PROCESSES FOR THE PREPARATION OF PYRIMIDINYLCYCLOPENTANE COMPOUNDS

• US 20160297773A1
• Filed: 11/13/2014
• Published: 10/13/2016
• Est. Priority Date: 11/15/2013
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: IDING, Hans, REENTS, Reinhard, SCALONE, Michelangelo, GOSSELIN, Francis
• Granted Patent: US 9,862,689 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 269/06 by reactions not involving the formation of carbamate groups
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07D 239/70 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C12P 17/165 Heterorings having nitrogen atoms as the only ring heteroatoms
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a process for the preparation of a compound of formula (I), wherein R¹ is as defined herein, which is useful as an intermediate in the preparation of active pharmaceutical compounds.

Claims

1. A process for the preparation of a compound of formula (I)

2. The process according to claim 1, wherein R¹ is tert-butoxycarbonyl (BOC).

3. The process according to any of claim 1 or 2, wherein R² is tert-butoxycarbonyl (BOC).

4. The process according to any of claims 1 to 3, wherein M is an alkali metal ion.

5. The process according to any of claims 1 to 4, wherein M is Na⁺.

6. The process according to any of claims 1 to 5, comprising the following reaction steps:

a) Deprotection of the compound of formula (III) in a solvent under acidic conditions;

b) adjustment to an alkaline pH using a base;

c) Addition of a solution comprising the compound of formula (II) in a solvent;

d) Addition of a solution comprising a coupling agent in a solvent.

7. The process according to any of claims 1 to 6, wherein the deprotection in step a) is performed using hydrochloric acid.

8. The process according to any of claims 1 to 7, wherein the solvent used for deprotection in step a) is selected from n-propanol or isopropanol.

9. The process according to any of claims 1 to 8, wherein the base in step b) is selected from N-ethyl morpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), diisopropylethylamine (DIPEA), pyridine and lutidine.

10. The process according to any of claims 1 to 9, wherein the base in step b) is N-ethyl morpholine (NEM).

11. The process according to any of claims 1 to 10, wherein the solvent in step c) is selected from n-propanol or isopropanol.

12. The process according to any of claims 1 to 11, wherein the coupling agent used in step d) is propylphosphonic anhydride (T3P).

13. The process according to any of claims 1 to 12, wherein the solvent used in step d) is a mixture of n-propanol and toluene.

14. The process according to any of claims 1 to 13, wherein after step d) the product is worked up by aqueous extraction.

15. The process according to any of claims 1 to 14, further comprising a process for the manufacture of compounds of formula (II)

16. A process for the manufacture of compounds of formula (II)

17. The process according to claim 15 or 16, wherein the metal complex catalyst (C) is a ruthenium complex catalyst selected from a compound of formula (C1), (C2) or (C3):

Ru(Z)₂D 

 

(C1)

[Ru(Z)_2-p(D)(L)_m](Y)_p 

 

(C2)

Ru(E)(E′

)(D)(F) 

 

(C3)

wherein;

D is a chiral phosphine ligand;

L is a neutral ligand selected from C_2-7alkene, cyclooctene, 1,3-hexadiene, norbornadiene, 1,5-cyclooctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene, p-cymene, tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene and methanol;

Z is an anionic ligand selected from hydride, fluoride, chloride, bromide, η

⁵-2,4-pentadienyl, η

⁵-2,4-dimethyl-pentadienyl or the group A-COO⁻

, with the proviso that when two Z are attached to the Ru atom they can either be the same or different;

A is C_1-7 alkyl, C_1-7 haloalkyl, aryl, or haloaryl;

Y is a non-coordinating anion selected from fluoride, chloride, bromide, BF₄⁻

, ClO₄⁻

, SbF₆⁻

, PF₆⁻

, B(phenyl)₄, B(3,5-di-trifluoromethyl-phenyl)₄⁻

, CF₃SO₃—

, and C₆H₅SO₃⁻

;

F is an optionally chiral diamine;

E and E′

are both halogen ions, or E is hydride and E′

is BH₄⁻

;

m is 1, 2, 3 or 4; and

p is 1 or 2.

18. The process according to any of claims 15 to 17, wherein the ruthenium complex catalysts is Ru(Z)₂D, wherein Z and D are as defined in claim 17.

19. The process according to any of claims 15 to 18, wherein the anionic ligand (Z) is independently selected from chloride, bromide, iodide, OAc, and TFA.

20. The process according to any of claims 15 to 19, wherein the anionic ligand (Z) is trifluoroacetate (TFA).

21. The process according to any of claims 15 to 17, wherein the neutral ligand (L) is independently selected from benzene (C₆H₆), p-cymene (pCym), and acetonitrile (AN).

