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ALK Inhibitor CEP-28122



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(1S,2S,3R,4R)-3-[5-Chloro-2-(S)-1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]bicycle[2.2.1]hept-5-ene-2-carboxylic Acid Amide
(1S,2S,3R,4R)-3-[5-Chloro-2-(S)-1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]bicycle[2.2.1]hept-5-ene-2-carboxylic Acid Amide Methanesulfonic Acid Hydrochloride Salt
 (l S,2S,3R,4R)-3-[5-Chloro-2-((R)-l-methoxy-7-morpholin-4-yl-6,7,8,9- tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide

CAS:  1022958-60-6

Chemical Formula: C28H35ClN6O3

Molecular Weight: 539.06890

Elemental Analysis: C, 62.39; H, 6.54; Cl, 6.58; N, 15.59; O, 8.90

CEP-28122 is a Highly Potent and Selective Orally Active Inhibitor of Anaplastic Lymphoma Kinase with Antitumor Activity in Experimental Models of Human Cancers. (source: Mol Cancer Ther; 11(3); 670-9.)
CEP-28122 is used as an orally efficacious inhibitor of (ALK), analplastic lymphoma kinase, in the treatment of cancer.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) member of the insulin receptor superfamily identified as part of the NPM–ALK fusion gene in anaplastic large cell lymphoma (ALCL) with a t(2;5) chromosomal translocation.(1) ALK, when fused with NPM, is constitutively activated and shown to be involved in proliferation and survival of a variety of human cancers.(2) The aberrant signaling of ALK resulting from rearrangements or mutations/gene amplification leads to an “oncogenic addiction” which can be targeted with kinase inhibitors.(3)
 Crizotinib is the first ALK inhibitor to be approved and has shown a clinical impact with patients that are highly refractory.(4) The need for novel ALK inhibitors to impact emergence of resistance mechanisms as well as to provide improved kinase selectivity profiles is of great importance. CEP-28122 is a selective, potent ALK inhibitor, demonstrating robust antitumor efficacy in tumor xenograft mouse models, which advanced into preclinical development.(5)
 It is a complex small molecule comprised of three core subunits, two of which contain one or more chiral centers

Various ALK inhibitors have been reported, such as indazoloisoquinolines (WO 2005/009389), thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005080393), and pyrimidinediamines (WO 2005/016894).

WO 2008/051547 discloses fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors. The lead drug candidate disclosed in the ‘547 application is CEP-28122, a potent ALK inhibitor with oral efficacy against SUP-M2 and Karpas-299 ALK-dependent tumors in mouse xenograft models. CEP-28122 progressed to IND- enabling studies until its development was terminated due to the unexpected occurrence of severe lung toxicity in CEP-28122-treated monke s.

Figure imgf000003_0001


closest or analogues please check …………reader caution

Example 1047: (lS,2S,3R,4R)-3-[5-Chloro-2-(3-methoxy-7-moφholin-4-yl-6,7,8,9- tetrahydro-5H-benzocyclohepten-2-ylarnino)-pyrimidin-4-ylamino]- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Single Diasteromer A) 1047a) (2-Hydroxymethyl-4-methoxy-phenyl)-methanol To a stirred suspension of Lithium tetrahydroaluminate (16.6 g, 0.436 mol) in Tetrahydrofuran (300 mL, 4 mol) at 0 °C under nitrogen was added dropwise a solution of 4-Methoxy-phthalic acid dimethyl ester (24.46 g, 0.1091 mol) in Tetrahydrofuran (100 mL, 1 mol). The reaction was stirred at 0 °C for 1 h then warmed to room temperature overnight. HPLC indicated no starting material present. Reaction was recooled at 0 °C and quenched with addition of water (125 mL) carefully dropwise, 1 N NaOH (100 mL) and water (125 mL). Evolution of gas was observed upon initial quenching with water. A white solid precipitated out of solution (aluminum salts). Following complete quenching of the reaction mixture, the aluminum salts were removed by filtration. The filtrate was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 17.80 grams (97%) of (2-Hydroxvmethyl-4-methoxy- phenyl)-methanol as a colorless oil.

1047b) 1 ,2-Bis-bromomethyl-4-methoxy-benzene

Using the procedure outlined in J. Am. Chem. Soc. 1994, 116, 10593 – 10600, (2-

Hydroxymethyl-4-methoxy-phenyl)-methanol (17.80 g, 0.1058 mol) was dissolved in

Chloroform (200 mL, 2 mol) and the reaction was treated with Phosphorus tribromide (60.2 g, 0.222 mol) dropwise over 6 hours. After stirring overnight at room temperature, the mixture was cooled at 0 °C and was treated with 50 mL of water. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The product, 16.0 grams (51%), was used without further purification.

