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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 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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BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA


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BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA

WO2018005328) DEUTERATED BICTEGRAVIR 

CONCERT PHARMACEUTICALS, INC.

TUNG, Roger, D.; (US)

How A Kidney Drug Almost Torpedoed Concert Pharma’s IPO

Concert CEO Roger Tung

Novel deuterated forms of bictegravir is claimed.  Gilead Sciences is developing the integrase inhibitor bictegravir as an oral tablet for the treatment of HIV-1 infection.

This invention relates to deuterated forms of bictegravir, and pharmaceutically acceptable salts thereof. In one aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11b is independently hydrogen or deuterium; provided that if each Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, and Y11 is hydrogen, then Y11b is deuterium.

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Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the

CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p.35 and Fisher at p.101).

[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

Exemplary Synthesis

[72] Deuterium-modified analogs of bictegravir can be synthesized by means known in the art of organic chemistry. For instance, using methods described in US Patent No.9,216,996 (Haolun J. et al., assigned to Gilead Sciences, Inc. and incorporated herein by reference), using deuterium-containing reagents provides the desired deuterated analogs.

[73] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

[74] A convenient method for synthesizing compounds of Formula I is depicted in the Schemes below.

 [75] A generic scheme for the synthesis of compounds of Formula I is shown in Scheme 1 above. In a manner analogous to the procedure described in Wang, H. et al. Org. Lett.2015, 17, 564-567, aldol condensation of compound 1 with appropriately deuterated compound 2 affords enamine 3. Enamine 3 is then reacted with primary amine 4 to afford enamine 5, which then undergoes cyclization with dimethyl oxalate followed by ester hydrolysis to provide carboxylic acid 7.

[76] In a manner analogous to the procedure described in US 9,216,996, acetal deprotection of carboxylic acid 7 followed by cyclization with appropriately deuterated aminocyclopentanol 9 provides carboxylic acid intermediate 10. Amide coupling with appropriately deuterated benzylamine 11 followed by deprotection of the methyl ether ultimately affords a compound of Formula I in eight overall steps from compound 1.

[77] Use of appropriately deuterated reagents allows deuterium incorporation at the Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11bpositions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and/or Y11b.

[78] Appropriately deuterated intermediates 2a and 2b, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 2 below.

S h 2 S th i f C d 2 d 2b

[79] Synthesis of compound 2a (wherein Y3=H) by acetal formation of N,N-dimethylformamide (DMF) with dimethylsulfate has been described in Mesnard, D. et. al. J. Organomet. Chem.1989, 373, 1-10. Replacing DMF with N,N-dimethylformamide-d1 (98-99 atom % D; commercially available from Cambridge Isotope Laboratories) in this reaction would thereby provide compound 2b (wherein Y3=D).

[80] Use of appropriately deuterated reagents allows deuterium incorporation at the Y3 position of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at Y3.

[81] Appropriately deuterated intermediates 4a-4d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 3 below.

[82] As described in Malik, M. S. et. al. Org. Prep. Proc. Int.1991, 26, 764-766, acetaldehyde is converted to alkylhalide 14a via reaction with chlorine gas and subsequent acetal protection with CaCl2 in methanol. As described in CN 103739506, reaction of 14a with aqueous ammonia and then sodium hydroxide provides primary amine 4a (wherein Y9=Y10a=Y10b=H). Replacing acetaldehyde with acetaldehyde-d1, acetaldehyde-2,2,2-d3, or acetaldehyde-d4 (all commercially available from CDN Isotopes with 98-99 atom % D) in the sequence then provides access to compounds 4b (Y9=D, Y10a=Y10b=H), 4c (Y9=H,

Y10a=Y10b=D) and 4d (Y9=Y10a=Y10b=D) respectively (Schemes 3b-d).

[83] Use of appropriately deuterated reagents allows deuterium incorporation at the Y9, Y10a, and Y10b positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y9, Y10a, and/or Y10b.

[84] Appropriately deuterated intermediates 9a-9d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 4 below.

 [85] Following the procedures described by Gurjar, M. et. al. Heterocycles, 2009, 77, 909-925, meso-diacetate 16a is prepared in 2 steps from cyclopentadiene. Desymmetrization of 16a is then achieved enzymatically by treatment with Lipase as described in Specklin, S. et. al. Tet. Lett.201455, 6987-6991, providing 17a which is subsequently converted to aminocyclopentanol 9a (wherein Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b=Y8=H) via a 3 step sequence as reported in WO 2015195656.

[86] As depicted in Scheme 4b, aminocyclopentanol 9b (Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b= Y8=D) is obtained through an analogous synthetic sequence using cyclopentadiene-d6 and performing the penultimate hydrogenation with D2 in place of H2. Cyclopentadiene-d6 is prepared according to the procedure described in Cangoenuel, A. et. al. Inorg. Chem.2013, 52, 11859-11866.

[87] Alternatively, as shown in Scheme 4c, the meso-diol obtained in Scheme 4a is oxidized to the diketone following the procedure reported by Rasmusson, G.H. et. al. Org. Syn.1962, 42, 36-38. Subsequent mono-reduction with sodium borodeuteride and CeCl3 then affords the D1-alcohol in analogy to the method described in WO 2001044254 for the all-protio analog using sodium borohydride. Reduction of the remaining ketone using similar conditions provides the meso-D2-diol in analogy to the method reported in Specklin, S. et. al. Tet. Lett.2014, 55, 6987-6991 for the all protio analog using sodium borohydride. The meso-D2-diol is then converted to 9c (Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=H, Y6=Y8=D) following the same procedures outlined in Scheme 4a.

[88] Likewise, the meso-diol obtained in Scheme 4b may be converted to 9d

(Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=D, Y6=Y8=H) in an analogous manner as depicted in Scheme 4d. The use of deuterated solvents such as D2O or MeOD may be considered to reduce the risk of D to H exchange for ketone containing intermediates.

[89] Use of appropriately deuterated reagents allows deuterium incorporation at the Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and Y8 positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and/or Y8.

[90] Appropriately deuterated intermediates 11a-11d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 5 below.

Scheme 5. Synthesis of Benzylamines 11a-11d

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WO-2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD


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WO-2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

 (WO2018001353) METHOD FOR PREPARING APREMILAST

ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

DU, Xiaoqiu; (CN).
ZHOU, Lianchao; (CN).
LIU, Jiegen; (CN)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018001353&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

EN)Method one: (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl-L-leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an aprotic solvent to produce the compound of formula I; method two: (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl-L- leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an organic solvent in the presence of an organic alkaline or an alkali metal hydride to produce the compound of formula I. The method for preparing apremilast requires inexpensive raw materials and reagents , is suitable for industrialized production, and has great economic effects.

