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Msg  10310 of 10539  at  9/22/2022 9:39:39 AM  by

JBWIN


Building IP: BMY Patent Appl. re "PROCESS FOR PREPARING CARBAMOYLOXYMETHYL TRIAZOLE

 
United States Patent Application20220298122
Kind CodeA1
Fox; Richard J. ; et al.September 22, 2022

PROCESS FOR PREPARING CARBAMOYLOXYMETHYL TRIAZOLE CYCLOHEXYL ACID COMPOUNDS

Abstract

Improved methods and intermediates thereof for preparing carbamoyloxy methyl triazole cyclohexyl acid compounds are described. These compounds are useful as LPA antagonists. Formula (I). ##STR00001##


Inventors:Fox; Richard J.; (Yardley, PA) ; Guerrero; Carlos A.; (North Wales, PA) ; Dummeldinger; Michael; (Plainsboro, NJ) ; Skliar; Dimitri; (Staten Island, NY) ; Patel; Harshkumar; (Somerset, NJ) ; Tan; Yichen; (East Brunswick, NJ) ; George; David Thomas; (Ewing, NJ)
Applicant:
NameCityStateCountryType

BRISTOL-MYERS SQUIBB COMPANY

Princeton

NJ

US
Family ID:1000006444804
Appl. No.:17/603659
Filed:April 14, 2020
PCT Filed:April 14, 2020
PCT NO:PCT/US2020/028039
371 Date:October 14, 2021

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
62834538Apr 16, 2019

Current U.S. Class:1/1
Current CPC Class:C07C 51/12 20130101; C07C 51/29 20130101; C07D 233/60 20130101; C07D 401/04 20130101; C07C 51/09 20130101; C07D 249/04 20130101
International Class:C07D 249/04 20060101 C07D249/04; C07C 51/09 20060101 C07C051/09; C07C 51/12 20060101 C07C051/12; C07C 51/29 20060101 C07C051/29; C07D 401/04 20060101 C07D401/04; C07D 233/60 20060101 C07D233/60

Claims



1. A method of making a compound of Formula (I): ##STR00165## wherein R.sup.1 is C.sub.1-6 alkyl; and R.sup.2 and R.sup.2a are halogen; comprising contacting a compound of Formula (III): ##STR00166## wherein R.sup.1 is C.sub.1-6 alkyl; R.sup.2 is halogen; and R.sup.3 is halogen; with Reagent 2 that is an organolithium, in Solvent 2 that is a polar aprotic or nonpolar aprotic solvent, or a solvent mixture thereof; for a time and at a temperature sufficient for lithium halogen exchange; followed by an alkylating agent in Solvent 3 that is a polar, polar aprotic, or nonpolar aprotic solvent, or a solvent mixture thereof; for a time and at a temperature sufficient for alkylation; followed by a strong acid to produce the compound of Formula (I).

2. The method of claim 1, for making a compound of Formula (I), wherein: comprising contacting the compound of Formula (III), with Reagent 2 selected from n-BuLi, n-HexLi and PhLi in Solvent 2 selected from hexanes, THF, MeTHF and a solvent mixture thereof; for a time and at -30 to -10.degree. C. sufficient for lithium halogen exchange; followed by an alkylating agent selected from benzyl chloromethyl ether for a time and at -30 to -10.degree. C. sufficient for alkylation, and a strong acid selected from HBr in acetic acid, or a mixture of acetyl bromide and 2-propanol in Solvent 3 selected from THF, CH.sub.3CN, IPAc, MeTHF and a solvent mixture thereof to produce the compound of Formula (I).

3. The method claim 2, making a compound of Formula (Ia): ##STR00167## comprising contacting a compound of Formula (IIIa): ##STR00168## with n-BuLi in hexanes; for <1 hour and at -30 to -10.degree. C. sufficient for lithium halogen exchange, followed by benzyl chloromethyl ether; for 5 to 24 hours and at -30 to -10.degree. C. sufficient for alkylation and 33 wt % HBr in acetic acid in CH.sub.3CN to produce the compound of Formula (Ia).

