Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof

Patent metadata

Field	Value
Publication number	US-2019284231-A1
Application number	US-201916433862-A
Country	US
Kind code	A1
Filing date	Jun 6, 2019
Priority date	May 21, 2015
Publication date	Sep 19, 2019
Grant date	—

Abstract

The present invention relates to an improved process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of amorphous form of carfilzomib.

First claim

1 - 48 . (canceled)

49 : A process for preparation of tert-butyl ((2S)-4-methyl-1-((2R)-2-methyloxirane-2-yl)-1-oxo-pentan-2-yl)-carbamate of Formula XVI,

comprising:
i) reacting a compound of Formula XVII with alkyl magnesium halide to obtain a compound of Formula XVIII,

ii) crystallizing the compound of Formula XVIII from a first solvent system to obtain a crystalline compound of Formula XVIII;
iii) reducing the crystalline compound of Formula XVIII in the presence of a reducing agent to obtain a diastereomeric mixture of a compound of Formula XIXa and a compound of Formula XIXb,

iv) crystallizing the mixture obtained in step iii) from a second solvent system to obtain a mixture of a crystalline compound of Formula XIXa and a crystalline compound of Formula XIXb;
v) epoxidating and then oxidizing the mixture obtained in step iv) to obtain a diastereomeric mixture of a compound of Formula XVI and a compound of Formula XVIa,

vi) separating the compound of Formula XVI from the diastereomeric mixture obtained in step v) by chromatography; and
vii) crystallizing the compound of Formula XVI obtained in step vi) from a third solvent system to obtain a crystalline compound of Formula XVI.

50 : The process of claim 49 , wherein the alkyl magnesium halide is isopropenyl magnesium bromide.

51 : The process of claim 49 , wherein the step ii) further comprises:
a) providing a solution of the compound of Formula XVIII in the first solvent; b) optionally cooling the step a) solution to less than 20° C.; c) adding an anti-solvent to the step b) solution to form a mixture; and d) isolating from the mixture obtained in step c) the crystalline compound of Formula XVIII.

52 : The process of claim 51 , wherein the first solvent is selected from the group consisting of alcohols selected from one of methanol, ethanol, propanol and isopropanol; ketones selected from one of acetone, methyl isobutyl ketone and methyl ethyl ketone; esters selected from one of methyl acetate, ethyl acetate and isopropyl acetate; nitriles selected from one of acetonitrile and propionitrile; and mixtures thereof.

53 : The process of claim 51 , wherein the anti-solvent is selected from the group consisting of aliphatic hydrocarbons selected from one of n-hexane, n-heptane and n-pentane; cyclic hydrocarbons selected from one of cyclopentane and cyclohexane; ethers selected from one of methyl tertiary butyl ether and diethyl ether; water; and mixtures thereof.

54 . (canceled)

55 : The process of claim 49 , wherein the reducing agent is a mixture of sodium borohydride and cerium trichloride.

56 : The process of claim 49 , wherein the step iv) further comprises:
a) providing a solution of a diastereomeric mixture of the compound of Formula XIXa and Formula XIXb in the second solvent; b) cooling the solution obtained in step a) to less than 10° C.; c) adding an anti-solvent to the solution of step b); and d) isolating from the mixture obtained in step c) the mixture of crystalline compound of Formula XIXa and Formula XIXb.

57 : The process of claim 56 , wherein the second solvent is selected from the group consisting of alcohols selected from one of methanol, ethanol, propanol and isopropanol; ketones selected from one of acetone, methyl isobutyl ketone and methyl ethyl ketone; esters selected from one of methyl acetate, ethyl acetate and isopropyl acetate; nitriles selected from one of acetonitrile and propionitrile; and mixtures thereof.

58 : The process of claim 56 , wherein the anti-solvent is selected from the group consisting of aliphatic hydrocarbons selected from one of n-hexane, n-heptane and n-pentane; cyclic hydrocarbons selected from one of cyclopentane and cyclohexane; ethers selected from one of methyl tertiary butyl ether and diethyl ether; water; and mixtures thereof.

59 : The process of claim 56 , wherein the second solvent is methanol and the anti-solvent is water.

60 : The process of claim 49 , wherein the step vii) further comprises:
a) providing a solution of the compound of Formula XVI in the third solvent; b) cooling the solution obtained in step a) to less than 5° C.; c) optionally adding a seed compound of Formula XVI to the solution of step b); and d) isolating from the solution of step b) or step c) the compound of Formula XVI.

61 : The process of claim 60 , wherein the third solvent system of step a) is selected from the group consisting of aliphatic hydrocarbons selected from one of n-hexane, n-heptane and n-pentane; cyclic hydrocarbons selected from one of cyclopentane and cyclohexane; ethers selected from one of methyl tertiary butyl ether and diethyl ether; and mixtures thereof.

62 - 76 . (canceled)

77 : The process of claim 49 , further comprising:
viii) converting the crystalline compound of Formula XVI into carfilzomib of Formula I or a pharmaceutically acceptable salt thereof.

Assignees

• Laurus Labs Ltd

Inventors

• Dehury Sanjay Kumar
• Mekala Nagaraju
• Shaik Jahangeer Baba
• Buddepu Srinivasa Rao
• Kola Lakshmi Kanth
• Indukuri Venkata Sunil Kumar
• Gorantla Seeta Rama Anjaneyulu
• Chava Satyanarayana

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D303/32

  by aldehydo- or ketonic radicals · CPC title

• C07D303/36

  with hydrocarbon radicals, substituted by nitrogen atoms (nitro, nitroso radicals C07D303/08) · CPC title

• C07C271/16

  to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms · CPC title