Method for the production of praziquantel and precursors thereof

Patent metadata

Field	Value
Publication number	US-10273213-B2
Application number	US-201615756267-A
Country	US
Kind code	B2
Filing date	Aug 10, 2016
Priority date	Sep 1, 2015
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

Abstract

The present invention provides methods of preparing Praziquantel, in particular (R)-Praziquantel and analogues thereof in a stereoselective manner. One method involves asymmetric hydrogenation of the following intermediate compound

and subsequent cyclization.

First claim

The invention claimed is:

1. A method of preparing
(i) an optically active compound according to the following Formula (X1)

or

(ii) an optically active compound according to the following Formula (X2)

or

(iii) a mixture of the two,
wherein R is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or unsubstituted or substituted aryl,
comprising:
subjecting a compound according to the following Formula (Y)

with R as above,
to a hydrogenation step.

2. The method according to claim 1 , wherein R is methyl or cyclohexyl.

3. The method according to claim 1 , wherein the mixture comprises either the compound according to Formula (X1) or the compound according to Formula (X2) in excess and wherein the hydrogenation step is an asymmetric hydrogenation step in the presence of a catalyst.

4. The method according to claim 3 , wherein the compound according to Formula (X1) is present in the mixture in an enantiomeric excess of at least 10%.

5. The method according to claim 3 , wherein the catalyst is an iridium based catalyst.

6. The method according to claim 5 , wherein the catalyst comprises an iridium compound in combination with a chiral phosphine ligand.

7. The method according to claim 5 , wherein the iridium based catalyst is or comprises a mixture of [Ir(COD)Cl] 2 and one of the following ligands:

(R)-(S p )-Josiphos

R1 = t-Bu
R2 = Ph

R1 = Ph
R2 = Ph

R1 = Ph
R2 = Xylyl (═(R)-Xyliphos)

(S)-(R p )-Josiphos

R1 = t-Bu
R2 = Ph

R1 = Ph
R2 = Ph

R1 = Ph
R2 = Xylyl (═(S)-Xyliphos)

(R)-BoPhoz

(R)-Me-BoPhoz:
R = Me, R′ = Ph

(R)-Me-BoPhoz (Xyl):
R = Me, R′ = Xylyl

(R)-Me-BoPhoz (3,5-F—Ph)
R = Me, R′ = 3,5-F—Ph

(S)-BoPhoz

(S)-Me-BoPhoz:
R = Me, R′ = Ph

(S)-Me-BoPhoz (Xyl):
R = Me, R′ = Xylyl

(S)-Me-BoPhoz (3,5-F—Ph)
R = Me, R′ = 3,5-F—Ph

(R)-(S p )-Taniaphos

(R)-1-[(S p )-α-(Dimethylamino-2-

(diphenylphosphino)benzyl]-

2-diphenylphosphinoferrocene

R1 = Ph R2 = Ph

(S)-(R p )-Taniaphos

(S)-1-[(R p )-α-(Dimethylamino-2-

(diphenylphosphino)benzyl]-

2-diphenylphosphinoferrocene

R1 = Ph R2 = Ph

(R)-Xylyl-BINAP

Ar = 3,5-Me 2 —Ph

(S)-Xylyl-BINAP

Ar = 3,5-Me 2 —Ph

(R)-6,6′-Bis(diphenylphosphino)-2,2′,3,3′-tetrahydro-

5,5′-bi-1,4-benzodioxine

(S)-6,6′-Bis(diphenylphosphino)-2,2′,3,3′-tetrahydro-

5,5′-bi-1,4-benzodioxine

(S)-5,5′-Bis(di(3,5-xylyl)phosphino)-4,4′-bi-1,3-benzodioxole

(R)-5,5′-Bis(di(3,5-xylyl)phosphino)-4,4′-bi-1,3-benzodioxole

(R)-7,7′-Bis[di(3,5-dimethylphenylphosphino]-2,2′,3,3′-

tetrahydro-1,1′-spirobiindane

(S)-7,7′-Bis[di(3,5-dimethylphenylphosphino]-2,2′,3,3′-

tetrahydro-1,1′-spirobiindane

(R)-1-{(S)-2-[Bis[3,5-di-

trifluoromethylphenyl)phosphino]ferrocenyl}ethyldi-3,5-

xylylphosphine

(S)-

Assignees

• Merck Patent Gmbh

Inventors

• Eberhardt Luc
• Waechtler Andreas
• Maillard David
• Lehmann Stefan

Classifications

• C07D217/14 Primary

  other than aralkyl radicals · CPC title

• C07B53/00

  Asymmetric syntheses · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• B01J2531/827

  Iridium · CPC title

• B01J2531/0266

  Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL" · CPC title