4. A method of making a compound of Formula (IV) or a salt thereof: ##STR00169## wherein R.sup.a is --N(C.sub.1-4 alkyl).sub.2; comprising contacting a compound of Formula (V): ##STR00170## wherein R.sup.6 is halogen; with a compound of Formula (VI) or a salt thereof: ##STR00171## wherein R.sup.a is --N(C.sub.1-4 alkyl).sub.2; in presence of an inorganic base and a phase-transfer catalyst in Solvent 4 that is a polar aprotic solvent, or a solvent mixture thereof; for a time and at a temperature sufficient for reaction completion to produce the compound of Formula (IV) or a salt thereof.

5. The method of claim 4, for making a compound of Formula (IVa) or a salt thereof: ##STR00172## comprising contacting a compound of Formula (V) with a compound of Formula (VIa) or a salt thereof: ##STR00173## in presence of KHCO.sub.3 and (C.sub.1-4 alkyl).sub.4NBr, in Solvent 4 selected from DMF, CH.sub.3CN, NMP, DMAc, HMPA, DMPU, DME, THF, and a solvent mixture thereof; for a time and at 25 to 35.degree. C. sufficient for reaction completion to produce the compound of Formula (IVa) or a salt thereof.

6. A method of making a compound of Formula (IVb): ##STR00174## comprising contacting a compound of Formula (Va): ##STR00175## with a compound of Formula (VIa): ##STR00176## in presence of KHCO.sub.3 and (Et).sub.4NBr in DMF; for 4 to 72 hours and at 25 to 35.degree. C. sufficient for reaction completion to produce the compound of Formula (IVb).

7. A method of making a compound of Formula (VII), or a stereoisomer or a salt thereof: ##STR00177## wherein R.sup.a is --N(C.sub.1-4 alkyl).sub.2; comprising contacting a compound of Formula (VIII) or a salt thereof: ##STR00178## in presence of ##STR00179## and a co-catalyst selected from ##STR00180## and 4-DMAP, with or without an aqueous base, in Solvent 5 that is a nonpolar solvent, or a solvent mixture thereof; for a time and at a temperature sufficient for reaction completion to produce the compound of Formula (VII) or a stereoisomer or a salt thereof.

8. The method of claim 7, for making a compound of Formula (VIIa) or a salt thereof: ##STR00181## comprising contacting a compound of Formula (VIII) or a salt thereof; in presence of ##STR00182## with or without aqueous KOH, in Solvent 5 selected from toluene, CH.sub.2Cl.sub.2, trifluorotoluene, 1,2-dichlorobenzene, and a solvent mixture thereof; for a time and at 25 to 35.degree. C. sufficient for reaction completion to produce the compound of Formula (VIIa) or a salt thereof.

9. The method of claim 8, for making a compound of Formula (VIIb): ##STR00183## comprising contacting a compound of Formula (VIII) or a salt thereof; in presence of ##STR00184## with or without aqueous KOH, in toluene; for 24 to 48 hours and at 25 to 35.degree. C. sufficient for reaction completion to produce the compound of Formula (VIIb).

10. A method of making a compound of Formula (IX), or a stereoisomer or a salt thereof: ##STR00185## wherein R.sup.a is --N(C.sub.1-4 alkyl).sub.2; comprising contacting a compound of Formula (VII) or a salt thereof: ##STR00186## wherein R.sup.a is --N(C.sub.1-4 alkyl).sub.2; with a transition-metal catalyst in presence of a diprotic acid in Solvent 6 that is a protic or polar aprotic solvent or a solvent mixture thereof; for a time and at a temperature sufficient for ketone reduction to produce the compound of Formula (IX) or a stereoisomer or a salt thereof.

11. The method of claim 10, for making a compound of Formula (IXa) or a salt thereof: ##STR00187## comprising contacting a compound of Formula (VIIa) or a salt thereof: ##STR00188## with a transition-metal catalyst selected from IrCl.sub.4, IrCl.sub.4*hydrate or [Ir(COD)Cl].sub.2 in presence of phosphorous acid in Solvent 6 selected from IPA, MeOH, EtOH, t-AmOH, H.sub.2O, NMP, DMF, DMAc, sulfolane, and a solvent mixture thereof; for a time and at 65 to 100.degree. C. sufficient for ketone reduction to produce the compound of Formula (IXa) or a salt thereof.

