bases, such as potassium carbonate or phosphate bases (sodium, potassium, or cesium) could be used. Brominating agents:

Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Different amounts of the brominating reagent can be used, from 0.8 equiv to 2 equiv. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. Seeding levels from 0.0001% to 50% can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying.

1.5: Cross-coupling of 2 and 3 to Produce Target Compound 1

[0249] 1 is synthesized by Suzuki cross-coupling of 3 and 2 according to Scheme 10 and as described below.

Scheme 10: Synthesis of 1

[0250] Acetonitrile (1.6L) was charged to a mixture of Compound 2 (156.7g, 460 mmol), Compovmd 3 (lOOg, 420 mmol) and potassium phosphate tribasic (223 g, l.OSmol). Agitation was begun and water (400mL) charged to the batch. The system was vacuum purged three times with nitrogen and charged with Pd(PPh3)2Cl2 (2.9g, 4 mmol) and the system vacuum

purged three times with nitrogen. The batch was heated to 65 to 75°C and contents stirred for at least 16 hours until reaction was complete by HPLC analysis. The batch was cooled to 60 to 70°C, agitation halted and the mixture allowed to settle. The bottom aqueous layer was removed. Water (150mL) and acetonitrile (700mL) were charged at 60 to 70°C. Ecosorb C-941 (15g) and Celite (lOg) were charged to the reaction vessel at 60 to 70°C. After lh, the mixture was filtered to remove solids. The solids were washed twice each with 18% water in acetonitrile (500 mL) at 60 to 70°C. The filtrates were combined and concentrated under atmospheric pressure to a final volume of 1.5L. The batch was cooled to 60 to 65°C and seeded with Compound 1 (1 g). After lh, water (500 mL) was charged over at least 1 hour at 60 to 65°C. The slurry was cooled to 15 to 25°C over 4 hours. The product was collected by suction filtration. The wet cake was washed with 45% water in acetonitrile (500mL) twice. The product was dried under vacuum at 40°C with nitrogen purge. Yield: 139g of 1.

[0251] The above procedure for coupling Compound 3 and Compound 2 to produce

Compound 1 may be modified in any of the ways that follow. Reaction solvents: Different reaction solvents from acetonitrile can be used, including tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, and isopropanol. Boronic ester: Different boronic esters from Compound 2 can be used, including pinacolato ester compound 7, and the free boronic acid of Compound 2. Examples of boronic esters can be found in Lennox, Alister, J.J., Lloyd-Jones, Guy C. Chem. Soc. Rev., 2014, 43, 412. Carbon treatment: Different carbon treatments from Ecosorb C-941 could be used. Different amounts of carbon, from 0.01 to 0.5X weight can be used. The carbon can be eliminated. Different amounts of Celite, from 0.01 to 0.5X weight can be used. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1);

cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCk(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy3 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5); Pd(PPh3)2Cl2 (Cas# 13965-03-2). Examples of

catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

1.6: Crystallization of 1

[0252] The final isolation of Compound 1 requires a polish filtration. For this, the batch must be completely soluble. Unfortunately, Compound 1 has low solubility in almost all

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Class 3 and common Class 2 (e.g. THF, MeCN) solvents (ICH

Harmonized Guideline“Impurities: Guideline for Residual Solvents Q3C(R6)” October 20, 2016). A reasonable solubility was obtained in a warm MeCN-water mix, but this is not an optimal system (requires a heated filtration, MeCN has a residual solvent limit of only 410 ppm). Additional solvents with reasonable solubility (>50 mg/ml) include N-methyl-2- pyrrolidone (NMP) and dimethylacetamide (DMAc); but the development of isolations from these solvents required large volumes and raised residual solvent limit concerns (530 ppm or less for NMT and 1090 ppm or less for DMAc).

catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

1.6: Crystallization of 1

[0252] The final isolation of Compoxmd 1 requires a polish filtration. For this, the batch must be completely soluble. Unfortunately, Compound 1 has low solubility in almost all

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Class 3 and common Class 2 (e.g. THF, MeCN) solvents (ICH

Harmonized Guideline“Impurities: Guideline for Residual Solvents Q3C(R6)” October 20, 2016). A reasonable solubility was obtained in a warm MeCN-water mix, but this is not an optimal system (requires a heated filtration, MeCN has a residual solvent limit of only 410 ppm). Additional solvents with reasonable solubility (>50 mg/ml) include N-methyl-2- pyrrolidone (NMP) and dimethylacetamide (DMAc); but the development of isolations from these solvents required large volumes and raised residual solvent limit concerns (530 ppm or less for NMT and 1090 ppm or less for DMAc).

[0253] Formic acid is one ICH Class 3 solvent in which Compound 1 is highly soluble, having a solubility greater than 250 mg/ml at 20 °C. The solubility curve of Compound 1 in formic acid-Water is quite steep (see Figure 7), which enables a volumetrically efficient process.

[0254] Initial attempts to recrystallize crude Compound 1 involved dissolving in formic acid, polish filtering, and charging polish filtered water to about 20% supersaturation, followed by seeding with the thermodynamically most stable form (Form 1), followed by slow addition of water to the final solvent ratio, filtration, washing, and drying. Applicant observed that during the initial water charge, if the batch self-seeded it formed a thick slurry. X-ray diffraction (XRD), differential scanning calorimetry (DSC), and photomicroscopy demonstrated that a metastable form was produced. Once seeded with Form 1, the batch converted to the desired form (Form 1) prior to the addition of the remaining water. This process worked well during multiple lab runs, consistently delivering the desired form and purity with about 85% yield.

[0255] Unfortunately, upon scale-up, the batch did not convert to Form 1 after seeding. Additional water was charged and the batch began to convert to the desired form (mix of Form 1 and the metastable form by X-ray powder diffraction (XRPD)). When additional water was charged, the XRPD indicated only the metastable form. After a few hours with no change, Applicant continued the water charge to the final solvent ratio, during which time the batch eventually converted to Form 1. This process is summarized in Figure 8.

[0256] It was subsequently found by closer analysis of the plant and laboratory retains that a new metastable form was formed during scale up, with a similar, but different XRPD pattern. This form (metastable B) could be reproduced in the laboratory, but only when the batch has a high formic acid:water ratio and is seeded with Form 1. Without Form 1 seeds, metastable A is the kinetic form. Both metastable forms converted to Form 1 with additional water and/or upon drying, leading Applicant to believe that the metastable forms are formic acid solvates. These findings are summarized in Figure 9.

[0257] While there is little risk in not being able to control the final form, there is a risk of forming a difficult-to-stir slurry which can lead to processing issues. The crystallization procedure was therefore modified to keep a constant formic acid-water ratio. This was performed by charging 2.4X wt. formic acid and 1.75X wt. water (final solvent composition)

to the crystallizer with 0.03X wt. Form 1 seeds, and performing a simultaneous addition of Compound 1 in 6. IX wt. formic acid and 4.4X wt. water. The batch filtered easily and was washed with formic acid/water, then water, and dried under reduced pressure to yield 8.9 kg of Compound 1 (92% yield) with 99.85% LCAP and N.D. formic acid.

Example 2: Exemplary high throughput experimentation reaction

[0258] The following procedure is an exemplary high throughput experimentation reaction.

[0259] An overview of the reaction is shown below in Scheme 5:

Scheme 5: Reaction conditions tested for cross-coupling reaction of 2 and 3

[0260] Pd catalysts were dosed into the 24-well reactor vial as solutions (100 pL of 0.01 M solution in tetrahydrofuran (THF) or dichloroethane (DCE) depending upon the solubility of the ligand). Plates of these ligands are typically dosed in advance of the reaction, the solvent is removed by evacuation in an evaporative centrifuge and plates are stored in the glovebox. The catalysts screened in the coupling are the following: XPhos, SPhos, CataCXium A, APhos, P(Cy)3, PEPPSI-IPent. For the first five ligands, these were initially screened as the Buchwald Pd G2/G3 precatalysts.

[0261] To the plates was then added a stock solution of Compound 3 (10 pmol) and Compound 2 (12 pmol) dissolved in the following solvents: dimethylformamide (DMF),

tetrahydrofuran (THF), butanol (/r-BuOH), and toluene. The base was then added as a stock solution (30 mmol) in 20 mL of water.

[0262] A heatmap summarizing catalyst performance is shown in Figs. 10A and 10B. High performance liquid chromatography (HPLC) yields for this screening span from <5% up to -85%. Larger circles indicate higher yield. Lighter circles indicate higher cleanliness.

[0263] A similarly designed screening of base and solvent also indicate that a range of alcoholic solvents (methanol, ethanol, propanol, 2-butanol, 2-propanol, and /-amyl alcohol) are also all viable in this coupling chemistry. Bases such as potassium phosphate, potassium carbonate, potassium acetate, and potassium hydroxide were all successful in achieving the coupling. Fig. 10B shows a heatmap with HPLC yields ranging from -50 – 95%. Larger, darker circles indicate higher yield.

[0264] This chemistry from microvial screening has been scaled to a laboratory process. To a 3 -necked jacketed 250 mL flask equipped with overhead stirring, nitrogen inlet, and thermocouple was added Compound 3 (1.0 eq, 4.00 grams), Compound 2 (1.2 eq, 1.71 x wt), potassium carbonate (3.0 eq, 1.74 x wt). The reactor was inerted three times and then degassed 2-propanol (24 x vol.) followed by degassed water (6 x vol) was then added.

Stirring was then initiated at 300 rpms. The reactor was then stirred and blanketed with nitrogen for 1 hour. The catalyst was then added (0.01 eq, 0.028 x wt) and stirring continued (300 rpms) and the reactor was heated into the Tj = 65 °C.

[0265] After 2 hours, with full conversion confirmed analytically, trioctylphosphine (0.1 eq, 0.16 x wt) dosed, and reaction mixture allowed to cool slowly to room temperature hours.

The reaction mixture was then filtered, washed with 2-propanol (4 x vol), 2-propanol: water (4: 1, 4 x vol), and then with water (4 x vol). Note: If 2 is dimer present in cake, an additional ethyl acetate (EtOAc) wash (4 x vol) can be added for purging. The cake was then transferred to a vacuum oven to dry overnight at 40 °C, -40 cm Hg, under nitrogen flow. After transfer to a bottle, 6.03 grams of 1 were isolated, 98.6% assay, 91% overall yield.

Scheme 6: Alternative reagents and solvents for cross-coupling

[0266] Based on the previously delineated results, it was expected that a variety of monodentate (PPI13 [triphenylphosphine], PBu3 [tributylphosphine], etc) and bidentate phosphines (dppf [1,1 ‘-bis(diphenylphosphino)ferrocene], BINAP [2,2 -bis(diphenylphosphino)- 1 , 1 -binaphthyl], Xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene], dppe [l,2-bis(diphenylphosphino)ethane], etc) ligated to any number of Pd sources (Pd halides, Pd(H) precatalyts, Pd(0) sources) could reasonably be employed to arrive at the Compound 1 crude material. A range of organic solvents ranging from non-polar (heptane, benzene), protic (alcohols), polar aprotic (dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile) as well as a variety of esters and ketones (acetone, 2-butanone, ethylacetate) should also serve as effective solvents for this reactivity. Finally, inorganic bases of varying strength (phosphates, carbonates, acetates, etc) along with organic variants such as triethylamine, l,8-diazabicyclo(5.4.0)undec-7-ene, and others in a wide pKa range are viable as stoichiometric basic additives.

Example 3: Exemplary Compound 5 process

[0267] The purpose of this example was to describe an exemplary process for making Compound 5.

[0268] Charge 4 (lOg, 58mmol) and acetonitrile (lOOmL) to a reaction vessel and start the stirrer. Adjust the batch to -18 °C to -22 °C (target -20 °C). Charge triflic acid (5.5mL, 62mmol) to the batch maintaining -10 °C to -25 °C (target -20 °C). Stir the batch at -10 °C to -25 °C (target -20 °C) for 10 to 20 minutes. Charge NBS (11.38g, 64mmol) to the batch at -10 °C to -25 °C (target -20 °C) and stir for ca. 30 min at -10 °C to -25 °C (target -20 °C). Warm the batch to 20 °C over 3-4 hours (reaction will occur when internal temp is between 5 °C and 15 °C). Stir the batch at 15 °C to 25 °C (target 20 °C) for approximately 1 hour and sample for reaction completion.

[0269] If Compound 4 relative to Compound 5 is more than 5%:

[0270] Cool the bath to -5 °C to -15 °C (target -10 °C) (cooling below 0 °C to ensure selectivity). Charge NBS to the batch according to the follow formula: Mass of NBS = (% Compound 4 x lOg). Warm the batch to 20 °C over 1-2 hours. Stir the batch at 15 °C to 25 °C (target 20 °C) for approximately 1 hour and check reaction for completion. Proceed to next line.

[0271] If Compound 4 relative to Compound 5 is less than 5%:

[0272] Warm the batch to 40 °C to 50 °C (target 48 °C). Concentrate the batch under reduced pressure to a final volume of ~40mL. Cool the batch to -15 °C to -5 °C (target -10 °C) and stir for ca. lh. Filter the batch by suction filtration. Slurry wash the filter cake with purified water (3 x 20mL) at 15 °C to 25 °C (target 20 °C) for 10 to 15 minutes each wash. Remove a sample of the filter cake for analysis by ¾ NMR. Continue washing cake until the residual succimide is below 1.0%mol% relative to 5. Dry the filter cake at up to 60°C under vacuum and nitrogen purge. Analyse the 5 by HPLC analysis (97%w/w to 99%w/w). Expected yield: 60-85% theory (90-110% w/w).

Example 4: Purification of Compound 1 (CC-90010) by crystallization from formic acid and water.

[0273] This example describes a method for the purification of Compound 1 by

crystallization from formic acid and water. Also detailed are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1.

[0274] Figure 11 shows XH NMR of Compound 1 (CC-90010). Solvent: d6DMSO; and Figure 12 shows microscopy of Compound 1 (CC-90010) Form I. Figure 13 shows XRPD of Compound 1 (CC-90010) Form I, with peak information detailed in Table 6:

PATENT

US 20190008852

WO 2018081475

US 20180042914

WO 2016172618

WO 2015058160

/////////CC-90010, solid tumors , non-Hodgkin’s lymphoma, PHASE 1, CANCER, QUANTICEL

CS(=O)(=O)c4cc(C1=CN(C)C(=O)c2ccccc12)c(OCC3CC3)cc4

GRAPIPRANT


Grapiprant.svg

Grapiprant.png

ChemSpider 2D Image | grapiprant | C26H29N5O3S

Structure of GRAPIPRANT

GRAPIPRANT

  • Molecular FormulaC26H29N5O3S
  • Average mass491.605 Da

CAS 415903-37-6

UNII-J9F5ZPH7NB, CJ 023423, CJ-023423,

Phase II, Arrys Therapeutics, CANCER,

PAIN, AskAt Phase II, 

N-{2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}-N’-[(4-methylphenyl)sulfonyl]urea
RQ-00000007, MR10A7
9763
AAT-007
Benzenesulfonamide, N-[[[2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4-methyl-
CJ-023,423
  • N-[[[2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4-methylbenzenesulfonamide
  • 1-[2-[4-(2-Ethyl-4,6-dimethylimidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]-3-(4-methylphenyl)sulfonylurea
  • 2-Ethyl-4,6-dimethyl-1-[4-[2-[[[[(4-methylphenyl)sulfonyl]amino]carbonyl]amino]ethyl]phenyl]-1H-imidazo[4,5-c]pyridine
  • AAT 007
  • CJ 023423
  • Grapiprant
  • MR 10A7
  • RQ 00000007
  • RQ 7

Synonyms and Mappings

  • 415903-37-6
  • GRAPIPRANT [GREEN BOOK]
  • CJ-023
  • GRAPIPRANT [INN]
  • GRAPIPRANT [WHO-DD]
  • MR-10A7
  • AAT-007
  • MR10A7
  • RQ-00000007
  • RQ-7
  • GRAPIPRANT [USAN]
  • GRAPIPRANT
  • 2-ETHYL-4,6-DIMETHYL-1-(4-(2-(((((4-METHYLPHENYL)SULFONYL)AMINO)CARBONYL)AMINO)ETHYL)PHENYL)-1H-IMIDAZO(4,5-C)PYRIDINE
  • N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYLBENZENESULFONAMIDE
  • CJ 023423
  • BENZENESULFONAMIDE, N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYL-
  • CJ-023,423
  • N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYL-BENZENESULFONAMIDE
  • CJ-023423

SYN

Arrys Therapeutics (under license from AskAt ) and affiliate Ikena Oncology (formerly known as Kyn Therapeutics ) are developing ARY-007 , an oral formulation of grapiprant, for treating cancers; in December 2019, preliminary data were expected in 2020

Grapiprant (trade name Galliprant) is a small molecule drug that belongs in the piprant class. This analgesic and anti-inflammatory drug is primarily used as a pain relief for mild to moderate inflammation related to osteoarthritis in dogs. Grapiprant has been approved by the FDA’s Center  for Veterinary  Medicine  and was  categorized  as a  non-cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID) in March 2016.[1]

Preclinical studies also indicate that grapiprant is not only efficacious as a acute pain but also in chronic pain relief and inflammation drug. The effect of the drug is directly proportional to the dosage and its effects were comparable to human medication such as rofecoxib and piroxicam.[2]

Grapiprant, a prostanoid EP4 receptor antagonist, is in phase II clinical trials at AskAt for the treatment of chronic pain. Phase I/II clinical trials are ongoing at Arrys Therapeutics in combination with pembrolizumab for the treatment of patients with microsatellite stable colorectal cancer and in patients with advanced or metastatic PD-1/L1 refractory non-small cell lung cancer (NSCLC).

Grapiprant  is also  used  in humans,  and  was researched  to be  used  as a pain  control  and inflammation associated with osteoarthritis. The effect of grapiprant could be explained through the function of prostaglandin E2, in which acts as a pro-inflammatory mediator of redness of the skin, edema and pain which are the typical signs of inflammation. The effect of PGE2 stems from its action through the four prostaglandin receptor subgroups EP1, EP2, EP3 and EP4, in which the prostaglandin EP4 receptor acts as the main intermediary of the prostaglandin-E2-driven inflammation. Grapiprant is widely accepted in veterinary medicine due to its specific and targeted approach to pain management in dogs. The serum concentration of grapiprant is increased when used in conjunction with other drugs such as acetaminophenalbendazole, and alitretinoin.

Common side effects are intestinal related effects such as mild diarrhea, appetite loss, and vomiting.[3] Additionally, it is found that it might lead to reduced tear production due to it being a sulfa-based medication and also reduced albumin levels.

Grapiprant, a prostanoid EP4 receptor antagonist, is in phase II clinical trials at AskAt for the treatment of chronic pain. Phase I/II clinical trials are ongoing at Arrys Therapeutics in combination with pembrolizumab for the treatment of patients with microsatellite stable colorectal cancer and in patients with advanced or metastatic PD-1/L1 refractory non-small cell lung cancer (NSCLC).

Medical uses

Grapiprant is used once a day as an oral pain relief for dogs with inflammation-related osteoarthritis. It is a non-steroidal anti-inflammatory (NSAID) that functions as a targeted action to treat osteoarthritis pain and inflammation in dogs.

Mechanism of action

Grapiprant acts as a specific antagonist that binds and blocks the prostaglandin EP4 receptor, one out of the four prostaglandin E2 (PGE2) receptor subgroups. The EP4 receptor then mediates the prostaglandin-E2-elicited response to pain, and hence grapiprant was proven to be effective in the decrease of pain in several inflammatory pain models of rats. It was also proven to be effective in reducing osteoarthritis-related pain in humans, which serves as a proof for its mechanism of action. The approximate calculation for  canine efficacy  dose  is between the range of 1.3 and 1.7 mg/kg, in conjunction with a methylcellulose suspending agent. Based on the calculations from the comparisons of binding affinity of grapiprant to the EP4 receptors of  dogs, rats, and humans, the study of plasma and serum protein binding determinations, the effective doses determined in inflammation pain models of rats, and  human-related clinical  studies, it  is  evaluated that  Grapiprant should be administered just once a day. The approved dose of the commercial Grapiprant tablet by the FDA for the pain relief and inflammation associated with osteoarthritis to dogs is reported to be 2 mg/kg a day.[4]

Absorption

Studies in animals such as horses have shown the presence of Grapiprant in serum 72 hours with a concentration >0.005 ng/ml after the initial administration of a dose of 2 mg/kg. Grapiprant is expeditiously absorbed and the reported serum concentration was reported to be 31.9 ng/ml in an amount of time of 1.5 hours. The actual body exposure to grapiprant after administration of one dose was shown to be 2000 ng.hr/ml. The degree and rate at which grapiprant is absorbed into the body, presents a mean bioavailability of 39%. A significant reduction in the bioavailability, concentration time and maximal concentration were reported to have occurred after food intake.[1] And thus, grapiprant is usually not administered with food as it will not be as efficient.[5]

Distribution

The volume of distribution in cat studies was reported to be 918 ml/kg.[1]

Route of elimination

Following an oral administration, the majority of the dose was metabolized within the first 72 hours. Equine studies have shown that grapiprant is present in urine 96 hours after the first administration of a dose of 2 mg/kg and has a concentration >0.005 ng/ml. From the excreted dose conducted in horses, it is found that 55%, 15% and 19% of the orally-administered dose was excreted in bile, urine, and faeces respectively.[1]

Toxicity

Safety studies conducted on grapiprant have demonstrated that it generally possesses an exceptional safety profile and a wide safety margin in veterinary studies.[6] In animal studies, a research on 2.5-12 times overdose was conducted for grapiprant and the study resulted in soft-blobs and mucous-filled faeces, occasional bloody stools and emesis.

PATENT

WO-2020014465

Novel crystalline forms of grapiprant and their salts eg HCl (designated as Form A), useful for inhibiting prostaglandin EP4 receptor activity and treating cancers.

Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Prostaglandin E2 (PGE2) is the predominant eicosanoid detected in inflammation conditions. In addition, it is also involved in various physiological and/or pathological conditions such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis or the like.

[0003] Four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) displaying different pharmacological properties exist. The EP4 subtype, a Gs-coupled receptor, stimulates cAMP production as well as PI3K and GSK3P signaling, and is distributed in a wide variety of tissue suggesting a major role in PGE2-mediated biological events. Various EP4 inhibitors have been described previously, for example, in WO 2002/032900, WO 2005/021508, EiS 6,710,054, and US 7,238,714, the contents of which are incorporated herein by reference in their entireties.

