Method for the production of praziquantel and precursors thereof

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

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

xylylphosphine

(R)-C3-TunePhos

(R)-1,13-Bis(diphenylphosphino)-7,8-dihydro-6H-

dibenzo[f,h][1,5]dioxonin

(S)-C3-TunePhos

(S)-1,13-Bis(diphenylphosphino)-7,8-dihydro-6H-

dibenzo[f,h][1,5]dioxonin.

8. The method according to claim 3 , wherein the asymmetric hydrogenation step in the presence of a catalyst is carried out involving at least one of:

elevated temperature;

a solvent, which is dioxane, THF, Me-THF, IPA, DCE, DCM, ethyl acetate, toluene, α,α,α-trifluorotoluene, xylene, mesitylene or a mixture of any two or more thereof;

at least one additive;

a substrate concentration of at least 0.05 mmol/l;

a catalyst loading of at least 50/1 substrate/catalyst; and

elevated pressure.

9. A method of preparing an enantiomerically pure or enantiomerically enriched compound according to Formula (Q1) or Formula (Q2)

comprising

(a) preparing according to the method of claim 1 (i) the optically active compound according to Formula (X1) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X1) is present in excess, for the preparation of the compound according to Formula (Q1)

or

(b) preparing according to the method of claim 1 (i) the optically active compound according to the Formula (X2) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X2) is present in excess, for the preparation of the compound according to Formula (Q2),

wherein R in Formulae (Q1) and (Q2) is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, and optionally substituted aryl.

10. The method of preparing the enantiomerically pure or enantiomerically enriched compound according to Formula (Q1) or Formula (Q2) according to claim 9 , further comprising

(a) reacting (i) the optically active compound according to Formula (X1) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X1) is present in excess, with a compound Y—CO—CH 2 —X, wherein Y is F, Cl or Br or —O—CO-alkyl and X is F, Cl or Br, to give the compound according to Formula (Q1);

or

(b) reacting the optically active compound according to the Formula (X2) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X2) is present in excess, with a compound Y—CO—CH 2 —X, wherein Y is F, Cl or Br or —O—CO-alkyl and X is F, Cl or Br, to give the compound according to Formula (Q2).

11. A method of preparing an enantiomerically pure or enantiomerically enriched compound according to Formula (Q1) or Formula (Q2)

comprising preparing a mixture of compounds according to Formula (X1) and Formula (X2) according to the method of claim 1 ,

separating the compound according to Formula (X1) from the compound according to Formula (X2),

and reacting

(a) the compound according to Formula (X1) with a compound Y—CO—CH 2 —X, wherein Y is F, Cl or Br or —O—CO-alkyl and X is F, Cl or Br, to obtain the enantiomerically pure or at least enantiomerically enriched compound according to Formula (Q1);

or

(b) the compound according to Formula (X2) with a compound Y—CO—CH 2 —X, wherein Y is F, Cl or Br or —O—CO-alkyl and X is F, Cl or Br, to obtain the enantiomerically pure or at least enantiomerically enriched compound according to Formula (Q2),

wherein R is the same in Formulae (Q1) and (Q2) as in Formulae (X1) and (X2).

12. A method of preparing enantiomerically pure or enantiomerically enriched (R)-Praziquantel

comprising preparing by the method according to claim 9 , the optically active compound according to Formula (X1) or (iii) the mixture of compounds according to Formula (X1) and Formula (X2), in which mixture the compound according to Formula (X1) is present in excess, wherein R is cyclohexyl in the compound according to Formula (X1).

13. A method of preparing a mixture of an optically active compound according to the following Formula (X1) and an optically active compound according to the following Formula (X2)

or a salt thereof,

wherein R is selected from the group consisting of C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl;

wherein the compounds or salt(s) thereof are present in said mixture in a first ratio of RM1=X1:X2, which is from 0.8 to 1.2;

comprising the following steps:

(a) dehydrogenating a mixture of compounds according to Formulae (X1) and (X2), wherein the compounds are present in said mixture in a second ratio RM2=X1:X2, which is either smaller than 0.8 or larger than 1.2, to produce a mixture of compounds according to the following Formula (Y) and to Formula (Z), wherein R is the same as in Formulae (X1) and (X2)

or salt(s) thereof and

(b) hydrogenating said mixture of compounds according to Formula (Y) and to Formula (Z) or salt(s) thereof to obtain the mixture of compounds of Formulae (X1) and (X2) or salt(s) thereof in the first ratio RM1,

wherein the mixture of compounds according to Formulae (X1) and (X2) or salt(s) thereof in the second ratio RM2 is optionally prepared either by asymmetric hyrogenation of a compound according to Formula (Y) in accordance with the method according to claim 3 or by separation of a mixture of compounds according to Formulae (X1) and (X2).

14. A compound according to the following Formula (Y1)

15. A method

for the preparation of

(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 selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, and optionally substituted aryl,

comprising a reaction of a compound of Formula (Y)

16. A method for the preparation of (R)-Praziquantel comprising a reaction of a compound of Formula (Y1) according to claim 14 .

17. A method of preparing a compound of Formula (Y1) according to claim 14

comprising reacting [isoquinolin-1-yl)-methyl]-amine

with a cyclohexane carboxylic acid based acylating agent.

18. 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 80%.

19. The method according to claim 3 , wherein the asymmetric hydrogenation step in the presence of a catalyst is carried out involving at least one of:

elevated temperature of at least 60° C.;

at least one additive, which is iodine (I 2 ), iodide, phosphoric acid (H 3 PO 4 ), acetic acid (AcOH), HI, or HBF 4 , in an amount of at least 5 mol %;

a substrate concentration of at least 10 mmol/l;

a catalyst loading of at least 100/1 substrate/catalyst; and

elevated pressure of at least 1 bar H 2.

20. A method of preparing a mixture of an optically active compound according to the following Formula (X1) and an optically active compound according to the following Formula (X2)

or a salt thereof,

wherein R is selected from the group consisting of C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl;

wherein the compounds or salt(s) thereof are present in said mixture in a first ratio of RM1=X1:X2, which is from 0.8 to 1.2; comprising the following steps:

(c) dehydrogenating a mixture of compounds according to Formulae (X1) and (X2), wherein the compounds are present in said mixture in a second ratio RM2=X1:X2, which is either smaller than 0.8 or larger than 1.2, to produce a mixture of compounds according to the following Formula (Y) and to Formula (Z), wherein R is the same as in Formulae (X1) and (X2)

or salt(s) thereof and

(d) hydrogenating said mixture of compounds according to Formula (Y) and to Formula (Z) or salt(s) thereof to obtain the mixture of compounds of Formulae (X1) and (X2) or salt(s) thereof in the first ratio RM1, wherein the mixture of compounds according to Formulae (X1) and (X2) or salt(s) thereof in the second ratio RM2 is prepared by asymmetric hyrogenation of a compound according to Formula (Y) in accordance with the method according to claim 3 .