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(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido) benzoic acid,



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Figure imgf000132_0001

(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5 -(4-methyl-2-oxopiperazin- 1 -yl)- 1,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamido)benzoic acid

(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido) benzoic acid

(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5-(4-methyl-2- oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinoline-l-carboxamido)benzoic acid

4-​[[[(1S)​-​2-​[(2E)​-​3-​[3-​chloro-​2-​fluoro-​6-​(1H– ​tetrazol-​1-​yl)​phenyl]​-​1-​oxo-​2-​propen-​1-​yl]​-​1,​2,​3,​4-​ tetrahydro-​5-​(4-​methyl-​2-​oxo-​1-​piperazinyl)​-​1-​isoquinolinyl]​ carbonyl]​amino]​-Benzoic acid,has cas 1430114-34-3

Benzoic acid,4-​[[[(1S)​-​2-​[(2E)​-​3-​[3-​chloro-​2-​fluoro-​6-​(1H– ​tetrazol-​1-​yl)​phenyl]​-​1-​oxo-​2-​propen-​1-​yl]​-​1,​2,​3,​4-​ tetrahydro-​5-​(4-​methyl-​2-​oxo-​1-​piperazinyl)​-​1-​isoquinolinyl]​ carbonyl]​amino]​-​, 2,​2,​2-​trifluoroacetate (1:1)  has cas 1430114-35-4

hydrochloride  ……1430115-97-1

Bristol-Myers Squibb Company innovator

Acute coronary syndrome; Thromboembolism; Unstable angina Factor XIa antagonist


WO-2014059203 describes  Crystalline forms of (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido) benzoic acid, and their use for treating thromboembolic disorders eg unstable angina or acute coronary syndrome, are claimed. This compound appears to have emerged as a lead from the factor XIa antagonists claimed in WO2013056060. This compound may be the parenteral factor XIa inhibitor or the oral factor XIa inhibitor which were being investigated by BMS. However both programs were no longer listed on the company website in February 2014. The concurrently published WO2014059202 and ‘214 claim similar compounds.


CRYSTALLINE FORMS OF A FACTOR XIA INHIBITOR (Fri, 18 Apr 2014) The instant invention provides crystalline forms of (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid and its solvates thereof; processes for the production of such crystalline forms; pharmaceutical compositions comprising such crystalline forms; and methods of treating thromboembolic disorders with such crystalline forms or such pharmaceutical compositions. >> read more;jsessionid=510CB24BFD57B0C6EA3C7FAC7EA701D3.wapp1nB?docId=WO2014059203&recNum=1&maxRec=4340&office=&prevFilter=&sortOption=&queryString=EN_ALL%3Anmr+AND+PA%3A%28Bristol-Myers+Squibb%29+&tab=PCTDescription   WO 2013/056060, which is herein incorporated by reference, discloses a factor XIa inhibitor, (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5 -(4-methyl-2-oxopiperazin- 1 -yl)- 1,2,3 ,4-tetrahydroisoquinoline- 1 -carboxamido)benzoic acid, (hereinafter referred to as “Compound (I)”):


(I) which is useful in preventing or treating thromboembolic disorders.   Compound (II) is obtained through Ugi reaction (Schuster, I. et al. {Letters in Organic Chemistry, 4(2): 102-108 (2007)). Deprotection of Compound (II) leads to Compound (I). (II)                                                                                                                         (I)



WO 2013056060

Scheme 1 :

Figure imgf000080_0001

[00223] Scheme 2 describes an alternative method to access compounds of this invention. Reaction of acid le, isocyanide 2a, and imine 2b can give Ugi product 2d (Schuster, I. et al, Letters in Organic Chemistry, 4(2): 102-108 (2007)). Selective oxidation of tetrahydroisoquinoline 2c using known methods such as Mn02 (Aoyama, T. et al, Synlett, 1 :35-36 (1998)) can yield imine 2b, which can then be used via the three component Ugi coupling procedures described above. The Ugi coupling procedures can be used extensively with other imino derived intermediates contained in this invention. Further manipulations of the Ugi derived products can afford compounds of this invention.

Scheme 2:

Figure imgf000081_0001

[00224] Scheme 3 describes methods for preparing the tetrahydroisoquinoline intermediate 3c and 3e. Method A uses Bischler-Napieralski cyclization to access compounds such as intermediate 3c (Al-Hiari, Y. M. et al, Journal of Heterocyclic Chemistry, 42(4): 647-659 (2005)) or 3e (Zalan, Z. et al, Tetrahedron, 62(12): 2883- 2891 (2006)). Method B uses the Friedel-Crafts alkylation reaction to access compounds such as intermediate 3c (Topsom, R. D. et al, Journal of the Chemical Society [Section] D: Chemical Communications, 15:799 (1971)). Alternatively, as described in Method C, cyclization of intermediate 3h and 3-aminopropanol (3i) can afford 3j. Reduction with NaBH4, followed by PCC oxidation gave β-amino aldehyde, which can be converted to 3c under basic conditions (Umetsu, K.; Asao, N., Tetrahedron Letters, 49(17): 2722-2725 (2008)). In Method D, lactam 31 can be synthesized from ketone 3k by the Beckmann rearrangement. Reduction of 31 can afford intermediates such as 3c (Vernier, J. et al, WO 2008024398 (2008)). In Method E, the dihydroisoquinoline carbaldehyde (3m) was converted to 3c under basic conditions (Martin, S. et al, WO 2006134143 (2006)). In Method F, dihydroisoquinolinethione was converted to 3c treating the thione 3o with bromopropene followed by treatment with perchloric acid and sodium borohydride (Mohinder, B, et al, Indian Journal of Chemistry, Section B: Organic Chemistry