12. The method of claim 11, for making a compound of Formula (IXb): ##STR00189## comprising contacting a compound of Formula (VIIb): ##STR00190## with IrCl.sub.4*hydrate or [Ir(COD)Cl].sub.2 in presence of phosphorous acid in IPA/H.sub.2O or a solvent mixture thereof; for 24 to 96 hours and at 80 to 85.degree. C. sufficient for ketone reduction to produce the compound of Formula (IXb).

13. A method of making a compound of Formula (Xa) or a salt thereof: ##STR00191## comprising (1) contacting a compound of Formula (IXa) or a salt thereof: ##STR00192## with Reagent 3 selected from NaOH, KOH, LiOH, tetraalkylammonium hydroxide, and a mixture thereof, in an aqueous R.sup.7--OH solution, wherein R.sup.7 are independently C.sub.1-6 alkyl; for up to 48 hours at 80 to 85.degree. C. sufficient for hydrolysis of all three ester moieties to produce the compound of Formula (XI); ##STR00193## wherein M is selected from a metal element selected from Li, Na, and K, and tetraalkylammonium; (2) contacting an acid in a protic solvent; and (3) contacting periodic acid in a protic solvent; for up to 48 hours at 20-25.degree. C. sufficient for oxidation to produce the compound of Formula (Xa) or a salt thereof.

14. The method of claim 13, for making a compound of Formula (Xa): ##STR00194## comprising (1) contacting a compound of Formula (IXb) or a salt thereof: ##STR00195## with NaOH in an aqueous IPA solution for at least 12 hours at 80 to 85.degree. C. sufficient to produce the compound of Formula (XIa); ##STR00196## (2) contacting aqueous HCl; and (3) contacting periodic acid in an aqueous IPA solution; for up to 48 hours at 20-25.degree. C. sufficient for oxidation to produce the compound of Formula (Xa).

15. A method of making a compound of Formula (XII), or a stereoisomer or a salt thereof: ##STR00197## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-6 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; and R.sup.11 is independently Br, Cl or I; comprising contacting a compound of Formula (XIII) or a salt thereof: ##STR00198## wherein: R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are the same as above in the Formula (XII) and R.sup.11a is halogen; with the compound of Formula (X) or a stereoisomer or a salt thereof: ##STR00199## in presence of a metal alkoxide in Solvent 7 that is a polar aprotic or nonpolar solvent, or a solvent mixture thereof; for a time and at a temperature sufficient for reaction completion to produce the compound of Formula (XII) or a stereoisomer or a salt thereof.

16. The method of claim 15, for making a compound of Formula (XIIa) or a salt thereof: ##STR00200## comprising contacting a compound of Formula (XIIIa) or a salt thereof: ##STR00201## with the compound of Formula (Xa) or a salt thereof: ##STR00202## in presence of a metal alkoxide selected from KOtBu, KHMDS, NaHMDS, and potassium amylate; in Solvent 7 selected from DMF, MTBE, DMAc, NMP, DMPU, THF, 2-MeTHF, CPME, diisopropyl ether, toluene and a solvent mixture thereof; for a time and at 20 to 35.degree. C. sufficient for reaction completion to produce the compound of Formula (XIIa) or a salt thereof.

17. The method of claim 16, for making a compound of Formula (XIIb) or a salt thereof: ##STR00203## comprising contacting a compound of Formula (XIIIb) or a salt thereof: ##STR00204## with the compound of Formula (Xa) or a salt thereof: ##STR00205## in presence of KOtBu in a DMF/MTBE mixture; for 18 to >48 hours and at 20 to 35.degree. C. sufficient for fluoride displacement to produce the compound of Formula (XIIb) or a salt thereof.

