WO2009045489A2

WO2009045489A2 - Process for the synthesis of cmhtp, a paliperidone intermediate

Info

Publication number: WO2009045489A2
Application number: PCT/US2008/011433
Authority: WO
Inventors: Santiago Ini; Yaron Shmuely
Original assignee: Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals Usa, Inc.
Priority date: 2007-10-03
Filing date: 2008-10-02
Publication date: 2009-04-09
Also published as: WO2009045489A3

Abstract

The present invention provides a process for 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[1,2-a]- pyrimidin-4-one (CMHTP), comprising reacting 3-(2- chIoroethyl)-2-methyl-9-hydoxy-4H-pyrido[1,2-a]pyrimidine-4-one (CMHP) and/or 3-(2-chIoroethyi)-2-methyl-9-benzyIoxy-4H-pyrido[1,2-a]pyrimidine-4-one (CMBP) with a hydrogen source and at least one hydrogenation catalyst to form CMHTP, wherein the hydrogen source is cyclohexene, cyclohexadiene or ammonium formate, and wherein the ammonium formate is mixed with formic acid, and its conversion to paliperidone.

Description

PROCESS FOR THE SYNTHESIS OF CMHTP, A PALIPERIDONE

INTERMEDIATE

CROSS REFERENCE TO RELATED APPLICATION [0001] This patent application claims the benefits of U.S. Provisional

Application No. 60/997,755 filed October 3, 2007.

FIELD OF THE INVENTION

[0002] The invention concerns a process for the synthesis of 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]pyrimidin-4- one (CMHTP), an intermediate in the synthesis of Paliperidone.

BACKGROUND OF THE INVENTION

[0003] Paliperidone, 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l- piperidyl] ethyl] -7-hydroxy-4-methyl-l ,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one, is a serotonin (5-HT) antagonist belonging to the chemical class of benzisoxazole derivatives and has a racemic mixture of the following structural formula:

Paliperidone

[0004] Paliperidone is a metabolite of Risperidone. Marketed under the name

Invega^®, Paliperidone is a psychotropic agent approved in the United States for the treatment of schizophrenia.

[0005] A process for the synthesis of Paliperidone, is described in U.S. Patent

No. 5,158,952 according to the following scheme:

[0006] The preparation of paliperidone via the intermediate 3-(2-chloroethyl)-

6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one

(CMHTP) is depicted in the last step of the above scheme.

[0007] Processes for the synthesis of Paliperidone are further described in publication Nos. WO08/021345 and WO08/024415.

[0008] A process for the synthesis of intermediates of Paliperidone is also described in U.S. Patent No. 5,688,799.

[0009] The processes described in the above publications are long, and result in low chemical yields, making their application in the industry very hard.

[00010] Furthermore, these processes make use of hydrogen gas which requires special handling.

[00011] There is a need in the art for a new process for preparing Paliperidone and its intermediates.

SUMMARY OF THE INVENTION

[00012] In one embodiment, the present invention provides a process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2- a]- pyrimidin-4-one (CMHTP), comprising reacting 3-(2-chloroethyl)-2-methyl-9- benzyloxy-4H-pyrido[l,2-a]pyrimidine-4-one (CMBP) and/or 3-(2-chloroethyl)-2- methyl-9-hydoxy-4H-pyrido[l,2-a]pyrimidine-4-one (CMHP) with cyclohexene, cyclohexadiene or ammonium formate, in the presence of a hydrogenation catalyst to form CMHTP, wherein when ammonium formate is used, formic acid is also introduced into the reaction mixture.

[00013] In another embodiment, the present invention provides a process for preparing 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l-piperidyl]ethyl]-7-hydroxy-4- methyl-1 ,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one (paliperidone), comprising preparing CMHTP as described above, and converting the obtained CMHTP to paliperidone.