22. The process according to any of claims 15 to 17, wherein the neutral ligand (L) is benzene (C₆H₆).

23. The process according to any of claims 15 to 17, wherein the non-coordinating anion (Y) is selected from chloride, bromide, iodide and BF₄⁻

.

24. The process according to any of claims 15 to 17, wherein the non-coordinating anion (Y) is BF₄⁻

.

25. The process according to any of claims 15 to 17, wherein m is 1 or 4.

26. The process according to any of claims 15 to 17, wherein E and E′

are both chloride;

27. The process according to any of claims 15 to 17, wherein the chiral diamine F is (1S,2S)-1,2-diphenylethylenediamine (S,S-DPEN).

28. The process according to any of claims 15 to 17, wherein the chiral phosphine ligand D is selected from a compound of formula (D1) to (D12):

29. The process according to any of claims 15 to 17, wherein the chiral phosphine ligand (D) is selected from the compound of formula (D1), wherein R¹¹ to R¹⁵ are as described in claim 28.

30. The process according to any of claims 15 to 17 and 28 to 29, wherein the chiral phosphine ligand (D) is selected from (R)-3,5-Xyl-BINAP, (R)-BINAP, (S)-2-Furyl-MeOBIPHEP, (S)-BINAP, (S)-BIPHEMP, (S)-MeOBIPHEP, (S)-pTol-BINAP), (S)-TMBTP and (S,S)-iPr-DUPHOS.

31. The process according to any of claims 15 to 17 and 28 to 30, wherein the chiral phosphine ligand (D) is selected from (S)-BIPHEMP, (S)-BINAP, and (S)-MeOBIPHEP.

32. The process according to any of claims 15 to 17 and 28 to 31, wherein the chiral phosphine ligand (D) is (S)-BINAP.

33. The process according to any of claims 15 to 17, wherein the ruthenium complex catalyst is selected from the group of:

Ru(TFA)₂((R)-3,5-Xyl-BINAP),

Ru(OAc)₂((S)-2-Furyl-MeOBIPHEP),

Ru(OAc)₂((S)-BINAP),

[Ru(OAc)₂((S)-BINAP)]AlCl₃,

Ru(TFA)₂((S)-BINAP),

Ru(TFA)₂((S)-BINAPHANE),

Ru(TFA)₂((S)-BIPHEMP),

Ru(OAc)₂((S)-MeOBIPHEP),

Ru(TFA)₂((S)-TMBTP),

Ru(TFA)₂((S,S)-iPr-DUPHOS),

[Ru((R)-BINAP)(pCym)(AN)](BF₄)₂,

[RuBr((S)-BINAP)(C₆H₆)]Br,

[RuCl((S)-BINAP)(C₆H₆)]BF₄,

[RuI((S)-BINAP)(C₆H₆)]I,

[Ru((S)-BINAP)(AN))₄](BF₄)₂, and

RuCl₂((S)-pTol-BINAP)(S,S-DPEN).

34. The process according to any of claims 15 to 17, wherein the ruthenium complex catalyst is Ru(TFA)₂((S)-BINAP).

35. The process according to any of claims 15 to 34, wherein the asymmetric hydrogenation of a compound of formula (IV) is carried out in a solvent selected from alcohols, hydrocarbons, chlorinated hydrocarbons, fluorinated and polyfluorinated aliphatic or aromatic hydrocarbons, supercritical or liquid carbon dioxide, THF, water or mixtures thereof.

36. The process according to any of claims 15 to 35, wherein the asymmetric hydrogenation of a compound of formula (IV) is carried out in a solvent selected from the list of MeOH, EtOH, i-PrOH, EtOH/cyclopentyl methyl ether, EtOH/CH₂Cl₂, EtOH/EtOAc, EtOH/THF, EtOH/H₂O, CH₂Cl₂ and THF.

37. The process according to any of claims 15 to 36, wherein the asymmetric hydrogenation of a compound of formula (IV) is carried out in ethanol (EtOH).

38. The process according to any of claims 15 to 37, wherein the asymmetric hydrogenation of a compound of formula (IV) further comprises one or more additives selected from the list of LiBF₄, LiPF₆, LiO₃SCF₃, NaCl, NaBr, NaI, KCl, KBr, KI, LiCL, LiBr, LiI, HBF₄, HCl, HBr, H₂SO₄, and CH₃SO₃H.