18. A method of making a compound of Formula (XIVc), or a stereoisomer or a salt thereof: ##STR00206## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-6 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; and R.sup.12 is C.sub.1-4 alkyl; comprising (1) contacting a compound of Formula (I): ##STR00207## wherein R.sup.1 is C.sub.1-6 alkyl; and R.sup.2 and R.sup.2a are halogen; with an organometallic reagent and with or without an inorganic reagent in Solvent 8 that is a polar aprotic, or nonpolar solvent, or a solvent mixture thereof; for a time and at a temperature sufficient for metal-halogen exchange; then (2) contacting a compound of Formula (XII) or a stereoisomer or a salt: ##STR00208## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-6 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; and R.sup.11 is Br or Cl; with the metal-halogen exchanged product and a Palladium catalyst in Solvent 8; for a time and at a temperature sufficient for C--C coupling; and (3) contacting a metal binding agent in Solvent 8; for a time and at a temperature sufficient for reaction quench to produce the compound of Formula (XIVc) or a stereoisomer or a salt thereof.

19. The method of claim 18, for making a compound of Formula (XIVd) or a salt thereof: ##STR00209## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-4 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; and R.sup.12 is C.sub.1-4 alkyl; comprising (1) contacting a compound of Formula (I), with the organometallic reagent that is a Grignard reagent selected from i-PrMgCl, i-PrMgCl*LiCl, and i-PrMgBr or an organolithium reagent selected from methyllithium, n-butyllithium, iso-propyllithium, sec-butyllithium, tert-butyllithium, and phenyllithium; with or without an inorganic reagent selected from ZnCl.sub.2, ZnBr.sub.2, and ZnI.sub.2 in Solvent 8 selected from THF, 2-MeTHF, DMF, DMA, DMPU, NMP, 1,4-dioxane and a solvent mixture thereof; for a time and at -5 to 25.degree. C. sufficient for metal-halogen exchange and organozinc formation; (2) contacting a compound of Formula (XIIa) or a salt: ##STR00210## with the metal-halogen exchanged product that is organometallic reagent and a Palladium catalyst selected from PdCl.sub.2(Xantphos), Pd(dppf)Cl.sub.2 or Pd(OAc).sub.2+Brettphos, BINAP, dppf, DPEPhos and xantphos in Solvent 8; for a time and at -5 to 40.degree. C. sufficient for C--C coupling; and (3) contacting a metal binding agent selected from tribasic sodium ethylenediaminetetraacetic acid or dibasic sodium ethylenediaminetetraacetic acid in Solvent 8; for a time and at -5 to 25.degree. C. sufficient for reaction quench to produce the compound of Formula (XIVd) or a salt thereof.

20. The method of claim 19, for making a compound of Formula (XIVe), isolated as either the free acid or a salt thereof selected from potassium, tetramethylammonium, tert-butylamine, dicyclohexylamine and tromethamine salt: ##STR00211## comprising (1) contacting a compound of Formula (Ia): ##STR00212## with i-PrMgCl (2.15 M in THF), with or without ZnCl.sub.2, in THF; for a time and at -5 to 25.degree. C. sufficient for metal-halogen exchange and organozinc formation (if ZnCl.sub.2 present); (2) contacting a compound of Formula (XIIb) or a salt thereof: ##STR00213## with i-PrMgCl (2.15 M in THF), with or without ZnCl.sub.2, the organomagnesium (or organozinc) Reagent and PdCl.sub.2(Xantphos) in THF; for >12 hours and at -5 to 40.degree. C. sufficient for C--C coupling; and (3) sequentially contacting tribasic sodium ethylenediaminetetraacetic acid or dibasic sodium ethylenediaminetetraacetic acid in the THF solvent mixture, with or without sodium percarbonate and sodium bisulfite (or sodium metabisulfite); for >1 hour and at -5 to 25.degree. C. sufficient for reaction quench to produce the compound of Formula (XIVe), then isolated as either the free acid or a salt thereof selected from potassium, tetramethylammonium, tert-butylamine, dicyclohexylamine and tromethamine salt.

21. A method of making a compound of Formula (XV), or a stereoisomer or a salt thereof: ##STR00214## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-6 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; and R.sup.12 is C.sub.1-4 alkyl; comprising contacting a compound of Formula (XIVc) or a stereoisomer or a salt thereof: ##STR00215## with a transition-metal catalyst and with or without an inorganic or organic acid in Solvent 9 that is a polar protic or polar aprotic solvent, or a solvent mixture thereof; for a time and at a temperature sufficient for hydrogenolysis to produce the compound of Formula (XV) or a stereoisomer or a salt thereof.