[0004] Accordingly, there is a need for treating, preventing, and/or reducing severity of a proliferative disorder associated with prostaglandin EP4 receptor activity. The present invention addresses such a need.

It has now been found that compounds of the present invention, and compositions thereof, are useful for treating, preventing, and/or reducing severity of a proliferative disorder associated with prostaglandin EP4 receptor activity. In general, salt forms and co-crystal forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of proliferative disorders associated with prostaglandin EP4 receptor activity, as described in detail herein. Such compounds are represented by the chemical structure below, denoted as compound A (also known as grapiprant):

A

or a pharmaceutically acceptable salt thereof.

United States Patent 7,960,407, filed March 1, 2006 and issued June 14, 2011 (“the ‘407 patent,” the entirety of which is hereby incorporated herein by reference), describes certain EP4 inhibitor compounds. Such compounds include compound A:

or a pharmaceutically acceptable salt thereof.

[0037] Compound A, N-[({2-[4-(2-Ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl) phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide, is described in detail in the ‘407

patent, including its synthetic route. The ‘407 patent also discloses a variety of physical forms of compound A.

[0038] It would be desirable to provide a solid form of compound A (e.g., as a co-crystal thereof or salt thereof) that imparts characteristics such as improved aqueous solubility, stability and ease of formulation. Accordingly, the present invention provides both co-crystal forms and salt forms of compound A:

A.

PATENT

WO 2002032900

PATENT

WO 2002032422

Family members of the product case ( WO0232422 ) of grapiprant have protection in most of the EU states until October 2021 and expire in the US in October 15, 2021.

PATENT

WO 2003086371

PATENT

WO2020014445 covering combinations of grapiprant and an immuno-oncology agent.

WO 2005102389

WO 2006095268

US 7960407

US 20190314390

References

  1. Jump up to:a b c d “Grapiprant”http://www.drugbank.ca. Retrieved 2019-05-15.
  2. ^ PubChem. “Grapiprant”pubchem.ncbi.nlm.nih.gov. Retrieved 2019-05-15.
  3. ^ Paul Pion, D. V. M.; Spadafori, Gina (2017-08-08). “Veterinary Partner”VIN.com.
  4. ^ Nagahisa, A.; Okumura, T. (2017). “Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs”. Journal of Veterinary Pharmacology and Therapeutics40 (3): 285–292. doi:10.1111/jvp.12349ISSN 1365-2885PMID 27597397.
  5. ^ Paul Pion, D. V. M.; Spadafori, Gina (2017-08-08). “Veterinary Partner”VIN.com.
  6. ^ Kirkby Shaw, Kristin; Rausch-Derra, Lesley C.; Rhodes, Linda (February 2016). “Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation”Veterinary Medicine and Science2 (1): 3–9. doi:10.1002/vms3.13ISSN 2053-1095PMC 5645826PMID 29067176.
Grapiprant
Grapiprant.svg
Clinical data
Trade names Galliprant
Routes of
administration
Oral
ATCvet code
Pharmacokinetic data
Bioavailability 6.6 L/kg, high volume of distribution
Elimination half-life 5.86 hours in horses
Excretion Urine
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C26H29N5O3S
Molar mass 491.61 g·mol−1
3D model (JSmol)

//////////////GRAPIPRANT, 415903-37-6, UNII-J9F5ZPH7NB, CJ 023423, CJ-023423, RQ-00000007, MR10A7, Galliprant, Phase II, Arrys Therapeutics, CANCER, PAIN, AskAt

CCC1=NC2=C(N1C3=CC=C(C=C3)CCNC(=O)NS(=O)(=O)C4=CC=C(C=C4)C)C=C(N=C2C)C

CK-101


N-[3-[2-[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]anilino]quinazolin-8-yl]phenyl]prop-2-enamide.png

CK-101, RX-518

CAS 1660963-42-7

MF C29 H28 F2 N6 O2
MW 530.57
2-Propenamide, N-[3-[2-[[2,3-difluoro-4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-8-quinazolinyl]phenyl]-

N-[3-[2-[[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]amino]quinazolin-8-yl]phenyl]acrylamide

N-(3-(2-((2,3-Difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide

EGFR-IN-3

UNII-708TLB8J3Y

708TLB8J3Y

AK543910

Suzhou NeuPharma (Originator)
Checkpoint Therapeutics

Non-Small Cell Lung Cancer Therapy
Solid Tumors Therapy

PHASE 2 Checkpoint Therapeutics, Cancer, lung (non-small cell) (NSCLC), solid tumour

RX518(CK-101) is an orally available third-generation and selective inhibitor of certain epidermal growth factor receptor (EGFR) activating mutations, including the resistance mutation T790M, and the L858R and exon 19 deletion (del 19) mutations, with potential antineoplastic activity.

In August 2019, Suzhou Neupharma and its licensee Checkpoint Therapeutics are developing CK-101 (phase II clinical trial), a novel third-generation, covalent, EGFR inhibitor, as a capsule formulation, for the treatment of cancers including NSCLC and other advanced solid tumors. In September 2017, the FDA granted Orphan Drug designation to this compound, for the treatment of EGFR mutation-positive NSCLC; in January 2018, the capsule was being developed as a class 1 chemical drug in China.

CK-101 (RX-518), a small-molecule inhibitor of epidermal growth factor receptor (EGFR), is in early clinical development at Checkpoint Therapeutics and Suzhou NeuPharma for the potential treatment of EGFR-mutated non-small cell lung cancer (NSCLC) and other advanced solid malignancies.

In 2015, Suzhou NeuPharma granted a global development and commercialization license to its EGFR inhibitor program, excluding certain Asian countries, to Coronado Biosciences (now Fortress Biotech). Subsequently, Coronado assigned the newly acquired program to its subsidiary Checkpoint Therapeutics.

In 2017, the product was granted orphan drug designation in the U.S. for the treatment of EGFR mutation-positive NSCLC.

There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.

[0003] The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.

[0004] The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of compounds that specifically inhibit the function of a kinase which is essential for processes leading to cancer would be beneficial.

[0005] While such compounds are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance, such as a kinase inhibitor, can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties

can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers. For example, polymorphism has been evaluated in many multi-million dollar and even multi-billion dollar drugs, such as warfarin sodium, famotidine, and ranitidine. Polymorphism can affect the quality, safety, and/or efficacy of a drug product, such as a kinase inhibitor. Thus, there still remains a need for polymorphs of kinase inhibitors. The present disclosure addresses this need and provides related advantages as well.

PATENT

WO2015027222

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015027222

PATENT

WO-2019157225

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019157225&tab=PCTDESCRIPTION&_cid=P10-JZNKMN-12945-1

Crystalline form II-VIII of the compound presumed to be CK-101 (first disclosed in WO2015027222 ), for treating a disorder mediated by epidermal growth factor receptor (EGFR) eg cancer.

SCHEME A

Scheme B

General Procedures

Example 1: Preparation of the compound of Formula I (N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide)

[0253] To a solution of l,2,3-trifluoro-4-nitrobenzene (2.5 g, 14 mmol, 1.0 eq.) in DMF (20 mL) was added K2C03 (3.8 g, 28 mmol, 2.0 eq.) followed by 2-(piperazin-l-yl)ethanol (1.8 g, 14 mmol, 1.0 eq.) at 0 °C and the mixture was stirred at r.t. overnight. The mixture was poured into ice-water (200 mL), filtered and dried in vacuo to afford 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 67.5%).

[0254] To a solution of 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 9.0 mmol) in MeOH (30 mL) was added Pd/C (270 mg) and the resulting mixture was stirred at r.t.

overnight. The Pd/C was removed by filtration and the filtrate was concentrated to afford 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (2.39 g, 99% yield) as off-white solid.

[0255] To a solution of 8-bromo-2-chloroquinazoline (15.4 g, 63.6 mmol, 1 eq. ) and (3-aminophenyl)boronic acid (8.7 g, 63.6 mmol, 1 eq.) in dioxane/H20 (200 mL/20 mL) was added Na2C03 (13.5 g, 127.2 mmol, 2 eq.), followed by Pd(dppf)Cl2 (2.6 g, 3.2 mmol, 0.05 eq.) under N2, then the mixture was stirred at 80 °C for 12 h. Then the solution was cooled to r.t.,

concentrated and the residue was purified via column chromatography (PE/EA=3 :2, v/v) to afford 3-(2-chloroquinazolin-8-yl)aniline as yellow solid (8.7 g, 53.7% yield).

[0256] To a solution of 3-(2-chloroquinazolin-8-yl)aniline (8.7 g, 34 mmol, 1 eq.) in DCM ( 200 mL ) cooled in ice-bath was added TEA (9.5 mL, 68 mmol, 2 eq. ), followed by acryloyl chloride (4.1 mL, 51 mmol, 1.5 eq.) dropwise. The resulting mixture was stirred at r.t. for 1 h, then washed with brine, dried over anhydrous N2S04 concentrated and the residue was purified via column chromatography (PE/EA=l : 1, v:v) to afford N-(3-(2-chloroquinazolin-8-yl)phenyl)acryl amide as yellow solid(6.6 g, 65% yield).

[0257] To a suspension of 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (83 mg,

0.32 mmol, 1 eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg, 0.32 mmol, 1 eq.) in n-BuOH (5 mL) was added TFA (68 mg, 0.64 mmol, 2 eq.) and the resulting mixture was stirred at 90 °C overnight. The mixture was concentrated, diluted with DCM (20 mL) , washed with Na2C03 solution (20 mL), dried over anhydrous Na2S04, concentrated and the residue was purified via column chromatography (MeOH/DCM=l/30, v:v) to afford N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide as a yellow solid(l6.3 mg, 9.5% yield). LRMS (M+H+) m/z calculated 531.2, found 531.2. 1H NMR

(CD3OD, 400 MHz) d 9.21 (s, 1 H), 7.19-8.01 (m, 10 H), 8.90 (s, 1 H), 6.41-6.49 (m, 3 H), 5.86 (m, 1 H), 3.98-4.01 (m, 3 H), 3.70-3.76 (m, 3 H), 3.40-3.49 (m, 2 H), 3.37-3.39 (m, 4 H), 3.18 (m, 2H).

Example 2. Preparation of Form I of the compound of Formula I

[0258] Crude compound of Formula I (~30 g, 75% of weight based assay) was dissolved in ethyl acetate (3 L) at 55-65 °C under nitrogen. The resulting solution was filtered via silica gel pad and washed with ethyl acetate (3 L><2) at 55-65 °C. The filtrate was concentrated via vacuum at 30-40 °C to ~2.4 L. The mixture was heated up to 75-85 °C and maintained about 1 hour.

Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and the mixture was then cooled down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with ethyl acetate (60 mL><2). The wet cake was dried via vacuum at 30-40 °C to get (about 16 g) of the purified Form I of the compound of Formula I.

Example 3. Preparation of Form III of the compound of Formula I

[0259] The compound of Formula I (2 g) was dissolved in EtOH (40 mL) at 75-85 °C under nitrogen. n-Heptane (40 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 75-85 °C for 1 hour. Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with EtOH/n-Heptane (1/1, 5 mL><2). The wet cake was dried via vacuum at 30-40 °C to get the purified Form III of the compound of Formula I (1.7 g).

Example 4. Preparation of Form IV of the compound of Formula I The crude compound of Formula I (15 g) was dissolved in ethyl acetate (600 mL) at 75-85 °C under nitrogen and treated with anhydrous Na2S04, activated carbon, silica metal scavenger for 1 hour. The resulting mixture was filtered via neutral Al203 and washed with ethyl acetate (300 mL><2) at 75-85 °C. The filtrate was concentrated under vacuum at 30-40 °C and swapped with DCM (150 mL). n-Heptane (75 mL) was added into this DCM solution at 35-45 °C, and then the mixture was cooled down to 20-30 °C slowly. The resulting mixture was filtered and washed with DCM/n-Heptane (2/1, 10 mL><3). The wet cake was dried via vacuum at 35-40 °C to get the purified Form IV of the compound of Formula I (9.6 g).

Example 5. Preparation of Form V of the compound of Formula I

[0260] Polymorph Form III of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form V.

Example 6. Preparation of Form VI of the compound of Formula I

[0261] The compound of Formula I (1 g) was dissolved in IPA (20 mL) at 75-85 °C under nitrogen. n-Heptane (20 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 45-55 °C for 16 hours. Then heated up to 75-85 °C and maintained about 0.5 hour.

Then cooled down to 45-55 °C for 0.5 hour and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. Filtered and washed with IPA/n-Heptane (1/1, 3 mL><2). The wet cake was dried via vacuum at 75-80 °C for 2 hours to get the purified Form VI of the compound of Formula I.

Example 7. Preparation of Form VIII of the compound of Formula I

[0262] The polymorph Form VI of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form VIII.

Example 8. X-ray powder diffraction (XRD)

[0263] X-ray powder diffraction (XRD) patterns were obtained on a Bruker D8 Advance. A CuK source (=1.54056 angstrom) operating minimally at 40 kV and 40 mA scans each sample between 4 and 40 degrees 2-theta. The step size is 0.05°C and scan speed is 0.5 second per step.

Example 9. Thermogravimetric Analyses (TGA)

[0264] Thermogravimetric analyses were carried out on a TA Instrument TGA unit (Model TGA 500). Samples were heated in platinum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 60mL/min (sample purge) and 40mL/min (balance purge). The TGA temperature was calibrated with nickel standard, MP=354.4 °C. The weight calibration was performed with manufacturer-supplied standards and verified against sodium citrate dihydrate desolvation.

Example 10. Differential scanning calorimetry (DSC)

[0265] Differential scanning calorimetry analyses were carried out on a TA Instrument DSC unit (Model DSC 1000 or 2000). Samples were heated in non-hermetic aluminum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 50mL/min. The DSC temperature was calibrated with indium standard, onset of l56-l58°C, enthalpy of 25-29J/g.

Example 11. Hygroscopicity (DVS)

[0266] The moisture sorption profile was generated at 25°C using a DVS Moisture Balance Flow System (Model Advantage) with the following conditions: sample size approximately 5 to 10 mg, drying 25°C for 60 minutes, adsorption range 0% to 95% RH, desorption range 95% to 0% RH, and step interval 5%. The equilibrium criterion was <0.01% weight change in 5 minutes for a maximum of 120 minutes.

Example 12: Microscopy

[0267] Microscopy was performed using a Leica DMLP polarized light microscope equipped with 2.5X, 10X and 20X objectives and a digital camera to capture images showing particle shape, size, and crystallinity. Crossed polars were used to show birefringence and crystal habit for the samples dispersed in immersion oil.

Example 13: HPLC

[0256] HPLCs were preformed using the following instrument and/or conditions.

///////////////CK-101 , CK 101 , CK101 , phase II , Suzhou Neupharma, Checkpoint Therapeutics ,  Orphan Drug designation, EGFR mutation-positive NSCLC, NSCLC, CANCER, SOLID TUMOUR,  China, RX-518, AK543910

OCCN1CCN(CC1)c5ccc(Nc2nc3c(cccc3cn2)c4cccc(NC(=O)C=C)c4)c(F)c5F

FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor


FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor 

FDA also approves drug for second indication in a type of lung cancer

The U.S. Food and Drug Administration today granted accelerated approval to Rozlytrek (entrectinib), a treatment for adult and adolescent patients whose cancers have the specific genetic defect, NTRK (neurotrophic tyrosine receptor kinase) gene fusion and for whom there are no effective treatments.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” said FDA Acting Commissioner Ned Sharpless, M.D. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The approval marks a new paradigm in the development of cancer drugs that are “tissue agnostic.” It follows the policies that the FDA developed in a guidance document released in 2018. The previous tissue agnostic indications approved by the FDA were pembrolizumab for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib for NTRK gene fusion tumors in 2018.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

The ability of Rozlytrek to shrink tumors was evaluated in four clinical trials studying 54 adults with NTRK fusion-positive tumors. The proportion of patients with substantial tumor shrinkage (overall response rate) was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for nine months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid and colon/rectum.

Rozlytrek was also approved today for the treatment of adults with non-small cell lung cancer whose tumors are ROS1-positive (mutation of the ROS1 gene) and has spread to other parts of the body (metastatic). Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

Rozlytrek’s common side effects are fatigue, constipation, dysgeusia (distorted sense of taste), edema (swelling), dizziness, diarrhea, nausea, dysesthesia (distorted sense of touch), dyspnea (shortness of breath), myalgia (painful or aching muscles), cognitive impairment (confusion, problems with memory or attention, difficulty speaking, or hallucinations), weight gain, cough, vomiting, fever, arthralgia and vision disorders (blurred vision, sensitivity to light, double vision, worsening of vision, cataracts, or floaters). The most serious side effects of Rozlytrek are congestive heart failure (weakening or damage to the heart muscle), central nervous system effects (cognitive impairment, anxiety, depression including suicidal thinking, dizziness or loss of balance, and change in sleep pattern, including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity (damage to the liver), hyperuricemia (elevated uric acid), QT prolongation (abnormal heart rhythm) and vision disorders. Health care professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Rozlytrek. Women who are pregnant or breastfeeding should not take Rozlytrek because it may cause harm to a developing fetus or newborn baby.

Rozlytrek was granted accelerated approval. This approval commits the sponsor to provide additional data to the FDA. Rozlytrek also received Priority ReviewBreakthrough Therapy and Orphan Drug designation. The approval of Rozlytrek was granted to Genentech, Inc.

link http://s2027422842.t.en25.com/e/es?s=2027422842&e=244904&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=46563b1749694ceb96d9f79a6d5cd8a7&elqaid=9150&elqat=1

///////////////Rozlytrek, entrectinib, accelerated approval, priority ReviewBreakthrough Therapy,  Orphan Drug designation, fda 2019, Genentech, cancer

CC-90009


str1

2-(4-Chlorophenyl)-N-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl]-2,2-difluoroacetamide.png

CC-90009

CC-90009-AML-001

CAS 1860875-51-9

461.8 g/mol, C22H18ClF2N3O4

2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

  • 4-Chloro-N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α,α-difluorobenzeneacetamide
  • Benzeneacetamide, 4-chloro-N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α,α-difluoro-

Phase 1 Clinical, Acute myelogenous leukemia, Protein cereblon modulator

Useful for treating chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myeloid leukemia.

Celgene is developing CC-90009, a cereblon E3 ligase modulator, for treating AML; in January 2019, data from a phase I trial were expected later that year.

  • 0iginator Celgene Corporation
  • Class Antineoplastics
  • Mechanism of Action CRBN protein modulators; Ubiquitin protein ligase complex modulators
  • Phase I Acute myeloid leukaemia
  • 28 Mar 2019 No recent reports of development identified for clinical-Phase-Unknown development in Acute-myeloid-leukaemia in USA (IV)
  • 01 Sep 2016 Phase-I clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) in Canada (IV) (NCT02848001)
  • 04 Aug 2016 Celgene plans a phase I trial for Acute Myeloid Leukaemia in USA and Canada (NCT02848001)

In September 2016, Celgene initiated a phase I dose-finding trial of CC 90009 in patients with relapsed or refractory acute myeloid leukaemia (NCT02848001; CC-90009-AML-001). The open-label study intends to enrol 60 patients in the US and Canada

CC-90009 is a cereblon modulator. CC-90009 specifically binds to CRBN, thereby affecting the activity of the ubiquitin E3 ligase complex. This leads to the ubiquitination of certain substrate proteins and induces the proteasome-mediated degradation of certain transcription factors, including Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors in T-cells. This reduces the levels of these transcription factors, and modulates the activity of the immune system, which may include the activation of T-lymphocytes. .

Development Overview

cereblon modulator CC-90009A modulator of cereblon (CRBN), which is part of the cullin 4-RING E3 ubiquitin ligase complex (CRL4-CRBN E3 ubiquitin ligase; CUL4-CRBN E3 ubiquitin ligase), with potential immunomodulating and pro-apoptotic activities. Upon administration, CC-90009 specifically binds to CRBN, thereby affecting the activity of the ubiquitin E3 ligase complex. This leads to the ubiquitination of certain substrate proteins and induces the proteasome-mediated degradation of certain transcription factors, including Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors in T-cells. This reduces the levels of these transcription factors, and modulates the activity of the immune system, which may include the activation of T-lymphocytes. In addition, this downregulates the expression of other proteins, including interferon regulatory factor 4 (IRF4) and c-myc, which plays a key role in the proliferation of certain cancer cell types. CRBN, the substrate recognition component of the E3 ubiquitin ligase complex, plays a key role in the ubiquitination of certain proteins. Check for active clinical trials using this agent. (NCI Thesaurus)

WO 2017120446,

PATENT

WO2016007848

US 20170348298

WO 2017120415

WO 2017120446

WO 2017120437

PATENT

WO2017214014

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017214014&tab=PCTDESCRIPTION

Provided herein are methods of treating, preventing, managing, and/or ameliorating a hematologic malignancy with 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of

stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Further provided is a compound for use in methods of treating, preventing, managing, and/or ameliorating a hematologic malignancy, wherein the compound is 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

The term Compound 1 refers to”2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide” having the structure:

and its stereoisomers or mixture of stereoisomers, isotopologues, pharmaceutically acceptable salts, tautomers, solvates, hydrates, co-crystals, clathrates, or polymorphs thereof. In certain embodiments, Compound 1 refers to 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide and its tautomers. In certain embodiments, Compound 1 refers to a polymorph of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-

oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide. In certain embodiments, Compound 1 refers to polymorph Form C of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide. In one embodiment, the stereoisomer is an enantiomer.

