(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- 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

http://patentscope.wipo.int/search/en/detail.jsf;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   http://www.google.com/patents/WO2013056060A1?cl=en

Scheme 1 :

[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:

[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:

[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.

4a 4b 4d

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

[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

[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

[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

[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

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

[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

[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.