1047c) 2-Methoxy-7-oxo-6,7,8,9-tetrahydro-5H-benzocycloh eptene-6,8-dicarboxylic acid diethyl ester

From an adapted procedure in Helvetic Chimica Acta, 2001, 84, 2051-2063, to a stirred solution of Tetra-n-butyl ammonium iodide (12.1 g, 0.0326 mol) in 0.6 M of Sodium bicarbonate in Water (300 mL) and Methylene chloride (130 mL, 2.1 mol) was added a solution of 1 ,2-Bis-bromomethyl-4-methoxy-benzene (16.00 g, 0.05442 mol) and 3- Oxopentanedioic acid, diethyl ester (14.31 g, 0.07075 mol) in Methylene chloride (40 mL, 0.6 mol). The solution was stirred vigorously at room temperature for -20 h. Saturated ammonium chloride solution was added to the reaction mixture. The product was extracted with ethyl acetate (3 X 100 mL). The ethyl acetate extracts were washed with water and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow oil. The oil was triturated with ether and a precipitate crashed out of solution and was removed by filtration (tetrabutyl ammonium salts). The filtrate was concentrated to an oil (20.0 grams, 100%) that was carried on to the next step without further purification. 1047d) 2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one

2-Methoxy-7-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6,8-dicarboxylic acid diethyl ester (18.2 g, 0.0544 mol) was dissolved in ethanol and the solution was treated with Potassium hydroxide (24.4 g, 0.435 mol) in Water (14O g, 7.6 mol). The reaction was then refluxed until HPLC showed consumption of starting material (~5 hours). The reaction was then acidified with IN HCl and the product was extracted with dichloromethane.

Organic extracts were dried over sodium sulfate, filtered and reduced. The crude mixture was filtered through a plug of silica rinsing with dichloromethane before purification. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 6.0 grams (58%) of 2-Methoxy- 5,6,8,9-tetrahydro-benzocyclohepten-7-one.

1047e) 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 2-Methoxy-l- nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one 2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one (6.00 g, 0.0315 mol) was dissolved in Acetonitrile (280 mL, 5.4 mol) and was added to a mixture of Trifiuoroacetic anhydride (13.4 mL, 0.0946 mol) in Acetonitrile at 0 °C. Potassium nitrate (3.19 g, 0.0315 mol) was then added and the reaction was allowed to warm to room temperature. When HPLC showed consumption of starting material, the mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). The gradient run was 0% EA-50% EA. Combined fractions were reduced en vacuo to afford 3.62 (49%) of 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 1.80 grams (25%). 1047f) 4-(2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (4.94 g, 0.0210 mol) in Methylene chloride (100 mL, 2 mol) was treated with Morpholine (18.30 g, 0.2100 mol) and then Acetic acid (12.61 g, 0.2100 mol). Two mass equivalents of powdered 4A molecular sieves were added and the mixture was heated to reflux and was allowed to stir for 4 hours. The solution was then cooled to room temp and Sodium triacetoxyborohydride (8.90 g, 0.0420 mol) was added. The reaction was then allowed to proceed until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (DCM/MeOH). Combined fractions were reduced en vacuo to afford 5.41 grams (84%) of 4-(2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-moφholine. 4-(2- Methoxy-l-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine was made in an analogous manner using the same conditions described above. 1047g) 3-Methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine 4-(2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-moφholine (5.40 g, 0.0176 mol) was dissolved in Ethanol (100 mL, 2 mol) and the reaction mixture was carefully added to 10% Palladium on Carbon (0.750 g) under nitrogen in a Parr vessel. The reaction was then placed on a Parr shaker until uptake of hydrogen had ceased (~5 hours). Catalyst was filtered and the filtrate was reduced en vacuo to afford 4.10 grams (84%) of 3-Methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2- ylamine. 2-Methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-l – ylamine was made in an analogous fashion. The following intermediates were made in an analogous fashion as above utilizing the appropriate amine precursors: N*7*-(2,2-Difluoro-ethyl)-3-methoxy-6,7,8,9-tetrahydro- 5H-benzocycloheptene-2,7-diamine, 3-Methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9- tetrahydro-5H-benzocycloheptene-2,7-diamine, N*7*-(2,2-Difluoro-ethyl)-2-methoxy- 6,7,8,9-tetrahydro-5H-benzocycloheptene-l ,7-diamine, 2-(2-Amino-3-methoxy-6,7,8,9- tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and 3-Methoxy-7-(4-methyl- piperazin-l-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine.