22. The method of claim 21, for making a compound of Formula (XVa) or a salt thereof: ##STR00216## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-4 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; and R.sup.12 is C.sub.1-4 alkyl; comprising contacting a compound of Formula (XIVd) or a salt thereof: ##STR00217## with a transition-metal catalyst selected from 5-20 wt % Pd/C, with or without an inorganic or organic acid selected from citric acid, oxalic acid, H.sub.2SO.sub.4 in Solvent 9 selected from EtOH, MeOH, water, THF, DMAc, NMP, IPA, t-AmOH, MeTHF, DMF, CH.sub.3CN, EtOAc, IPOAc and a solvent mixture thereof; for a time and at 20 to 60.degree. C. sufficient for hydrogenolysis to produce the compound of Formula (XVa) or a salt thereof.

23. The method of claim 22, for making a compound of Formula (XVb): ##STR00218## comprising contacting a compound of Formula (XIVe) or a salt thereof: ##STR00219## with 10 wt % Pd/C and with or without citric acid in Solvent 9 selected from EtOH, MeOH, water, THF, DMAc, NMP, and a solvent mixture thereof; for >12 hours and at 20 to 60.degree. C. sufficient for hydrogenolysis to produce the compound of Formula (XVb).

24. A method of making a compound of Formula (XVI), or a stereoisomer or a salt thereof: ##STR00220## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-6 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; R.sup.12 is C.sub.1-4 alkyl; and R.sup.14 and R.sup.14a are independently C.sub.1-6 alkyl; comprising contacting a compound of Formula (XV) or a stereoisomer or a salt thereof: ##STR00221## with a compound of Formula (XVII) or a salt thereof: ##STR00222## wherein R.sup.14 and R.sup.14a are independently C.sub.1-6 alkyl; in presence of a metal alkoxide in Solvent 9 that is a polar protic or polar aprotic solvent, or a solvent mixture thereof; for a time and at a temperature sufficient for carbamate formation to produce the compound of Formula (XVI) or a stereoisomer or a salt thereof.

25. The method of claim 24, for making a compound of Formula (XVIa) or a salt thereof: ##STR00223## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-4 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; R.sup.12 is C.sub.1-4 alkyl; and R.sup.14 and R.sup.14a are independently C.sub.1-4 alkyl; comprising contacting a compound of Formula (XVa) or a salt thereof: ##STR00224## with a compound of Formula (XVII) or a salt thereof: ##STR00225## in presence of a metal alkoxide selected from KOtBu (20 wt % in THF) or KOtBu (1 M in THF) in Solvent 9 selected from t-AmOH, DMF, THF, CH.sub.3CN, MEK, NMP, DMAc, acetone, MIBK, 2-MeTHF and a solvent mixture thereof; for a time and at 20-75.degree. C. sufficient for carbamate formation to produce the compound of Formula (XVIa) or a salt thereof.

26. The method of claim 25, for making a compound of Formula (XVIb) or a salt thereof: ##STR00226## comprising contacting a compound of Formula (XVb) or a salt thereof: ##STR00227## with a compound of Formula (XVIIa) or a salt thereof: ##STR00228## in presence of KOtBu (20 wt % in THF) in Solvent 9 selected from t-AmOH, DMF, THF, CH.sub.3CN, MEK and a solvent mixture thereof; for a time and at 20-75.degree. C. sufficient for carbamate formation to produce the compound of Formula (XVIb) or a salt thereof.

27. A compound of Formula (Ib), or a salt thereof: ##STR00229## wherein R.sup.1 is C.sub.1-6 alkyl; and R.sup.2 is halogen.