PATENT

WO-2019136016

Novel isotopologs of the compound presumed to be CC-90009 , processes for their preparation and compositions comprising them are claimed.

str2

Patent ID Title Submitted Date Granted Date
US2017199193 METHODS FOR TREATING CANCER AND THE USE OF BIOMARKERS AS A PREDICTOR OF CLINICAL SENSITIVITY TO THERAPIES 2017-01-06
US2018224435 METHODS FOR MEASURING SMALL MOLECULE AFFINITY TO CEREBLON 2018-02-02
US2018353496 FORMULATIONS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE 2018-07-19
US2017196847 FORMULATIONS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE 2017-01-06
US2017348298 TREATMENT OF A HEMATOLOGIC MALIGNANCY WITH 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE 2017-06-05
Patent ID Title Submitted Date Granted Date
US2018221361 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 2018-04-09
US9968596 Antiproliferative compounds and methods of use thereof 2017-10-02 2018-05-15
US2017197934 SOLID FORMS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES 2017-01-06
US9499514 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 2015-07-09 2016-01-14
US9808451 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 2016-09-23

////////CC-90009 , CC 90009  , CC90009, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, phase I, CANCER, CC-90009-AML-001

Clc1ccc(cc1)C(F)(F)C(=O)NCc2ccc3C(=O)N(Cc3c2)C4CCC(=O)NC4=O

Selinexor


Skeletal formula of selinexor

Selinexor.png

Selinexor

セリネクソル

KPT-330

UNII-31TZ62FO8F

(Z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-N‘-pyrazin-2-ylprop-2-enehydrazide

Formula
C17H11F6N7O
CAS
1393477-72-9
Mol weight
443.306

FDA, APPROVED 2019/7/3, Xpovio

CAS : 1393477-72-9 (free base)   1421923-86-5 (E-isomer)   1621865-82-4 (E-isomer)   Unknown (HCl)

Treatment of cancer, Antineoplastic, Nuclear export inhibitor

Selinexor (INN, trade name Xpovio; codenamed KPT-330) is a selective inhibitor of nuclear export used as an anti-cancer drug. It works by quasi-irreversibly binding to exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis.[1] It is the first drug with this mechanism of action.[2][3]

Selinexor was granted accelerated approval by the U.S. Food and Drug Administration in July 2019, for use as a drug of last resort in people with multiple myeloma. In clinical trials, it was associated with a high incidence of severe side effects, including low platelet counts and low blood sodium levels.[3][4]

Selinexor is an orally available, small molecule inhibitor of CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1), with potential antineoplastic activity. Selinexor modifies the essential CRM1-cargo binding residue cysteine-528, thereby irreversibly inactivates CRM1-mediated nuclear export of cargo proteins such as tumor suppressor proteins (TSPs), including p53, p21, BRCA1/2, pRB, FOXO, and other growth regulatory proteins. As a result, this agent, via the approach of selective inhibition of nuclear export (SINE), restores endogenous tumor suppressing processes to selectively eliminate tumor cells while sparing normal cells. CRM1, the major export factor for proteins from the nucleus to the cytoplasm, is overexpressed in a variety of cancer cell types.

Selinexor has been used in trials studying the treatment of AML, Glioma, Sarcoma, Leukemia, and Advanced, among others.

 Selinexor, also known as KPT-330, is an orally bioavailable, potent and selective XPO1/CRM1 Inhibitor. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Selinexor potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis. Selinexor has strong activity against primary AML cells while sparing normal stem and progenitor cells.

SYN

Medical uses

Selinexor is restricted for use in combination with the steroid dexamethasone in people with relapsed or refractory multiple myelomawhich has failed to respond to at least four or five other therapies (so-called “quad-refractory” or “penta-refractory” myeloma),[5] for whom no other treatment options are available.[3][4] It is the first drug to be approved for this indication.[6]

Adverse effects

In the clinical study used to support FDA approval, selinexor was associated with high rates of pancytopenia, including leukopenia(28%), neutropenia (34%, severe in 21%), thrombocytopenia (74%, severe in 61% of patients), and anemia (59%).[4][7] The most common non-hematological side effects were gastrointestinal reactions (nausea, anorexia, vomiting, and diarrhea), hyponatremia (low blood sodium levels, occurring in up to 40% of patients), and fatigue.[7][8] More than half of all patients who received the drug developed infections, including fatal cases of sepsis.[7] However, these data are from an open-label trial, and thus cannot be compared to placebo or directly attributed to treatment.

Mechanism of action

Schematic illustration of the Ran cycle of nuclear transport. Selinexor inhibits this process at the nuclear export receptor (upper right).

Like other so-called selective inhibitors of nuclear export (SINEs), selinexor works by binding to exportin 1 (also known as CRM1). CRM1 is a karyopherin which performs nuclear transport of several proteins, including tumor suppressorsoncogenes, and proteins involved in governing cell growth, from the cell nucleus to the cytoplasm; it is often overexpressed and its function misregulated in several types of cancer.[1] By restoring nuclear transport of these proteins to normal, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell proliferation. This ultimately leads to cell cycle arrest and death of cancer cells by apoptosis.[1][2][7] In vitro, this effect appeared to spare normal (non-malignant) cells.[1][8]

Because CRM1 is a pleiotropic gene, inhibiting it affects many different systems in the body, which explains the high incidence of adverse reactions to selinexor.[2] Thrombocytopenia, for example, is a mechanistic and dose-dependent effect, occurring because selinexor causes a buildup of the transcription factor STAT3 in the nucleus of hematopoietic stem cells, preventing their differentiation into mature megakaryocytes (platelet-producing cells) and thus slowing production of new platelets.[2]

Chemistry

Selinexor is a fully synthetic small-molecule compound, developed by means of a structure-based drug design process known as induced-fit docking. It binds to a cysteine residue in the nuclear export signal groove of exportin 1. Although this bond is covalent, it is not irreversible.[1]

History

Selinexor was developed by Karyopharm Therapeutics of Newton, Massachusetts, a pharmaceutical company devoted entirely to the development of drugs that target nuclear transport. It was approved by the FDA on July 3, 2019, on the basis of a single uncontrolled clinical trial. The decision was controversial, and overruled the previous recommendation of an FDA Advisory Panel which had voted 8–5 against approving the drug, due to concerns about efficacy and toxicity.[3]

Research

Under the codename KPT-330, selinexor was tested in several preclinical animal models of cancer, including pancreatic cancerbreast cancernon-small-cell lung cancerlymphomas, and acute and chronic leukemias.[9] In humans, early clinical trials (phase I) have been conducted in non-Hodgkin lymphomablast crisis, and a wide range of advanced or refractory solid tumors, including colon cancerhead and neck cancermelanomaovarian cancer, and prostate cancer.[9] Compassionate use in patients with acute myeloid leukemia has also been reported.[9]

The pivotal clinical trial which served to support approval of selinexor for people with relapsed/refractory multiple myeloma was an open-label study of 122 patients known as the STORM trial.[7] In all of the enrolled patients, selinexor was used as fifth-line or sixth-line therapy after conventional chemotherapytargeted therapy with bortezomibcarfilzomiblenalidomidepomalidomide, and a monoclonal antibody (daratumumab or isatuximab)[5]; nearly all had also undergone hematopoietic stem cell transplantation to no effect.[7] The overall response rate was 25%, and no patients had a complete response.[7] However, the response rate was higher in patients with high-risk myeloma (cytogenetic abnormalities associated with a worse prognosis).[5] The median time to progression was 2.3 months overall and 5 months in patients who responded to the drug.[2]

As of 2019, phase I/II and III trials are ongoing,[3][9] including the use of selinexor in other cancers and in combinations with other drugs used for multiple myeloma.[2]

PATENT

WO 2013019561

WO 2013019548

US 9079865

PATENT

WO 2016025904 A

https://patents.google.com/patent/WO2016025904A1/tr

International Publication No. WO 2013/019548 describes a series of compounds that are indicated to have inhibitory activity against chromosomal region maintenance 1 (CRM1, also referred to as exportin 1 or XPO1) and to be useful in the treatment of disorders associated with CRM1 activity, such as cancer. (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N’-(pyrazin-2-yl)acrylohydrazide (also referred to as selinexor) is one of the compounds disclosed in International Publication No. WO 2013/019548. Selinexor has the chemical structure shown in Structural Formula I:

Example 1. Preparation of Selinexor Lot No.1305365 (Form A).

[00274] Selinexor for Lot No. 1305365 was made in accordance with the following reaction scheme:

[00275] A solution of propane phosphonic acid anhydride (T3P®, 50% in ethyl acetate, 35Kg) in THF (24.6Kg) was cooled to about -40 °C. To this solution was added a solution of KG1 (13.8Kg) and diisopropylethylamine (12.4Kg) in tetrahydrofuran (THF, 24.6Kg). The resulting mixture was stirred at about -40°C for approximately 2.5 hours.

[00276] In a separate vessel, KJ8 (4.80Kg) was mixed with THF (122.7Kg), and the resulting mixture cooled to about -20°C. The cold activated ester solution was then added to the KJ8 mixture with stirring, and the reaction was maintained at about -20°C. The mixture was warmed to about 5°C, water (138.1Kg) was added and the temperature adjusted to about 20°C. After agitating for about an hour, the lower phase was allowed to separate from the mixture and discarded. The upper layer was diluted with ethyl acetate (EtOAc). The organic phase was then washed three times with potassium phosphate dibasic solution (~150Kg), then with water (138.6Kg).

[00277] The resulting organic solution was concentrated under reduced pressure to 95L, EtOAc (186.6Kg) was added and the distillation repeated to a volume of 90L. Additional EtOAc (186.8Kg) was added and the distillation repeated a third time to a volume of 90L. The batch was filtered to clarify, further distilled to 70L, then heated to about 75°C, and slowly cooled to 0 to 5°C. The resulting slurry was filtered and the filter cake washed with a mixture of EtOAc (6.3Kg) and toluene (17.9Kg) before being dried in a vacuum oven to provide selinexor designated Lot No. 1305365 (Form A).

Example 2. Preparation of Selinexor Lot No.1341-AK-109-2 (Form A).

[00278] The acetonitrile solvate of selinexor was prepared in accordance with Example 6.

[00279] The acetonitrile solvate of selinexor (2.7g) was suspended in a mixture of isopropanol (IPA, 8mL) and water (8mL), and the resulting mixture heated to 65 to 70 °C to effect dissolution. The solution was cooled to 45 °C, and water (28mL) was added over 15 minutes, maintaining the temperature between 40 and 45 °C. The slurry was cooled to 20 to 25 °C over an hour, then further cooled to 0 to 5 °C and held at that temperature for 30 minutes before being filtered. The filter cake was washed with 20% v/v IPA in water and the product dried under suction overnight, then in vacuo (40°C).

Example 3. Preparation of SelinexorSelinexorSelinexor Lot No. PC-14-005 (Form A).

[00280] The acetonitrile solvate of selinexor (Form D) was prepared in accordance with the procedure described in Example 6.

[00281] The acetonitrile solvate of selinexor (1.07Kg) was suspended in a mixture of IPA (2.52Kg) and water (3.2Kg) and the mixture heated to 70 to 75 °C to dissolve. The temperature was then adjusted to 40 to 45 °C and held at that temperature for 30 minutes. Water (10.7Kg) was added while maintaining the temperature at 40 to 45 °C, then the batch was cooled to 20 to 25 °C and agitated at that temperature for 4 hours before being further cooled to 0 to 5 °C. After a further hour of agitation, the slurry was filtered and the filter cake washed with a cold mixture of IPA (0.84Kg) and water (4.28Kg) before being dried.

Example 4. Preparation of SelinexorSelinexorSelinexor Lot No. PC-14-009 (Form A).

[00282] The acetonitrile solvate of selinexor (Form D) was prepared in accordance with the procedure described in Example 6.

[00283] The acetonitrile solvate of selinexor (1.5Kg) was suspended in IPA (3.6Kg) and water (4.5Kg) and warmed to 37 to 42 °C with gentle agitation. The suspension was agitated at that temperature for 4 hours, and was then cooled to 15 to 20 °C over 1 hour. Water (15.1Kg) was added, maintaining the temperature, then the agitation was continued for 1 hour and the batch was filtered. The filter cake was washed with a mixture of IPA (1.2Kg) and water (6Kg), then dried under a flow of nitrogen.

Example 5. Preparation of Selinexor Lot Nos.1339-BS-142-1, 1339-BS-142-2 and PC-14-008 (Form A).

[00284] A reactor, under nitrogen, was charged with KG1 (1Kg, 1.0 Eq), KJ8 (0.439 Kg, 1.4 Eq) and MeTHF (7L, 7 parts with respect to KG1). Diisopropylethylamine (0.902Kg, 2.45 Eq with respect to KG1) was added to the reaction mixture at -20 °C to -25 °C with a MeTHF rinse. To the reaction mixture, 50% T3P® in ethyl acetate (2.174Kg, 1.2 Eq with respect to KG1) was then charged, maintaining the temperature at -20 °C to -25 °C with a MeTHF rinse. After the completion of the addition, the reaction mixture was stirred briefly

and then warmed to 20 °C to 25 °C. Upon completion, the reaction mixture was washed first with water (5L, 5 parts with respect to KG1) and then with dilute brine (5L, 5 parts with respect to KG1). The organic layer was concentrated by vacuum distillation to a volume of 5 L (5 parts with respect to KG1), diluted with acetonitrile (15L, 15 parts with respect to KG1) at approximately 40 °C and concentrated again (5L, 5 parts with respect to KG1). After solvent exchange to acetonitrile, the reaction mixture was then heated to approximately 60 °C to obtain a clear solution. The reaction mixture was then cooled slowly to 0-5 °C, held briefly and filtered. The filter cake was washed with cold acetonitrile (2L, 5 parts with respect to KG1) and the filter cake was then dried under a stream of nitrogen to provide the acetonitrile solvate of selinexor (Form D) as a slightly off-white solid.

[00285] Form D of selinexor (0.9Kg) was suspended in IPA (2.1Kg, 2.7L, 3 parts with respect to Form D) and water (2.7Kg, 2.7L, 3 parts with respect to Form D) and warmed to approximately 40 °C. The resulting suspension was agitated for about 4 hours, selinexor, cooled to approximately 20 °C, and diluted with additional water (9Kg, 10 parts with respect to Form D). The mixture was stirred for a further 4-6 hours, then filtered, and the cake washed with a mixture of 20% IPA and water (4.5L, 5 parts with respect to Form D). The filter cake was then dried under vacuum to provide selinexor designated Lot No. PC-14-008 as a white crystalline powder with a >99.5% a/a UPLC purity (a/a=area to area of all peaks; UPLC-ultra performance HPLC).

Example 6. Preparation of Selinexor Lot No.1405463 (Form A).

[00286] Selinexor Lot No. 1405463 was prepared in accordance with the following reaction scheme:

 .

[00287] A reactor was charged with KG1 (15.8Kg), KJ8 (6.9Kg) and MeTHF (90Kg). Diisopropylethylamine (14.2Kg) was added to the reaction mixture over approximately 35 minutes at about -20 °C. Following the addition of the diisopropylethylamine, T3P® (50%

solution in EtAOc, 34.4Kg) was added maintaining the temperature at -20 °C. The mixture stirred to complete the reaction first at -20 °C, then at ambient temperature.

[00288] Upon completion of the reaction, water (79Kg) was added over about 1 hour. The layers were separated and the organic layer was washed with a mixture of water (55Kg) and brine (18Kg), The mixture was filtered, and the methyl-THF/ethyl acetate in the mixture distillatively replaced with acetonitrile (volume of approximately 220L). The mixture was warmed to dissolve the solids, then slowly cooled to 0 to 5 °C before being filtered. The filter cake was washed with acetonitrile to provide the acetonitrile solvate of

selinexorSelinexorSelinexor (Form D).

[00289] The acetonitrile solvate of selinexorSelinexorSelinexor was dried, then mixed with isopropanol (23Kg) and water (55Kg). The slurry was warmed to about 38 °C and held at that temperature for approximately 4 hours before being cooled to 15 to 20 °C. Water (182Kg) was added. After a further 5 hours of agitation, the mixture was filtered and the filter cake washed with a mixture of isopropanol (14Kg) and water (73Kg), before being dried under vacuum (45 °C). The dried product was packaged to provide

selinexorSelinexorSelinexor Lot No. 1405463 (Form A).

Example 7. Polymorphism Studies of Selinexor.

[00290] A comprehensive polymorphism assessment of selinexor was performed in a range of different solvents, solvent mixtures and under a number of experimental conditions based on the solubility of selinexor. Three anhydrous polymorphs of

selinexorSelinexorSelinexor were observed by XRPD investigation, designated Form A, Form B and Form C. Form A is a highly crystalline, high-melting form, having a melting point of 177 °C, and was observed to be stable from a physico-chemical point of view when exposed for 4 weeks to 25 °C/97% relative humidity (RH) and to 40 °C/75% RH. A solvated form of selinexor was also observed in acetonitrile, designated Form D. A competitive slurry experiment confirmed Form A as the stable anhydrous form under the conditions investigated, except in acetonitrile, in which solvate formation was observed. It was further found that in acetonitrile, below 50 °C, only Form D is observed, at 50 °C both Form A and Form D are observed, and at 55 °C, Form A is observed .

PATENT

CN 106831731

https://patents.google.com/patent/CN106831731A/en

Selinexor is an orally bioavailable selective nuclear export inhibitors, 2012 for the first time in clinical, so far carried out a total of 21 trials, indications include chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphatic leukemia, prostate cancer, melanoma, non-small cell lung cancer, glioma, neuroblastoma into, gynecological cancer, diffuse large B-cell lymphoma, squamous cell carcinoma, colorectal cancer and the like. May 2014, FDA granted orphan drug designation Selinexor treatment of acute myeloid leukemia and diffuse large B-cell lymphoma, in June 2014, EMA is also granted orphan drug designation Selinexor treatment of both diseases. January 2015, received FDA orphan drug to treat multiple myeloma identified.

[0003] Currently, the synthesis process has been disclosed, the following reaction equation:

Figure CN106831731AD00041

[0006] wherein the compound is 5 Selinexor drug.

[0007] In this method, however, easy to produce Intermediate 1-2 double bond is easily reversed when synthetically produced from trans impurities, in addition to more difficult to impact yield; Intermediate 3 Intermediate 4 Synthesis APIs 5 when required ultra-low temperature, and the product was purified by column required, only a yield of 20%.

SUMMARY

[0008] The object of the present invention to provide a novel compound Selinexor drug synthesis of 5, in order to solve technical problems.

[0009] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0010] A, Compound 7

[0011] Compound 6, dichloromethane and ethyl acetate mixture, stirred and dissolved, compound 4, T3P (n-propyl phosphoric anhydride) and DIPEA (N, N- diisopropylethylamine) at a low temperature; the reaction was stirred for 25-35min at a low temperature, dichloromethane and water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0012] B, Synthesis of Compound 8

[0013] the compound obtained in Step 7, and mixed sodium iodide acetic acid, warmed to 110-120 ° C, the reaction 2.5-3.5h; After completion of the reaction, the system cooled to room temperature, water and dichloromethane were added, stirred for 8 after -15min, standing layered organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in DMF (dimethyl fumarate) to give compound in DMF 8;

Synthesis [0014] C, of Compound 5

[0015] Compound 1, DBAC0 (triethylenediamine), the DMF mixed and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 3-4 hours; the reaction after completion, water and ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether and recrystallized from ethyl acetate to give compound 5.

[0016] Preferably, said step A, the low temperature is 0-2 ° C.

[0017] Preferably, said step B in DMF, the crude compound 8 concentration of less than 1%.

[0018] The novel synthetic methods of the present invention Selinexor drug, the chemical equation is as follows:

Figure CN106831731AD00051

[0020] The present invention has the following advantages: novel synthetic method Selinexor drug of the present invention to overcome the conventional synthesis process, is easy to produce trans impurities, more difficult in addition, the influence the yield and the need for ultra-low temperature, and the product requires problems purified by column, the yield is very low, reducing the synthetic steps, increased yield, there is provided a new process for the synthesis of the drug Selinexor.

[0021] In addition to the above-described objects, features and advantages of the present invention as well as other objects, features and advantages. Below the invention will be described in further detail present.

Example 1

[0024] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0025] A, Compound 7

[0026] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 0 ° C; the system at 0 ° C the reaction was stirred for 30min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0027] B, Synthesis of Compound 8

[0028] 50ml three-necked flask, added the compound obtained in Step 7,40ml of glacial acetic acid and 1.38g of sodium iodide was heated to 115. (:, The reaction 3H; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and IOOml dichloromethane, after stirring IOmin, standing separation, the organic phase was washed with saturated sodium bicarbonate and saturated washed with sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

Synthesis [0029] C, of Compound 5

[0030] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system in DMF compound obtained in Step 8, after the addition was complete, stirring continued for 3.5 hours; after completion of the reaction, 20ml water was added to the system and 50ml ethyl acetate, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.158g of compound 5, yield 50.9%.

[0031] Example 2

[0032] – new type Se Iinexor drug synthesis, comprising the steps of:

Synthesis [0033] A, Compound 7

[0034] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 1 ° C; system at 1 ° C the reaction was stirred for 35min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0035] B, Synthesis of Compound 8

Three-neck flask [0036] 50ml of addition of the compound obtained in Step 7,40ml glacial acetic acid and 1.38g of sodium iodide was heated to 120. (:, The reaction for 2.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 60ml water and 120ml dichloromethane was added, after stirring for 15min, allowed to stand for separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, 12mLDMF was dissolved in DMF to give a solution of compound 8;

Synthesis [0037] C, of Compound 5

[0038] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring continued for 3 hours; after completion of the reaction, 25ml of water and 50ml of ethyl acetate was added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.152g of compound 5, yield 49.0% billion

[0039] Example 3

[0040] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0041] A, Compound 7

Three [0042] 50ml of flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 2 ° C; system from 0 ° C the reaction was stirred for 25min, 40ml of dichloromethane and 35ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0043] B, Synthesis of Compound 8

Three-neck flask [0044] 50ml of addition of the compound obtained in Step 7,35ml glacial acetic acid and 1.38g of sodium iodide was heated to 110. (:, The reaction for 3.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and dichloromethane IOOml After Smin of stirring, standing separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

Synthesis [0045] C, of Compound 5

[0046] 50ml three-neck flask was added 0.2g compound 1,0.24gDBA⑶, 20mlDMF, and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 4 hours; after completion of the reaction, 20ml of water and 40ml ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.155g of compound 5, yield 49.9% billion

PATENT

WO 2017118940

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017118940&tab=PCTDESCRIPTION

The drug compound having the adopted name “Selinexor” has chemical name:(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-IH-l,2,4-triazol-1 -yl)-N’-(pyrazin-2yl) acrylohydrazide as below.

Figure imgf000003_0001

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE™ compound. Selinexor functions by binding with and inhibiting the nuclear export protein XP01 (also called CRM1 ), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Over 1 ,200 patients have been treated with Selinexor in company and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Karyopharm has initiated four later-phase clinical trials of Selinexor, including one in older patients with acute myeloid leukemia (SOPRA), one in patients with Richter’s transformation (SIRRT), one in patients with diffuse large B-cell lymphoma (SADAL) and a single-arm trial of Selinexor and lose-dose dexamethasone in patients with multiple myeloma (STORM). Patients may receive a twice-weekly combination of Selinexor in combination with low dose dexamethasone. Randomized 1 :1 , Selinexor will be dosed either at 60mg + dexamethasone or at 100 mg + dexamethasone.