Apremilast is a PDE4 inhibitor developed by Celgene. Currently, there are clinical indications such as rheumatoid arthritis, psoriatic arthritis, Behcet’s disease and ulcerative colitis. March 21, 2014 FDA approves first indication – adult active psoriatic arthritis (PsA). Name of Product: (FDA, as a post-marketing requirement, will evaluate the effect of this drug on pregnant women through a pregnancy registry study.) Three clinical trials evaluated the safety and efficacy of Asprate in the treatment of PsA, The response rates to ACR20 in the prest and placebo groups were 32-41% and 18-19%, respectively.
Aspast’s oral anti-rheumatic drug, a new mechanism of action, distinguishes itself from currently available anti-TNF monoclonal antibodies. Thomson Pharma predicts rapid sales growth of 201.2 million U.S. dollars in 2015 with sales of US $ 516 million in 2015 . Upstall’s sales are expected to reach a maximum of 2 billion U.S. dollars. Compared with its counterparts, Actuate has the following advantages: It inhibits the production of various proinflammatory mediators (PDE-4, TNF-α, IL-2, interferon γ, leukotriene, NO synthase) Inflammation; selective inhibitor of phosphodiesterase 4 (PDE4), approved for use in psoriatic arthritis in September 2014 FDA approved mid-to-severe treatment of plaque psoriasis for phototherapy or systemic therapy Patient, the first and only PDE4 inhibitor approved for the treatment of plaque psoriasis; clinical trials have shown that OTEZLA reduces erythema, thickening and scaling in patients with moderate to severe plaque psoriasis; clinical trials have demonstrated Painstrept was well tolerated and had minimal adverse reactions. Patients in the Otezla-treated and placebo clinical trials showed signs and symptoms of PsA improvement including tenderness, joint swelling and physical function.
The original patent CN 101683334A reports the synthesis of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- ) And 3-acetylaminophthalic anhydride (3) Prepared with acetic acid as solvent (1), and the synthetic route is as follows:
The method has low yield, needs lower than 50 DEG C to distill the high-boiling acetic acid, and produces one deacetyl impurity (4) during the reflux reaction and the acetic acid distillation, which affects the product purity. Acetic acid will corrode the equipment at high temperatures. Distillation of high-boiling acetic acid will also increase plant production time. Acetic acid, which is not distilled away, consumes a large amount of lye to neutralize and increases the amount of wastes and production costs, which is not conducive to industrialized production.
Example one
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- 4.6g (0.0224mol) 3-acetamidophthalic anhydride into a 250mL three-necked flask, then add 50mL of acetonitrile, heating 75 ~ 80 ℃, the reaction incubated for 18 hours and cooled to room temperature. After the reaction mixture was evaporated to dryness, 60 mL of methylene chloride was added, 25 g of 10% sodium carbonate solution was added thereto and the mixture was stirred for 10 to 30 minutes. The mixture was allowed to stand for further delamination and then 25 mL of water was added to the organic layer and stirred for 10-30 minutes. The layers were evaporated to dryness to give a light yellow solid, then add 30mL absolute ethanol, evaporated again. The mixture was hot beaten with ethanol, cooled to 0-5 ° C, stirred for 1-2 hours, filtered and drained. The filter cake was vacuum dried to give 9.4 g of a white powder in 91.2% yield. HPLC: 99.9% ) Has an HPLC area of 0.03%.
Example two
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- A solution of 4.6 g (0.0224 mol) of 3-acetylaminophthalic anhydride in a 250 mL three-necked flask was charged with 80 mL of toluene and 10 mL of N, N-dimethylformamide. The mixture was heated to 100 ° C and the reaction was incubated for 12 hours and then cooled to room temperature. After the reaction solution was evaporated to dryness, 80 mL of methylene chloride was added, 25 g of 10% sodium carbonate solution was added thereto and the mixture was stirred for 10 to 30 minutes. The mixture was allowed to stand for further delamination and then 50 mL of water was added to the organic layer and stirred for 10 to 30 minutes. Evaporated to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. Cooled to 0 ~ 5 ℃ and stirred for 1 ~ 2 hours, filtered and drained, the filter cake was dried in vacuo to give 9.2g white powder, yield 89.2%, HPLC: 99.9%, wherein the deacetyl impurities (4 ) Has an HPLC area of 0.03%.
Example three:
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- To a 250 mL three-necked flask was added 4.6 g (0.0224 mol) of 3-acetamidophthalic anhydride followed by 50 mL of ethyl acetate and 1.81 g (0.8 eq) of triethylamine. The mixture was heated at 75-80 ° C and incubated for 18 hours. The reaction was stopped, 100 mL of ethyl acetate was further added and the mixture was cooled to 20-30 ° C. The reaction solution was added 30g of 8% sodium carbonate solution, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. The mixture was heated to 0-5 ° C for 1 to 2 hours, filtered and drained. The filter cake was vacuum dried to give 9.8 g of a white powder in 95.1% yield. HPLC: 99.9% ) Had an HPLC area of 0.04%.
Example 4:
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- (0.0224mol) 3-acetamidophthalic anhydride into a 250mL three-necked flask, followed by the addition of 120mL of isopropyl acetate and 30mL of acetonitrile and 1.81g (0.8eq) of triethylamine, heating 75 ~ 80 ℃, incubated reaction 16 hours. Stop the reaction, cooled to 20 ~ 30 ℃. The reaction solution was added 30g of 8% sodium carbonate solution, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. The mixture was hot beaten with ethanol, cooled to 0-5 ° C, stirred for 1-2 hours, filtered and drained. The filter cake was vacuum dried to give 9.6 g of a white powder in 93.1% yield. HPLC: 99.9% ) Has an HPLC area of 0.03%.
Comparative Example:
According to the preparation example of Compound A in original patent CN 101683334A, 10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4- methoxyphenyl) -2- (methylsulfonyl) N-acetyl-L-leucinate and 4.6 g (0.0224 mol) of 3-acetylaminophthalic anhydride were placed in a 250 mL three-necked flask and 50 mL of acetic acid was added thereto. The mixture was heated at 75 to 80 ° C and the reaction was incubated for 18 hours. The reaction mixture was cooled to 40-50 ° C and the temperature of the water bath was controlled to 40-50 ° C. The reaction mixture was vortexed to glacial acetic acid without any significant fraction. 150 mL of ethyl acetate was added and the mixture was stirred to dissolve. 100 mL of water was added and the mixture was stirred 10 ~ 30 minutes, standing stratification, the organic layer was added 100mL water, stirred for 10 to 30 minutes, allowed to stand for stratification, the organic layer was added 100g 8% sodium bicarbonate solution, stirred for 10 to 30 minutes, The organic layer was added with 100g of 8% sodium bicarbonate solution and stirred for 10-30 minutes. The layers were separated and the organic layer was added with 100 mL of water. The mixture was stirred for 10-30 minutes, and the layers were separated. The organic layer was further added with 100 mL of water and stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. 68mL of anhydrous ethanol and 34mL of acetone were added to the solid, heated to 60-65 ° C, stirred to make it fully dissolved, and then cooled to 0-5 ° C and stirred for 1 to 2 hours, filtered and drained, and the filter cake was dried under vacuum to give 8.6 Class g white powder, yield 83.4%, HPLC: 99.7% with an HPLC area of deacetylated impurity (4) of 0.22%.

////////////WO 2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

Drug Patents International


All about Patents and Intellectual property by DR ANTHONY MELVIN CRASTO, worlddrugtracker, Ph.D ( ICT, Mumbai) , INDIA 30 Yrs Exp. in the feld of Organic Chemistry, Serving chemists around the world.

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

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Pexidartinib, New Patent, WO 2017215521, Crystal Pharmatech Co Ltd


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Pexidartinib, New Patent, WO, 2017215521, Crystal Pharmatech Co Ltd

(WO2017215521) PLX3397 HYDROCHLORIDE CRYSTAL FORM, PREPARATION METHOD THEREFOR AND USE THEREOF

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017215521

CRYSTAL PHARMACEUTICAL (SUZHOU) CO., LTD

INVENTORS

CHEN, Minhua; (CN).
ZHANG, Yanfeng; (CN).
ZOU, Po; (CN).
ZHANG, Xiaoyu; (CN)

Novel crystalline forms of PLX3397 hydrochloride (designated as Forms CS2 and CS3), processes for their preparation and compositions comprising them are claimed. Also claim is their use for treating giant cell tumor of the tendon sheath.

The present invention relates to a PLX3397 hydrochloride crystal form, a preparation method therefor and use thereof. The PLX3397 hydrochloride crystal form has higher solubility, larger particle size, and good stability, especially better mechanical stability, is favorable for separation of products in subsequent production, provides a better choice for preparing PLX3397-containing pharmaceutical preparations, and is very important to medicinal development.

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Pexidartinib (PLX3397) is a new drug used to treat tenosynovial giant cell tumor (TGCT). Tenoid sheath giant cell tumor is a rare type of tendon sheath cancer. At present, the disease is usually treated surgically by surgical resection, and the surgical treatment of the disease may lead to the deterioration of dysfunction and serious complications. And since TGCTs have multiple types, which typically occur at bone tissue and joints, the advent of new interventional therapies is urgently needed in the clinic. The PLX3397 is currently in Phase III clinical trials and has received the FDA’s breakthrough drug therapy certification. The structural formula of PLX3397 is shown in formula (I).
Example 1 Preparation of monohydrochloride form CS2

[0112]
Weigh 101.6 mg of PLX3397 solids in a 5 mL glass vial and add 2 mL of n-heptane at 5 ° C. Under magnetic stirring, 440 μL of 0.6 mol / L diluted hydrochloric acid was added and the reaction was carried out for 40 min. The mixture was filtered and dried to obtain an off-white solid.

[0113]
Upon testing, the solid obtained in this example is the monohydrochloride form CS2. The XRPD pattern is shown in Figure 1, and the XRPD data is shown in Table 1. The resulting solid was monohydrochloride salt of PLX3397 as determined by ion chromatography. 1 H NMR is shown in FIG. 4.

[0114]
When differential scanning calorimetry was used, the endothermic peak began to form when heated to about 72 ° C. When heated to around 227 ° C, the endothermic peak started to appear. The DSC is shown in FIG. 2.

[0115]
When subjected to thermogravimetric analysis, crystalline form CS2 has a mass loss gradient of about 8.3% when heated to 137 ° C, the TGA of which is shown in FIG. 3. Form CS2 is hydrate.

[Figure 0009]   

Fig. 1 H NMR chart of crystalline form CS3 in Example 3. Fig

//////////////Pexidartinib, New Patent, WO 2017215521, Crystal Pharmatech Co Ltd

ALCAFTADINE, WO 2017211246, NEW PATENT, SHENZHEN TARGETRX, INC.


Alcaftadine.svg

Alcaftadine

NEW PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017211246&redirectedID=true

WO-2017211246, SHENZHEN TARGETRX, INC.

SUBSTITUTED FUSED IMIDAZOLE CYCLIC COMPOUND AND PHARMACEUTICAL COMPOSITION THEREOF

WANG, Yihan; (CN).
XING, Qingfeng; (CN)

Novel deuterated analogs of substituted fused imidazole cyclic compounds, particularly alcaftadine are histamine H1-receptor antagonists and mast cell stabilizers, useful for treating allergy and nasal congestion.

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The present invention relates to a substituted fused imidazole cyclic compound and a composition containing said compound and application thereof. Specifically disclosed is the fused imidazole cyclic compound represented by formula (I), or a pharmaceutical composition of its crystalline form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate. The compound of the present invention may be used as a histamine H1-receptor antagonist and mast-cell stabilizer, and is capable of inhibiting mast-cell release of histamine and preventing histamine function, thereby reducing allergic reaction

str2

Example 1 Preparation of 6,11-dihydro -11- (1- (d3- methyl) piperidin-4-ylidene) -5H- imidazo [2,1-b] [3] benzazepine – 3- aldehyde (compound 8)

Step 1. Synthesis of compound 3.