39. The process according to any of claims 15 to 38, wherein the asymmetric hydrogenation of a compound of formula (IV) is carried out under hydrogen pressure of 1 to 150 bar.

40. The process according to any of claims 15 to 39, wherein the asymmetric hydrogenation of a compound of formula (IV) is carried out under hydrogen pressure of 10 to 30 bar.

41. The process according to any of claims 15 to 40, wherein the asymmetric hydrogenation of a compound of formula (IV) is carried out at a substrate/catalyst ratio (S/C) of 5 to 100'"'"'000.

42. The process according to any of claims 15 to 41, wherein the asymmetric hydrogenation of a compound of formula (IV) is carried out at a substrate/catalyst ratio (S/C) of 100 to 15'"'"'000.

43. The process according to any of claims 15 to 42, followed by forming a salt by adding to the hydrogenation reaction mixture an alcoholic solution of a metal alkoxide of formula C_1-7 alkyl-OM, wherein R¹ and M are as defined in claims 1 to 4.

44. The process according to any of claim 43, wherein the metal alkoxide employed in the salt forming step is MeOM, EtOM, iPrOM, nPrOM, nBuOM, iBuOM or tBuOM.

45. The process according to any of claim 43 or 44, wherein the metal alkoxide employed in the salt forming step is EtOM.

46. The process according to any of claims 43 to 45, wherein the alcohol used as solvent in the salt forming step is C_1-7 alkyl-OH, more particularly MeOH, EtOH, iPrOH, nPrOH, nBuOH, iBuOH or tBuOH

47. The process according to any of claims 43 to 46, wherein the alcohol used as solvent in the salt forming step is EtOH.

48. The process according to any of claims 1 to 14, further comprising a process for the manufacture of compounds of formula (III)

49. A process for the manufacture of compounds of formula (III)

50. The process according to any of claim 48 or 49, wherein the oxidoreductase catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) with a diastereoselectivity of at least 95% diastereomeric excess (de).

51. The process according to any of claims 48 to 50, wherein the oxidoreductase catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) with a diastereoselectivity of at least at least 98% de.

52. The process according to any of claims 48 to 51, wherein the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is catalyzed by an oxidoreductase in the presence of a cofactor.

53. The process according to any of claim 52, the cofactor which is oxidized in the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is NADH or NADPH.

54. The process according to any of claims 52 to 53, wherein the cofactor is in situ regenerated by enzyme-coupled cofactor regeneration using glucose and glucose dehydrogenase as cosubstrate.

55. The process according to any of claims 52 to 53, wherein the cofactor is in situ regenerated by substrate-coupled cofactor regeneration using a secondary alcohol as cosubstrate.

56. The process according to claim 55, wherein the secondary alcohol as cosubstrate for the substrate coupled regeneration is selected from 2-propanol, 2-butanol, butan-1.4-diol, 2-pentanol, pentan-1,5-diol, 4-methyl-2-pentanol, 2-hexanol, hexan-1,5-diol, 2-heptanol, or 2-octanol.

57. The process according to any of claims 55 to 56, wherein the secondary alcohol as cosubstrate for the substrate-coupled cofactor regeneration is 2-propanol.

58. The process according to any of claims 48 to 57, wherein the oxidoreductase is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-NADPH-111, KRED-NADPH-112, KRED-NADPH-113, KRED-NADPH-114, KRED-NADPH-115, KRED-NADPH-121, KRED-NADPH-123, KRED-NADPH-145, KRED-NADPH-155, A231, KRED-NADPH-136, KRED-X1, KRED-X2, KRED-X1-P1B06, KRED-X1.1-P1F01, KRED-X1.1-P1H10, KRED-X1.1-P1G11, KRED-X1.1-P1C04, KRED-X1.1-P1C11, and KRED-X1.1-P1C08.

59. The process according to any of claims 48 to 58, wherein the oxidoreductase is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-X1, KRED-X2, KRED-X1-P1B06, KRED-X1.1-P1F01, KRED-X1.1-P1H10, KRED-X1.1-P1G11, KRED-X1.1-P1C04, KRED-X1.1-P1C11, and KRED-X1.1-P1C08.

60. The process according to any of claims 48 to 59, wherein the oxidoreductase is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-X1, KRED-X2, KRED-X1-P1B06, KRED-X1.1-P1C04 and KRED-X1.1-P1F01.

61. The process according to any of claims 48 to 60, wherein the oxidoreductase is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-X1.1-P1C04 and KRED-X1.1-P1F01.

62. The process according to any of claims 48 to 61, wherein the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is performed in an aqueous medium in the presence of one or more organic cosolvents.