US 8999996 B2 discloses Selinexor and a pharmaceutically acceptable salt thereof, pharmaceutical compositions and use for treating disorders associated with CRM1 activity. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Selinexor by reacting (Z)-3-(3- (3,5-

bis(trifluoromethyl)phenyl)-IH-l,2,4-triazol-l-yl)acrylic acid in 1 :1 CH2CI2: AcOEt with 2-Hydrazinopyrazine at -40 °C followed by addition of T3P[Propylphosphonic anhydride] (50%) and DIPEA. After 30 minutes, the reaction mixture was concentrated and the crude oil was purified by preparative TLC using 5% MeOH in CH2CI2 as mobile phase (under ammonia atmosphere) to afford 40 mg of Selinexor with purity: 95.78%. However, it is not disclosed about the nature of the compound obtained therein.

WO 2016025904 A1 discloses various crystalline forms of Selinexor namely Form A, Form B, Form C, Form D, compositions and MoU thereof for the treatment of disorder associated with CRM1 activity and their preparative processes.

Prior art process for the preparation of Selinexor suffers from disadvantages interms of process such as the use of lengthy procedures to practice and resulting in low yields, which may not be viable at industrial scale. Synthetic product obtained therein has very low purity and contains significant amounts of unreacted starting materials and trans-isomer of Selinexor, which are further purified by time consuming and expensive chromatographic separations leading to loss of yield. Hence, there remains a need for improved process for the preparation of Selinexor which is industrially viable and reproducible. Particularly, it is desirable to have a process avoiding purification steps still meeting desired pharmaceutical quality.

EXAMPLES

Example-1 : Preparation of isopropyl (Z)-3-(3-(3,5-bis(trifluoromethyl) phenyl)-1 H- -triazol-1 -yl)acrylate

Figure imgf000061_0001

3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazole (250 g) was dissolved in tetrahydrofuran (2 I) under nitrogen atmosphere at 27°C and cooled to -5°C. 1 ,4- diazabicyclo[2.2.2]octane (DABCO, 1 99.5 g) was added to the reaction mixture at -5°C and stirred at the same temperature for 40 minutes. Isopropyl (Z)-3- iodoacrylate (234.8 g in 500 mL of tetrahydrofuran) was added drop wise to the reaction mixture in 1 hour 1 0 minutes at -5°C and stirred at the same temperature for 2 hours. After the completion of the reaction, the reaction mixture was added to ice cold water (2 I) and separated the organic layer. The aqueous layer was extracted with ethyl acetate (2 x 1 I). The combined organic layer was washed with brine solution (1 I) and dried over sodium sulphate. The dried solution was evaporated completely under vacuum at 40°C to obtain crude product with HPLC purity of 93.53% The crude product was triturated with hexane (700 mL) and stirred for 20 minutes at -30°C and filtered the solid. Trituration of crude product with hexane was repeated for three times and dried under vacuum to obtain the title compound with HPLC purity of 97.46% and trans-isomer content of 0.66%. Yield: 297 g Example-2: Preparation of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4- triazol-1 -yl)acr lic acid.

Figure imgf000062_0001

To a mixture of tetrahydrofuran (300 mL) and water (300 mL), Isopropyl (Z)-3-(3- (3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylate (30 g) was added and cooled to 0°C. Lithium hydroxide monohydrate (16.03 g) under cooling condition at 0°C was added to the reaction mixture and stirred the reaction mixture at same temperature for 7 hours. After completion of the reaction, 2 N HCI (180 mL) was added to adjust the pH of the reaction mixture to 2 and extracted it with ethyl acetate (300 mL). Organic layer was dried over sodium sulphate and evaporated under vacuum at 40°C. The crude compound was stirred with hexane (150 mL) and filtered the solid. Dried the compound under vacuum at 40°C for 0.5 hour to obtain the title compound with HPLC purity of 97.25% with trans-isomer content of 3 %. Yield: 24 g

Example-3: Purification of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4- tria

Figure imgf000062_0002

A mixture of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid (24 g) and acetone (240 mL) was stirred for complete dissolution at 30°C. Dicyclohexyl amine (1 5 mL) was added drop wise for 20 minutes under stirring at the same temperature. Acetone (50 mL) was added to the reaction mixture and stirred for 2 hours at 27°C. Filtered the solid and washed with hot acetone (150 mL) and dried in vacuum drier at 30°C for 1 hour to obtain the Dicyclohexyl amine salt of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid. To the above salt, dichloromethane (150 mL) and water (1 00 mL) was added and stirred for complete dissolution at 30and adjusted the pH of the solution with 2 N sulphuric acid (100 mL) to 2. Filtered the reaction mixture and washed the product with water (1 00 mL) and then with hexane (150 mL). The solid was dried under vacuum at 40°C for 0.5 hour to obtain title compound with HPLC purity 99.98% with no detectable content of trans-isomer. Yield: 17 g

Example-4: Preparation of Selinexor

Figure imgf000063_0001

(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid (10 g) was combined with a mixture of acetonitrile (1 00 mL) and ethyl acetate (50 mL) then added the 2-hydrazinylpyrazine (3.76 g) and stirred for 5 min. Reaction mixture was cooled to 0°C and diisopropyl ethyl amine (16.63 ml) and then Propylphosphonic anhydride (T3P, 33.31 mL) was added at 0°C and stirred the reaction mixture for 2.5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with cold water (100 mL) and extracted the product with ethyl acetate (2 x 150 mL). The combined organic layer was dried over sodium sulphate and evaporated the solvent under vacuum at 40°C to obtain the crude product as yellow syrup. The obtained crude product was combined with dichloromethane (1 00 mL) and filtered the solid and washed with dichloromethane (2 x 50 mL). The solid was dried under vacuum at 40°C to obtain the title compound with purity by HPLC of 99.86%. Yield : 7 g

PATENT
WO 2018129227

References

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Selinexor
Skeletal formula of selinexor
Clinical data
Trade names Xpovio
Pregnancy
category
  • Known to cause fetal harm
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Protein binding 95%
Metabolism Hepatic oxidation, glucuronidation, and conjugation, by CYP3A4UGTand GST
Elimination half-life 6–8 h
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
Formula C17H11F6N7O
Molar mass 443.313 g·mol−1
3D model (JSmol)

Karyopharm’s Selinexor Receives Fast Track Designation from FDA for the Treatment of Patients with Penta-Refractory Multiple Myeloma

NEWTON, Mass., April 10, 2018 (GLOBE NEWSWIRE) — Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the Company’s lead, oral Selective Inhibitor of Nuclear Export (SINE) compound selinexor for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy.  The FDA’s statement, consistent with the design of Karyopharm’s Phase 2b STORM study, noted that the three prior lines of therapy include regimens comprised of an alkylating agent, a glucocorticoid, Velcade® (bortezomib), Kyprolis® (carfilzomib), Revlimid® (lenalidomide), Pomalyst® (pomalidomide) and Darzalex® (daratumumab).  In addition, the patient’s disease must be refractory to at least one proteasome inhibitor (Velcade or Kyprolis), one immunomodulatory agent (Revlimid or Pomalyst), glucocorticoids and to Darzalex, as well as to the most recent therapy.  The Company expects to report top-line data from the STORM study at the end of April 2018.

ChemSpider 2D Image | selinexor | C17H11F6N7O

The FDA’s Fast Track program facilitates the development of drugs intended to treat serious conditions and that have the potential to address unmet medical needs.  A drug program with Fast Track status is afforded greater access to the FDA for the purpose of expediting the drug’s development, review and potential approval.  In addition, the Fast Track program allows for eligibility for Accelerated Approval and Priority Review, if relevant criteria are met, as well as for Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be submitted for review.

“The designation of Fast Track for selinexor represents important recognition by the FDA of the potential of this anti-cancer agent to address the significant unmet need in the treatment of patients with penta-refractory myeloma that has continued to progress despite available therapies,” said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm.  “We are fully committed to working closely with the FDA as we continue development of this potential new, orally-administered treatment for patients who currently have no other treatment options of proven benefit.”

About the Phase 2b STORM Study

In the multi-center, single-arm Phase 2b STORM (Selinexor Treatment oRefractory Myeloma) study, approximately 122 patients with heavily pretreated, penta-refractory myeloma receive 80mg oral selinexor twice weekly in combination with 20mg low-dose dexamethasone, also dosed orally twice weekly.  Patients with penta-refractory disease are those who have previously received an alkylating agent, a glucocorticoid, two immunomodulatory drugs (IMiDs) (Revlimid® (lenalidomide) and Pomalyst® (pomalidomide)), two proteasome inhibitors (PIs) (Velcade® (bortezomib) and Kyprolis® (carfilzomib)), and the anti-CD38 monoclonal antibody Darzalex® (daratumumab), and their disease is refractory to at least one PI, at least one IMiD, Darzalex, glucocorticoids and their most recent anti-myeloma therapy.  Overall response rate is the primary endpoint of the study, with duration of response and clinical benefit rate being secondary endpoints.  All responses will be adjudicated by an Independent Review Committee (IRC).

About Selinexor

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,300 patients have been treated with selinexor, and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), in combination with low-dose dexamethasone (STORM) and as a potential backbone therapy in combination with approved therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

About Karyopharm Therapeutics

Karyopharm Therapeutics Inc. (Nasdaq:KPTI) is a clinical-stage pharmaceutical company focused on the discovery, development and subsequent commercialization of novel first-in-class drugs directed against nuclear transport and related targets for the treatment of cancer and other major diseases. Karyopharm’s SINE compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). In addition to single-agent and combination activity against a variety of human cancers, SINE compounds have also shown biological activity in models of neurodegeneration, inflammation, autoimmune disease, certain viruses and wound-healing. Karyopharm, which was founded by Dr. Sharon Shacham, currently has several investigational programs in clinical or preclinical development.

/////////Selinexor, FDA 2019, セリネクソル  ,KPT-330, KPT 330 , KPT330,  AML, Glioma, Sarcoma, Leukemia, Fast Track, CANCER

Picropodophyllin


Picropodophyllin.png

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2D chemical structure of 477-47-4

Picropodophyllin

Picropodophyllotoxin

CAS 477-47-4

AXL1717, NSC 36407, BRN 0099161

414.4 g/mol, C22H22O8

(5R,5aR,8aS,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one

Furo(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6(5aH)-one, 5,8,8a,9-tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-, (5R-(5-alpha,5a-alpha,8a-alpha,9-alpha))-

5-19-10-00665 (Beilstein Handbook Reference)

Axelar is developing picropodophyllin, a small-molecule IGF-1 receptor antagonist for the treatment of cancer including NSCLC and malignant astrocytoma. In February 2019, a phase Ia study was planned to initiate for solid tumor in March 2019.

Picropodophyllin is a cyclolignan alkaloid found in the mayapple plant family (Podophyllum peltatum), and a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF1R) with potential antineoplastic activity. Picropodophyllin specifically inhibits the activity and downregulates the cellular expression of IGF1R without interfering with activities of other growth factor receptors, such as receptors for insulin, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor and mast/stem cell growth factor (KIT). This agent shows potent activity in the suppression o f tumor cell proliferation and the induction of tumor cell apoptosis. IGF1R, a receptor tyrosine kinase overexpressed in a variety of human cancers, plays a critical role in the growth and survival of many types of cancer cells.

Picropodophyllotoxin is an organic heterotetracyclic compound that has a furonaphthodioxole skeleton bearing 3,4,5-trimethoxyphenyl and hydroxy substituents. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor, an insulin-like growth factor receptor 1 antagonist and a plant metabolite. It is a lignan, a furonaphthodioxole and an organic heterotetracyclic compound.

Picropodophyllin has been investigated for the treatment of Non Small Cell Lung Cancer.

One of the largest challenges in pharmaceutical drug development is that drug compounds often are poorly soluble, or even insoluble, in aqeous media. Insufficient drug solubility means insufficient bioavailability, as well as poor plasma exposure of the drug when administered to humans and animals. Variability of plasma exposure in humans is yet a problem when developing drugs which are poorly soluble, or even insoluble, in aqeous media.

It is estimated that between 40% and 70 % of all new chemical entities identified in drug discovery programs, are insufficiently soluble in aqeous media (M. Lindenberg, S et al: European Journal of Pharmaceutics and Biopharmaceuticals, vol. 58, no.2, pp. 265-278, 2004). Scientists have investigated various ways of solving the problem with poor drug solubility in order to enhance bioavailability of poorly absorbed drugs, aiming at increasing their clinical efficacy when administered orally.

Technologies such as increase of the surface area and hence dissolution may sometimes solve solubility problems. Other techniques that may also solve bioavailability problems are addition of surfactants and polymers. However, each chemical compound has its own unique chemical and physical properties, and hence has its own unique challenges when being formulated into a pharmaceutical product that can exert its clinical efficacy.

Picropodophyllin is an insulin-like growth factor-1 receptor inhibitor fiGF-lR inhibitor) small-molecule compound belonging to the class of compounds denominated cyclolignans, having the chemical structure:

The patent applicant is presently entering clinical phase II development with its development compound picropodophyllin (AXL1717). However, picropodophyllin is poorly soluble in aqueous media. In a phase I clinical study performed by the applicant in 2012 (Ekman S et al; Acta Oncologica, 2016; 55: pp. 140-148), it was discovered that picropodophyllin, when administered as an oral suspension to lung cancer patients, resulted in unacceptable variability in drug exposure. A large variability in plasma exposure of the active drug picropodophyllin occurred not only within certain patients, but also between several patients.

Yet a problem with administering picropodophyllin as an aqeous solution, is that due to the poor solubility in aqueous media, it is difficult or even impossible to reach the required therapeutic doses.

The compound picropodophyllin is furthermore physically unstable, and transforms from amorphous picropodophyllin into crystalline picropodophyllin. Yet a stability problem with picropodophyllin is that it is chemically unstable in solution.

Image result for Picropodophyllin AND podophyllotoxin

Product case, WO02102804

Patent

WO-2019130194

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019130194&tab=PCTDESCRIPTION&_cid=P10-JXYAA3-53049-1

Novel amorphous forms of picropodophyllin , processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating cancers, such as neurologic cancer, lung cancer, breast cancer, head and neck cancer, gastrointestinal cancer, genitourinary cancer, gynecologic cancer, hematologic cancer, musculoskeletal cancer, skin cancer, endocrine cancer, and eye cancers. , claiming picropodophyllin derivatives as modulators of insulin-like growth factor-1 receptor (IGF-1), useful for treating cancers, assigned to Axelar AB ,

CLIP

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CLIP

https://pubs.rsc.org/en/content/articlelanding/2004/cc/b312245j/unauth#!divAbstract

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http://www.rsc.org/suppdata/cc/b3/b312245j/b312245j.pdf

dH(CDCl3; 300 MHz; Me4Si): 2.64-2.78 (1 H, m, 3-H), 3.23 (1 H, dd, J 4.4 and 8.2, 2-H), 3.81 (6 H, s, 2 x OMe), 3.85 (3 H, s, OMe), 4.09 (1 H, d, J 4.4, 1-H), 4.38–4.59 (3 H, m, 11-H2 and 4-H), 5.91 (1 H, d, J 1.5, OCH2O), 5.93 (1 H, d, J 1.5, OCH2O), 6.35 (1 H, s, 5-H/8-H), 6.46 (1 H, s, 2’-H and 6’-H) and 7.07 (1 H, s, 5-H/8-H).

CLIP

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PAPER

Organic Letters (2018), 20(6), 1651-1654

https://pubs.acs.org/doi/abs/10.1021/acs.orglett.8b00408

Abstract Image

A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally occurring podophyllotoxin and other members.

Synthesis of (−)-Podophyllotoxin (1)

https://pubs.acs.org/doi/suppl/10.1021/acs.orglett.8b00408/suppl_file/ol8b00408_si_001.pdf

The residue was purified by flash column chromatography (petroleum ether/EtOAc = 4 : 1 → petroleum ether/EtOAc = 2 : 1) on silica gel to afford 1 (8.6 mg, 87% yield) as a white solid; Rf = 0.23 (petroleum ether/EtOAc = 1 : 1); [α]20 D = –115.00 (c = 1.00, CHCl3) [ref.13: [α]20 D = –101.7 (c = 0.55, EtOH)]; Mp. 167–168 °C; 1H NMR (400 MHz, CDCl3): δ = 7.11 (s, 1H), 6.51 (s, 1H), 6.37 (s, 2H), 5.98 (s, 1H), 5.96 (s, 1H), 4.77 (t, J = 8.4 Hz, 1H), 4.60 (t, J = 8.0 Hz, 1H), 4.59 (d, J = 4.4 Hz, 1H), 4.08 (dd, J = 9.6, 8.8 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 6H), 2.84 (dd, J = 14.0, 4.4 Hz, 1H), 2.83−2.74 (m, 1H), 2.13 (d, J = 8.0 Hz, 1H, −OH) ppm; 13C NMR (100 MHz, CDCl3): δ = 174.6, 152.5 (2C), 147.7, 147.6, 137.1, 135.5, 133.3, 131.0, 109.7, 108.4 (2C), 106.3, 101.4, 72.6, 71.4, 60.7, 56.2 (2C), 45.2, 44.1, 40.6 ppm.

https://pubs.acs.org/doi/suppl/10.1021/acs.orglett.8b00408/suppl_file/ol8b00408_si_002.pdf

PAPER

Organic Letters (2017), 19(24), 6530-6533

https://pubs.acs.org/doi/abs/10.1021/acs.orglett.7b03236

Abstract Image

he first catalytic enantioselective total synthesis of (−)-podophyllotoxin is accomplished by a challenging organocatalytic cross-aldol Heck cyclization and distal stereocontrolled transfer hydrogenation in five steps from three aldehydes. Reversal of selectivity in hydrogenation led to the syntheses of other stereoisomers from the common precursor.

https://pubs.acs.org/doi/suppl/10.1021/acs.orglett.7b03236/suppl_file/ol7b03236_si_001.pdf

(-)-Picropodophyllin 4. The lactone 5 (0.2 g, 0.38 mmol) was taken in 1-pentanol (5 mL) in a double neck RB flask at rt. Water (0.14 mL, 7.6 mmol) was added to above mixture and it was then degassed with argon followed by addition of Pd/C (0.04 g, 20% by wt.) and HCO2Na (0.78g, 11.4 mmol). The reaction mixture was heated at 40 °C for 12 h. On completion, the reaction mixture was diluted with EtOAc (200 mL), filtered through a celite pad and solvent was removed under vacuum. This crude mixture was dissolved in THF (3.8 mL), TBAF (1.9 mL, 1.9 mmol, 1M in THF) was added and stirred for 6 h at 27 °C. On completion, EtOAc (250 mL) was added, washed with water (100 mL), brine and dried over Na2SO4. After removal of solvent, the crude product was purified by column chromatography (hexanes-EtOAc, 3:2) to get the title compound as a white solid (0.082 g, 52%): Rf 0.32 (hexanes/EtOAc, 1:1); [α]25 D = -10.6 (c = 0.4, CHCl3) [lit. -10 (c = 0.3, CHCl3), -11 (c = 0.41, CHCl3)]3a,b;

Mp 214-216 °C; 1H NMR (600 MHz, CDCl3) δ 7.05 (s, 1H), 6.47 (s, 2H), 6.41 (s, 1H), 5.95 (d, J = 14.1 Hz, 2H), 4.5 (m, 2H), 4.44 (t, J = 8.0 Hz, 1H), 4.15 (d, J = 4.1 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 6H), 3.24 (dd, J = 8.7, 5.0 Hz, 1H), 2.75 (m, 1H), 2.12 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 177.6, 153.7, 147.5, 147.1, 139.3, 137.4, 131.9, 130.6, 109.3, 105.9, 105.5, 101.2, 69.8, 69.6, 60.9, 56.3, 45.4, 44.1, 42.7; HRMS (ESI-TOF) m/z 437.1219 [(M+Na)+ ; calcd for C22H22O8Na+ : 437.1212].

PAPER

The Journal of organic chemistry (2000), 65(3), 847-60.

https://pubs.acs.org/doi/abs/10.1021/jo991582+

Abstract Image

REF

Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1932), 65B, 1846.

Justus Liebigs Annalen der Chemie (1932), 499, 59-76.

Justus Liebigs Annalen der Chemie (1932), 494, 126-42.

Journal of the American Chemical Society (1954), 76, 5890-1

Helvetica Chimica Acta (1954), 37, 190-202.

 Journal of the American Chemical Society (1988), 110(23), 7854-8.

//////////////Picropodophyllin, AXL1717, NSC 36407, BRN 0099161, Picropodophyllotoxin, AXELAR, PHASE 1, CANCER, neurologic cancer, lung cancer, breast cancer, head and neck cancer, gastrointestinal cancer, genitourinary cancer, gynecologic cancer, hematologic cancer, musculoskeletal cancer, skin cancer, endocrine cancer, eye cancers,  NSCLC, malignant astrocytoma, SOLID TUMOUR

COC1=CC(=CC(=C1OC)OC)C2C3C(COC3=O)C(C4=CC5=C(C=C24)OCO5)O

Podofilox, Podophyllotoxin, Wartec, Condyline, Condylox

J Org Chem 2000,65(3),847

The formylation of 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) with BuLi and DMF gives the 6-formyl derivative (II), which is reduced with NaBH4 in ethanol to yield the corresponding carbinol (III). The cyclization of (III) with dimethyl acetylenedicarboxylate (V) in hot acetic acid (through the nonisolated intermediate (IV)) affords dimethyl 1,4-epoxy-6,7-(methylenedioxy)naphthalene-2,3-dicarboxylate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the (1R*,2S*,3R*,4S*)-tetrahydro derivative (VII). The reduction of (VII) with LiAlH4 in refluxing ethyl ether affords the corresponding bis carbinol (VIII), which is treated with acetic anhydride to afford the diacetate (IX). The enzymatic monodeacetylation of (VIII) with PPL enzyme in DMSO/buffer gives (1R,2R,3S,4S)-2-(acetoxymethyl)-1,4-epoxy-3-(hydroxymethyl)-6,7-(methylenedioxy)-1,2,3,4-tetrahydronaphthalene (X), which is silylated with TBDMS-Cl and imidazole in DMF yielding the silyl ether (XI). The hydrolysis of the acetoxy group of (XI) with K2CO3 in methanol affords the carbinol (XII), which is oxidized with oxalyl chloride in dichloromethane affording the carbaldehyde (XIII). The exchange of the silyl protecting group of (XIII) (for stability problems) provided the triisopropylsilyl ether (XIV), which is treated with sodium methoxide in methanol to open the epoxide ring yielding the hydroxy aldehyde (XV). The protection of the hydroxy group of (XV) with 2-(trimethylsilyl)ethoxymethyl chloride and DIEA in dichloromethane provides the corresponding ether (XVI). The carbinol (III) can also be obtained directly from 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) by reaction with formaldehyde and BuLi in THF.