N-benzyloxycarbonylpiperidine-4-carboxylic acid (2.63 g, 10 mmol) was dissolved in 20 mL of dichloromethane, 6 mL of oxalyl chloride and 1 drop of DMF were added and the mixture was reacted at room temperature for 2 hours under nitrogen. The reaction mixture was concentrated to dryness under reduced pressure, dissolved in 20 mL of acetonitrile, and added with triethylamine (4.1 mL, 30 mmol) in an ice bath and stirred for 3 minutes. A solution of 1-phenethyl-1H-imidazole (2.06 g, 12 mmol) in 5 mL of acetonitrile was slowly added dropwise and the reaction was allowed to warm to room temperature overnight after the addition was completed. The reaction was completed, concentrated to dryness, 30 mL of ethyl acetate and 20 mL of water were added and the mixture was stirred for 5 minutes. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give 3.34 g of a colorless oil, benzyl-4- (1-phenethyl-1H-imidazole-2-formyl) piperidine-1-carboxylate (Compound 3) was obtained in a yield of 80%. ESI-MS: 418 [M ++ 1].

Step 2. Synthesis of compound 4.
Benzyl-4- (1-phenylethyl-1H-imidazole-2-formyl) piperidine-1-carboxylate (3.34 g, 8 mmol) was dissolved in 30 mL of absolute ethanol and 300 mg of 10% palladium on carbon , Hydrogen was substituted three times and stirred overnight at room temperature under a hydrogen atmosphere of 1 atmosphere. After completion of the reaction, the palladium carbon was filtered off and the filtrate was concentrated. 2.04 g of (1-phenethyl-1H-imidazol-2-yl) (piperidin-4-yl) methanone (Compound 4) 90%. ESI-MS: 284 [M ++ 1].
Step 3. Synthesis of compound 5.
(Piperidin-4-yl) methanone (2.04 g, 7.2 mmol) was dissolved in 10 mL of DMF and potassium carbonate (1.98 g, 14.4 mmol) The solution was cooled to -15 ° C and deuterated methyl iodide (1.02 g, 7.2 mmol) was slowly added dropwise under the protection of nitrogen. After the addition was completed, the mixture was stirred at room temperature for 0.5 hour. The mixture was extracted with ethyl acetate and extracted with ethyl acetate. The organic phase was washed once with 20 mL of water and 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated and separated on a silica gel column (1- (methyl-d3) piperidine (1-phenethyl-1H-imidazol-2-yl) methanone (Compound 5) was obtained in an amount of 70%. 1 H NMR (300 MHz, CDCl 3 ) δ 7.23 (d, J = 2.0Hz, 1H), 7.06 (td, J = 4.2,3.8,1.7Hz, 3H), 6.86 (d, J = 1.0Hz, 1H) (Dd, J = 10.2, 5.8 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H) J = 7.2 Hz, 2H), 2.85-2.65 (m, 2H), 2.15 (td, J = 7.5, 3.9 Hz, 4H); ESI-MS: 301 [M ++ l ].
Step 4. Synthesis of Compound 6.
(1-phenethyl-1H-imidazol-2-yl) methanone (1.5 g, 5.1 mmol) was placed in a reaction flask and the mixture was purged with nitrogen three times , 7mL trifluoromethanesulfonic acid was added dropwise, the reaction was warmed to 110 ° C overnight. Cooled to room temperature, the reaction solution was poured into 30mL ice water, 50% sodium hydroxide solution was added dropwise to adjust the pH = 10-11, extracted with dichloromethane, the organic phase was washed once with 20mL of water and 20mL of saturated brine, Dried over sodium sulfate, concentrated and separated by silica gel column to obtain 0.85 g of compound 6, yield 60%. 1 H NMR (300 MHz, CDCl 3 ) δ 7.28 (d, J = 4.4 Hz, 2H), 7.23 (d, J = 5.0 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 7.02 (D, J = 1.3Hz, 1H), 4.38 (dt, J = 12.7, 3.9Hz, 1H), 4.02 (td, J = 13.3,3.1Hz, 1H), 3.59 -3.34 (m, 3H), 3.21 (s, 2H), 3.04-2.87 (m, 3H), 2.78-2.63 (m, 2H). ESI-MS: 283 [M ++ l ].
Step 5. Synthesis of compound 7.
Compound 6 (850 mg, 3 mmol) was placed in a reaction flask, followed by the addition of 0.5 mL of acetic acid, 5 mL of 37% formaldehyde and sodium acetate (87 mg, 1.1 mmol) and warming to 100 ° C overnight. After the reaction was cooled to room temperature completely, 30 mL of methylene chloride was added to the reaction solution, 50% sodium hydroxide solution was added dropwise to adjust pH = 11-12, stirred for 0.5 hour, and the layers were separated and the organic phase was washed with 10 mL of saturated saline , Dried over anhydrous sodium sulfate, concentrated and separated on a silica gel column to give the compound 7 340 mg, yield 36%. ESI-MS: 313 [M ++ 1].
Step 6. Synthesis of Compound 8.
Compound 7 (340 mg, 1.1 mmol) was dissolved in 20 mL of dichloromethane and 4-dimethylaminopyridine (DMAP, 13 mg, 0.11 mmol) and Dess-Martin Periodinane 1.3 mmol) and reacted at room temperature for 3 hours. Join 20mL saturated sodium bicarbonate solution and 20mL dichloromethane, stirred for 5 minutes, filtered and the filtrate was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The compound 8 270mg was obtained by silica gel column, and the yield was 80%. 1 H NMR (300 MHz, CDCl 3 ) δ 9.64 (s, 1H), 7.76 (s, 1H), 7.34-7.26 (m, 3H), 7.16 (d, J = 6.7 Hz, 1H), 4.74 J = 14.5, 3.9 Hz, 1H), 4.31 (td, J = 14.1, 3.2 Hz, 1H), 3.53 (td, 3.03-2.89 (m, 4H), 2.64-2.81 (m, 4H); ESI-MS: 311 [M ++ l ].

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IMIGLIPTIN, NEW PATENT, WO 2017211293, XUANZHU PHARMA CO., LTD.



(WO2017211293) CRYSTALLINE FORM OF SUCCINATE USED AS DIPEPTIDYL PEPTIDASE-4 INHIBITOR 

WO-2017211293, 

XUANZHU PHARMA CO., LTD. [CN/CN]; 2518, Tianchen Street, National High-Tech Development Zone Jinan, Shandong 250101 (CN)

SHU, Chutian; (CN)



https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017211293&recNum=1&tab=PCTDocuments&maxRec=&office=&prevFilter=&sortOption=&queryString=


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The present invention relates to a crystalline form of a succinate used as a dipeptidyl peptidase-4 inhibitor, and a manufacturing method, pharmaceutical composition, and application thereof. The invention specifically relates to a dipeptidyl peptidase-4 inhibitor compound as represented by formula (1), a crystalline form of a succinate, wherein the succinate is an (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridin-1-yl)methyl)benzonitrile, and a manufacturing method, pharmaceutical composition, and application thereof.

 

Example 1: Preparation of the succinate salt form I of the compound of formula (1)

[0056]

[0057]

The compound of formula (1) (44.6 g, 0.12 mol) was added to a 2 L round bottom flask and suspended in 1593 mL of acetonitrile. The mixture was heated to 80 ° C. and dissolved in free form. Immediately after the addition of 15.4 g A white solid precipitated, maintained at 80 ℃ for 1 hour and then cooled to room temperature, filtered and the filter cake was dried in vacuo at 40 ℃ for 10 hours, weighed 57.6g, yield 98.3%. The succinate salt Form I was tested by XRPD.

[0058]

Example 2: Preparation of the succinate salt form I of the compound of formula (1) II

[0059]

A quantity of succinate salt of the compound of formula (1) was weighed into glass vials in a total of 26 parts. A total of 26 vials of methanol, ethanol, isopropanol, isobutanol, 2-butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, toluene, Isopropyl acetate, n-propanol, isoamyl alcohol, butyl acetate, ethyl formate, 1,4-dioxane, n-butanol, pentane, heptane, cyclohexane, Ketone, xylene, isobutyl acetate, diethyl ether). After stirring, ultrasound and other means to make the sample fully dissolved. Subsequently, about 2 mL of liquid was removed from each bottle and filtered into 26 reagent tubes numbered 1-26. The resulting 26 filtrates were distributed in two 96-well plates. One or two of the above 1-13 solvents are sequentially added into the first 96-well plate, one or two of the above-mentioned 14-26 kinds of solvents are sequentially added into the second 96-well plate, Zha Kong sealing film sealed, placed in a fume hood, the natural environment to dry. Wherein Form I is obtained in the following mixed solvent, and Form I is also precipitated in the methyl isobutyl ketone in the remaining solution after plating.