1047h) (lS,2S,3R,4R)-3-[5-Chloro-2-(3-methoxy-7-moφholin-4-yl-6,7,8,9-tetrahydro- 5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1 ]hept-5-ene-2- carboxylic acid amide (Single Diasteromer A)

3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (880.0 mg, 0.003184 mol), (l S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (952 mg, 0.00318 mol) and 4M of Hydrogen Chloride in 1 ,4-Dioxane (2 mL) were dissolved in 2-Methoxyethanol (30.0 mL, 0.380 mol) and the reaction was heated at 100 °C until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude residue was isolated and purified by Gilson prep HPLC as the first peak to elute to afford the desired product as a TFA salt. The TFA salt was taken up in dichloromethane and was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo to afford 439 mg (26%) of (lS,2S,3R,4R)-3-[5-Chloro-2-(3-methoxy-7-morpholin-4-yl- 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Single Diasteromer A). LC/MS (ESI): 539.22. 1H NMR (400 MHz, DMSO, d6) δ 9.60 (m, IH), 8.12 (s, IH), 7.90 (s, IH), 7.79 (m, IH), 7.39 (s, IH), 6.98 (s, IH), 6.36 (m, IH), 6.16 (m, IH), 4.00 (m, 3H), 3.83 (s, 3H), 3.30 (m, 5H), 2.74 – 2.90 (m, 6H), 2.39 (m, 3H), 1.94 (d, IH, J = 4.80 Hz), 1.44 (m, 3H), 1.28 (m, IH), 1.04 (s, IH), 0.74 (s, IH).

Org. Process Res. Dev.201216 (1), pp 148–155
DOI: 10.1021/op200313v
Abstract Image
Evolution of the process strategies to prepare CEP-28122, an anaplastic lymphoma kinase (ALK) inhibitor, is presented. The initial medicinal chemistry route, used for the preparation of key supplies for biological screening, is reviewed. In addition, the process research and development of the final optimized process for manufacture of preclinical and clinical supplies is discussed. Details regarding a blocking group strategy for selective nitration; discovery of a one-pot transfer hydrogenation to effect a reductive amination, nitro group reduction, and dehalogenation; an enzymatic resolution of a critical intermediate; and the discovery of a novel, stable, in situ generated mixed mesylate hydrochloride salt of the API are disclosed.
(1S,2S,3R,4R)-3-[5-Chloro-2-(S)-1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]bicycle[2.2.1]hept-5-ene-2-carboxylic Acid Amide Methanesulfonic Acid Hydrochloride Salt (CEP-28122)

 The solids were then dried to constant weight (50 mmHg, 50 °C), yielding 2.94 kg (4.37 mol, 87.1%) of CEP-28122 monomesylate/monohydrochloride with 97.4 A% chemical purity and 97% ee.
1H NMR (400 MHz, DMSO-d6) δ 10.6 (s, b, 1H), 9.93 (s, b, 1H), 9.58 (s, b, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.86 (d, J = 7.28 Hz, 1H), 7.48 (s, 1H), 7.09 (d, J = 8.36 Hz, 1H), 6.39 (dd, J = 2.88, 5.56 Hz, 1H), 6.23 (dd, J = 2.92, 5.52 Hz, 1H), 3.93 (m, 6H), 3.69 (s, 3H), 3.69 (s, b, 1H), 3.58 (m, 2H), 3.29 (m, b, 4H), 3.17 (m, 2H), 2.94 (m, 3H), 2.77 (t, J = 12.04 Hz, 1H), 2.53 (d, J = 8.00 Hz, 2H), 2.49 (d, b, J = 13.68 Hz, 2H), 2.34 (s, 3H), 1.96 (d, J = 8.80 Hz, 1H), 1.46 (m, b, 3H), 1.01 (d, J = 6.24 Hz, 1H).
Anal. Calcd for C29H40N6O6SCl2 (671.64): C, 51.86; H, 6.00; N, 12.51; Cl, 10.56. Found: C, 51.75; H, 6.07; N, 12.37; Cl, 10.57. Heavy metals <20 ppm.
  1. MorrisS. W.; KirsteinM. N.; ValentineM. B.; DittmerK. G.; ShapiroD. N.; SaltmanD. L.; LookA. T. Science 19942631281– 1284
  2. GrandeE.; BolosM.; ArriolaE. Mol. Cancer Ther. 201110 ( 4569– 571

  3. ShawA. T.; SolomonB. Clin. Cancer Res. 2011172081– 2086

  4. MosseY. P.; WoodA.; MarisJ. M. Clin. Cancer Res. 2009155608– 5614

    Gingrich, D. et al: J. Med Chem, 55, 4580 (2012);…

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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 AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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