63. The process according to claim 62, wherein the organic cosolvents are present in a total concentration from 1 to 50% V.

64. The process according to claim 62, the organic cosolvents are present in a total concentration from 5 to 30% V.

65. The process according to any of claims 48 to 64, wherein the organic cosolvents are selected from the list of glycerol, 2-propanol, diethylether, tert-butylmethylether, diisopropylether, dibutylether, methyl tetrahydrofurane, ethylacetate, butylacetat, toluene, heptane, hexane, cyclohexene and mixtures thereof.

66. The process according to any of claims 48 to 65, wherein the organic cosolvent is 2-propanol.

67. The process according to any of claims 48 to 61, wherein the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is performed in an aqueous buffer.

68. The process according to any of claim 67, wherein the buffer is 2-(N-morpholino)ethanesulfonic acid (MES) or potassium dihydrogen phosphate (PBS).

69. The process according to any of claims 50 to 68, followed by work up by extraction or by filtration.

70. The process according to any of claims 1 to 14, further comprising the process for the manufacture of compounds of formula (VI)

71. The process according to claim 70, comprising the following reaction steps:

i) Deprotection of the compound of formula (I) in a solvent under acidic conditions;

ii) Adjustment of the pH using a base in a solvent;

iii) Optionally crystallizing the compound of formula (VI).

72. The process according to any of claim 70 or 71, wherein the deprotection in step i) is performed using hydrochloric acid, sulfuric acid, trifluoro acetic acid or hydrobromic acid.

73. The process according to any of claims 70 to 72, wherein the deprotection in step i) is performed using hydrochloric acid.

74. The process according to any of claims 70 to 73, wherein the solvent used for deprotection in step i) is selected from n-propanol, isopropanol and a 1:

1 mixture of n-propanol/water.

75. The process according to any of claims 70 to 74, wherein the base in step ii) is NaOH or ammonia.

76. The process according to any of claims 70 to 75, wherein the solvent in step ii) is selected from n-propanol, isopropanol and a 1:

1 mixture of n-propanol/water.

77. The process according to any of claims 70 to 76, wherein the crystallization in step iii) is performed by a solvent switch to a crystallization solvent suitable for crystallization of the compound of formula (VI).

78. The process according to claim 77, wherein the crystallization solvent in step iii) is selected from toluene, heptane, tetrahydrofuran, 2-propanone, 2-butanone, ethylene glycol dimethyl ether, ethyl acetate, butyl acetate, isopropyl acetate and mixtures thereof.

79. The process according to claim 77, wherein the crystallization solvent in step iii) is ethyl acetate.

80. Compounds obtainable by a process according to any of claims 1 to 79.

81. Pharmaceutical compositions comprising compounds obtainable by a process according to any of claims 1 to 79.

82. A compound of formula (II)

83. The compound of formula (II) according to claim 82 which is sodium (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate.

84. A compound of formula (VI) according to claim 70 comprising between 1 ppb and 100 ppm of the compound of formula (I), wherein R¹ is as defined in any of claim 1 or 2.

85. A compound of formula (VI) according to claim 70 comprising between 1 ppb and 1 ppm of the compound of formula (I), wherein R¹ is as defined in any of claim 1 or 2.

86. A pharmaceutical composition comprising compounds of formula (VI) according to any of claim 84 or 85.

87. A compound of formula (I) according to claim 1 comprising between 1 ppb and 100 ppm of the compound of formula (II), wherein R¹ and M are as defined in any of claims 1 to 5.

88. A compound of formula (I) according to claim 1 comprising between 1 ppb and 1 ppm of the compound of formula (II), wherein R¹ and M are as defined in any of claims 1 to 5.

89. A compound of formula (I) according to claim 1 comprising between 1 ppb and 100 ppm of the compound of formula (III), wherein R¹ and R² are as defined in any of claims 1 to 3.

90. A compound of formula (I) according to claim 1 comprising between 1 ppb and 1 ppm of the compound of formula (III), wherein R¹ and R² are as defined in any of claims 1 to 3.

91. A compound of formula (I) according to claim 1 comprising between 1 ppb and 100 ppm of the compound of formula (II) and between 1 ppb and 100 ppm of the compound of formula (III), wherein R¹, R² and M are as defined in any of claims 1 to 5.

92. A compound of formula (I) according to claim 1 comprising between 1 ppb and 1 ppm of the compound of formula (II) and between 1 ppb and 1 ppm of the compound of formula (III), wherein R¹, R² and M are as defined in any of claims 1 to 5.

93. The invention as described herein before.