[0060]

The solvent used to prepare succinate salt Form I was prepared

[0061]

[Table 0001]

Mixed solvents Solvent 1 Solvent 2
1 Methyl isobutyl ketone Ether
2 Xylene Ether
3 Isobutyl acetate Ether
4 Ether Ether
5 1,4-dioxane Pentane
6 1,4-dioxane Heptane
7 1,4-dioxane Cyclohexane
8 1,4-dioxane Methyl isobutyl ketone
9 1,4-dioxane Xylene
10 1,4-dioxane Isobutyl acetate
11 Butyl acetate Ether
12 Butyl acetate 1,4-dioxane

[0062]

Example 3: Preparation of the succinate salt form II of the compound of formula (1)

[0063]

Take 8 parts of the compound of formula (1), 200mg each, placed in a 10mL round bottom flask, add the solvent in the following table to each solvent, warmed until the solvent is refluxed, after dissolving it, add 69mg (1.1eq) succinic acid and cool to At room temperature, the solid precipitated and was filtered. The resulting solid was subjected to XRPD testing as succinate crystal form II.

[0064]

[Table 0002]

Feeding amount Solvent and ratio
2mL Tetrahydrofuran
3mL acetone
5.5mL Acetonitrile: water = 10: 1
2mL Methanol
4mL Ethanol
1mL Ethanol: water = 10: 1
2mL Isopropanol: water = 19: 1
2mL Isopropyl alcohol: water = 9: 1

Enclomiphene citrate, New patent, WO 2017182097, F.I.S. – FABBRICA ITALIANA SINTETICI S.P.A


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Enclomiphene citrate, New patent, WO 2017182097, F.I.S. – FABBRICA ITALIANA SINTETICI S.P.A

WO-2017182097

F.I.S. – FABBRICA ITALIANA SINTETICI S.P.A

CARUANA, Lorenzo; (IT).
PADOVAN, Pierluigi; (IT).
DAL SANTO, Claudio; (IT)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017182097&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

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Enclomiphene citrate is an active pharmaceutical ingredient currently under evaluation in clinical phase III for the treatment of secondary hypergonadism. Moreover, it also could be potentially used for an adjuvant therapy in hypogonadal men with Type 2 diabetes.

Enclomiphene citrate of formula (I):

has chemical name of Ethanamine, 2-[4-[(1 )-2-chloro-1 ,2-diphenyl ethenyl]phenoxy]-/V,/V-diethyl-, 2-hydroxy-1 ,2,3-propanetricarboxylate (1 : 1 ); has CAS RN. 7599-79-3, and it is also named trans-Clomiphene monocitrate, E-Clomiphene citrate or Enclomiphene monocitrate.

Enclomiphene is component of Clomiphene, an active pharmaceutical ingredient, having chemical name Ethanamine, 2-[4-(2-chloro-1 ,2- diphenylethenyl)phenoxy]-N,N-diethyl, since Clomiphene is a mixture of the geometric isomers trans-Clomiphene (i.e. Enclomiphene) and cis- Clomiphene.

The US patent 3,848,030, in examples 31 and 32, discloses a process for the resolution of the geometric isomers of Clomiphene through the preparation of salts with racemic binaphthyl-phosphoric acid.

In the later publication Acta Cryst. (1976), B32, pag. 291 -293, the actual geometric isomery has been definitely established by single crystal X-Ray diffraction.

Finally, in the publication “Analytical profiles of drug substances and excipients”, vol. 25, (1998), pag. 85-121 , in particular at pag. 99, it is stated that prior to 1976 the cis stereochemistry was wrongly assigned to the trans-isomer of Clomiphene (E-Chlomiphene or Enclomiphene), and only after the above publication on Acta Cryst. the correct geometric isomery has been definitively assigned.

These observations in the prior art have been confirmed by our experimentation. In particular, repeating the experiment 31 of US patent 3,848,030, the trans-Clomiphene salt with racemic binaphthyl-phosphoric acid was isolated and not the salt with cis-Clomiphene as stated in said patent, as confirmed by 2D H-NMR analysis (NOESY experiment). Thus, Example 31 of US3,848,030, provides, at the end, Enclomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 133-135°C. Example 32, instead provided Cis-Clomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 120-126°C.

Thus, with the aim of preparing Enclomiphene citrate, whole experiment 31 of US3,848,030 has been reworked also carrying out the crystallization of the product form a mixture of ethyl ether and ethanol, hence providing a not crystalline solid with two DSC peaks respectively at 1 14°C and 188°C, although the starting material used for the reworking example was quite a pure substance (HPLC Analysis (A A%) is 98.95% of Enclomiphene), and having a substantially the same chemical purity of that used in the prior art experiment (m.p. of our Enclomiphene BPA salt was 218°C versus 220- 222°C of the prior art Enclomiphene BPA salt of Example 31 ).

The patent US2,914,563, in example 3, discloses a process for the preparation of trans-Clomiphene citrate, containing from 30% to 50% of cis-Clomiphene, as citrate, by reaction of 1 -ρ-(β- diethylaminoethoxy)phenyl]-1 ,2-diphenylethylene hydrochloride with N- chlorosuccinimmide in dry chloroform under reflux.

Khimiko-Farmatsevticheskii Zhurnal (1984), 18(1 1 ), 1318-24 English translation in the review Pharmaceutical Chemistry Journal November 1984, Volume 18, Issue 1 1 , pag. 758-764 (Title: Synthesis and biological study of the cis- and trans-isomers of Clomiphene citrate and some intermediates of its synthesis) discloses the trans-isomer of Clomiphene citrate, i.e. Enclomiphene citrate, characterized by:

1 H-NMR (MeOD) d 7.4-6.7 (m, 14H); 4.27 (t, 2H, -OCH2); 3.51 (t, 2H, CH2- N); 3.28 (q, 4H, 2xN-CH2)); 2.73 (2H); 2.78 (2H); 1.31 (t, 6H, 2xN-C-CHs)) Melting point: 138-139°C (98% purity by GLC);

IR spectrum, v cm-1 (suspension in mineral oil): 3640, 3430, 1720, 1710

(citrate), 1600-1555 (broad band, stilbene system); 750.

UV spectrum: λ max = 243 nm, ε 21 ,800 and λ max 300 nm, ε 1 1 ,400.

These prior art methods for the preparation of Enclomiphene citrate do not allow the preparation of Enclomiphene citrate having needle shaped crystal habit, indeed the crystallization by means of a mixture of ethyl ether and ethanol does not provide a crystalline solid having needle crystals.

Moreover, Enclomiphene citrate was described in literature with different melting points, in particular, 133-135°C and 138-139°C. Said solid forms of Enclomiphene citrate fail to comply with stabilities studies and furthermore show relatively poor solubility in water either in neutral or acid pH.

Furthermore, the prior art methods have the drawbacks related to the poor reproducibility of the process and of the solid form thus obtained.

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EXPERIMENTAL SECTION

The starting material Clomiphene citrate can be prepared according to well-known prior art methods, or for example, as described in the example 1 of PCT/EP2015/074746 or can be purchased on the market.

[00190] Example 1 : Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric acid, starting from Clomiphene citrate.

Clomiphene citrate

[00191] A round bottom flask was charged 100 gr of Clomiphene Citrate (HPLC analysis (A/A%): 65.21 % Enclomiphene, 34.06% Z-Clomiphene) and 1000 mL of methanol. The suspension was stirred at 30°C up the complete

dissolution. Then a solution of racemic binaphthyl-phosphoric acid (abbreviated BPA) 30 gr (0.515 eq) in 30 ml_ of DMF was added. At the end of addition the mixture was stirred for 1 h at 30°C. The obtained suspension was filtered and the solid was washed with 100 ml_ of methanol.

[00192] 50.4 gr of Enclomiphene BPA salt (III) were obtained.

[00193] HPLC Analysis (A/A%): 97.04% Enchlomiphene, 2.5% Z-Clomiphene.

[00194] Example 1 b: Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric acid, starting from Clomiphene citrate.

[00195] A round bottom flask was charged 50 gr of Clomiphene Citrate and 500 ml_ of methanol. The suspension was heated at 40-45°C and stirred up to the complete dissolution. Then a solution of BPA 15 gr (0.515 eq) in 300 ml_ of methanol was added. At the end of addition the mixture was stirred for 1 h at 20°C. The obtained suspension was filtered and the solid was washed with 100 ml_ of methanol.

24.1 gr of Enclomiphene BPA salt were obtained.

HPLC Analysis (A/A%): 98.96% Enchlomiphene, 0.69% Z-Clomiphene.

[00196] Example 1 c: Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric acid, starting from Clomiphene citrate.

[00197] In a round bottom flask was charged 100 gr of Clomiphene Citrate and 1000 ml_ of methanol. The suspension was heated at 40-45°C and stirred up the complete dissolution. Then a solution of BPA 30 gr (0.515 eq) in 1000 ml_ of methanol was added. At the end of addition the mixture was stirred for 1 h at 20°C. the obtained suspension was filtered and the solid was wash with 100 ml_ of methanol.

47.9 gr of Enclomiphene BPA salt were obtained.

HPLC Analysis (A/A%): 98.81 % Enclomiphene, 0.79% Z-Clomiphene.

[00198] Example 1d: Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric, starting from Clomiphene citrate.

[00199] In a round bottom flask was charged 150 gr of Clomiphene citrate and 1500 mL of methanol. The suspension was heater at 40-45°C and stirred up the complete dissolution. Then a solution of BPA 45 gr (0.515 eq) in 900 mL of methanol was added. At the end of addition the mixture was

stirred for 1 h at 20°C. the obtained suspension was filtered and the solid was wash with 100 ml_ of methanol.