Including Medicinal Chemistry, 18B (4); 312-15 (1979)).

Scheme 3:

Figure imgf000082_0001

[00225] Preparation of substituted THQ analogs is shown in Scheme 4. Bromide 4a can be converted to nitrile 4b under lithiation conditions. Hydrolysis under basic conditions should lead to acid 4c, which can be converted to carbamate 4e via Curtius rearrangement. Formation of the THQ intermediate 4f can then be accomplished by treatment with paraformaldehyde in a mixture of acetic and sulfuric acid (Bigge, C. F. et al, Bioorganic & Medicinal Chemistry Letters, 3(1): 39-42 (1993)). Deprotection of carbamate 4f followed by protection with B0C2O should afford intermediate 4h, which can be subjected to the Suzuki cross coupling reaction with an appropriate boronate or boronic acid or the Stille coupling procedures known to those in the art.

Scheme 4:

Isobutyronitrile, DPPA/TEA,

LiHMDS/THF, Toluene, NaH (60%), 0 °C to rt, 0 °C, 1 h, MeOH/THF, 3 h 110 °C, 4 h. 0 °C to rt, 3 h.

Figure imgf000083_0001

4a 4b 4d

Figure imgf000083_0002
Intermediate 1 : (E)-2,5-Dioxopyrrolidin-l-yl 3-(5-chloro-2-(lH-tetrazol-l- yl)phenyl)acrylate

Figure imgf000084_0001

[00231] The synthesis was described as Intermediate 1 in PCT International Application, WO 2009/1 14677 published 09/17/09. Intermediate 2: (E)-3-(5-chloro-2-tetrazol-l-yl-phenyl)-acrylic acid

Figure imgf000084_0002

[00232] The synthesis was described as Intermediate IB in PCT International Application, WO 2009/1 14677 published 09/17/09. Intermediate 3: (E)-3-(3-Chloro-2-fluoro-6-tetrazol-l-yl-phenyl)-acrylic acid 2,5-dioxo- pyrrolidin-l-yl ester

Figure imgf000084_0003

[00233] Intermediate 3A: (E)-3-(3-chloro-2-fluoro-6-(lH-tetrazol-l-yl)phenyl)acrylic acid: The synthesis of Intermediate 3A was described as Intermediate 7 in PCTInternational Application, WO 2009/1 14677 published 09/17/09. [00234] Intermediate 3 : To a slightly turbid mixture of Intermediate 3 A (1.0 g, 3.72 mmol) in THF (18.70 mL) and DMF (1.870 mL) was added l-hydroxypyrrolidine-2,5- dione (0.471 g, 4.09 mmol) and DIC (0.638 mL, 4.09 mmol). The reaction was stirred at rt and a white precipitate formed overtime. The solid was collected by suction filtration and washed with MeOH and H20. The crude product was then air-dried and finally dried under vacuum to give Intermediate 3 (0.98 g, 72%), as a white solid. ¾ NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.06 (t, J= 8.12 Hz, 1H), 7.72 (d, J= 8.80 Hz, 1H), 7.36 (d, J = 16.23 Hz, 1H), 6.81 (d, J = 16.51 Hz, 1H), 2.84 (s, 4 H) ppm. MS (ESI) m/z: 366.2 (M+H)+. Intermediate 4: (E)-3-(2-acetyl-5-chlorophenyl)acrylic acid

Figure imgf000085_0001

[00235] Intermediate 4A: (E)-tert-butyl 3-(2-acetyl-5-chlorophenyl)acrylate: To a degassed solution of l-(2-bromo-4-chlorophenyl)ethanone (1.0 g, 4.28 mmol), tributylamine (2.041 mL, 8.57 mmol), and tert-butyl acrylate (1.255 mL, 8.57 mmol) in DMF (10 mL) was added palladium on carbon (0.456 g, 0.428 mmol) and palladium (II) acetate (0.096 g, 0.428 mmol). The reaction mixture was warmed to 100 °C. After 16 h, the reaction was cooled to rt and filtered. The solid was rinsed with DMF and the filtrate was diluted with EtOAc and washed with H20 (2x) followed by brine. The crude product was then dried over a2S04, filtered and concentrated. Purification by normal phase chromatography afforded Intermediate 4A (0.760 g, 63%), as a brown oil. MS (ESI) m/z: 225.0 (M-C4H8+H)+. [00236] Intermediate 4: A solution of Intermediate 4A (0.048 g, 0.171 mmol) in 50% TFA/DCM (2 mL) was stirred at rt. After 1 h, the reaction was concentrated to give Intermediate 4 (0.038 g, 100%) as a yellow solid. The material was carried onto the next step without further purification. MS (ESI) m/z: 225.1 (M+H)+. Intermediate 5: (E)-3-(5-chloro-4-fluoro-2-(lH-tetrazol-l-yl)phenyl)acrylic acid