28. The compound of claim 27, wherein the compound is of Formula (Ic), or a salt thereof: ##STR00230##

29. A compound of Formula (IV) or a salt thereof: ##STR00231##

30. The compound of claim 29, wherein the compound is of Formula (IVa) or a salt thereof: ##STR00232##

31. The compound of claim 30, wherein the compound is of Formula (IVb) or a salt thereof: ##STR00233##

32. A compound of Formula (VII), or a salt thereof: ##STR00234## wherein R.sup.a is --N(C.sub.1-4 alkyl).sub.2.

33. The compound of claim 32, wherein the compound is of Formula (VIIa) or a salt thereof: ##STR00235##

34. The compound of claim 33, wherein the compound is of Formula (VIIb), or a salt thereof: ##STR00236##

35. A compound of Formula (IX) or a stereoisomer or a salt thereof: ##STR00237## wherein R.sup.a is --N(C.sub.1-4 alkyl).sub.2.

36. The compound of claim 35, wherein the compound is of Formula (IXa) or a salt thereof: ##STR00238##

37. The compound of claim 36, wherein the compound is of Formula (IXb) or a salt thereof: ##STR00239##

38. A compound of Formula (XII) or a stereoisomer or a salt thereof: ##STR00240## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-6 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; and R.sup.11 is independently Br, Cl or I.

39. The compound of claim 38, wherein the compound is of Formula (XIIa) or a salt thereof: ##STR00241## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-4 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; and R.sup.11 is independently Br, Cl or I.

40. The compound of claim 39, wherein the compound is of Formula (XIIb) or a salt thereof: ##STR00242##

41. A compound of Formula (XIV) or a stereoisomer or a salt thereof: ##STR00243## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-6 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; R.sup.12 is C.sub.1-4 alkyl; and R.sup.13 is independently H, C.sub.1-4 alkyl or benzyl.

42. The compound of claim 41, wherein the compound is of Formula (XIVa) or a salt thereof: ##STR00244## wherein: R.sup.8 and R.sup.9 are independently N, CH or C(C.sub.1-4 alkyl); R.sup.10 is independently C.sub.1-4 alkyl or halogen; R.sup.12 is C.sub.1-4 alkyl; and R.sup.13 is independently H, C.sub.1-4 alkyl or benzyl.

43. The compound of claim 42, wherein the compound is of Formula (XIVb) or a salt thereof: ##STR00245## wherein: R.sup.13 is independently H or benzyl.

44. A compound of Formula (XVIIa): ##STR00246##

45. A method of making a compound of Formula (XVII), or a salt thereof: ##STR00247## wherein R.sup.14 and R.sup.14a are independently C.sub.1-6 alkyl; comprising contacting a compound of Formula (XVIII): ##STR00248## with NHR.sup.14R.sup.14a in presence of Solvent 10 that is a polar protic, aprotic, or nonpolar solvent or a solvent mixture thereof; for a time and at -5 to 25.degree. C. sufficient for carboxamide formation to produce the compound of Formula (XVII).

46. The method of claim 45, for making a compound of Formula (XVIIa): ##STR00249## comprising contacting a compound of Formula (XVIII): ##STR00250## with N-methylpropylamine, in presence of Solvent 10 selected from DCM, t-AmOH, water, MTBE, acetonitrile, THF, MeTHF, acetone, MEK, MIBK, MeOAc, EtOAc, IPAc, DMF, NMP, DMAc, and a solvent mixture thereof; for at least 1 hour and at -5 to 25.degree. C. sufficient for carboxamide formation; followed by adding (HO.sub.2C).sub.2 to produce the compound of Formula (XVIIa).

47. The method of claim 46, for making a compound of Formula (XVIIa); comprising contacting a compound of Formula (XVIII); with N-methylpropylamine in presence of Solvent 10 selected from DCM, t-AmOH, water, MTBE, acetonitrile, and a solvent mixture thereof; for at least 1 hour and at -5 to 25.degree. C. sufficient for carboxamide formation; followed by adding (HO.sub.2C).sub.2 to produce the compound of Formula (XVIIa).

48. A method of making a compound of Formula (Xa) or a salt thereof: ##STR00251## comprising (1) contacting a compound of Formula (XIX) or a salt thereof: ##STR00252## with an ene reductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic cosolvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof; for a time and at a temperature sufficient to produce the compound of Formula (XX); ##STR00253## followed by (2) addition of a keto reductase biocatalyst with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof; for additional time and at a temperature sufficient to produce the compound of Formula (Xa) or a salt thereof.