76.4 gr of E-Clomiphene BPA salt were obtained.

HPLC Analysis (A/A%): 98.82% Enchlomiphene, 0.80% Z-Clomiphene.

[00200] Example 2: Recrystallization of Enclomiphene BPA salt of formula (III) (the step A).

(Ill)

[00201] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene BPA salt (III) (50 g) and having Z-isomer of 1.64 % was suspended in DMF (2.1 L/Kg of Enclomiphene BPA (III)) and methanol (1.4 L/Kg of Enclomiphene BPA salt (III)). The suspension was heated to reflux (~ 76-79°C). Further DMF (0.1 L/Kg of Enclomiphene BPA (III)) might be required to improve the solubility of the starting material. Once the starting material was completely dissolved, methanol was added as anti-solvent (3.5 L/Kg of Enclomiphene BPA (III)). The temperature was decreased to 60°C and the mixture was stirred for 2 – 3 h. Then, the temperature was further decreased to 20 °C and filtered. The wet cake was washed twice with methanol (1.5 L/Kg of Enclomiphene BPA salt (III)). The product was dried under vacuum at 60 – 70 °C for 12 – 24 h. Time of drying could be prolonged until residual DMF is < 2500 ppm.

[00202] Analysis of quality of the final product of the above mentioned example and of the same product, obtained from repetition following the same process, it is shown in the following table:

Enclomiphene BPA (III) salt Enclomiphene BPA (III) salt rixx (Starting product) (finale product)

Z-isomer = 1.64 A/A% Z-isomer = 0.07 A/A%

Z-isomer = 0.79 A/A% Z- isomer = 0.03 A/A%

[00203] Example 3: Preparation of Enclomiphene citrate of formula (I), having needle shaped crystal habit, starting from Enclomiphene BPA salt formula (III).

(II)

[00204] Into a proper 4 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene BPA salt of formula (III) (400 g, assay 99.8 wt% 0.528 mol, 1 equiv.) was suspended in methyl-tert-butyl ether (MTBE, 2 L), isopropanol (IPA, 0.5 L) and water (2 L). The mixture was stirred for 15 minutes, then 0.48 L of ammonia solution 30 wt% was added and the mixture was further stirred for one hour. The aqueous phase was separated and the organic layer was washed with a solution of ammonia solution 30 wt% (0.12 L) and water (0.6 L). The aqueous phase was separated and the organic layer was finally washed with water (0.6 L). The organic solution was evaporated to residue under vacuum at 60-65°C. The residue was dissolved in 1.36 L of absolute ethanol. The assay of the solution was determined at this stage through a potentiometric titration and results in 15.125 wt% as Enclomiphene of formula (II) (0.466 mol). Then 0.24 L of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (100.8 g, 0.475 mol, 1.02 equiv.) was dissolved in absolute ethanol (1.7 L) and water (0.3 L), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 0.4 L of absolute ethanol. The product was dried under vacuum at 65°C. At the end of drying, 269 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 91.8% molar yield.

[00205] HPLC Analysis (A/A%): 99.79% Enchlomiphene, 0.04% Z-Clomiphene (i.e. Z-isomer).

[00206] Example 4: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of ethanol and water, wherein the amount of water is 15%.

(I)

[00207] Into a proper 1 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (15,0 g, assay 99.9 wt% 0.0369 mol, 1 equiv.) was dissolved in absolute ethanol (102 ml_, 6.8 mL/g of free base), then 18 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (7.92 g, 0.0377 mol, 1.02 equiv.) was dissolved in absolute ethanol (127 ml_) and water (23 ml_), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30-40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle-shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 ml_ of absolute ethanol. The product was dried under

vacuum at 65°C. At the end of drying, 20.2 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 91.4% molar yield.

[00208] HPLC Analysis (A/A%): 99.86% Enchlomiphene, 0.03% Z-Clomiphene.

[00209] Example 4a: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of isopropanol and water, wherein the amount of water is 15%.

[00210] Into a proper 1 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (40,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in isopropanol (272 ml_, 6.8 mL/g of free base), then 48 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (21.10 g, 0.100 mol, 1.02 equiv.) was dissolved in isopropanol (340 ml_, 8.5 mL/g of free base) and water (60 mL, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of isopropanol. The product was dried under vacuum at 65°C. At the end of drying, 56.5 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 95.9% molar yield.

[0021 1] Example 4b: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of n-propanol and water, wherein the amount of water is 15%.

[00212] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (9,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in 7-propanol (61 mL, 6.8 mL/g of free base), then 1 1 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (4.70 g, 0.0224 mol, 1.02 equiv.) was dissolved in 7-propanol (77 ml_, 8.5 mL/g of free base) and water (14 ml_, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of 7-propanol I. The product was dried under vacuum at 65°C. At the end of drying, 1 1.7 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 88.1 % molar yield

[00213] Example 4c: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of n-butanol and water, wherein the amount of water is 15%.

[00214] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (9,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in 7-butanol (61 mL, 6.8 mL/g of free base), then 1 1 mL (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (4.70 g, 0.0224 mol, 1.02 equiv.) was dissolved in 7-butanol (77 mL, 8.5 mL/g of free base) and water (14 mL, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 ml_ of 7-butanol. The product was dried under vacuum at 65°C. At the end of drying, 1 1.6 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 87.4% molar yield.

[00215] Example 4d: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of tert-butanol and water, wherein the amount of water is 15%.

[00216] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (9,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in te T-butanol (61 ml_, 6.8 mL/g of free base), then 1 1 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (4.70 g, 0.0224 mol, 1.02 equiv.) was dissolved in te T-butanol (77 ml_, 8.5 mL/g of free base) and water (14 mL, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of te T-butanol. The product was dried under vacuum at 65°C. At the end of drying, 1 1.2 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 84.4% molar yield.

[00217] Example 5: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit. Preparation of the seed crystal.

[00218] Into a proper 1 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (15,0 g, assay 99.9 wt% 0.0369 mol, 1 equiv.) was dissolved in absolute ethanol (102 ml_, 6.8 mL/g of free base), then 18 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (7.92 g,

0.0377 mol, 1.02 equiv.) was dissolved in absolute ethanol (127 ml_, 8.5 mL/g of free base) and water (23 mL 1.5 mL/g of free base), the solution was heated to 50°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 50°C. The dosage takes place in 30-40 minutes. At the end of the dosage, the stirring was turned off and the mixture was allowed to cool down to room temperature without stirring. The product began to crystallize at 40-30°C. Once reached 20- 25°C the stirring was turned on and the temperature was further decreased to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of absolute ethanol. The product was dried under vacuum at 65°C. At the end of drying, 13.9 g of Enclomiphene citrate of formula (I) were isolated, corresponding to 62.3% molar yield

[00219] Example 6: Preparation of Enclomiphene citrate of formula (I), having a non-needle shaped crystals, with a mixture of acetone and water, wherein the amount of water is 15%.

Comparative example (see Fig. 8) and evidence example of the invention. Following the same process described in the example 4, substituting ethanol solvent with acetone solvent. Starting from 15,0 g of Enclomiphene of formula (II), following the above mentioned process, 22.3 g of Enclomiphene citrate of formula (I) were isolated, corresponding to 94.2% molar yield product. For the morphology of the crystal see fig. 8.

[00220] Indeed, the microscopy analysis provides a better further evidence of the crystal habit of Enclomiphene citrate (I) of the example 6 (see Fig.8) which has a form more different than/to Enclomiphene citrate (I) having a needle shaped crystal habit, obtained according to above described examples,

1. e. 4, 4a, 4b, 4c, 4d (see Fig. 5, 6 and 7).

[00221] HPLC Analysis (A/A%): 99.63% Enchlomiphene, 0.20% Z-Clomiphene.

[00222] Example 7: Analytical method to identify and quantify Z-Clomiphene of formula (IV) into Enclomiphene of formula (II) or Enclomiphene citrate of formula (I) or Enclomiphene BPA salt of formula (III) and for determining the chemical purity.

[00223] Chromatographic conditions:

Dim. Column: 250 mm x 4.6 mm , 5 pm

Stationaly phase: Butyl sylane (USP phase L26, Vydac 4C is suggested) Temp. Column: room temperature

Mobile Phase: Methanol / water / triethylamine 55 : 45 : 0.3 v/v

Adjust at pH 2.5 with phosphoric acid

Flow: 1.0 mL/min

Detector UV a 233 nm,

Injection Volume: 10 μΙ_

Sample diluent: mobile phase.