The oxidation of the aldehyde group of (XVI) with NaClO2 in tert-butanol affords the corresponding carboxylic acid (XVII), which is condensed with 2-oxazolidinone (XVIII) by means of carbonyldiimidazole (CDI) in THF to give the acyl imidazolide (XIX). The arylation of (XIX) with 3,4,5-trimethoxyphenylmagnesium bromide (XX) in THF yields the expected addition product (XXI), which is cyclized by means of TBAF in hot THF to afford the tetracyclic intermediate (XXII). Isomerization of the cis-lactone ring of (XXII) with LDA in THF affords intermediate (XXIII) with its lactone ring with the correct trans-conformation. Finally, this compound is deprotected with ethyl mercaptane and MgBr2 in ethyl ether to provide the target compound.

Synthesis 1992,719

The intermediate trans-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetra-hydronaphtho[2,3-d][1,3]benzodioxole-6-carboxylic acid ethyl ester (XI) has been obtained by several different ways: (a) The condensation of benzophenone (XXXVIII) with diethyl malonate (XXXIX) by means of t-BuOK gives the alkylidenemalonate (XL), which is hydrogenated with H2 over Pd/C to the alkylmalonate hemiester (XLI). The reaction of (XLI) with acetyl chloride affords the mixed anhydride (XLII), which is finally cyclized to the target (XI) by means of SnCl4. (b) The cyclization of the malonic ester derivative (XLIII) by means of Ti(CF3–CO2)3 gives the 5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho [2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLIV), which is finally oxidized and decarboxylated with NBS and NaOH in methanol to afford the target intermediate (XI). (c) The cyclization of the benzylidenemalonate (XLV) with the aryllithium derivative (XLVI) gives the 8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLVII), which is demethylated with TFA and oxidized with CrO3 and pyridine to the target compound (XI). (d) The cyclopropanation of the chalcone (XLVIII) with (ethoxycarbonyl) (dimethylsulfonium)methylide (XLIX) gives the cyclopropanecarboxylate (L), which is finally rearranged with BF3/Et2O to the target intermediate (IX).

The cyclization of 3,4,5-trimethoxycinnamic acid ethyl ester (LI) with malonic acid ethyl ester potassium salt (LII) by means of Mn(OAc)3 gives the tetrahydrofuranone (LIII), which is acylated with 1,3-benzodioxol-5-ylcarbonyl chloride (LIV) yielding the tetrahydrofuranone (LV). Finally, this compound is rearranged and decarboxylated with SnCl4 to the target intermediate (XI).

The cyclization of 6-[1-hydroxy-1-(3,4,5-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-carbaldehyde dimethylacetal (LVI) by means of AcOH gives 5-(3,4,5-trimethoxyphenyl)-1,3-dioxolo[4,5-f]isobenzofuran (LVII), which is submitted to a Diels-Alder cyclization with acetylenedicarboxylic acid dimethyl ester (LVIII) yielding the epoxy derivative (LIX). The selective reduction of (LIX) with LiBEt3H and H2 affords the carbinol (LX), which is treated with H2 over RaNi in order to open the epoxide ring to give the diol (LXI) with the wrong configuration at the secondary OH group. The treatment of (LXI) with aqueous acid isomerizes the secondary OH group to (LXII) with the suitable configuration. Finally, this compound is cyclized with DCC to the desired target compound.

The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl maleate (LXIII) gives the expected adduct (LXIV), which by thermal extrusion of CO2 yields the dihydronaphthodioxole (LXV). This compound is then converted to dihydroxycompound (X), which is finally cyclized by means of ZnCl2 to provide the target compound. The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl fumarate (LXVI) gives the expected adduct (LXVII), which by hydrogenation with H2 over Pd/C yields the tricarboxylic acid derivative (LXVIII). The reaction of (LXVIII) with Pb(OAc)4 affords the acetoxy derivative (LXIX), which is selectively reduced with LiBEt3H providing the diol (LXI) with the wrong configuration at the secondary OH group. The treatment of (LXI) with aqueous acid isomerizes the secondary OH group to give the previously described (X) with the suitable configuration.

The reaction of benzocyclobutane derivative (LXX) with isocyanate (LXXI) by means of Ph3SnOAc gives the carbamate (LXXII), which is cyclized by a thermal treatment with LiOH yielding the tetracyclic carboxylic acid (LXXIII). The opening of the oxazinone ring of (LXXIII) in basic medium affords the tricyclic amino acid (LXXIV), which is finally cyclized to the target compound by reaction with sodium nitrite in acidic medium (pH = 4).

J Chem Soc Chem Commun 1993,1200

The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with the chiral dihydrofuranone (II) in hot acetonitrile gives the pentacyclic anhydride (III), which is opened with warm acetic acid yielding the carboxylic acid (IV). Hydrogenation of the benzylic double bond of (IV) with H2 over Pd/C affords (V), which is treated with lead tetraacetate and acetic acid in THF to give the acetoxy compound (VI). The hydrolysis of the acetoxy group and the menthol hemiacetal group with HCl in hot dioxane yields the diol (VII), which is treated with diazomethane in ether/methanol affording the aldehyde (VIII). The reduction of the aldehyde group of (VIII) with LiEt3BH in THF gives the diol (IX) as a diastereomeric mixture, which is treated with HCl in THF to afford the diol (X) with the right conformation. Finally, this compound is lactonized to the target compound with ZnCl2 in THF.

//////////

HS 10340


HS-10340

CAS 2156639-66-4

MF C26 H31 N7 O5
MW 521.57
1,8-Naphthyridine-1(2H)-carboxamide, N-[5-cyano-4-[[(1R)-2-methoxy-1-methylethyl]amino]-2-pyridinyl]-7-formyl-3,4-dihydro-6-[(tetrahydro-2-oxo-1,3-oxazepin-3(2H)-yl)methyl]-
(R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl)-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide

CAS 2307670-65-9

Jiangsu Hansoh Pharmaceutical Group Co Ltd

Being investigated by Jiangsu Hansoh, Shanghai Hansoh Biomedical and Changzhou Hengbang Pharmaceutical ; in June 2018, the product was being developed as a class 1 chemical drug in China.

Useful for treating liver cancer, gastric cancer and prostate cancer.

Use for treating cancers, liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma and rhabdomyosarcoma

The fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor and includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.
FGFR4, a member of the FGFR receptor family, forms dimers on the cell membrane by binding to its ligand, fibroblast growth factor 19 (FGF19), and the formation of these dimers can cause critical tyrosine in FGFR4’s own cells. The phosphorylation of the amino acid residue activates multiple downstream signaling pathways in the cell, and these intracellular signaling pathways play an important role in cell proliferation, survival, and anti-apoptosis. FGFR4 is overexpressed in many cancers and is a predictor of malignant invasion of tumors. Decreasing and reducing FGFR4 expression can reduce cell proliferation and promote apoptosis. Recently, more and more studies have shown that about one-third of liver cancer patients with continuous activation of FGF19/FGFR4 signaling pathway are the main carcinogenic factors leading to liver cancer in this part of patients. At the same time, FGFR4 expression or high expression is also closely related to many other tumors, such as gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and the like.
The incidence of liver cancer ranks first in the world in China, with new and dead patients accounting for about half of the total number of liver cancers worldwide each year. At present, the incidence of liver cancer in China is about 28.7/100,000. In 2012, there were 394,770 new cases, which became the third most serious malignant tumor after gastric cancer and lung cancer. The onset of primary liver cancer is a multi-factor, multi-step complex process with strong invasiveness and poor prognosis. Surgical treatments such as hepatectomy and liver transplantation can improve the survival rate of some patients, but only limited patients can undergo surgery, and most patients have a poor prognosis due to recurrence and metastasis after surgery. Sorafenib is the only liver cancer treatment drug approved on the market. It can only prolong the overall survival period of about 3 months, and the treatment effect is not satisfactory. Therefore, it is urgent to develop a liver cancer system treatment drug targeting new molecules. FGFR4 is a major carcinogenic factor in liver cancer, and its development of small molecule inhibitors has great clinical application potential.
At present, some FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors of FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia. Such as target related side effects. Highly selective inhibitor of FGFR4 can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathway, and can avoid the side effects of hyperphosphatemia caused by FGFR1-3 inhibition. Highly selective small molecule inhibitors against FGFR4 in tumor targeted therapy The field has significant application prospects.
SYN

PATENT

WO2017198149

where it is claimed to be an FGFR-4 inhibitor for treating liver and prostate cancers, assigned to Jiangsu Hansoh Pharmaceutical Group Co Ltd and Shanghai Hansoh Biomedical Co Ltd .

PATENT

WO2019085860

Compound (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-) 1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (shown as Formula I). The compound of formula (I) is disclosed in Hausen Patent PCT/CN2017/084564, the compound of formula I is a fibroblast growth factor receptor inhibitor, and the fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor. The body includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.

[0003]
Example 1: Preparation of a compound of formula (I)

[0048]
First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol

[0049]

[0050]
2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) . 3 (1.35 g of, 6.4 mmol), stirred at room temperature overnight. The reaction was treated with CH 2 CI 2 was diluted (100 mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 – (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .

[0051]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.13 (S, IH), 5.17 (S, IH), 4.84 (S, IH), 3.73 (S, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);

[0052]
MS m/z (ESI): 310.2 [M+H] + .

[0053]
The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone

[0054]

[0055]
4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH 2 Cl 2 (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).

[0056]
MS m/z (ESI): 336.2 [M+H] + .

[0057]
The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate

[0058]

[0059]
3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixing in of THF (15 mL), N 2 in an atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH 4 Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .

[0060]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.56 (S, IH), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (S, IH), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);

[0061]
MS m/z (ESI): 456.2 [M+H] + .

[0062]
The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis

[0063]

[0064]
(R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N 2atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH 4 Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).

[0065]
1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);

[0066]
MS m/z (ESI): 568.3 [M+H] + .

[0067]
Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide

[0068]

[0069]
(R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated NaHC03 . 3 solution (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).

[0070]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 13.57 (S, IH), 10.26 (S, IH), 8.17 (S, IH), 7.71 (S, IH), 7.63 (S, IH), 5.27 (S, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 – 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);

[0071]
MS m/z (ESI): 522.2 [M+H] + .

PATENT

WO-2019085927

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019085927&tab=FULLTEXT

Novel crystalline salt (such as hydrochloride, sulfate, methane sulfonate, mesylate, besylate, ethanesulfonate, oxalate, maleate, p-toluenesulfonate) forms of FGFR4 inhibitor, particularly N-[5-cyano-4-[[(1R)-2-methoxy-1-methyl-ethyl]amino]-2-pyridyl]-7-formyl-6-[(2-oxo-1,3-oxazepan-3-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide (designated as Forms I- IX), compositions comprising them and their use as an FGFR4 inhibitor for the treatment of cancer such as liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and glioma or rhabdomyosarcoma are claimed.

Example 1: Preparation of a compound of formula (I)
First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol
2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) . 3 (1.35 g of, 6.4 mmol), stirred at room temperature overnight. The reaction was treated with CH 2 CI 2 was diluted (100 mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 – (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.13 (S, IH), 5.17 (S, IH), 4.84 (S, IH), 3.73 (S, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);
MS m/z (ESI): 310.2 [M+H] + .
The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone
4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH 2 Cl 2 (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).
MS m/z (ESI): 336.2 [M+H] + .
The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate
3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixing in of THF (15 mL), N 2 in an atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH 4 Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.56 (S, IH), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (S, IH), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);
MS m/z (ESI): 456.2 [M+H] + .
The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis
(R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N 2atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH 4 Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).
1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);
MS m/z (ESI): 568.3 [M+H] + .
Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide
(R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated NaHC03 . 3 solution (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 13.57 (S, IH), 10.26 (S, IH), 8.17 (S, IH), 7.71 (S, IH), 7.63 (S, IH), 5.27 (S, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 – 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);
MS m/z (ESI): 522.2 [M+H] + .

///////////HS-10340 , HS 10340 , HS10340, CANCER, Jiangsu Hansoh, Shanghai Hansoh Biomedical,  Changzhou Hengbang, CHINA,  liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma,  rhabdomyosarcoma

C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

CCS(=O)(=O)O.C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

GFH 018


(E)-3-[6-[2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-enamide.png

GFH-018

CAS 2169299-67-4

C21 H19 N7 O, 385.42
(E)-3-[6-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-enamide
2-Propenamide, 3-[6-[5,6-dihydro-2-(6-methyl-2-pyridinyl)-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,2,4]triazolo[1,5-a]pyridin-5-yl]-, (2E)-

GenFleet Therapeutics

Advanced solid tumor; Cancer

TGF-beta Receptor Type-1 (TGFBR1; ALK5; SKR4; TbetaR-I) Inhibitors

Signal Transduction Modulators

GFH-018 , a TGFBR1 inhibitor, being investigated by GenFleet as an oral tablet formulation, for the treatment of cancer, including advanced solid tumors and hepatocellular carcinoma,  in March 2019, the company was developing GFH-018 as a class 1 chemical drug in China, with a clinical trial expected to begin in the second half of 2019.

Transforming growth factor-β (TGF-β) is a multifunctional growth factor superfamily with extensive biological activity, involved in early embryonic development, cartilage and bone formation, extracellular matrix synthesis, inflammation, Interstitial fibrosis, regulation of immune and endocrine functions, tumor formation and development.
The TGF-β superfamily consists of a class of structural and functionally related polypeptide growth factors, including TGF-βs (ie, narrowly defined TGF-β), activins (axivins), inhibins, and bone morphogenetic proteins (BMPs). Müllerian inhibitors (mullerian), etc., TGF-β is one of the important members of this family. In mammals, TGF-β mainly exists in three forms of TGF-β1, TGF-β2 and TGF-β3, which are located on different chromosomes, and TGF-β1 accounts for the highest proportion (>90%) in somatic cells. It has the strongest activity, the most functions, and the widest distribution. The newly synthesized TGF-β appears as an inactive precursor consisting of a signal peptide, a latent-associated polypeptide (LAP) and a mature TGF-β. After enzymatic hydrolysis, it forms active TGF-β, and then Receptor binding exerts a biological effect.
TGF-[beta] signaling molecules signal through a transmembrane receptor complex. TGF-β receptor is a transmembrane protein present on the cell surface and is divided into type I receptor (TGF-βRI), type II receptor (TGF-βRII) and type III receptor (TGF-βRIII), of which TGF- βRI is also known as activin receptor-like kinase 5 (ALK5). TGF-βRIII lacks intrinsic activity and is primarily involved in the storage of TGF-β. TGF-βRI and TGF-βRII belong to the serine/threonine kinase family. Type II receptors bind to TGF-β ligands with higher affinity and form heterologous receptor complexes with type I receptors. Phosphorylation of a region rich in glycine and serine residues (GS domain) of the proximal membrane of the receptor initiates an intracellular signal cascade reaction.
Smads are important TGF-β signal transduction and regulatory molecules in cells, which can directly transduce TGF-β signaling from the cell membrane, such as the nucleus. TGF-β/Smads signaling pathway plays an important role in the occurrence and development of tumors. . In TGF-β/Smads signal transduction, activated TGF-β first binds to TGF-βRII on the cell membrane surface to form a heterodimeric complex, and TGF-βRI recognizes and binds to the binary complex.
TGF-βRII phosphorylates serine/threonine in the GS domain of the cytoplasmic domain of TGF-βRI, thereby activating TGF-βRI; activated TGF-βRI further phosphorylates R-Smads (Smad2/Smad3) protein, which in turn Co-Smad (Smad4) binds to a heterotrimeric complex that enters the nucleus and acts synergistically with other co-activators and co-inhibitors to regulate transcription of target genes. . Any change in any part of the TGF-β/Smads signaling pathway leads to abnormalities in the signal transduction pathway.
Current research indicates that in tumor cells, TGF-β can directly affect tumor growth (non-inherent effects of TGF-β signaling), or by inducing epithelial-mesenchymal transition, blocking anti-tumor immune responses, and increasing tumor-associated fibrosis And enhanced angiogenesis indirectly affects tumor growth (the intrinsic effect of TGF-β). At the same time, TGF-β has a strong fibrotic induction, which is an activator of tumor-associated fibroblasts. These fibroblasts are a major source of collagen type I and other fibrotic factors. Induction products of fibroblasts and other fibrotic factors may continue to develop a microenvironment that reduces immune responses, increases drug resistance, and enhances tumor angiogenesis. In addition, TGF-β affects blood vessels during individual development and tumor growth. Raw regeneration. For example, TGF-βRI-deficient mouse embryos show severe vascular development defects, demonstrating that the TGF-β signaling pathway is a key regulator in vascular endothelium and smooth muscle cell development.
In 2013, the FDA awarded Lilly’s small molecule TGF-βRI inhibitor LY2157299 (WO 2002/094833) for the treatment of glioma and liver cancer. LY2157299 is an orphan drug under research, named Galunisertib. Galunisertib inhibits tumor cell invasion and metastasis while inhibiting the infiltration of tumor cells into blood vessels. In the phase 2 clinical trial of patients with liver cancer, about 23% of patients treated with Galunisertib had a decrease in serum alpha-fetoprotein (AFP) levels of more than 20%. Compared with patients without AFP response, these patients had slower tumor progression and longer survival, and increased expression of cadherin in epithelial cells was also observed in these patients, suggesting that Galunisertib can be regulated by inhibiting TGF-β signaling pathway. EMT, thereby inhibiting the progression of liver cancer, the structure of Galunisertib (LY2157299) is shown in formula (II):
Background research and development materials refer to the following documents:
WO2009/009059; WO2007/076127; WO2004/026306; WO2004/072033; WO2002/094833.
Synthesis
WO2017215506