DETAILED DESCRIPTION OF THE INVENTION

[00014] The process of the present invention relates to the preparation of

CMHTP by a hydrogen transfer reaction or transfer hydrogenation. [00015] Hydrogen transfer reactions have been described in the literature using

2-azapyracridones, as disclosed in Fullop et al, Tetrahedron, 43(6), 1987, 1157-1160). [00016] The preparation of CMHTP of the present invention is typically a one- pot process that is performed with a hydrogen source that is not hydrogen gas and also without the presence of 2-azapyracridones. The process of the present invention is thus more industrially suitable, as it doesn't require hydrogen gas handling. Moreover, it requires fewer components, which also contributes to its industrial applicability. The "hydrogen source" is cyclohexene, cyclohexadiene or ammonium formate mixed with formic acid. Preferably, the "hydrogen source" is cyclohexene. [00017] In the process of the present invention mild reduction conditions may be applied, therefore avoiding esterification of CMHTP and also avoiding cleavage of the Cl group from CMHTP. The mild reduction conditions may be achieved by performing the reduction without pressurized hydrogen gas. [00018] In one embodiment, the present invention provides a process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2- a]- pyrimidin-4-one (CMHTP), comprising reacting 3-(2-chloroethyl)-2-methyl-9- benzyloxy-4H-pyrido[l,2-a]pyrimidine-4-one (CMBP) with cyclohexene, cyclohexadiene or ammonium formate, in the presence of a hydrogenation catalyst to form CMHTP, wherein when ammonium formate is used, formic acid is also introduced into the reaction mixture.

[00019] Alternatively, the starting material for the process of preparing

CMHTP of the present invention can be 3-(2-chloroethyl)-2-methyl-9-hydoxy-4H- pyrido[l,2-a]pyrimidine-4-one (CMHP). CMHP can be obtained by any method know in the art, for example, as described in co-pending US application no. 2008/0200676 ("US '676"). As therein described the benzyl protection group is removed from 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (HMBP) during chlorination. CMBP can also be obtained as described in US '676.

[00020] Not to be limited by any mechanism, typically when CMBP is used as the starting material in the processes of the present invention for preparing CMHTP, a one pot process is performed, so that the benzyl protection group is first removed to give CMHP, and the CMHP is further hydrogenised to give CMHTP. [00021] In one specific embodiment CMHTP is prepared in a process comprising reacting CMBP with cyclohexene in the presence of a hydrogenation catalyst, e.g., Pd/C, as can be depicted in the following scheme:

CMBP CMHTP

[00022] In yet another specific embodiment CMHTP is prepared by a process comprising reacting CMBP with ammonium formate and formic acid, in the presence of a hydrogenation catalyst, e.g., Pd/C, as can be depicted in the following scheme:

CMBP CMHTP

[00023] In another embodiment, the present invention provides a process for preparing CMHTP, comprising reacting CMHP with cyclohexene, cyclohexadiene or ammonium formate, in the presence of a hydrogenation catalyst to form CMHTP, wherein when ammonium formate is used, formic acid is also introduced into the reaction mixture. [00024] The paragraphs disclosed below are related to all the processes for preparing CMHTP of the present invention.

[00025] An inert solvent may also be employed in the reaction mixture of the processes for preparing CMHTP of the present invention. A preferred inert solvent is

Ci-C₅ alcohol, such as methanol. If a solvent is present, the ratio of the solvent to the reagent is about 6 to 15 ml/g (v/w).

[00026] If the hydrogen source is ammonium formate in the processes for preparing CMHTP of the present invention, the molar ratio of ammonium formate to formic acid is preferably ranging from about 6 to 12 mol/mol.

[00027] Examples of "hydrogenation catalyst" include palladium on charcoal,

Raney nickel, NaBH₄ reduced nickel, platinum metal or its oxide, rhodium, ruthenium zinc oxide and Wilkinson's catalyst, i.e., chlorotris(triphenylphosphine) rodium

(RhCl(Ph₃P)₃). The hydrogenation catalyst used in the present invention is preferably Pd/C. The hydrogenation catalyst is more preferably 10% Pd/C.