Applying the conditions described above the expected retention times are as indicated below:

/////////////////Enclomiphene citrate, New patent, WO 2017182097, F.I.S. – FABBRICA ITALIANA SINTETICI S.P.A

File:Enclomiphene.png

Enclomiphene

Synonyms: Chloramiphene Citrate; Citrato de cloramifeno; Clomifencitrat; Clomifène, citrate de; Clomifeni Citras; Clomifeno, citrato de; Clomiphene Citrate; Klomifeenisitraatti; Klomifen Sitrat; Klomifen-citrát; Klomifén-citrát; Klomifencitrat; Klomifeno citratas; MER-41; MRL-41; NSC-35770; クロミフェンクエン酸塩
BAN: Clomifene Citrate [BANM]
USAN: Clomiphene Citrate
INN: Clomifene Citrate [rINNM (en)]
INN: Citrato de clomifeno [rINNM (es)]
INN: Clomifène, Citrate de [rINNM (fr)]
INN: Clomifeni Citras [rINNM (la)]
INN: Кломифена Цитрат [rINNM (ru)]
Chemical name: A mixture of the E and isomers of 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine dihydrogen citrate
Molecular formula: C26H28ClNO,C6H8O7 =598.1
CAS: 911-45-5 (clomifene);15690-57-0((E)-clomifene ); 15690-55-8 ((Z)-clomifene); 50-41-9 (clomifene citrate); 7599-79-3 ((E)-clomifene
citrate); 7619-53-6 ((Z)-clomifene citrate)
ATC code: G03GB02
ATC code (veterinary): QG03GB02
UNII code: 1B8447E7YI (clomifene citrate); UY5X264QZV ((Z)-clomifene citrate)

Chemical Structure of ClomifeneChemical Structure of Clomifene

NOTE:

Clomifene may be separated into its Z-and E-isomers, zuclomifene and enclomifene
.

WO 2017163257, NEW PATENT, IBRUTINIB, IND-SWIFT LABORATORIES LIMITED


WO 2017163257, NEW PATENT, IBRUTINIB, IND-SWIFT LABORATORIES LIMITED

WO2017163257) PROCESS FOR PREPARING PURE LH-PYRAZOLO[3,4-D] PYRIMIDINE DERIVATIVE

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017163257&recNum=1&maxRec=145&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28IND+SWIFT%29&tab=PCTDescription

IND-SWIFT LABORATORIES LIMITED

ARUL, Ramakrishnan; (IN).
SARIN, Gurdeep Singh; (IN).
WAS, Sandeep; (IN).
KUMAR, Vishal; (IN)

The present invention relates to an efficient and industrially advantageous process for the preparation of pure lH-pyrazolo[3,4-d] pyrimidine derivative. In particular the present invention provides a process for the preparation of pure 4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate of ibrutinib. Particularly, the present invention provides a process for the preparation of 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, wherein none of the intermediates have been isolated, an important precursor for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d] pyrimidine.

The present invention relates to an efficient and industrially advantageous process for the preparation of pure lH-pyrazolo[3,4-d] pyrimidine derivative. In particular the present invention provides a process for the preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate of ibrutinib, wherein none of the intermediates have been isolated to prepare 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, an important precursor.

Ibrutinib (IMBRUVICA), chemically known as l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidin- 1 -yl] prop-2-en- 1 -one is an orally administered drug that targets Bruton’s tyrosine kinase (BTK). Ibrutinib may be used for treating both B cell-related hematological cancers/ B cell chronic lymphocytic leukemia, and autoimmune diseases such as rheumatoid arthritis, Sjogrens syndrome, lupus and asthma and is represented by following chemical formula:

Ibrutinib and its pharmaceutically acceptable salts were first disclosed in US patent US7,514,444. This patent discloses a process for the preparation of Ibrutinib by involving use of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, as intermediate as shown below:

4-Amino-3-(4-phenoxyphenyl)- l H-pyrazolo[3,4-d]pyrimidine, a key intermediate of ibrutinib, and its preparation from 3-amino-4-cyano-5-(4-phenoxyphenyl) pyrazole was first disclosed in a PCT patent publication WO2001/019829 A2 as shown in below scheme.

Various other publications like US patents US7,514,444; US7.718,662; US8,883,803 and PCT publications WO2012/158843 A2; WO2013/010136A2 follow the same process for the preparation of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine as described above.

The process comprises the conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, which is then taken up in mixture of toluene and tetrahydrofuran and further reacted with malononitrile in the presence of diisopropylethylethylamine in toluene. The reaction mixture is stirred overnight and after completion of reaction, followed by work up 1 , 1 -dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is isolated as a residue and which is further purified.

The resulting l, l-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is reacted with trimethylsilyldiazomethane in a mixture of acetonitrile and methanol in the presence of diisopropylethylamine as a base. The resulting reaction mixture is stirred for 2 days to give l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product) as an oil, which is purified by flash chromatography.

The O-methylated product is treated with hydrazine hydrate to give 3-amino-4-cyano- 5-(4-phenoxyphenyl)pyrazole, which is further reacted with formamide at a temperature of 180°C to give 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4- d]pyrimidine as pale brown-grey solid.

Since, the above process involves the isolation of intermediates and takes long time during reaction completion. Therefore, it is lengthy, not efficient. Further publication is silent about the purity of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine. Acetonitrile solvent has been used in methylation reaction, which is carcinogenic.

The cyclization reaction has been carried out at 180°C and it is observed that the cyclization reaction at high temperature of 180°C, results in grey brown solid colour of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, may be due to presence of inorganic impurities.

The said process also requires the use of expensive (trimethylsilyl)diazomethane to obtain O-methylated product, which is sensitive to air and water, and hence, the methylation reaction has to be carried out in the absence of water, under anaerobic conditions; silica and flash chromatography are also used for purifying O-methylated product. Since the above process involves complicated operation processes, which leads to high production cost and therefore is not an attractive option at industrially scale.

PCT publication WO2014/173289A1 discloses a process for preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as shown below and its conversion into 4- amino-3-(4-phenoxy phenyl)- lH-pyrazolo[3,4-d]pyrimidine has not been disclosed.

The process involves conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, followed by reaction with malononitrile in the presence of diisopropylethylethylamine in tetrahydrofuran. The reaction mixture has been stirred for 16 hours and thereafter l, l -dicyano-2-hydroxy-2-(4-phenoxyphenyl) ethene is isolated from reaction mixture. A solution of l, l-dicyano-2-hydroxy-2-(4- phenoxyphenyl)ethene in trimethoxymethane has been heated for 16 hours to give l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product), which is then reacted with hydrazine hydrate to give 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole.

The above process is inefficient, since it involves isolation of intermediates and takes long time to complete the reactions and purity of 3-amino-4-cyano-5-(4- phenoxypheny pyrazole has not been disclosed.

A similar approach has been described in a PCT publication WO2014/082598 A 1 for preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole and is presented as below:

The process involves conversion of 4-phenoxybenzoic acid to the corresponding acyl chloride by using sulfurous dichloride, followed by reaction with malononitrile in the presence of sodium hydride to obtain l, l-dicyano-2-hydroxy-2-(4-phenoxy phenyl)ethene, which is recrystallized from 1,4-dioxane. The hydroxy moiety is then methylated using dimethyl sulphate to give l, l-dicyano-2-methoxy-2-(4-phenoxy phenyl)ethene (O-methylated product) which is recrystallized from a mixture of hexane and ethylactetate. The solution of resulting O-methylated product in ethanol was treated with hydrazine hydrate at reflux temperature to give 3-amino-4-cyano-5- (4-phenoxy phenyl)pyrazole, followed by its recrystallization in hexane and further, its conversion into 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine was not disclosed.

The above process also involves isolation of intermediates; their purification which leads to longer time in reaction completion, and it does not disclose the purity of 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole. Further the above process involves use of sodium hydride, which is a hazardous reagent and can ignite in air during scale up. Several alternative methods have been reported in literature, wherein process for the preparation of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine has been disclosed and are discussed herein.

A Chinese patent application CN103121999A discloses a process of preparation of 4- amino-3 -(4-phenoxy phenyl)- 1 H-pyrazolo[3 ,4-d] pyrimidine, as below :

The process involves reaction of 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine with (4-phenoxyphenyl)boronic acid in the presence of alkali agents and aprotic solvents to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine.

The said Chinese application is also silent about the purity of target compound and even starts with the advance intermediates, which are expensive and make the process unattractive from industrial point of view.

A similar approach has been described in US patent US8,940,893; PCT publication WO2013/1 13097A1 and WO2015/018333 A 1 for preparing 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine .

In US patent US8,940,893 and PCT publication WO2013/1 13097A1, 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine is purified by using Combi-flash chromatography on silica gel. In PCT publication WO2015/018333A1, 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine is purified by recrystallization in ethyl acetate.

The purity of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine has not been reported in above publications too. Further two of the above processes involve tedious step of chromatographic purification, which is not industrial viable.

Another Chinese patent application CN 103965201 A discloses a process for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, wherein 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine was reacted with trimethyl tin (4- phenoxy phenyl) to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidine and followed by its recrystallization in isopropanol, as shown below:

The said Chinese application is also silent about the purity of 4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine and is not cost-effective because it starts with advance intermediates, which are expensive. Therefore, said route of synthesis is not industrially applicable.

Purity of an API as well as intermediates is of great importance in the field of pharmaceutical chemistry. It is well documented in the art that direct product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. The impurities that can be present in pharmaceutical compounds are starting materials, by-products of the reaction, products of side reactions, or degradation products.