Figure imgf000086_0001
Example 183: (R,E)-4-(2-(3-(3-chloro-2-fluoro-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5-(4-methyl-2- oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinoline-l-carboxamido)benzoic acid, TFA salt

Figure imgf000131_0001

[00312] Example 57 (Table 7): (E)-tert-butyl 4-(2-(3-(3-chloro-2-fluoro-6-(lH- tetrazol- 1 -yl)phenyl)acryloyl)-5 -(4-methyl-2-oxopiperazin- 1 -yl)- 1,2,3,4- tetrahydroisoquinoline-l-carboxamido)benzoate: Intermediate 3A (0.320 g, 1.192 mmol) and Intermediate 22 (0.29 g, 1.192 mmol) were combined in a vial in EtOH (5mL) and after 10 min., Intermediate 6 (0.315 g, 1.550 mmol) in EtOH (3mL) was added and reaction was heated at 55 °C for 24 h. The reaction was concentrated and the residue was purified by silica gel column chromatography followed by reverse phase HPLC and freeze-dried to afford 0.339g (32.6%) of Example 57 (Table 7) as a white solid. ¾ NMR (400 MHz, MeOD) δ: 9.44 (1 H, s), 7.74 – 7.84 (2 H, m), 7.62 – 7.73 (1 H, m), 7.43 – 7.58 (3 H, m), 7.37 (1 H, dd, J= 8.72, 1.64 Hz), 7.31 (1 H, td, J= 7.83, 2.78 Hz), 7.19 (1 H, t, J= 6.82 Hz), 6.98 – 7.1 1 (1 H, m), 6.79 – 6.94 (1 H, m), 5.80 (1 H, s), 3.94 – 4.20 (3 H, m), 3.84 – 3.95 (1 H, m), 3.62 – 3.80 (3 H, m), 3.53 – 3.64 (1 H, m), 2.99 (3 H, s), 2.92 – 2.96 (1 H, m), 2.61 – 2.77 (1 H, m), 1.47 (9 H, d, J= 2.02 Hz) ppm. MS (ESI) m/z: 715.3. Analytical HPLC: RT = 6.82 min. [00313] Example 183 was prepared from Example 57 (Table 7) and isolated as the first eluting peak after chiral HPLC separation using Chiralpak AD-H, 250 X 30 mm, 5μιη, using 60/40 C02/1 : 1 EtOH-IPA-0.1% DEA at 90 mL/min, 150 bar BP, 35 °C followed by deprotection with TFA/DCM and HPLC purification to afford 96.8 mgs (25.8%) of a white solid. XH NMR (400 MHz, MeOD) δ: 9.44 (1 H, s), 7.78 – 7.95 (2 H, m), 7.69 (1 H, td, J=8.08, 2.53 Hz), 7.44 – 7.60 (3 H, m), 7.27 – 7.41 (2 H, m), 7.15 – 7.25 (1 H, m), 6.98 – 7.11 (1 H, m), 6.77 – 6.98 (1 H, m), 5.78 – 5.88 (1 H, m), 3.83 – 4.19 (4 H, m), 3.64 – 3.80 (3 H, m), 3.54 – 3.64 (1 H, m), 3.03 (3 H, s), 2.93 – 3.00 (1 H, m), 2.63 – 2.78 (1 H, m) ppm MS (ESI) m/z: 659.3 (M+H)+. Analytical HPLC: RT = 4.90 min. Example 184: (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5-(4-methyl-2- oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinoline-l-carboxamido)benzoic acid, TFA salt

Figure imgf000132_0001

[00314] Example 184 was isolated as the second eluting enantiomer from Example 57 (Table 7) and deprotected and purified as described in Example 183 to afford 104 mgs (27.7%) of a white solid. ¾ NMR (400 MHz, MeOD) δ: 9.45 (1 H, s), 7.79 – 7.92 (2 H, m), 7.64 – 7.74 (1 H, m), 7.44 – 7.62 (3 H, m), 7.27 – 7.43 (2 H, m), 7.15 – 7.24 (1 H, m), 6.97 – 7.12 (1 H, m), 6.72 – 6.90 (1 H, m), 5.77 – 5.88 (1 H, m), 3.82 – 4.17 (4 H, m), 3.53 – 3.82 (4 H, m), 2.99 – 3.03 (1 H, m), 2.98 (3 H, s), 2.60 – 2.77 (1 H, m) ppm. MS (ESI) m/z: 659.3 (M+H)+. Analytical HPLC: RT = 4.94 min.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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