Method For The Production of Praziquantel and Precursors Thereof

Patent metadata

Field	Value
Publication number	US-2017320873-A1
Application number	US-201515528116-A
Country	US
Kind code	A1
Filing date	Nov 19, 2015
Priority date	Nov 21, 2014
Publication date	Nov 9, 2017
Grant date	—

Abstract

The present invention relates to methods for the production of enantiopure or enantioenriched Praziquantel precursors and to methods for the production of enantiopure or enantioenriched Praziquantel comprising the methods for the production of the Praziquantel precursors. The present invention further relates to compounds or intermediates useful in such methods.

First claim

1 . Method for the production of enantiopure or enantiomerically enriched (R)-Praziquanamine comprising the following step:
Chiral resolution of a mixture of the enantiomers (S)-(I) and (R)-(I) of Praziquanamine,

via precipitation of a diastereomeric salt formed by one of the enantiomers (S)-(I) or (R)-(I) with an enantiopure or enantioenriched chiral 2-aryl-propionic acid containing at least 14 C-atoms.

2 . Method according to claim 1 , wherein the 2-aryl-propionic acid is (S)-Naproxen or (S)-Ketoprofen.

3 . Method according to claim 2 , wherein the 2-aryl-propionic acid is (S)-Naproxen and the precipitated diastereomeric salt comprises (S)-Naproxen and (R)-Praziquanamine (R)-(I).

4 . Method according to claim 3 , and wherein the diastereomeric salt is [(S)-Naproxen:(R)-Praziquanamine], which has a stoichiometry of X:1, wherein X is a real number between 1 and 3.

5 . Method according to claim 4 , wherein the method comprises following steps:
Separation of [(S)-Naproxen:(R)-Praziquanamine] 2:1 salt via liquid/solid separation; a Isolation of (R)-Praziquanamine from the [(S)-Naproxen: (R)-Praziquanamine] 2:1 salt via acidification of the reaction mixture and liquid/solid separation.

6 . Method according to claim 5 , wherein an inorganic acid or an organic sulfonic acid or trifluoroacetic acid is used for the acidification.

7 . Method according to claim 1 , wherein
the 2-aryl-propionic acid is (S)-Naproxen and the precipitated diastereomeric salt comprises (S)-Naproxen and (R)-Praziquanamine (R)-(I); the diastereomeric salt is [(S)-Naproxen:(R)-Praziquanamine], which has a stoichiometry of X:1, wherein X is a real number between 1 and 3; the method further comprises following steps:
Separation of the diastereomeric salt [(S)-Naproxen:(R)-Praziquanamine] via liquid/solid separation;
Isolation of (R)-Praziquanamine via acidification of the reaction mixture and liquid/solid separation.

8 . Method for the production of enantiopure or enantiomerically enriched (R)-Praziquantel comprising a method according to claim 1 and following step:
Reaction of (R)-Praziquanamine (R)-(I) with a cyclohexylcarboxylic acid derivative.

9 . Method according to claim 8 , wherein the cyclohexylcarboxylic acid derivative used is cyclohexylcarboxylic acid chloride.

10 . Method according to claim 9 , wherein the reaction with cyclohexylcarboxylic acid chloride is performed in the presence of a biphasic solvent system, wherein one solvent is water.

11 . Method for the production of enantiopure or enantiomerically enriched (R)-Praziquanacetamide comprising the following step:
Chiral resolution of a mixture of the enantiomers (S)-(II) and (R)-(II) of N-substituted Praziquandiamine

via precipitation of a diastereomeric salt formed by one of the enantiomers (S)-(II) or (R)-(II) with an enantiopure or enantioenriched chiral 2-aryl-propionic acid containing at least 14 C-atoms, wherein R 2 denotes denotes tert.-butyloxycarbonyl, benzoyl, cyclohexanoyl or acetyl.

12 . Method according to claim 11 , wherein the 2-aryl-propionic acid is (S)-Naproxen or (S)-Ketoprofen.

13 . Method according to claim 12 , wherein the method comprises following steps:
Separation of the diastereomeric salt via liquid/solid separation; a Isolation of N-substituted (R)-Praziquandiamine from the diastereomeric salt via acidification of the reaction mixture and liquid/solid separation.

14 . Method for the production of enantiopure or enantiomerically enriched (R)-Praziquantel comprising a method according to claim 11 and following steps:
Deprotection of the N-substituted (R)-Praziquandiamine (R)-(II);
Reaction of unprotected (R)-Praziquandiamine obtained in a) with a reactive cyclohexylcarboxylic acid derivative;
Cyclisation of the carboxamide obtained in b) with chloroacetyl chloride.

15 . Method according to claim 1 , wherein the method further comprises following step:
Racemization of enantiomerically pure or enantiomerically enriched compound according formula (I′)

 wherein
 a base is used, and
 R 1 denotes H, tert.-butyloxycarbonyl, benzoyl or acetyl.

16 . Method according to claim 15 , wherein the base is a tertiary alkali alkoxide.

17 . Method according to claim 15 , wherein:
the base is a tertiary alkali alkoxide; the dipolar aprotic reaction medium is selected from a group consisting of N-Methyl-2-pyrrolidone, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, methyltetrahydrofuran, dioxane and mixtures thereof in all ratios, preferably the reaction medium is tetrahydrofuran; the amount of base used in for the racemization is in the range between 0.05 eq to 1.5 eq; the racemization is performed at a temperature in the range between −50° C. and +40° C.

18 . Diastereomeric salt comprising (R)-Praziquanamine and (S)-Naproxen or a solvate thereof or (R)-Praziquanacetamide and (S)-Naproxen or (S)-Ketoprofen or a solvate thereof.

19 . Diastereomeric salt according to claim 18 comprising (R)-Praziquanacetamide and (S)-Naproxen or (S)-Ketoprofen or a solvate thereof.

20 . Diastereomeric salt according to claim 18 comprising (R)-Praziquanamine and (S)-Naproxen or a solvate thereof.

Assignees

• Merck Patent Gmbh

Inventors

• Maillard David
• Waechtler Andreas
• Maurin Jeremy
• Wakaresko Ewgenij
• Jasper Christian

Classifications

• A61P33/10

  Anthelmintics · CPC title

• C07C59/84

  containing six membered aromatic rings · CPC title

• C07D217/14

  other than aralkyl radicals · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07C59/64

  containing six-membered aromatic rings · CPC title