Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof

Patent metadata

Field	Value
Publication number	US-10364269-B2
Application number	US-201615573912-A
Country	US
Kind code	B2
Filing date	May 21, 2016
Priority date	May 21, 2015
Publication date	Jul 30, 2019
Grant date	Jul 30, 2019

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

We claim:

1. An improved process for the preparation of carfilzomib of Formula I or a pharmaceutically acceptable salt thereof,

comprising:
a) reacting a compound of Formula II with a compound of Formula III or a salt thereof in the presence of a coupling agent (C1), an additive (A1) and a base (B1) in a solvent (S1) to obtain a compound of Formula IV,

b) reacting the compound of Formula IV with a suitable acid to obtain a compound of Formula V or a salt thereof,

c) reacting the compound of Formula V or a salt thereof with a compound of Formula VI in presence of a coupling agent (C2), an additive (A2) and a base (B2) in a solvent (S2) to obtain a compound of Formula VII,

d) deprotecting the compound of Formula VII in presence of a deprotecting agent to obtain a compound of Formula VIII,

e) reacting the compound of Formula VIII with a compound of Formula IX or a salt thereof in the presence of a coupling agent (C3), an additive (A3) and a base (B3) in a solvent (S3) to obtain a compound of Formula X,

f) reacting the compound of Formula X with a acid to obtain a compound of Formula XI or a salt thereof,

 and
g) reacting the compound of Formula XI or a salt thereof with a compound of Formula XII or a salt thereof in presence of a coupling agent (C4), an additive (A4) and a base (B4) in a suitable solvent (S4) to obtain carfilzomib or a pharmaceutically acceptable salt thereof,

wherein the amount of the coupling agent (C1), (C2), (C3) and (C4) used is about 0.9 to about 1.3 w/w mole equivalents per mole of Formula III, Formula IV, Formula VIII and Formula X respectively and
wherein the amount of the additive (A1), (A2), (A3) and (A4) used is about 0.05 to about 0.5 w/w mole equivalents per mole of Formula III, Formula IV, Formula VIII and Formula X respectively.

2. The process of claim 1 , wherein the amount of D-isomers and isoleucine compounds corresponding to each of the compounds of Formula II, Formula III, Formula VI and Formula IX is less than 0.1% measured by HPLC.

3. The process of claim 2 , wherein the compound of Formula II includes less than 0.1% measured by HPLC of its corresponding D-isomer and isoleucine of Formula A and Formula B,

4. The process of claim 2 , wherein the compound of Formula III includes less than 0.1% measured by HPLC of its corresponding D-isomer of Formula C,

5. The process of claim 1 , wherein each of the coupling agents (C1), (C2), (C3) and (C4) is selected from the group consisting of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate, bromo-tripyrrolidino-phosphonium hexafluorophosphate, Propylphosphonic anhydride, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, 1,1′-Carbonyldiimidazole, diisopropylcarbodiimide, dicyclohexyl carbodiimide, and mixtures thereof.

6. The process of claim 1 , wherein each of the additives (A1), (A2), (A3) and (A4) is selected from the group consisting of 1-Hydroxybenzotriazole, 1-Hydroxy-7-aza-1H-benzotriazole, 2-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminium tetrafluoroborate/hexafluoro phosphate, 2-(7-Aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminium hexafluorophosphate), and mixture thereof.

7. The process of claim 1 , wherein each of the bases (B1), (B2), (B3) and (B4) is is selected from the group consisting of diisopropylethyl amine, Imidazole or its salts, 1,8-Diazabicyclo[5.4.0]undec-7-en, tertiary amines or its hydro halide salts thereof.

8. The process of claim 1 , wherein each of the solvents (S1), (S2), (S3) and (S4) is selected from the group consisting of ethers selected from one of tetrahydrofuran and 2-methyltetrahydrofuran; esters selected from one of methyl acetate, ethyl acetate, propyl acetate, and butyl acetate; halogenated hydrocarbons selected from one of methylene chloride, ethylene chloride and chloroform; amides selected from one of dimethyl formamide, dimethyl acetamide and N-methyl pyrrolidinone; aromatic solvents selected from one of toluene, xylene, and chlorobenzene; nitriles selected from one of acetonitrile, propionitrile and benzonitrile; and mixtures thereof.

9. The process of claim 1 , wherein the step a) is carried out using about 1.2 w/w mole equivalents of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate per mole of Formula III as coupling agent (C1), about 0.1 w/w mole equivalents of 1-hydroxybenzotriazole per mole of Formula III as an additive (A1) in presence of diisopropylethyl amine as base in dimethyl formamide.

10. The process of claim 1 , wherein the acid of step b) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid, and mixture thereof.

11. The process of claim 1 , wherein the step b) is carried out in an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, and mixture thereof.

12. The process of claim 1 , wherein the step b) is carried out using trifluoro acetic acid in methylene chloride.

13. The process of claim 2 , wherein the compound of Formula VI includes less than 0.1% measured by HPLC of its corresponding D-isomer Formula D,

14. The process of claim 1 , wherein the step c) is carried out using about 1.2 w/w mole equivalents of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate per mole of Formula IV as coupling agent (C2), about 0.1 w/w mole equivalents of 1-hydroxybenzotriazole per mole of Formula IV as an additive (A2) in presence of diisopropylethyl amine as base in dimethyl formamide.

15. The process of claim 1 , wherein the deprotecting agent is selected from the group consisting of palladium on carbon/ammonium formate, palladium on carbon/ammonium acetate, palladium on carbon/hydrogen gas, palladium hydroxide/hydrogen gas, raney nickel/hydrogen gas, platinum oxide/hydrogen gas and zinc/hydrogen gas.

16. The process of claim 1 , wherein the step d) is carried out in a solvent selected from the group consisting of methanol, ethanol, isopropanol, methyl acetate, ethyl aceta

Assignees

• Laurus Labs Private Ltd
• 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

• C07C271/16

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

• A61K38/07

  Tetrapeptides · CPC title

• A61K47/42

  Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34) · CPC title

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title