PATENT

WO2017215506

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017215506

Example 1
Preparation of intermediates 1-6:
Step A: Ethyl acetate (291.41 ml, 2.98 mol) was dissolved in toluene (750.00 ml), and then sodium ethoxide (135.06 g, 1.98 mol) was added portionwise at room temperature, and the mixture was stirred at room temperature for 1 hour. Methyl 6-methylpyridine-2-carboxylate (150.00 g, 992.33 mmol) was added to the above reaction solution at 25 ° C, then heated to 95 ° C and stirred for 15 hours. The reaction mixture was cooled to 30 ° C, the pH was adjusted to 7 with acetic acid, diluted with water (500 ml), and ethyl acetate (500 ml). The organic phase was dried with anhydrous sodium s The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc Rate: 58.35%).
Step B: Ethyl 3-(6-methyl-2-pyridine)-3-oxo-propanoate (120.00 g, 579.07 mmol) was dissolved in pyridine (300 mL) then 1-aminopyrrolidine- 2-keto-p-toluenesulfonate (172.01 g, 631.66 mmol). The reaction mixture was stirred at 25 ° C for 16 hours and then concentrated under reduced pressure to remove solvent. The residue was diluted with water (300 ml) and then extracted with ethyl acetate (300 ml). The combined organic phases were dried with anhydrous sodium s , yield: 90.28%).
Step C: Dissolving 3-(6-methyl-2-pyridine)-3-(2-carbonyl-pyrrolidine)imino-propionic acid ethyl ester (155.00 g, 535.72 mmol) in toluene and then adding ethanol Sodium (72.91 g, 1.07 mol). The reaction mixture was heated to 100 ° C and stirred for 16 hours, then cooled to room temperature. It was slowly diluted with water (1.5 liters), adjusted to pH 4 with concentrated hydrochloric acid, and extracted with dichloromethane / isopropyl alcohol (10/1) (1 liter x 7). The combined organic layers were dried with anhydrous sodium s The residue was triturated with petroleum ether / ethyl acetate = 10/1 (200 mL). The solid was dried under reduced pressure to give 2-(6-methyl-2-pyridine)-5,6-dihydro-4H-pyrrole[1,2-b]pyrazole-3-carboxylic acid (52.80 g, yield : 40.52%).
Step D: Dissolving 2-(6-methyl-2-pyridyl)-5,6-dihydro-4H-pyrrole[1,2-b]pyrazole-3-carboxylic acid (45.00 g, 184.99 mmol) In N,N-dimethylformamide (650.00 ml), then NBS (49.09 g, 258.99 mmol). The reaction mixture was stirred at 30-40 ° C for 60 hours, then diluted with water (600 mL) and extracted with dichloromethane / isopropyl alcohol (10/1) (500 mL × 3). The combined organic phases were washed with EtOAc (EtOAc m. The resulting solid was slurried with EtOAc/EtOAc =EtOAc (EtOAc). The solid was dried under reduced pressure to give 3-bromo-2-(6-methyl-2-pyridine)-5,6-dihydro-4H-pyrrole[1,2-b]pyrazole (33.00 g, yield: 64.13%).
Step E: 3-Bromo-2-(6-methyl-2-pyridyl)-5,6-dihydro-4H-pyrrole [1,2-b]pyrazole (1.00 g, 3.60 mmol) and boric acid Triisopropyl ester (1.79 g, 9.54 mmol) was dissolved in tetrahydrofuran (20.00 mL). The reaction mixture was cooled to minus 70 ° C, then n-butyllithium (2.5 M, 3.74 mL) was then added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at 25 ° C for 1 hour, and then the pH was adjusted to 7 with aqueous hydrochloric acid (0.5 mol / liter). The tetrahydrofuran was then concentrated under reduced pressure and cooled to 15 °C. The mixture was filtered, and the filtered cake was purified with EtOAc EtOAc EtOAc (EtOAc) 5,6-Dihydro-4H-pyrrole[1,2-b]pyrazol-3-yl]boronic acid (750 mg, yield: 85.71%).
Preparation of Example 1:
Step A: 6-Iodo-[1,2,4]triazolo[1,5-a]pyridine (16.00 g, 65.30 mmol) was dissolved in tetrahydrofuran (800.00 mL) and cooled to below 60-70 ° C. Thereafter, lithium hexamethyldisilazide (1 mol/liter, 130.60 ml, 65.30 mmol) was added dropwise. The reaction mixture was stirred at minus 60-70 ° C for 15 minutes and N,N-dimethylformamide (14.32 g, 195.90 mmol, 15.07 mL). Stirring was then continued at minus 60 to 70 degrees C for 15 minutes and then quenched with saturated aqueous ammonium chloride (500 mL). The reaction mixture was warmed to room temperature and then extracted with ethyl acetate (500 ml). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with a silica gel column (eluent: methylene chloride / ethyl acetate = 10/1) to afford 6-iodo-[1,2,4]triazolo[1,5-a]pyridine-5- Formaldehyde (6.40 g, yield: 35.90%). . 1H NMR (400 MHz, DMSO-d6) 10.46 (S, IH), 8.62 (S, IH), 8.16 (D, J = 9.3Hz, IH), 7.88 (D, J = 9.3Hz, IH).
Step B: To a 500 ml three-necked flask equipped with a thermometer and a nitrogen balloon, 2-diethoxyphosphorylacetonitrile (3.83 g, 21.61 mmol, 3.48 ml) and tetrahydrofuran (80 ml) were added. The mixture was cooled to 0.degree. C. and then potassium tert-butoxide (2.42 g, 21.61 mmol). The reaction mixture was stirred at 0 ° C for 15 minutes and then added dropwise to another suspension through a dropping funnel (dispersing 6-iodo-[1,2,4]triazolo[1,5-a]pyridine-5-carbaldehyde In tetrahydrofuran (120 ml) and cooled to 0 ° C). The reaction mixture was stirred at 0<0>C for 15 min then EtOAc (EtOAc)EtOAc. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with a silica gel column (eluent: methylene chloride / ethyl acetate = 200/1 to 10/1) to afford (E)-3-(6-iodo-[1,2,4]triazole. [1,5-a]pyridin-5-yl)prop-2-enenitrile (4.2 g, yield: 65.66%). . 1 H NMR (400 MHz, CHLOROFORM-D) [delta] 8.42 (S, IH), 8.03 (D, J = 9.3Hz, IH), 7.98-7.91 (m, IH), 7.85-7.78 (m, IH), 7.60 (d, J = 9.2 Hz, 1H).
Step C: (E)-3-(6-Iodo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-enenitrile (4.50 g, 15.20 m Mole), [2-(6-methyl-2-pyridyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]boronic acid (4.43 g, 18.24 m Mole), sodium carbonate (4.83 g, 45.60 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (556.07 mg, 759.96 μmol), 2-dicyclohexylphosphine- 2′,6′-dimethoxybiphenyl (311.98 mg, 759.96 μmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium-cyclohexyl-[2-(2,6- Dimethoxyphenyl)phenyl]phosphine (547.64 mg, 759.96 μmol) was added to a mixed solvent of dioxane (100 ml) and water (20 ml). It was replaced with nitrogen 3 times and then heated to 90-100 ° C and stirred for 2 hours. The reaction mixture was poured into water (200 ml) and evaporated and evaporated. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The solid was concentrated and dried under reduced pressure to give (E)-3-[6-[2-(6-methyl-2-pyridyl)-5,6-dihydro-4H-pyrrolo[1,2-b] Pyrazol-3-yl]-[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-enenitrile (5.37 g, yield: 96.16%). . 1 H NMR (400 MHz, CHLOROFORM-D) [delta] 8.49 (S, IH), 7.82-7.74 (m, 2H), 7.59-7.46 (m, 4H), 6.99 (dd, J = 2.6,6.1Hz, IH) , 4.39 (d, J = 6.3 Hz, 2H), 2.90 – 2.70 (m, 4H), 2.20 (s, 3H).
Step D: (E)-3-[6-[2-(6-Methyl-2-pyridyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3 -yl]-[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-enenitrile (5.37 g, 14.62 mmol) dissolved in dichloromethane (20 mL) , a mixed solvent of dimethyl sulfoxide (70 ml) and water (20 ml), then separately added hydrogen peroxide (8.29 g 73.10 mmol, 7.02 ml, 30%) and sodium hydroxide (2 mol / liter, 14.62 ml) ). The mixture was stirred at 15-20 degrees Celsius for 12 hours. The mixture was poured into water (200 ml), and extracted with a mixture solvent of dichloromethane/isopropanol (3/1) (200 ml × 1). The organic layer was washed with EtOAc EtOAc m. The residue was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini C18 250 x 50 mm x 10 μm; mobile phase: [water (0.05% ammonia v/v)-acetonitrile]; gradient: 5%-32%, 33 80% min) Example 1 (3.6 g, yield: 63.82%) was obtained. . 1 H NMR (400 MHz, CHLOROFORM-D) [delta] 8.45 (S, IH), 8.09 (D, J = 15.6Hz, IH), 7.85 (D, J = 15.6Hz, IH), 7.69 (D, J = 9.2 Hz, 1H), 7.55-7.45 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 5.93-5.65 (m, 2H), 4.35 (br .s., 2H), 2.99-2.64 (m, 4H), 2.33 (s, 3H).

PATENT

WO-2019114792

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019114792&tab=FULLTEXT&maxRec=1000

Novel crystalline and salt (hydrochloride, sulfate and mesylate) forms of a TGF-βRI inhibitor, designated as Forms A and B, processes for their preparation and compositions comprising them are claimed for treating cancers. The compound was originally claimed in WO2017215506 , assigned to Medshine Discovery Inc alone.

Example 1 Preparation of a compound of formula (I)
Preparation of intermediates 1-6:
Step A: Ethyl acetate (291.41 ml, 2.98 mol) was dissolved in toluene (750.00 ml), and then sodium ethoxide (135.06 g, 1.98 mol) was added portionwise at room temperature, and the mixture was stirred at room temperature for 1 hour. 1-1 (150.00 g, 992.33 mmol) was added to the above reaction liquid at 25 ° C, and then heated to 95 ° C and stirred for 15 hours. The reaction mixture was cooled to about 30 ° C, and the pH was adjusted to 7 with acetic acid, diluted with water (500 ml), and ethyl acetate (500 ml). The organic phase was dried with anhydrous sodium s The residue was purified with a silica gel column (eluent: petroleum ether/ethyl acetate v/v = 50/1) to afford 1-2.
Step B: Dissolve 1-2 (120.00 g, 579.07 mmol) in pyridine (300 mL), then add 1-aminopyrrolidin-2-one p-toluenesulfonate (172.01 g, 631.66 mmol) ). The reaction mixture was stirred at 25 ° C for 16 hours and then concentrated under reduced vacuo. The residue was diluted with water (300 ml) and then extracted with ethyl acetate (300 ml). The combined organic layers were dried with anhydrous sodium s
Step C: 1-3 (155.00 g, 535.72 mmol) was dissolved in toluene then sodium ethoxide (72.91 g, 1.07 mol). The reaction mixture was heated to 100 ° C and stirred for 16 hours, then cooled to room temperature. It was slowly diluted with water (1.5 liters), adjusted to pH 4 with concentrated hydrochloric acid, and extracted with dichloromethane/isopropanol (v/v = 10/1, 1 liter x 7). The combined organic layers were dried with anhydrous sodium s The residue was triturated with petroleum ether / ethyl acetate (v/v = 10/1, 200 mL). The solid was dried under reduced pressure to give 1-4.
Step D: 1-4 (45.00 g, 184.99 mmol) was dissolved in N,N-dimethylformamide (650.00 ml), then NBS (49.09 g, 258.99 mmol). The reaction mixture was stirred at 30 to 40 ° C for 60 hours, then diluted with water (600 ml), and extracted with dichloromethane / isopropyl alcohol (v / v = 10 / 1,500 ml × 3). The combined organic phases were washed with EtOAc (EtOAc m. The resulting solid was slurried with EtOAc/EtOAc (EtOAc/EtOAc) The solid was dried under reduced pressure to give 1-5.
Step E: 1-5 (1.00 g, 3.60 mmol) and triisopropyl borate (1.79 g, 9.54 mmol) were dissolved in tetrahydrofuran (20.00 mL). The reaction mixture was cooled to minus 70 ° C, then n-butyllithium (2.5 M, 3.74 mL) was added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at 25 ° C for 1 hour, and then the pH was adjusted to 7 with aqueous hydrochloric acid (0.5 mol / liter). It was then concentrated under reduced pressure to remove tetrahydrofuran and cooled to 15 °C. The mixture was filtered, and the EtOAc EtOAc m.
Preparation of the compound of formula (I):
Step A: 1-7 (16.00 g, 65.30 mmol) was dissolved in tetrahydrofuran (800.00 ml), cooled to minus 60-70 ° C, and lithium hexamethyldisilazide (1 mol/L, 130.60) was added dropwise. ML, 65.30 mmol). The reaction mixture was stirred at -60 to 70 ° C for 15 minutes, and N,N-dimethylformamide (14.32 g, 195.90 mmol, 15.07 ml) was added. Stirring was then continued at minus 60-70 ° C for 15 minutes and then quenched with saturated aqueous ammonium chloride (500 mL). The reaction mixture was warmed to room temperature and then extracted with ethyl acetate (500 ml). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with a silica gel column (eluent: methylene chloride / ethyl acetate v/v = 10/1) to afford 1-8. . 1 H NMR (400 MHz, DMSO-d6) 10.46 (S, IH), 8.62 (S, IH), 8.16 (D, J = 9.3Hz, IH), 7.88 (D, J = 9.3Hz, IH).
Step B: To a 500 ml three-necked flask equipped with a thermometer and a nitrogen balloon, 2-diethoxyphosphorylacetonitrile (3.83 g, 21.61 mmol, 3.48 ml) and tetrahydrofuran (80 ml) were added. The mixture was cooled to 0 ° C then potassium tert-butoxide (2.42 g, 21.61 mmol). The reaction mixture was stirred at 0<0>C for 15 min then added dropwise to a further suspension (1~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The reaction mixture was stirred at 0<0>C for 15 min then EtOAc (EtOAc)EtOAc. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with a silica gel column (eluent: methylene chloride/ethyl acetate v/v = 200/1 to 10/1) to afford 1-9. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 8.42 (S, IH), 8.03 (D, J = 9.3Hz, IH), 7.98-7.91 (m, IH), 7.85-7.78 (m, IH), 7.60 ( d, J = 9.2 Hz, 1H).

Step C: 1-9 (4.50 g, 15.20 mmol), 1-6 (4.43 g, 18.24 mmol), sodium carbonate (4.83 g, 45.60 mmol), [1,1′-bis (diphenyl) Phosphine) ferrocene] palladium dichloride (556.07 mg, 759.96 μmol), 2-biscyclohexylphosphine-2′, 6′-dimethoxybiphenyl (311.98 mg, 759.96 μmol) and [2-( 2-Aminophenyl)phenyl]-chloro-palladium-cyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine (547.64 mg, 759.96 μmol) was added to the dioxane (100 ml) and water (20 ml) in a mixed solvent. It was replaced with nitrogen three times and then heated to 90 to 100 ° C and stirred for 2 hours. The reaction mixture was poured into water (200 ml) and evaporated and evaporated. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified on a silica gel column (eluent: methylene chloride/methanol, v/v=30/1) to afford crude crude product in petroleum ether/ethyl acetate (v/v=5/1) After stirring for 12 hours, the solid was collected by filtration, and the solid was concentrated and dried under reduced pressure to give 1-10. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 8.49 (S, IH), 7.82-7.74 (m, 2H), 7.59-7.46 (m, 4H), 6.99 (dd, J = 2.6,6.1Hz, IH), 4.39 (d, J = 6.3 Hz, 2H), 2.90 – 2.70 (m, 4H), 2.20 (s, 3H).

Step D: 1-10 (5.37 g, 14.62 mmol) was dissolved in a mixed solvent of dichloromethane (20 ml), dimethyl sulfoxide (70 ml) and water (20 ml), and then hydrogen peroxide ( 8.29 g 73.10 mmol, 7.02 mL, 30%) and sodium hydroxide (2 mol/L, 14.62 mL). The mixture was stirred at 15 to 20 ° C for 12 hours. The mixture was poured into water (200 ml), and extracted with a mixture solvent of dichloromethane/isopropanol (3/1) (200 ml × 1). The organic layer was washed with EtOAc EtOAc m. The residue was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini C18 250 x 50 mm x 10 μm; mobile phase: [water (0.05% ammonia v/v)-acetonitrile]; gradient: 5%-32%, 33 80% minute) to give a compound of formula (I). . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 8.45 (S, IH), 8.09 (D, J = 15.6Hz, IH), 7.85 (D, J = 15.6Hz, IH), 7.69 (D, J = 9.2Hz , 1H), 7.55-7.45 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 5.93-5.65 (m, 2H), 4.35 (br. s., 2H), 2.99-2.64 (m, 4H), 2.33 (s, 3H).
Example 2 Preparation of a compound of formula (II)
115 mg of the compound of formula (I) was added to an 8 ml glass vial, 4 ml of tetrahydrofuran was added, and the solution was sonicated by ultrasonication; then 1.05 equivalent of p-toluenesulfonic acid monohydrate was slowly added. The suspension sample was placed on a magnetic stirrer (40 ° C) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35 ° C for 16 hours to obtain a compound of the formula (II). 1 H NMR (400 MHz, CD 3 OD) δ 8.61 (s, 1H), 8.14 (t, J = 8.0 Hz, 1H), 8.05 (d, J = 15.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.70 (dd, J=8.4, 15.6 Hz, 4H), 7.54 (d, J = 15.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.6) Hz, 2H), 4.42 (m, 2H), 3.05-2.87 (m, 2H), 2.82 (s, 3H), 2.81-2.74 (m, 2H), 2.35 (s, 3H).
Example 3 Preparation of a compound of formula (IV)
115 mg of the compound of formula (I) was added to an 8 ml glass vial, 4 ml of tetrahydrofuran was added, and the solution was sonicated by ultrasonication; then 1.05 equivalent of hydrochloric acid was slowly added. The suspension sample was placed on a magnetic stirrer (40 ° C) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35 ° C for 16 hours. The obtained solid was added to an appropriate amount of acetone to prepare a suspension and stirred at 40 ° C, and the supernatant was discarded by centrifugation, and the solid sample was drained with an oil pump at room temperature to obtain a compound of the formula (IV).
Example 4 Preparation of a compound of formula (V)
115 mg of the compound of formula (I) was added to an 8 ml glass vial, 4 ml of tetrahydrofuran was added, and the solution was sonicated by ultrasonication; then 1.05 equivalent of sulfuric acid was slowly added. The suspension sample was placed on a magnetic stirrer (40 ° C) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35 ° C for 16 hours to obtain a compound of the formula (V).
Example 5 Preparation of a compound of formula (VI)
115 mg of the compound of formula (I) was added to an 8 ml glass vial, 4 ml of tetrahydrofuran was added, and the solution was sonicated by ultrasonication; then 1.05 equivalent of methanesulfonic acid was slowly added. The suspension sample was placed on a magnetic stirrer (40 ° C) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35 ° C for 16 hours to obtain a compound of the formula (VI).
Example 6 Preparation of Form A of Compound of Formula (I)
10 g of the compound of the formula (I) was placed in a mixed solvent of ethanol (80 ml) and water (40 ml), heated to 70-75 ° C and stirred until clarified, and filtered while hot, and the filtrate was distilled under reduced pressure to a volume of the remaining solution. 50 ml, followed by cooling to stand for crystallisation, filtration, and the resulting filter cake was dried under reduced pressure to give a solid of the compound of formula (I).
Example 7 Preparation of Form B of Compound of Formula (II)

192 mg of the compound of formula (I) was weighed into a glass bottle. 10 ml of a tetrahydrofuran:acetic acid (v/v=9/1) mixed solvent was added, and after ultrasonic assisted for 30 minutes, the sample was dissolved into a clear solution. Stir on a magnetic stirrer (40 ° C). After 1.05 equivalents of p-toluenesulfonic acid monohydrate was slowly added, the sample was stirred overnight. After naturally cooling to room temperature, the supernatant was discarded by centrifugation, stirred for 10 hours by adding 10 ml of tetrahydrofuran, and the supernatant was discarded by centrifugation, and the same procedure was repeated twice more. The obtained solid was dried in a vacuum oven at 40 ° C for 1 hour, and after milling, it was further dried in a vacuum oven at 30 ° C for 16 hours to obtain a crystal form B of the compound of the formula (II).

.///////////////////GFH-018, GFH 018, GenFleet Therapeutics, Advanced solid tumor,  Cancer, PRECLINICAL

NC(=O)/C=C/c4n5ncnc5ccc4c2c3CCCn3nc2c1cccc(C)n1

SEVITERONEL, севитеронел , سيفيتيرونيل , 赛维罗奈 ,


VT-464.svg

SEVITERONEL

CAS Registry Number 1610537-15-9

Molecular formulaC18 H17 F4 N3 O3, MW 399.34

1H-1,2,3-Triazole-5-methanol, α-[6,7-bis(difluoromethoxy)-2-naphthalenyl]-α-(1-methylethyl)-, (αS)-

(αS)-α-[6,7-Bis(difluoromethoxy)-2-naphthalenyl]-α-(1-methylethyl)-1H-1,2,3-triazole-5-methanol

8S5OIN36X4

севитеронел [Russian] [INN]
سيفيتيرونيل [Arabic] [INN]
赛维罗奈 [Chinese] [INN]
  • Mechanism of ActionAndrogen receptor antagonists; Estrogen receptor antagonists; Steroid 17-alpha-hydroxylase inhibitors; Steroid 17-alpha-hydroxylase modulators
  • WHO ATC codeL01 (Antineoplastic Agents)L01X-X (Other antineoplastic agents)
  • EPhMRA codeL1 (Antineoplastics)L1X9 (All other antineoplastics)

1H-1,2,3-Triazole-5-methanol, alpha-(6,7-bis(difluoromethoxy)-2-naphthalenyl)-alpha-(1-methylethyl)-, (alphaS)-

Seviteronel (developmental codes VT-464 and, formerly, INO-464) is an experimental cancer medication which is under development by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment of prostate cancer and breast cancer.[1] It is a nonsteroidalCYP17A1 inhibitor and works by inhibiting the production of androgens and estrogens in the body.[1] As of July 2017, seviteronel is in phase II clinical trials for both prostate cancer and breast cancer.[1] In January 2016, it was designated fast-track status by the United States Food and Drug Administration for prostate cancer.[1][2] In April 2017, seviteronel received fast-track designation for breast cancer as well.[1]

  • Originator Viamet Pharmaceuticals
  • Developer Innocrin Pharmaceuticals
  • Clas sAntiandrogens; Antineoplastics; Fluorine compounds; Naphthalenes; Propanols; Small molecules; Triazoles
  • Mechanism of Action Androgen receptor antagonists; Estrogen receptor antagonists; Steroid 17-alpha-hydroxylase inhibitors; Steroid 17-alpha-hydroxylase modulators
  • Phase II Breast cancer; Prostate cancer; Solid tumours
  • 31 Jan 2019 Innocrin Pharmaceutical completes a phase II trial in Prostate Cancer (Second-line therapy or greater, Hormone refractory) in the US (NCT02445976)
  • 31 Jan 2019 Innocrin Pharmaceutical completes a phase II trial for Prostate Cancer (Hormone refractory) in the US, UK, Switzerland and Greece (NCT02012920)
  • 31 Jan 2019 Innocrin Pharmaceuticals completes the phase I/II CLARITY-01 trial for Breast cancer (Late stage disease) in USA (NCT02580448)
  • CYP-17 useful for treating fungal infections, prostate cancer, and polycystic ovary syndrome, assigned to Viamet Pharmaceuticals Inc , naming Hoekstra and Rafferty. Innocrin Pharmaceuticals , a spin-out of Viamet is developing oral seviteronel, the lead dual selective inhibitors of the 17,20-lyase activity of P450c17 (CYP17) and androgen receptor antagonist, which also includes VT-478 and VT-489, developed using the company’s Metallophile technology, for treating castration-resistant prostate cancer (CRPC) in men, breast cancer and androgen (AR) related cancers.

Pharmacology

Pharmacodynamics

Seviteronel is a nonsteroidal antiandrogen, acting specifically as an androgen synthesis inhibitor via inhibition of the enzyme CYP17A1, for the treatment of castration-resistant prostate cancer.[3][4][5][6][7][8] It has approximately 10-fold selectivity for the inhibition of 17,20-lyase (IC50 = 69 nM) over 17α-hydroxylase (IC50 = 670 nM), which results in less interference with corticosteroid production relative to the approved CYP17A1 inhibitor abiraterone acetate (which must be administered in combination with prednisone to avoid glucocorticoid deficiency and mineralocorticoid excess due to 17α-hydroxylase inhibition) and hence may be administerable without a concomitant exogenous glucocorticoid.[4][5][6][7][8] Seviteronel is 58-fold more selective for inhibition of 17,20-lyase than abiraterone (the active metabolite of abiraterone acetate), which has IC50 values for inhibition of 17,20-lyase and 17α-hydroxylase of 15 nM and 2.5 nM, respectively.[7] In addition, in in vitro models, seviteronel appears to possess greater efficacy as an antiandrogen relative to abiraterone.[6] Similarly to abiraterone acetate, seviteronel has also been found to act to some extent as an antagonist of the androgen receptor.[6]

Society and culture

Generic names

Seviteronel is the generic name of the drug and its INN.[9]

PATENT

WO2012064943

PATENT

WO-2019113312

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019113312&redirectedID=true

The present invention relates to a process for preparing compound 1 that is useful as an anticancer agent. In particular, the invention seeks to provide a new methodology for preparing compound 1 and substituted derivatives thereof.

Living organisms have developed tightly regulated processes that specifically import metals, transport them to intracellular storage sites and ultimately transport them to sites of use. One of the most important functions of metals such as zinc and iron in biological systems is to enable the activity of metalloenzymes. Metalloenzymes are enzymes that incorporate metal ions into the enzyme active site and utilize the metal as a part of the catalytic process. More than one-third of all characterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence of the metal ion in the active site of the enzyme. It is well recognized that agents which bind to and inactivate the active site metal ion dramatically decrease the activity of the enzyme. Nature employs this same strategy to decrease the activity of certain metalloenzymes during periods in which the enzymatic activity is undesirable. For example, the protein TIMP (tissue inhibitor of metalloproteases) binds to the zinc ion in the active site of various matrix metalloprotease enzymes and thereby arrests the enzymatic activity. The pharmaceutical industry has used the same strategy in the design of therapeutic agents. For example, the azole antifungal agents fluconazole and voriconazole contain a l-( 1,2, 4-triazole) group that binds to the heme iron present in the active site of the target enzyme lanosterol demethylase and thereby inactivates the enzyme.