According to ICH guidelines, process impurities should be maintained below set limits by specifying the quality of raw materials, their stoichiometric ratios, controlling process parameters, such as temperature, pressure, time and including purification steps, such as crystallization, distillation and liquid-liquid extraction etc., in the manufacturing process. Typically, these limits should less than about 0.15 % by weight of each identified impurity. Limits for unidentified and/or uncharacterized impurities are obviously lower, typically less than 0.10 % by weight. The limits for genotoxic impurities could be much lower depending upon the daily dose of the drug and duration of the treatment. Therefore, in the manufacture of a drug substance, the purity of the starting materials is also important, as impurities may carry forward to the active pharmaceutical ingredient such as ibrutinib.

In view of the above, most of the prior art processes involve isolation of intermediates, additional purification steps and silent about the purity or the assay of 4-amino-3-(4-phenoxy phenyl)- lH-pyrazolo[3,4-d]pyrimidine.

Thus, there is an urgent need for the development of a synthetic process which produces pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine or its acid addition salts.

The present invention fulfills the need in the art and provides an improved, industrially advantageous process for the synthesis of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate in the preparation of ibrutinib, through preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole from 4-phenoxy benzoic acid using same organic solvent and none of the intermediates have been isolated.

Examples:

Example 1: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole

4-Phenoxybenzoic acid (200g) was slowly added to thionyl chloride (400ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 60-65°C for 5 hours. Thionyl chloride was distilled off under vacuum at temperature below 60°C. Toluene (2x400ml) was added to the resulting oily residue and thereafter distilled out completely under vacuum below 60°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (2000ml). Malononitile (80g) and diisopropylethylamine (320ml) were sucessively added to the reuslting solution at a temperature of 25-30°C slowly, maintaining reaction temperature 50-55°C. The reaction mass was further stirred for 30 minutes. After completion of the reaction, the reaction mass was cooled to 25-30°C and a solution of sulfuric acid ( 1.25 M) was added. The reaction mixture was then stirred at a temperature of 25-30°C for 30 minutes, and the layers were separated. The organic layer was washed with a solution of sodium chloride ( 10%) and the resulting organic layer was used directly in next reaction.

Dimethyl sulfate (200ml) and sodium bicarbonate (200g) were added to the resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 25-30°C, demineralized water (2000ml) was added and stirred for 10-15 minutes. The layers were separated and the aqueous layer was extracted with toluene (1000ml). All the organic layers were combined and washed with sodium chloride solution ( 10%). Activated carbon (20g) was added and reaction mixture was stirred for 30 minutes. The solution was filtered through hyflo bed and to the resulting organic layer hydrazine hydrate ( 120ml) was added at a temperature of 25-30°C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-50°C. Thereafter, the reaction mass was stirred at a temperature of 25-30°C for 1 -2 hours. The resulting precipitated solid was filtered, slurry washed with dichloromethane (400ml) and finally, dried to obtain title compound of formula V ( 140g) purity 93.28% measured by HPLC.

Example 2: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole

4-Phenoxybenzoic acid (lOOg) was slowly added to thionyl chloride (200ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 50-55°C for 5 hours. Thionyl chloride was distilled off under vacuum at temperature below 50°C. Toluene (250ml) was added to the resulting oily residue and thereafter distilled out completely under vacuum below 50°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (500ml). Malononitile (35.58ml) and diisopropylethylamine (160ml) were sucessively added to the reuslting solution at a temperature of 25-30°C slowly, maintaining reaction temperature around 50-55°C. The reaction mass was further stirred for 10 minutes. After completion of the reaction, the reaction mass was cooled to 25-30°C and a solution of sulfuric acid (70 ml in 1000 ml water) was added. The reaction mixture was then stirred at a temperature of 25-30°C for 30 minutes, and the layers were separated. The organic layer was washed with a solution of sodium chloride (10%) and the resulting organic layer was used directly in next reaction.

Dimethyl sulfate (95.1 1ml) and sodium bicarbonate (96.16g) were added to the resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 55- 60°C, demineralized water ( 1000ml) was added. The reaction mass was cooled to a temperature of 25-30°C and stirred for 10- 15 minutes. The layers were separated and the aqueous layer was extracted with toluene (500ml). All the organic layers were combined and washed with sodium chloride solution ( 10%). To the resulting organic layer hydrazine hydrate (50ml) was added at a temperature of 25-30°C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-45°C. Thereafter, the reaction mass was stirred at a temperature of 25-30°C for 1-2 hours. The resulting precipitated solid was filtered, suck dried to obtain 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V ( 123g) purity 86.96% measured by HPLC.

Example 3: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised and allowed to reflux to dissolve the solid completely to provide a clear solution. Then, solvent was distilled off under vacuum to obtain a residue and isopropanol (50ml) was added and after stirring for hours the solid was filtered and dried to afford 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (26g) and having purity of 97.54 % by HPLC .

Example 4: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised upto reflux to dissolve the solid completely upto clear solution. Water (1050ml) was added to the solution and the reaction mixture was gradually cooled to crystallize the product. The resulting solid was filtered, washed with two volumes of isopropanol, dried in vacuum oven at a temperature of 40-45 °C to afford 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (20g) and having a HPLC purity of 97.23% .

Example 5: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d] pyrimidine compound of formula I

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (20g) was suspended in formamide (100 ml) and heated at a temperature of 130°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (500ml) was added and the reaction mixture was stirred at a temperature of 25-30°C for 45 minutes. The resulting solid was filtered and acetone (200ml) was added stirred the reaction mixture for 30-45 minutes. The resulting solid was filtered, washed, dried to afford pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine compound of formula 1 (12g) having purity 99.6% measured by HPLC.

Example 6: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d] pyrimidine compound of formula I

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (lOOg) was suspended in formamide (500ml) and heated at a temperature of 135-140°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (1000ml) was added and the reaction mixture was stirred at a temperature of 20-25°C for 1 hour. The resulting solid was filtered, washed with water (500ml) then successively slurry washed with toluene (2 x 500ml) and dried to afford pure 4- amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine compound of formula I

(70g) having purity 99.8% measured by HPLC; assay > 98%; residue on ignition 0.05%; heavy metals < 20ppm.

Example 7: Preparation of (lS)-l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-l,2,5,7-tetraza-lH-inden-4-ylamine

Diisopropyl diazodicarboxylate (DAID, 1.2 ml,) was added to a solution of 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine ( l .Og,) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p-phenoxyphenyl)-l ,2,5,7-tetraza- lH-inden-4-ylamine (l .Og). was added and warmed till dissolution, and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 % ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-( l S)- l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)- l,2,5,7-tetraza- lH-inden-4-ylamine as a light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0 ml). The layers were separated and the aqueous layer was basified with potassium carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title compound as light yellow oil.

Example 8: Preparation of l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo [3,4- d]pyrimidin-l-yl)piperidin-l-yI)prop-2-en-l-one (Ibrutinib)

To a solution of acryloyl chloride (0.06g) in tetrahydrofuran (15.0 ml), a mixture of triethylamine (O. lg) and (lS)-l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-l,2,5,7- tetraza- lH-inden-4-ylamine (0.2g) in tetrahydrofuran (7.8 ml) was added. The reaction mixture was stirred at 25-30°C for 18 hous and filtered. The solvent was removed under vacuum to obtain crude ibrutinib, which was further purified by column chromatography on silica gel to obtain pure ibrutinib as crystalline solid.

Formula VI

Formula VII

Formula I

Formula II

 

Formula III

 

Formula IV

 

Formula V

///////WO 2017163257, NEW PATENT, IBRUTINIB, IND-SWIFT LABORATORIES LIMITED

NEW PATENT, PONESIMOD, CRYSTAL PHARMATECH, WO 2017107972


NEW PATENT, PONESIMOD,  CRYSTAL PHARMATECH, WO 2017107972

Novel crystalline forms I, II and III of ponesimod . Useful as a selective sphingosine-1-phosphate receptor-1 (S1P1) receptor agonist, for the treatment of psoriasis. Appears to be first filing from Crystal Pharmatech claiming ponesimod. Johnson & Johnson , following its acquisition of Actelion , is developing ponesimod (phase III clinical trial), a S1P1 agonist, for the treatment of autoimmune disorders.

Applicants: CRYSTAL PHARMATECH CO., LTD. [CN/CN]; B4-101, Biobay, 218 Xinghu Street,
Suzhou Industrial Park Suzhou, Jiangsu 215123 (CN)
Inventors: CHEN, Minhua; (CN).
ZHANG, Yanfeng; (CN).
LI, Jiaoyang; (CN).
ZHANG, Xiaoyu; (CN)

Most of the family members of the product case ( WO2005054215 ) of ponesimod expire in European countries until November, 2023 and in the US by December, 2024 with US154 extension.

front page image

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017107972&redirectedID=true

Disclosed are crystalline forms 1, 2, and 3 of a selective S1P1 receptor agonist, namely Ponesimod, and a method for preparing the same. An X-ray powder diffraction pattern of the crystalline form 1 has characteristic peaks at 2 theta values of 18.1° ± 0.2°, 14.6° ± 0.2°, and 11.3° ± 0.2°. An X-ray powder diffraction pattern of the crystalline form 2 has characteristic peaks at 2 theta values of 3.8° ± 0.2°, 10.8° ± 0.2°, and 6.1° ± 0.2°. An X-ray powder diffraction pattern of the crystalline form 3 has characteristic peaks at 2 theta values of 12.2° ± 0.2°, 6.2° ± 0.2°, and 5.6° ± 0.2°. Compared with existing crystalline forms, the present invention has better stability and a greatly increased solubility, and is more suitable for development of a pharmaceutical preparation containing Ponesimod

Ponesimod (compound of formula I) is a selective S1P1 receptor antagonist developed by Actelion. The drug was used to treat moderate to severe chronic plaque psoriasis in the two medium-term trial was successful, and will carry out the treatment of psoriasis in 3 clinical trials.