[00028] Preferably, in the processes for preparing CMHTP of the present invention, the reaction is performed under elevated temperatures, more preferably under reflux. The reaction mixture is then cooled, preferably to room temperature.

[00029] As used herein, the term "elevated temperatures" refer to temperatures above room temperature, and can be as high as the reflux temperature.

[00030] As used herein, the term "room temperature" means a temperature of about 15⁰C to about 35⁰C. Preferably, "room temperature" is about 2O⁰C to about

25⁰C

[00031 ] In the processes for preparing CMHTP of the present invention, the reaction mixture is typically maintained for sufficient time to ensure the conversion of

CMBP or CMHP to CMHTP. When cyclohexene is used as the hydrogen source, preferably the maintaining is for at least about 10 hours (for example, about 10 hours to about 100 hours), preferably for at least 15 hours, more preferably for at least about

19 hours (for example, about 19 hours to about 50 hours). When ammonium formate is used as the hydrogen source, the maintaining is for at least about an hour (for example, about 1 hour to about 20 hours), preferably for at least 2 hours (for example, about 2 hours to about 10 hours).

[00032] The obtained CMHTP is preferably then recovered by methods known in the art, such as filtering and evaporating the remaining solvent under reduced pressure. [00033] In another embodiment, the present invention provides a process for preparing paliperidone, comprising preparing CMHTP as described above, and converting the obtained CMHTP to paliperidone.

[00034] CMHTP may be converted to paliperidone by any method known in the art, e.g., via condensation of the CMHTP with 6-fluoro-3-piperidino-l,2- benisoxazol (FBIP), such as by the process described in U.S. Patent No. 5,158,952, wherein CMHTP is reacted with 6-fluoro-3-piperidino-l,2-benisoxazol (FBIP) in the presence of a base, e.g., diethylamine or diisopropylamine, and an organic solvent, e.g., methanol.

[00035] Alternatively, CMHTP can be converted to paliperidone in a process comprising providing recovered or substantially isolated CMHTP; mixing the recovered or substantially isolated CMHTP, e.g., solid CMHTP, FBIP, sodium carbonate, potassium iodide and dimethylformamide (DMF) to form a mixture; and heating the mixture to a temperature ranging from about 90° C to reflux to form paliperidone, wherein optionally the reaction mixture is then combined with water and extracted with dichloromethane (DCM) to obtain paliperidone. [00036] In any one of the processes from converting CMHTP to paliperidone, the obtained paliperidone is optionally isolated or recovered by a process known in the art.

[00037] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the synthesis of CMHTP. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Example 1 : Preparation of CMHTP using cyclohexene

[00038] To a mixture of Ig CMBP in 25 ml cyclohexene was added 0.5g of

Pd/C 10% and the mixture was heated to reflux for about 19 hours. After cooling, the mixture was filtrated and the solvent evaporated under reduce pressure to give CMHTP. Example 2: Preparation of CMHTP using ammonium formate

[00039] A 100 ml flask, equipped with a magnetic stirrer and a reflux condenser, was charged with 3g CMBP, 5.76g Ammonium formate, 46 ml methanol, 0.3g Pd/C 10% and 0.5ml formic acid. The mixture was heated to reflux and stirred for about 2 hours. After cooling, the mixture was filtrated and the solvent evaporated under reduced pressure to give CMHTP.

Claims

We Claim:

1. A process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl- 4H-pyrrido[l,2-a]- pyrimidin-4-one (CMHTP), comprising reacting 3-(2- chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMHP) and/or 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMBP) with a hydrogen source and at least one hydrogenation catalyst to form CMHTP, wherein the hydrogen source is cyclohexene, cyclohexadiene or ammonium formate, and wherein the ammonium formate is mixed with formic acid.