In the design of clinically safe and effective metalloenzyme inhibitors, use of the most appropriate metal-binding group for the particular target and clinical indication is critical. If a weakly binding metal-binding group is utilized, potency may be suboptimal. On the other hand, if a very tightly binding metal-binding group is utilized, selectivity for the target enzyme versus related metalloenzymes may be suboptimal. The lack of optimal selectivity can be a cause for clinical toxicity due to unintended inhibition of these off-target metalloenzymes.

One example of such clinical toxicity is the unintended inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 by the currently-available azole antifungal agents such as fluconazole and voriconazole. It is believed that this off-target inhibition is caused primarily by the indiscriminate binding of the currently utilized l-(l,2,4-triazole) to iron in the active site of CYP2C9, CYP2C19 and CYP3A4. Another example of this is the joint pain that has been observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is considered to be related to inhibition of off-target metalloenzymes due to indiscriminate binding of the hydroxamic acid group to zinc in the off-target active sites.

Therefore, the search for metal-binding groups that can achieve a better balance of potency and selectivity remains an important goal and would be significant in the realization of therapeutic agents and methods to address currently unmet needs in treating and preventing diseases, disorders and symptoms thereof. Similarly, methods of synthesizing such therapeutic agents on the laboratory and, ultimately, commercial scale is needed. Addition of metal-based nucleophiles (Zn, Zr, Ce, Ti, Mg, Mn, Li) to azole-methyl substituted ketones have been effected in the synthesis of voriconazole (M. Butters, Org. Process Res. Dev. 2001, 5, 28-36). The nucleophile in these examples was an ethyl-pyrimidine substrate. Similarly, optically active azole-methyl epoxide has been prepared as precursor electrophile toward the synthesis of ravuconazole (A. Tsuruoka, Chem. Pharm. Bull. 1998, 46, 623-630). Despite this, the development of methodology with improved efficiency and selectivity is desirable

Preparation of Compound 4:

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Acetone (850 L), 2,3-dihydroxynaphthalene (85.00 kg, 530.7 moles), and potassium carbonate (219.3 kg, 1,586.7 moles) were charged to a clean, fixed reactor with stirring and with the temperature maintained at 20 – 35 °C. Dimethyl sulfate (200.6 kg, 2131.09) was added to the stirred reaction at a rate that maintains the internal temperature of the exothermic reaction below 60 °C. This addition typically requires about 3 hours. At the end of the dimethyl sulfate addition, the reaction is continued to allow to stir while maintaining the internal temperature at 50 – 60 °C. After about 3 hours, the reaction was analyzed by HPLC. The reaction was concentrated by atmospheric pressure distillation of acetone. The distillation was continued until 340 – 425 L of distillate was collected. This represents 40 – 50 % of the initial charge of acetone. At the end of the distillation, the reaction mass is present as a thick suspension. While maintaining the internal temperature below 60 °C, the reactor contents were slowly diluted with water (850 L). When the addition is complete, the reaction was cooled to an internal temperature of 25 – 35 °C and stirring was continued for 1 – 2 hours after the designated internal temperature was reached. Compound 2 was isolated by filtration and the cake was washed with water (at least 3 X 85 L). Compound 2 was dried at 40 – 45 °C and full vacuum until the water content by Karl Fisher titration is found to be NMT 2.0 %. Typically, greater than 90 kg of dry product is obtained with an assay of >99.5% AUC by HPLC.

Dichloromethane (with a water content by Karl Fisher Titration of NMT 0.50%) (928 L) and 2,3-dimethoxynaphthalene (2, 116.00 kg, 616.3 moles) were charged to a clean, fixed reactor with stirring and with the temperature maintained at 20 – 35 °C. The reactor contents were cooled to an internal temperature of -5 to 0 °C. Aluminum chloride (164.72 kg, 1235.3 moles, 2.00 molar equivalents) was carefully added in portions to the reaction, while maintaining the internal temperature at -5 to +5 °C. This addition typically requires 5 – 6 hours. At the end of the addition, the reactor contents were cooled to an internal temperature of -15 to -5 °C. Isobutyryl chloride (102.08 kg, 958.05 moles, 1.55 molar equivalents) was slowly added to the reaction while maintaining the internal temperature at -15 to -5 °C. The addition typically requires about 3 hours. At the end of the isobutyryl chloride addition, the reaction was warmed to an internal temperature of 20 – 35 °C. When the temperature was reached, these conditions were maintained for 2 – 3 hours until the IPC indicated a level of residual starting material of NMT 2.0 % AUC by HPLC. The reactor contents were then cooled to 0 – 5 °C. The reaction was quenched by adding the reaction to a precooled (0 – 5 °C) 3M aqueous solution of hydrochloric hcid (Water, 754 L: cone. HC1, 406 L). The mixture was vigorously stirred for 15 – 20 minutes then the layers were allowed to settle. The lower, dichloromethane, product-containing layer was washed sequentially with 10 % aqueous sodium bicarbonate (1044 L), water (1160 L), then 10 % aqueous sodium chloride (1044 L). The reaction was concentrated by distillation under full vacuum and at an internal temperature of NMT 40 °C. The reaction concentrate was cooled to 20 – 35 °C and diluted with hexanes (812 L). The resultant slurry was warmed to 45 – 50 °C and these conditions were maintained for 1 – 2 hours. The reactor contents were cooled to 20 – 35 °C for 1 – 2 hours. Compound 3 was isolated by filtration. The cake was washed with fresh hexanes (232 L) twice, the filter was cooled, and the cake was washed an additional two times with hexanes. Compound 3 was dried under full vacuum at a jacket temperature of 45 °C. Typically, about 95 kg of dry product was isolated with a product purity of >90% by HPLC.

Acetic acid (212.5 L L) and l-(6,7-dimethoxynaphthalene-2-yl)-2-methylpropane-l- one (42.5 kg, 164.5 moles) were charged to a clean, fixed reactor with stirring and with the temperature maintained at 25 – 45 °C. Concentrated hydrochloric acid (425.0 L) was added carefully to the stirring reactor contents while maintaining reactor contents at an internal temperature of 25 – 45 °C. When the addition was complete, the internal temperature of the reaction was raised to 100 – 105 °C. Note that the reaction is a heterogeneous mixture. The reaction was stirred under these conditions for 6 – 8 hours. The reaction was cooled to 85 – 90 °C to which was carefully added a fresh portion of hydrochloric acid (127.5 L). The reaction was warmed to 100 – 105 °C and stirred for another 6 – 8 hours. The reaction was cooled to 85 – 90 °C. The reaction was cooled further to 70 – 80 °C. Water (212.5 L) was added to the well stirred reaction and the reactor contents were cooled to an internal temperature of 35 – 45 °C and stirred for 3 – 4 hours. Compound 4 was collected by filtration. The wet cake was washed with water (212.5 L). The wet cake was added to a clean reactor with a 5% aqueous sodium bicarbonate solution and stirred at an internal temperature of 35 – 45 °C for 1 – 2 hours.

Compound 4 was collected by filtration and washed with water (212.5 L). Compound 4 was dried under full vacuum and a temperature of < 50 °C until the water content of the dried material was found to be NMT 5.0% by Karl Fisher Titration. The yield is typically >31 kg with a purity >99.5 %.

Preparation of Compound 5:

The following difluoromethylation conditions listed in Table 1 were investigated:

Preparation 1:

The reaction flask was dried under an argon flow at 120 °C. (lS,2R)-l-Phenyl-2-(l- pyrrolidinyl)propan-l-ol (ligand 45) (196.6 g, 0.96 mol, 2.2 eq.) was added into the flask and then toluene (195 mL) was added. The solution was cooled to <12 °C. A solution of diethyl zinc (716.4 g, 0.87 mol, 15 wt%, 2 eq.) in toluene was added through a septum over 30 min at 0-10 °C. Further, a solution of ((Trimethylsilyl)ethynyl)-magnesium bromide in THF (1.81 kg; 0.87 mol, 9.7 wt%, 2 eq.) was added over 30 min at 0-10 °C. Finally, trifluoroethanol (87.0 g; 0.87 mol; 2 eq.) was added over 10 min at 0-10 °C. The reaction solution was stirred at 10-12 °C for 3 h. Compound 5 (143.4 g; 0.434 mol; 1 eq.) was added (as a solid) at room

temperature. The reaction mixture was stirred at room temperature for 1 h and at 55 °C for 17 h. The reaction solution was cooled to room temperature and dosed with aqueous HC1 (3600 mL; 7.5 wt%) within 20 min. The temperature of the mixture was kept below 25 °C. Toluene (1250 mL) was added and the mixture was stirred at room temperature for 5 min. The aqueous phase was separated and stored for the recycling of ligand 45. The organic phases were washed with water (638 mL) and concentrated via distillation under reduced pressure (50 mbar). The residue (approx. 184 g) was treated with heptane (200 mL), which was removed

via distillation. The residue was dissolved in heptane (2050 mL) at 50 °C. The mixture was cooled to room temperature and subsequently to -8 °C within 2 hours. The obtained suspension was stirred at -8 °C for 1 h. Crystallized compound 5 (20.0 g; 14%) was isolated via filtration, washed twice with cold (0 °C) heptane (2×20 mL) and dried under vacuum at 50 °C for 12 hours. The combined heptane phases were concentrated under reduced pressure to obtain a 48 wt% solution of compound 18b in heptane (yield: 83.0%). The solution was directly used for the next step.

1H-NMR (600.6 MHz, DMSO-D6) d: 0.23 (s, 9H), 0.77 (d, J = 6.7 Hz, 3H), 0.93 (d, 7 = 6.7 Hz, 3H), 2.04 (sept., 7 = 6.7 Hz, 1H), 6.11 (s, 1H), 7.32 (t, 27H,F = 73.4 Hz, 1H), 7.35 (t, 27H,F = 73.4 Hz, 1H), 7.68 (dd, 7 = 8.6, 1.5 Hz, 1H), 7.84 (s, 1H), 7.87 (s, 1H), 7.93 (d, 7 = 8.6 Hz, 1H), 8.03 (s (broad), 1H);

HPLC (purity): 94%;

chiral HPLC: e.r. = 18:82.

Preparation 2:

(7S,2R)-l-Phenyl-2-(l-pyrrolidinyl)propan-l-ol (ligand 45) (13.0 kg, 63.3 mol, 2.2 eq.) was charged into the reactor and toluene (60 L) was added. The solution was cooled to < 12 °C. A solution of diethyl zinc (35.6 kg, 57.3 mol, 20 wt%, 2 eq.) in toluene was added via mass flow controller at 8-16 °C. Further, a solution of ((trimethylsilyl)ethynyl)-magnesium bromide in THF (11.5 kg; 57.3 mol, 9.7 wt%, 2 eq.) was added at 8-16 °C. Finally, trifluoroethanol (5.7 kg; 57.3 mol; 2 eq.) was added over 10 min at 8-16 °C.The reaction solution was stirred at 22-25 °C for 3 h. A solution of compound 5 (9.5 kg; 28.7 mol; 1 eq.) in toluene (20 L) was added at room temperature. The reaction mixture was stirred at 25 °C for 1 h and at 55 °C for 17 h. The reaction solution was cooled to room temperature and dosed in aqueous HC1 (225L; 7.5 wt%) within 20 min. The temperature of the mixture should be kept below 25 °C. Toluene (80 L) was added and the mixture was stirred at room temperature for 5 min. The organic phases was washed with water (50 L) and concentrated via distillation under reduced pressure (50 mbar). The residue was treated with heptane (100 L), which was removed via distillation. The residue was dissolved in heptane (100 L) at 50°C, which was removed via distillation. The residue was dissolved in heptane (25 L). Heptane (110 L) was added, the mixture was cooled to room temperature and subsequently to 0-5 °C and seeded with compound 5 (0.15 kg). The obtained suspension was cooled to -8 °C within 1 h and stirred at this temperature for 2 h. Crystallized compound 5 was removed via filtration. The filtrate was concentrated under reduced pressure to obtain a 48 wt% solution of compound 18b in heptane (calculated 8.8 kg, 71.6%). This solution was directly used for the next step.

1H-NMR (600.6 MHz, DMSO-D6) d: 0.23 (s, 9H), 0.77 (d, J = 6.7 Hz, 3H), 0.93 (d, 7 = 6.7 Hz, 3H), 2.04 (sept., 7 = 6.7 Hz, 1H), 6.11 (s, 1H), 7.32 (t, 27H,F = 73.4 Hz, 1H), 7.35 (t, 27H,F = 73.4 Hz, 1H), 7.68 (dd, 7 = 8.6, 1.5 Hz, 1H), 7.84 (s, 1H), 7.87 (s, 1H), 7.93 (d, 7 = 8.6 Hz, 1H), 8.03 (s (broad), 1H);

HPLC (purity): 94%;

chiral HPLC: e.r. = 18:82.

Recovery of the chiral ligand ( lS,2R)-l-Phenvl-2- 
-l-ol from the

Preparation 1:

The above acidic aqueous phase was diluted with toluene (1000 mL) and the mixture was treated with sodium hydroxide (50 wt% solution) to adjust the pH to 12. The mixture was warmed to 50 °C and sodium chloride (100 g) was added. The aqueous phase was separated and washed with toluene (1000 mL). The combined organic phases were washed with water (200 mL). The combined toluene phases were treated with water (1000 mL) and the pH was adjusted to 2 by the addition of a cone. HC1 solution. The aqueous phase was separated and the mixture was treated with sodium hydroxide (50 wt% solution) at 5 °C to adjust the pH to 12. After seeding, the suspension was stirred at 5 °C for 30 min. The solids were isolated, washed with cold (0 °C) water (4×100 mL) and dried under vacuum at 30 °C for 24 hours. Ligand 45 (178.9g; 91%) was obtained as slightly yellow crystalline solid.

HPLC (purity): 99%.

Preparation 2:

The acidic aqueous phase containing ligand 45 (500 L) was diluted with toluene (125 L) and treated with“Kieselgur” (20 L). The mixture was treated with sodium hydroxide (40 L; 50 wt% solution) to adjust the pH to 12 whereas the temperature was kept <55 °C. The suspension was stirred for 15-20 min and filtered to remove all solids. Toluene (80 L) was added and the aqueous phase was separated. The organic phase was treated with water (150 mL) and the pH was adjusted to 1.5-2 by the addition of an aqueous HC1 solution (10 L; 32 wt%). The aqueous phase was separated, toluene (150 L) was added, and the mixture was treated with sodium hydroxide (5 L; 50 wt% solution) at 5 °C to adjust the pH to 12-12.5. The organic phase was separated, washed with water (30 L), and concentrated under reduced

pressure at 50 °C. Approx. 100L of distillate was removed. A sample of the solution of ligand 45 in toluene was analyzed:

The NMR results indicated a 21.6 wt% solution of ligand 45 in toluene which corresponds to a calculated amount of 118.4 kg (83.6%) of ligand 45.

Preparation of Compound 18a

Preparation 1:

A solution of tertiary alcohol 18b (320 g; 48 wt%; 0.36 mol; 1 eq.) in heptane was dissolved in methanol (800 mL). Potassium carbonate (219 g; 1.58 mol; 4.4 eq.) was added (temperature was kept < 30 °C) and the suspension was stirred at room temperature for 3 h. Water (1250 mL) was added and the mixture was treated with a cone. HC1 solution (approx. 130 mL) to adjust the pH to 7.8. The reaction mixture was extracted twice with methyl- /-butyl ether (MTBE; 2×465 mL). The combined MTBE phases were washed with water (155 mL). Water (190 mL) was added to the MTBE phase and the organic solvent was distilled off under reduced pressure (50 mbar). The obtained emulsion of compound 18a (yield: 99%) was directly used for the next step.

1H-NMR (600.6 MHz, CDC13) d: 0.87 (d, J = 6.8 Hz, 3H), 1.09 (d, / = 6.8 Hz, 3H), 2.20 (sept. / = 6.8 Hz, 1H), 2.47 (s, 1H), 2.77 (s, 1H), 6.63 (t, 27H,F = 73.5 Hz, 1H), 6.63 (t, 2/H,F = 73.5 Hz, 1H), 7.65 (s, 1H), 7.69 (s, 1H), 7.74 (dd, 7 = 8.6, 1.7 Hz, 1H), 7.79 (d, / =

8.6 Hz, 1H), 8.06 (s (broad), 1H);

HPLC (purity): 95%.

Preparation 2:

The solution of tertiary alcohol 18b (48 wt%; 57.5 mol; 1 eq.) in heptane was dissolved in methanol (128 L). Potassium carbonate (35.0 kg; 253 mol; 4.4 eq.) was added (temperature was kept < 30 °C) and the suspension was stirred at 20-30 °C for 3 h. Water (200 L) was added and the mixture was treated with an aqueous HC1 solution (approx. 25 L; 32 wt%) to adjust the pH to 7.5 – 7.8. The reaction mixture was extracted twice with MTBE

(2×66.6 L). The combined MTBE phases were washed with water (25 L). Water (30 L) was added to the MTBE phase and the organic solvent was distilled off under reduced pressure (<80 mbar; 55°C). The residue was dissolved in tert-butanol (25 L). The resulting 18a was cooled to <30°C and used directly in the next step.

^-NMR (600.6 MHz, CDC13) d: 0.87 (d, / = 6.8 Hz, 3H), 1.09 (d, / = 6.8 Hz, 3H), 2.20 (sept. / = 6.8 Hz, 1H), 2.47 (s, 1H), 2.77 (s, 1H), 6.63 (t, 27H,F = 73.5 Hz, 1H), 6.63 (t, 2/H,F = 73.5 Hz, 1H), 7.65 (s, 1H), 7.69 (s, 1H), 7.74 (dd, 7 = 8.6, 1.7 Hz, 1H), 7.79 (d, / = 8.6 Hz, 1H), 8.06 (s (broad), 1H);

HPLC (purity): 95%.

Preparation of Compound 31

Preparation 1:

Benzyl bromide (39.4 g; 0.23 mol; 1 eq.) was dissolved in water (177 mL) and t-BuOH (200 mL). Diisopropylethylamine (DIPEA; 59.4 g; 0.46 mol; 2 eq.) and sodium azide (15.0 g; 0.23 mol; 1 eq.) were added. The suspension was stirred for 5 min at room temperature. A suspension of compound 18a (82 g; 0.23 mol; 1 eq.) in water (123 mL) was treated with t-BuOH (100 mL) and copper (I) iodide (8.8 g; 46 mmol; 0.2 eq.) was added and the temperature was kept below 30 °C. The yellow-brown suspension was stirred for 5 h at room temperature. Zinc powder (5.0 g; 76 mmol) and ammonium chloride (7.4 g; 0.14 mol) were added and the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with MTBE (800 mL), water (280 mL), and an aqueous ammonia solution (120 g; 25 wt%). Solids were removed by filtration and additional MTBE (200 mL) and brine (200 mL) were added. The aqueous phase was separated and extracted with MTBE (400 mL). The combined organic phases were treated with water (150 mL) and MTBE was distilled off under reduced pressure (100 mbar). The obtained suspension of compound 31 (113 g; 50 wt%) in water (approx. 113 mL) was directly used for the next step.

Ή-NMEI (600.6 MHz, DMSO-D6) d: 0.66 (d, / = 6.8 Hz, 3H), 0.83 (d, / = 6.7 Hz, 3H), 2.78 (sept. / = 6.8 Hz, 1H), 5.55 (s, 2H), 5.68 (s, 1H), 7.29 (t, 27H,F = 73.4 Hz, 1H), 7.32 (t, 27H,F = 73.4 Hz, 1H), 7.36 – 7.26 (m, 5H), 7.79 (s, 1H), 7.82 (s, 1H), 7.82 (dd, 7 = 8.8, 1.7 Hz, 1H), 7.86 (d, / = 8.8 Hz, 1H), 7.94 (s, 1H), 8.10 (s (broad), 1H);

HPLC (purity): 87%.

Preparation 2:

Benzyl bromide (11.0 kg g; 64.4 mol; 1,12 eq.) was dissolved in water (40 L) and t-BuOH (60 L). DIPEA (16.4 kg; 126.5 mol; 2,2 eq.) and sodium azide (4.12 kg; 63.3 mol; 1 eq.) were added. The suspension was stirred 5 min at room temperature. A mixture of compound 18a (20.5 kg; 57.5 mol; 1 eq.) in ieri-butanol (see previous step) was added together with water (5 L) and copper (I) iodide (2.2 kg; 11.5 mol; 0.2 eq.) at a temperature < 30 °C. The yellow-brown suspension was stirred for 5 h at room temperature. Zinc powder (1.25 kg; 19 mol, 0.33 eq.) and an aqueous solution of ammonium chloride (2.14 kg; 20 wt%; 40 mol; 0.7 eq.) were added and the reaction mixture was stirred at 20-30 °C for 2 hours. The reaction mixture was concentrated under vacuum (<200 mbar, 55 °C). The residue was diluted with MTBE (200 L), water (30 L), and an aqueous ammonia solution (30 kg; 25 wt%). Solids were removed by filtration over a pad of“Kieselgur NF” (2 kg). Brine (50 L) was added for a better phase separation. The aqueous phase was separated and washed with MTBE (200 L). The combined organic phases were washed with an aqueous HC1 solution (1 N, 52 L) and water (50 L). MTBE was distilled off under reduced pressure (<400 mbar, 55°C; distillate min. 230L). The oily residue was dissolved in ethanol (150 L), which was distilled off under reduced pressure (<300 mbar; 55°C; distillate min. 150-155L) and the residue was dissolved in additional ethanol (60 L). To the resulting solution of compound 31 was added water (24 L) and the mixture was warmed to 50-55 °C. The mixture was cooled to 30 °C and crystallization started. The suspension was stirred at 30 °C for 1 h, cooled to <0 °C within 2 hours, and stirred at -5-0 °C for an additional 2 hours. The solids were isolated and washed with ethanol/water (1/1; v/v) (2 x 12 L). The wet product was dissolved in ethanol (115L) at 60 °C and water (24 L) was added. The mixture was cooled to 40 °C and the crystallization started. The suspension was stirred at 30 °C for 1 h, cooled to <0 °C within 2 hours, and stirred at -5-0 °C for additional 2 hours. The solids were isolated and washed (without stirring) with ethanol/water (1/1; v/v) (3 x 8 L). Pure, wet compound 31 was isolated as a white solid, which was used for the next step without drying. 14.0 kg of wet 31 were obtained with a 31 content of 81.6 wt%. Based on the determined content, the calculated amount of pure 31 was 11.4 kg with a yield of 41% over two steps (from 18b).