49. A method of making a compound of Formula (Xa) or a salt thereof: ##STR00254## comprising contacting a compound of Formula (XIX) or a salt thereof: ##STR00255## with a combination of an ene reductase biocatalyst with a keto reductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof; for a time and at a temperature sufficient to produce the compound of Formula (Xa) or a salt thereof.

50. A method of making a compound of Formula (Xa) or a salt thereof: ##STR00256## comprising (1) contacting a compound of Formula (XXI) thereof: ##STR00257## with a sulfonyl chloride reagent in an aprotic polar solvent and an inorganic or organic base; for a time and at a temperature sufficient for O-sulfonylation to produce the compound of Formula (XXII); ##STR00258## (2) either (a) contacting the compound of Formula (XXII) with a transition-metal catalyst, a phosphine ligand and an organic or inorganic base in the presence of (C.sub.1-4 alkyl)-OH purged with carbon monoxide; for a time, at a temperature and pressure sufficient for carbonylation to produce the compound of Formula (XXIII); ##STR00259## then followed by contacting a compound of Formula (XXIII) with an aqueous base to produce a compound of Formula (XIX) or a salt thereof: ##STR00260## or (b) contacting the compound of Formula (XXII) with a transition-metal catalyst, a phosphine ligand in presence of an inorganic or organic base, in water and another polar aprotic solvent; purged with carbon monoxide; for a time, at a temperature and pressure sufficient for carbonylation to produce the compound of Formula (XIX) or a salt thereof; (3) contacting the compound of Formula (XIX) or a salt thereof with an ene reductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic cosolvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof; for a time and at a temperature sufficient to produce the compound of Formula (XX); ##STR00261## followed by (4) addition of a keto reductase biocatalyst with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof; for additional time and at a temperature sufficient to produce the compound of Formula (Xa) or a salt thereof.

51. A method of making a compound of Formula (Xa) or a salt thereof: ##STR00262## comprising (1) contacting a compound of Formula (XXI) thereof: ##STR00263## with a sulfonyl chloride reagent in an aprotic polar solvent and an inorganic or organic base; for a time and at a temperature sufficient for O-sulfonylation to produce the compound of Formula (XXII); ##STR00264## (2) either (a) contacting the compound of Formula (XXII) with a transition-metal catalyst, a phosphine ligand and an organic amine base in the presence of (C.sub.1-4 alkyl)-OH purged with carbon monoxide; for a time, at a temperature and pressure sufficient for carbonylation to produce the compound of Formula (XXIII); ##STR00265## then followed by contacting a compound of Formula (XXIII) with an aqueous base to produce a compound of Formula (XIX) or a salt thereof: ##STR00266## or (b) contacting the compound of Formula (XXII) with a transition-metal catalyst, a phosphine ligand in presence of an inorganic or organic base, in water and another polar aprotic solvent; purged with carbon monoxide; for a time and at a temperature and carbon monoxide pressure sufficient for carbonylation to produce the compound of Formula (XIX) or a salt thereof; (3) contacting a compound of Formula (XIX) or a salt thereof, with a combination of an ene reductase biocatalyst with a keto reductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof; for a time and at a temperature sufficient to produce the compound of Formula (Xa) or a salt thereof.
Description



CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the priority benefit of U.S. Provisional Application No. 62/834,538, filed Apr. 16, 2019; the content of which is herein incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The present invention relates to improved methods for preparing carbamoyloxymethyl triazole cyclohexyl acid compounds and novel intermediates thereof.

BACKGROUND

[0003] Carbamoyloxymethyl triazole cyclohexyl acid LPA (especially LPAi) antagonists that are useful for the treatment of fibrosis have been described. See, e.g., WO2017/223016 (US 2017/0360759). Improved methods of making carbamoyloxymethyl triazole cyclohexyl acid compounds, which provide practical, large-scale synthesis, and improved production quality, efficiency and safety, are needed.

SUMMARY

[0004] The present invention provides novel processes, and novel intermediates thereof, for making carbamoyloxymethyl triazole cyclohexyl acid compounds.

[0005] Also described are methods of making intermediate compounds, stereoisomers and salts thereof.


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