The present invention discloses a process for the preparation of a compound of formula I, which is disclosed in patent CN 102177144B, which is an amorphous form prepared by the process of CN100567275C, and discloses a process for the preparation of a compound of formula I, crystalline form C, crystalline form III, Type II. The results show that the crystallinity of crystalline form III is poor and it is converted to crystalline form II at room temperature. The crystalline form II is difficult to repeat and prepare a certain amount of propionic acid. The thermodynamics stability of crystalline form A is inferior to that of crystal form C. In contrast, For the crystal form suitable for the development of the drug, the solubility of the crystalline form C is not ideal.

Example 1

 

Preparation of Ponesimod Form 1:

 

48.1 mg of Ponesimod was added to 0.40 mL of 1,4-dioxane and the filtrate was filtered. To the solution was stirred at room temperature, 1.20 mL of n-heptane was added dropwise to precipitate the crystals and stirred overnight. The supernatant was filtered off by centrifugation Liquid to obtain Ponesimod crystal form 1.

Follow “‘2014’ Suzhou International Elite Entrepreneurship Week” with interest Over 88 billion venture capital investment helps your pioneering dreams come true

 

Since 2009, there have been 1267 overseas high-level talent projects settled in Suzhou through International Elite Entrepreneurship Week and 54 talents have been introduced and fostered for the national “Thousand Talents Plan”. Among these 53 talents, Dr. Chen Minhua, the founder of Suzhou Crystal Pharmatech Co., Ltd., was deeply impressed by thoughtful services in Suzhou for innovative pioneering talents when he recalled the development in Suzhou. “Investment and financing services are placed with particular importance. Everything is thoroughly considered for fear that enterprise

In 2010, Chen Minhua quitted his job in a well-known pharmaceutical company in the United States and returned with his core 4-people R&D team. He founded Crystal Pharmatech Co., Ltd. in Suzhou Biobay through the Entrepreneurship Week. Till 2013, Crystal Pharmatech has made profits year by year. The yearly output value in 2013 reached 18 million Yuan, while the profits reached as high as 4 million Yuan. His clients involve half of top 20 pharmaceutical companies globally. Chen Minhua longs to fill the vacancy of drug crystals in China and take the lead in the international drug crystal research. Chen Minhua introduced that government service is an integral part to his growth. “Since it was settled down, Suzhou public sector organized several investment and financing activities and offered training and services in various aspects like the mode of financing, finance docking and enterprise strategic investment, which laid a solid foundation for Crystal Pharmatech’s capital expansion”, said by Chen Minhua.

To help high-level talents solve financial difficulty, Suzhou lays stress on the docking of science & technology and finance. The person in charge of the Municipal Science and Technology Bureau said that Suzhou guides and integrates social capital for equity investment of hi-tech enterprises at the start-up stage via the guiding funds set up by the government and follow-up investment, etc, thus evolving the venture capital investment cluster based on Shahu Equity Investment Center. After the national “Thousand Talents Plan” venture capital investment center was set up, pioneering talents and venture capital are further converging here. As of the end of 2013, there are 270 effective organizations engaged in various venture capital investment in Suzhou that manage the funds in excess of 88 billion Yuan. 30 million Yuan will be appropriated from the municipal science and technology fund budget for the newly established FOF of Angel Investment this year, so as to take avail of social capital for the development of small and medium-sized hi-tech enterprises.

Meanwhile, Suzhou sets up the special compensation fund against credit risks and offers “Kedaitong” with “low threshold and low interest rate”, so as to solve financial difficulty of small and medium-sized hi-tech enterprises and create favorable financing environment for the pioneering work of talents and corporate development. At present, the fund of credit risk pool has reached 500 million Yuan and “Kedaitong” loans of 8.52 billion Yuan have been granted for 1023 small and medium-sized hi-tech enterprises. Particularly, 120 pioneering enterprises that feature independent intellectual property, high content of technology and light assets were backed up with 1.314 billion Yuan, the special risk compensation fund of “Kedaitong”, thus vigorously supporting innovation and pioneering work of leading talents in the science and technology community in Suzhou.

Reporter Qian Yi

Quoted from Suzhou Daily on July 6, 2014

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Imigliptin dihydrochloride, Xuanzhu Pharma Co Ltd, NEW PATENT, WO 2017107945


Imigliptin dihydrochloride, Xuanzhu Pharma Co Ltd, NEW PATENT, WO 2017107945

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017107945&redirectedID=true

Applicants: XUANZHU PHARMA CO.,LTD. [CN/CN]; 2518, Tianchen Street, National High-tech Development Zone Jinan, Shandong 250101 (CN)
Inventors: SHU, Chutian; (CN).
WANG, Zhenhua; (CN)

str1

The present invention relates to a crystalline form of benzoate of a dipeptidyl peptidase-IV inhibitor, a method for preparing the same, a pharmaceutical composition,and a use thereof. Specifically, the present invention relates to a crystalline form of benzoate of a compound used as a dipeptidyl peptidase-IV inhibitor and represented by formula (1), namely (R)-2-((7-(3-aminopiperidine-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridine-1-yl)methyl)benzonitrile, a method for preparing the same, a pharmaceutical composition, and a use thereof.

Novel crystalline form I of imigliptin dihydrochloride as dipeptidyl peptidase IV inhibitor (DPP-IV) for the treatment of and/or prevention of non-insulin dependent diabetes, hyperglycemia and hyperlipidemia. In June 2017, KBP Biosciences and Xuanzhu Pharma , subsidiaries of Sihuan Pharmaceutical , are developing an imigliptin dihydrochloride (phase II clinical trial), a DPP-IV inhibitor and a hypoglycemic agent,, for the treatment of type II diabetes. Follows on from WO2013007167 , claiming similar composition.

Dipeptidyl peptidase-IV (DPP-IV) inhibitor is a new generation of oral type 2 diabetes treatment drugs, by enhancing the role of intestinal insulin to play a role, non-insulin therapy drugs. Compared with conventional drugs for the treatment of diabetes, DPP-IV inhibitors do not have weight gain and edema and other adverse reactions.
The compound (R) -2 – ((7- (3-aminopiperidin-1-yl) -3,5-dimethyl-2-oxo-2,3-dihydro- 1H-imidazo [4,5-b] pyridin-1-yl) methyl) benzonitrile (described in the specification as a compound of formula (1), as described in patent application PCT / CN2011 / 000068) Inhibitors of compounds, DPP-IV has a strong inhibitory effect and a high selectivity.
The study of crystal form plays an important role in drug development process. Application No. PCT / CN2012 / 078294 discloses the dihydrochloride crystal form I of the compound of formula (1), in order to meet the requirements of formulation, production and transportation , We further studied the crystal form of the compound of formula (1) in order to find a better crystal form.
Example 1 Preparation of benzoate form I of compound of formula (1)
40 g (0.1 mol) of the compound of the formula (1) was added to a 2 L round bottom flask, suspended in 1428 mL of acetonitrile, and the temperature was raised to 60 ° C. The free solution was dissolved, 14.3 g (0.1 mol) of benzoic acid was added, The precipitate was dried at 60 ° C for 1 hour and then allowed to stand at room temperature. The filter cake was dried in vacuo at 40 ° C for 10 hours and weighed 51.6 g in 97.4% yield. By XRPD test, for the benzoate crystal type Ⅰ.

////////////////Imigliptin dihydrochloride, Xuanzhu Pharma Co Ltd, NEW PATENT, WO 2017107945

CFDA Granted Approval of Phase II/III Clinical Trials for Imigliptin Hydrochloride
2016-08-04 15:25:37 Author:admin

        Phase II/ III Clinical Trials of Imigliptin Hydrochloride (KBP-3853) have been approved by CFDA; the Clinical Approval Numbers are 2016L05997 and 2016L06137.

        As we know, in Phase I study both single and multiple doses of Imigliptin Hydrochloride were safe and well tolerated in healthy volunteers and in Type 2 diabetes patients. Imigliptin Hydrochloride demonstrated good pharmacokinetic (PK) characteristics and exhibited dose-proportional plasma exposure. The potent and long duration inhibition of DPP-4 was validated in the PK/PD study. The results of Phase I study of Imigliptin Hydrochloride warranted its long-term safety and efficacy studies in Phase II/ III.
        Currently, the Imigliptin Hydrochloride team has completed the production of clinical trial drug product, as well as finalized the clinical protocols and the study sites. Phase II clinical trial of Imigliptin Hydrochloride will begin in the near future.
       The approval of Imigliptin Hydrochloride for the phase II/ III clinical trials represents another milestone in the SiHuan/ XuanZhu’s new drug discovery history. We enter into a new clinical stage of the development process, and we have many works remaining before us. It is still an urgent task for us to accelerate the clinical development, and to launch the drug product in the China market as soon as possible.
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