1H-NMR (600.6 MHz, DMSO-D6) d: 0.66 (d, J = 6.8 Hz, 3H), 0.83 (d, / = 6.7 Hz, 3H), 2.78 (sept. / = 6.8 Hz, 1H), 5.55 (s, 2H), 5.68 (s, 1H), 7.29 (t, 27H,F = 73.4 Hz, 1H), 7.32 (t, 27H,F = 73.4 HZ, 1H), 7.36 – 7.26 (m, 5H), 7.79 (s, 1H), 7.82 (s, 1H), 7.82 (dd, 7 = 8.8, 1.7 Hz, 1H), 7.86 (d, / = 8.8 Hz, 1H), 7.94 (s, 1H), 8.10 (s (broad), 1H);

HPLC (purity): 87%.

Preparation 3: Synthesis of compound 31 directly from compound 18b

Benzyl bromide (1.64 g, 9.59 mmol, 1.12 eq) was dissolved in water (2.4 mL) and

MeOH (2.4 mL). K2CO3 (2.38 g, 17.2 mmol, 2.00 eq), sodium ascorbate (0.34 g, 1.72 mmol, 0.20 eq) and finally sodium azide (0.62 g, 9.40 mmol, 1.10 eq.) were added. The suspension was stirred for 5 min at room temperature. A suspension of 18b (3.08 g; 8.64 mmol, 1.00 eq) in water (2.5 mL) and MeOH (2.5 mL) and the resulting mixture was stirred for 10 min.

CuS04 (0.21 g, 1.30 mmol, 0.15 eq) were added (slightly exothermic reaction). The reaction mixture was stirred for 19 h and the conversion was determined by HPLC (conv. 100%, purity of compound 31 by HPLC: 83 area%). To the yellow-green suspension was added zinc powder (0.24 g, 4.13 mmol, 0.43 eq) and ammonium chloride (0.34 g, 6.36 mmol, 0.74 eq) were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure (150 mbar, 50 °C). The mixture was diluted with MTBE (40 mL), water (15 mL), and an aqueous ammonia solution (6.5 mL). Solids were removed by filtration and brine (5.5 mL) was added. The aqueous phase was separated and extracted with MTBE (20 mL). The combined organic phases were treated with water (10 mL) and the pH was adjusted to a pH of 1 by addition of cone. HC1. After phase separation, the organic layer was washed with water (10 mL). MTBE was distilled off under reduced pressure (100 mbar, 50°C) to give the crude compound 31 as an oil. Water (2.5 mL) and EtOH (30 mL) were added and the mixture was warmed to 50 °C. After cooling to 30 °C, the mixture was seeded with compound 31 and compound 31 started to precipitate. The mixture was kept for 1 h at 30 °C, then cooled to 0 °C over 2 h and kept at 0 °C for 2 h. The resulting product, 31, was collected by filtration and the filter cake was washed with small portions of EtOH/water (1:1). After drying, the product (2.97 g) was obtained as a pale yellow, crystalline solid with an HPLC purity of 79 area% and a NMR content of ca. 70 wt%.

Recrystallization of 
31

Preparation 1:

To a suspension of compound 31 (96 g; 0.196 mol; 50 wt%) in water (96 mL) was added ethanol (480 mL) and the mixture was warmed to 50 °C. The mixture was cooled to 30 °C and crystallization started. The suspension was stirred at 30 °C for 1 h, cooled to 0 °C within 2 hours and stirred at 0 °C for additional 2 hours. The solids were isolated and washed with ethanol/water (1/1; v/v) (3 x 40 mL). The wet product was dissolved in ethanol (280 mL) at 60 °C and water (56 mL) was added. The mixture was cooled to 40 °C and crystallization started. The suspension was stirred at 30 °C for 1 h, cooled to 0 °C within 2 hours, and stirred at 0 °C for an additional 2 hours. The solids were isolated and washed with ethanol/water (1/1; v/v) (3 x 28 mL). Pure, wet compound 31 (46.8 g on dried basis; 49 % over 2 steps) was isolated as a white solid, which was used for the next step without drying.

1H-NMR (600.6 MHz, DMSO-D6) d: 0.66 (d, J = 6.8 Hz, 3H), 0.83 (d, / = 6.7 Hz, 3H), 2.78 (sept. / = 6.8 Hz, 1H), 5.55 (s, 2H), 5.68 (s, 1H), 7.29 (t, 27H,F = 73.4 Hz, 1H), 7.32 (t, 27H,F = 73.4 HZ, 1H), 7.36 – 7.26 (m, 5H), 7.79 (s, 1H), 7.82 (s, 1H), 7.82 (dd, 7 = 8.8, 1.7 Hz, 1H), 7.86 (d, / = 8.8 Hz, 1H), 7.94 (s, 1H), 8.10 (s (broad), 1H);

HPLC (purity): 99.5%;

chiral HPLC: e.r.: 0.2:99.8%.

mp of dried product: 110 °C.

Preparation 2:

14 kg of ethanol-wet 31 (content 81.6 wt%, calculated 11.4 kg, 23.7 mol) were suspended in ethanol (46 L) and the mixture was warmed to 50-55 °C, forming a homogenous solution at this temperature. Water (9 L) was added at 50-55 °C and the mixture was cooled to 40-45 °C. After the crystallization had started, the suspension was stirred at 40-45 °C for 1 h, cooled to 0 °C within 2 hours, and stirred at 0 °C for additional 2 hours. The solids were isolated and washed with ethanol/water (1/1; v/v) (3 x 8 L). Pure, wet compound 31 (14.5 kg) was isolated as a white solid, which was used for the next step without drying.

1H-NMR (600.6 MHz, DMSO-D6) d: 0.66 (d, / = 6.8 Hz, 3H), 0.83 (d, / = 6.7 Hz, 3H), 2.78 (sept. / = 6.8 Hz, 1H), 5.55 (s, 2H), 5.68 (s, 1H), 7.29 (t, 27H,F = 73.4 Hz, 1H), 7.32 (t, 27H,F = 73.4 Hz, 1H), 7.36 – 7.26 (m, 5H), 7.79 (s, 1H), 7.82 (s, 1H), 7.82 (dd, 7 = 8.8, 1.7 Hz, 1H), 7.86 (d, / = 8.8 Hz, 1H), 7.94 (s, 1H), 8.10 (s (broad), 1H);

HPLC (purity): 99.8%;

chiral HPLC: e.r.: 0.2:99.8%.

mp of dried product: 110 °C.

Preparation of Azidomethyl Pivalate Protected Triazole (6) from Compound 18a

1

Azidomethyl pivalate (1.42 g, 9.00 mmol, 1.05 eq) was suspended in water (6.0 mL) and t-BuOH (7.2 mL) and the suspension was stirred for 5 min. Compound 18a (theor. 3.08 g, 8.64 mmol, 1.00 eq), sodium ascorbate (0.48 g, 2.4 mmol, 0.30 eq), and CuS04 (0.08 g, 0.40 mmol, 0.05 eq.) were added. The reaction mixture was stirred for 19 h and conversion was determined by HPLC (conv. 98%, purity of the product by HPLC: 81 area%). To the green suspension was added MTBE (20 mL), water (10 mL), and an aqueous ammonia solution (2 g). A biphasic turbid mixture was formed. To improve phase separation, additional MTBE (20 mL) and water (10 mL) were added. The aqueous phase was separated and extracted with MTBE (20 mL). The combined organic phases were concentrated under reduced pressure (100 mbar, 50 °C) to give the crude product as a brown oil that solidified upon standing. HPLC purity: ca. 65 area%; NMR content of ca. 73 wt%.

1H-NMR (600.6 MHz, CDCL) d: 0.79 (d, 3H), 0.93 (d, 3H), 1.15 (s. 9H), 2.86 (sept, 1H), 3.12 (s, 1H), 6.20 (s, 2H), 6.59 (t/t, 27H,F = 73.5 Hz, 2H), 7.61 (1, 1H), 7.64 (s, 1H), 7.70 – 7.82 (m, 3H), 8.04 (s, 1H).

Preparation of Azidomethyl Pivalate Protected Triazole (6) from 18b

In a reaction flask, sodium ascorbate (277 mg, 1.4 mmol, 1.20 eq) and CuS04 (37 mg, 0.23 mmol, 0.20 eq.) were suspended in MeOH (11 mL). Azidomethyl pivalate (183 mg, 1.16 mmol, 1.00 eq) and 18b (183 mg, 1.16 mmol, 1.00 eq) were added and the mixture was warmed to 60 °C. The reaction mixture was stirred for 19 h and worked up. To the green suspension was added an aq NH4Cl solution (2 mL) and zinc powder, and the mixture was stirred for 2 h. MTBE (2 mL) was added and the aqueous phase was separated and extracted with MTBE (2 mL). The combined organic phases were concentrated under reduced pressure (100 mbar, 50 °C) to give 6 as a brown oil that solidified upon standing. HPLC purity: ca. 81 area%; NMR content of ca. 57 wt%.

1H-NMR (600.6 MHz, CDCL) d: 0.79 (d, 3H), 0.93 (d, 3H), 1.15 (s. 9H), 2.86 (sept, 1H), 3.12 (s, 1H), 6.20 (s, 2H), 6.59 (t/t, 27H,F = 73.5 Hz, 2H), 7.61 (1, 1H), 7.64 (s, 1H), 7.70 – 7.82 (m, 3H), 8.04 (s, 1H).

Preparation of Compound 1

Preparation 1:

Compound 31 (26 g; 53 mmol; 1 eq.) was dissolved in ethanol (260 mL) and Noblyst Pl 155 (2.2 g; 10 % Pd; 54 wt% water) was added. The autoclave was flushed with nitrogen and hydrogen (5 bar) was added. The reaction mixture was stirred at room temperature for 32 hours. The reaction mixture was treated with charcoal (2 g), stirred for 15 min, and the charcoal was filtered off. The filtrate was concentrated via distillation and the residue (approximately 42 g) was diluted with heptane (200 mL). The mixture was heated to reflux to

obtain a clear solution. The solution was cooled to room temperature within 1 h and the resulting suspension was cooled to 0 °C and stirred for 2 hours at 0 °C. The solids were isolated via filtration and washed with heptane/ethanol (10:1; v/v; 3×10 mL). Compound 1 (18.0 g; 85 %) was dried under vacuum at 60 °C for 24 hours and obtained as a white, crystalline solid.

1H-NMR (600 MHz) d: 0.80 (d, J = 6.8 Hz, 3H), 0.97 (d, / = 6.7 Hz, 3H), 2.83 (sept. / = 6.8 Hz, 1H), 6.60 (t, 27H,F = 73.5 Hz, 1H), 6.61 (t, 27H,F = 73.5 Hz, 1H), 7.61 (s, 1H), 7.65 (s, 1H), 7.68 (dd, / = 8.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.75 (d, / = 8.7 Hz, 1H), 8.02 (s (broad), 1H); HPLC (purity): 100%.

Preparation 2:

Compound 31 (26.5 kg; 53.5 mol; 1 eq.) was dissolved in ethanol (265 L) and Pd/C (2.0 kg; 10 % Pd; 54 wt% water) was added. The reactor was flushed with nitrogen, and hydrogen (4.5 bar) was added. The reaction mixture was stirred at 28-32 °C until the reaction was complete. The reaction mixture was treated with charcoal (1.3 kg) at a temperature of <

33 °C, stirred for 10 min, and the charcoal was filtered off, and the filter was washed with ethanol (10 L).The filtrates from two reactions were combined and concentrated via distillation under reduced pressure (max. 65 °C; distillate: min 480 L). The residue (approx. 50-60 L) was diluted with isopropylacetate (250 L). The mixture was again concentrated via distillation under reduced pressure (max. 65 °C; distillate: min 240-245 L). The residue (approx. 60-70 L) was cooled to 35-40 °C and isopropylacetate (125 L) and heptane (540 L) were added. The suspension was heated to reflux (approx. 88 °C) and stirred under reflux for 15-20 min. Subsequently, the mixture was cooled to 0-5 °C within 2 h and stirred at 0-5 °C for 2 hours. The solids were isolated via filtration and washed with heptane/isopropylacetate (5:1; v/v; 2×30 L; 0-5 °C). Wet 1 was dried under vacuum at 60 °C and was obtained as a white, crystalline solid (35.4 kg, 81.9%).

1H-NMR (600 MHz) d: 0.80 (d, / = 6.8 Hz, 3H), 0.97 (d, / = 6.7 Hz, 3H), 2.83 (sept. / = 6.8 Hz, 1H), 6.60 (t, 27H,F = 73.5 Hz, 1H), 6.61 (t, 27H,F = 73.5 Hz, 1H), 7.61 (s, 1H), 7.65 (s, 1H), 7.68 (dd, / = 8.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.75 (d, / = 8.7 Hz, 1H), 8.02 (s (broad), 1H); HPLC (purity): 100%.

Preparation 3: Preparation of Compound 1 from Compound 6

At room temperature, 6 (3.00 g, 5.84 mmol) was dissolved in MeOH (19.8 mL). NaOH (1.0 M, 19.8 mL) was added in one portion and the reaction mixture was stirred for 1 h at room temperature. The reaction progress was monitored by HPLC, which showed 98% conversion after 1 h. Aq. HC1 (19.8 mL) was added and the mixture was diluted with water (120 mL) and MTBE (60 mL), resulting in a clear biphasic solution. After phase separation, the organic phase was washed with aq NaHC03 (20 mL). The organic layer was concentrated under high vacuum (25 mbar, 45 °C) to yield 2.77 g of 1 as a greenish oil. The identity was confirmed by comparison of HPLC retention time with an authentic sample of 1 as well as by 1H NMR.

Recrystallization of Compound 1

Wet 1 (40 kg; isopropylacetate/heptane wet) was treated with isopropylacetate (110 L) and heptane (440 L). The suspension was heated to reflux (approx. 88 °C) and stirred under reflux for 15-20 min. Subsequently, the mixture was cooled to 0-5 °C within 2 h and stirred at 0-5 °C for 2 hours. The solids were isolated via filtration and washed with

heptane/isopropylacetate (5:1; v/v; 2×30 L; 0-5 °C). A sample was taken for analysis

(criterion: a) purity; NLT 99.0 A% by HPLC; b) single impurities, NMT 0.15 A% by HPLC; c) enantiomer VT-463, NMT 1.0 A% by HPLC). Wet 1 was dried under vacuum at 60 °C for not less than 12 h. A sample was taken for analysis: criterion: a) LOD; NMT 0.5 wt% by gravimetry; b) residual toluene, NMT 890 ppm by HS-GC. 1 was obtained as a white, crystalline solid (28.5 kg, 66.7% from 31).

PAPER

 Bioorganic & Medicinal Chemistry Letters (2014), 24(11), 2444-2447.

https://www.sciencedirect.com/science/article/pii/S0960894X14003606

PATENT

WO 2016040896

https://patents.google.com/patent/WO2016040896A1/en

References

  1. Jump up to:a b c d e http://adisinsight.springer.com/drugs/800035241
  2. ^ http://www.pharmaceutical-technology.com/news/newsfda-grants-fast-track-status-innocrins-seviteronel-treat-metastatic-crpc-4770025
  3. ^ Yin L, Hu Q, Hartmann RW (2013). “Recent progress in pharmaceutical therapies for castration-resistant prostate cancer”Int J Mol Sci14 (7): 13958–78. doi:10.3390/ijms140713958PMC 3742227PMID 23880851.
  4. Jump up to:a b Stein MN, Patel N, Bershadskiy A, Sokoloff A, Singer EA (2014). “Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer”Asian J. Androl16 (3): 387–400. doi:10.4103/1008-682X.129133PMC 4023364PMID 24759590.
  5. Jump up to:a b Rafferty SW, Eisner JR, Moore WR, Schotzinger RJ, Hoekstra WJ (2014). “Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors”. Bioorg. Med. Chem. Lett24 (11): 2444–7. doi:10.1016/j.bmcl.2014.04.024PMID 24775307.
  6. Jump up to:a b c d Toren PJ, Kim S, Pham S, Mangalji A, Adomat H, Guns ES, Zoubeidi A, Moore W, Gleave ME (2015). “Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer”. Mol. Cancer Ther14 (1): 59–69. doi:10.1158/1535-7163.MCT-14-0521PMID 25351916.
  7. Jump up to:a b c Stephen Neidle (30 September 2013). Cancer Drug Design and Discovery. Academic Press. pp. 341–342. ISBN 978-0-12-397228-6.
  8. Jump up to:a b Wm Kevin Kelly; Edouard J. Trabulsi, MD; Nicholas G. Zaorsky, MD (17 December 2014). Prostate Cancer: A Multidisciplinary Approach to Diagnosis and Management. Demos Medical Publishing. pp. 342–. ISBN 978-1-936287-59-8.
  9. ^ http://www.who.int/medicines/publications/druginformation/innlists/RL76.pdf

Further reading

External links[

Seviteronel
VT-464.svg
Clinical data
Synonyms VT-464; INO-464
Routes of
administration
By mouth
Drug class Androgen biosynthesis inhibitorNonsteroidal antiandrogen
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C18H17F4N3O3
Molar mass 399.339 g/mol g·mol−1
3D model (JSmol)

References

  1. Innocrin Pharmaceuticals Created as a Spin-out of the Prostate Cancer Program from Viamet Pharmaceuticals.

    Media Release 

  2. Viamet Pharmaceuticals and the Novartis Option Fund Enter Agreement for Development of Novel Metalloenzyme Inhibitors.

    Media Release 

  3. Innocrin Pharmaceuticals, Inc. Granted SME Status Designation by the European Medicines Agency.

    Media Release 

  4. A Single arm, open label, signal seeking, Phase II a trial of the activity of seviteronel in patients with androgen receptor (AR) positive solid tumours

    ctiprofile 

  5. Innocrin Pharmaceuticals and the Prostate Cancer Foundation (PCF) Join Forces for Innovative Phase 2 Clinical Study.

    Media Release 

  6. A Phase 2 Open-label Study to Evaluate the Efficacy and Safety of Seviteronel in Subjects With Castration-Resistant Prostate Cancer Progressing on Enzalutamide or Abiraterone

    ctiprofile 

  7. Innocrin Pharmaceuticals, Inc. Granted Fast Track Designation by FDA for VT-464 Treatment of Patients with Metastatic Castrate-resistant Prostate Cancer.

    Media Release 

  8. Innocrin Pharmaceuticals, Inc. Begins Phase 2 Study of Seviteronel in Women with Estrogen Receptor-positive or Triple-negative Breast Cancer and Expands Two Phase 2 Studies of Seviteronel in Men with Metastatic Castrate-resistant Prostate Cancer.

    Media Release 

  9. A Phase 2 Open-Label Study to Evaluate the Efficacy and Safety of VT-464 in Patients With Metastatic Castration Resistant Prostate Cancer Who Have Previously Been Treated With Enzalutamide, Androgen Receptor Positive Triple-Negative Breast Cancer Patients, and Men With ER Positive Breast Cancer

    ctiprofile 

  10. Innocrin Pharmaceuticals Inc. to Present Interim Results from Its Phase 1/2 Prostate Cancer Clinical Study and Preclinical Results That Demonstrate VT-464 Efficacy in a Clinically-Relevant Enzalutamide-Resistant Mouse Model.

    Media Release 

  11. A Phase 1/2 Open-Label Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Seviteronel in Subjects With Castration-Resistant Prostate Cancer

    ctiprofile 

  12. A Phase 1/2 Open-Label, Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Once-Daily VT-464 in Patients With Castration-Resistant Prostate Cancer

    ctiprofile 

  13. Viamet Pharmaceuticals Appoints Former Novartis Executive Marc Rudoltz, M.D. as Chief Medical Officer.

    Media Release 

  14. VIAMET PHARMACEUTICALS AND THE NATIONAL INSTITUTES OF HEALTH TO JOINTLY DEVELOP NOVEL VIAMET COMPOUND.

    Media Release 

  15. Viamet Pharmaceuticals Initiates Phase 1/2 Clinical Trial of Novel Prostate Cancer Therapy, VT-464.

    Media Release 

  16. Viamet Pharmaceuticals to Present at the 32nd Annual J.P. Morgan Healthcare Conference.

    Media Release 

  17. VIAMET PHARMACEUTICALS TO PRESENT AT THE 31st Annual J.P. MORGAN HEALTHCARE CONFERENCE.

    Media Release 

  18. Innocrin Pharmaceuticals, Inc. Initiates Phase 2 Castration-Resistant Prostate Cancer (CRPC) Study in Men Who Have Failed Enzalutmaide or Abiraterone.

    Media Release 

  19. Innocrin Pharmaceuticals Appoints Fred Eshelman, PharmD as CEO and is Granted Fast Track Designation by FDA for Seviteronel Treatment of Women with Triple-negative Breast Cancer and Women or Men with Estrogen Receptor-positive Breast Cancer.

    Media Release 

  20. Gucalp A, Bardia A, Gabrail N, DaCosta N, Danso M, Elias AD, et al. Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC). SABCS-2016 2016; abstr. P2-08-04.

    Available from: URL:http://www.abstracts2view.com/sabcs/view.php?nu=SABCS16L_1479

  21. Innocrin Pharmaceuticals Presents Data from the Ongoing Phase 2 Trial of Seviteronel in Estrogen Receptor-positive or Triple-negative Breast Cancer (CLARITY-01) at the San Antonio Breast Cancer Symposium.

    Media Release 

  22. Innocrin Pharmaceuticals, Inc. Appoints Edwina Baskin-Bey, MD as Chief Medical Officer and Expands the Ongoing Phase 2 Study of Seviteronel in Women with Estrogen Receptor-positive or Triple-negative Breast Cancer (TNBC).

    Media Release 

  23. Innocrin Pharmaceuticals, Inc. Raises $28 Million in Series D Financing.

    Media Release 

  24. A Phase 1/2 Open-Label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of Seviteronel in Subjects With Advanced Breast Cancer

    ctiprofile 

  25. Speers CW, Chandler B, Zhao S, Liu M, Wilder-Romans K, Olsen E, et al. Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor. ASCO-2017 2017; abstr. e12102.

    Available from: URL: http://abstracts.asco.org/199/AbstView_199_193240.html

  26. Innocrin Pharmaceuticals, Inc. Appoints Charles F. Osborne Jr. as its Chief Financial Officer.

    Media Release 

  27. Viamet Pharmaceuticals Secures $18 Million Financing.

    Media Release 

  28. Viamet Pharmaceuticals Raises $4 Million Round of Financing.

    Media Release 

///////////SEVITERONEL, VT-464, INO-464, VT 464, INO 464, Phase II,  Breast cancer,  Prostate cancer,  Solid tumours, viamet, CANCER, севитеронел سيفيتيرونيل 赛维罗奈 

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