2. The process of claim 1, wherein the hydrogen source is cyclohexadiene.

3. The process of claim 1, wherein the hydrogen source is cyclohexene.

4. The process of claim 1, wherein the hydrogen source is ammonium formate, wherein the ammonium formate is mixed with formic acid.

5. The process of any one of claims 1-4, further comprising isolating or recovering the CMHTP.

6. The process of any one of claims 1 to 5, wherein the at least one hydrogenation catalyst is selected from the group consisting of palladium on charcoal, Raney nickel, NaBtLj reduced nickel, platinum metal or its oxide, rhodium, ruthenium zinc oxide and chlorotris(triphenylphosphine) rodium (RhCl(Ph₃P)₃).

7. The process of claim 6, wherein the at least one hydrogenation catalyst is palladium on charcoal.

8. The process of any one of claims 1 to 7, wherein the reaction mixture of CMHP and/or CMBP, the hydrogen source and the at least one hydrogenation catalyst is heated to conduct the hydrogen transfer reaction at a temperature ranging from higher than room temperature (about 15⁰C to about 35⁰C) to about reflux temperature.

9. The process of claim 8, wherein the reaction mixture is heated at reflux.

10. The process of any one of claims 1, 3 and 5 to 9, wherein the CMHP and/or CMBP is reacted with the hydrogen source in the presence of the at least one hydrogenation catalyst for at least about 10 hours to form the CMHTP when the hydrogen source is cyclohexene.

11. The process of any one of claims 1 and 4 to 9, wherein the CMHP and/or CMBP is reacted with the hydrogen source in the presence of the at least one hydrogenation catalyst for at least about an hour to form the CMHTP when the hydrogen source is ammonium formate.

12. The process of claim 11 , wherein the molar ratio of ammonium formate to formic acid ranges from about 6 to 12.

13. The process of any one of claims 1 to 12, wherein the at least one hydrogenation catalyst is 10% Pd/C.

14. The process of any one of claims 1 to 13, wherein the CMHP and/or CMBP is reacted with the hydrogen source and the at least one hydrogenation catalyst in the absence of any 2-azapyracridones to form the CMHTP.

15. The process of any one of claims 1 to 14, wherein the CMHP and/or CMBP is not reduced with gaseous hydrogen.

16. The process of any one of claims 1 to 15, wherein the CMHP is reacted with the hydrogen source and the at least one hydrogenation catalyst to form CMHTP.

17. The process of any one of claims 1 to 15, wherein the CMBP is reacted with the hydrogen source and the at least one hydrogenation catalyst to form CMHTP.

18. The process of any one of claims 1-17, wherein the reaction mixture further comprises an inert solvent.

19. The process of claim 18, wherein the inert solvent is C₁-C₄ alcohol.

20. The process of claim 19, wherein the inert solvent is methanol.

21. A process for preparing paliperidone, comprising providing CMHTP prepared with the process of any one of claims 1 to 20; and condensing the CMHTP with 6- fluoro-3-piperidino-l,2-benisoxazol (FBIP) to form the paliperidone.

22. The process of claim 21, wherein the CMHTP is condensed with the FBIP in the presence of a base and an organic solvent.

23. The process of claim 22, wherein the base is diethylamine or diisopropylamine, and the organic solvent is methanol.

24. The process of claim 21, wherein the CMHTP is condensed with the FBEP in a process comprising: providing recovered or substantially isolated CMHTP; mixing the recovered or substantially isolated CMHTP, FPBI, sodium carbonate, potassium iodide and dimethylformamide (DMF) to form a mixture; and heating the mixture to a temperature ranging from about 90° C to reflux to form paliperidone.

25. The process of claim 24, further comprising, after the heating step, combining the reaction mixture with water; and extracting with dichloromethane (DCM) to obtain paliperidone.

26. The process of any one of claims 21-25, wherein the paliperidone is recovered or substantially isolated.