WO2009109222A1 - Process for the preparation of rimonabant - Google Patents

Process for the preparation of rimonabant Download PDF

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Publication number
WO2009109222A1
WO2009109222A1 PCT/EP2008/052636 EP2008052636W WO2009109222A1 WO 2009109222 A1 WO2009109222 A1 WO 2009109222A1 EP 2008052636 W EP2008052636 W EP 2008052636W WO 2009109222 A1 WO2009109222 A1 WO 2009109222A1
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Prior art keywords
formula
vii
process according
preparation
compound
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PCT/EP2008/052636
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French (fr)
Inventor
José AMATO
Gustavo Enrique ALDOMÁ
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Maprimed, S. A.
Barlocci Pennati, Anna
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Priority to PCT/EP2008/052636 priority Critical patent/WO2009109222A1/en
Publication of WO2009109222A1 publication Critical patent/WO2009109222A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues

Definitions

  • the present invention relates to a new process for the preparation of
  • Rimonabant is a CB1 receptor antagonist.
  • the CB1 is one of the two receptors located in the endocannabinoid system (or EC system) that plays a fundamental role in the regulation of food ingestion and energy consumption.
  • Rimonabant acts over the control of appetite and nicotinism.
  • Its chemical name is 5-(p-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-/V- (piperidin-1 -yl)-1 H-pyrazole-3-carboxamide, with the following structure:
  • European Patent EP-B1 -656354 discloses Rimonabant and processes for the preparation thereof.
  • the process for the preparation of Rimonabant disclosed in said European Patent is shown in Scheme I and is based on the reaction of N-aminopiperidine with a functional derivative of the acid of formula IV: Scheme I
  • the preparation of Rimonabant is always carried out through an intermediate compound of formula IV or a derivative thereof.
  • the authors of the present invention have discovered a new alternative process for the preparation of Rimonabant using the hydrazone of formula Il as precursor, without using said intermediate compound of formula IV, characterized in that the process may be carried out in a single reaction pot without the need of isolating the intermediate.
  • the process of the present invention needs less synthetic steps and provides higher yields than the processes known in the art.
  • the aim of the present invention is to provide a new process for the preparation of Rimonabant through a new intermediate.
  • the process of the present invention proceeds with high yield, is fast, clearly reproducible, and may be readily performed and monitorized.
  • the object of present invention is to provide a new one-pot process for the preparation of Rimonabant employing a new intermediate compound, wherein yield is significantly improved and the number of synthetic steps is reduced.
  • the synthetic intermediate is a further object of the invention.
  • the process for the preparation and isolation of the intermediate is also an object of the present invention.
  • a first aspect of the invention relates to a one-pot process for the preparation of Rimonabant of the following formula:
  • Starting compound (II) can be prepared according to the methods known in the state of the art, e.g. Preparation 2B-1 ) of EP-B1 -656354.
  • the process of the present invention is a one-pot process, i.e. all reactions are carried out in the same reaction pot without isolating the intermediate, adding successively the reacting agents, and, therefore, the process can be carried out in a continuous way.
  • the process of the invention starts with the reaction of the hydrazone of formula (II) with N-amino-piperidine in a suitable solvent, preferably heated and stirred under nitrogen atmosphere.
  • suitable solvents include, but are not limited to, toluene, ethanol, ethylacetate, and the like.
  • the suitable temperature is comprised in a range between 60 and 75 0 C, preferably at 70 0 C.
  • the reaction is continued for a suitable time until the starting hydrazone (II) disappears.
  • the reaction time may be comprised between 6 and 12 hours, preferably 6 hours.
  • the disappearance of the hydrazone of formula (II) may be verified by TLC (Thin-Layer Chromatography).
  • intermediate compound (VII) obtained which is not isolated, is reacted with anhydrous zinc chloride, which is a dehydrating agent capable to induce the cyclization and the formation of the pyrazole group. This reaction is carried out in the same solvent, maintaining the same temperature, for additional 6 to 12 hours, until the complete transformation of compound (VII) into Rimonabant. The disappearance of intermediate (VII) may be verified by TLC (Thin-Layer Chromatography).
  • the reaction is complete, water is added and a residue may be obtained after filtration, decantation and concentration.
  • the residue is preferably crystallized in a solvent to render Rimonabant.
  • the solvent is isopropyl ether, toluene and methylcyclohexane or mixtures thereof.
  • compound of formula (VII) obtained in the first synthetic step, as described above, is isolated from the reaction medium.
  • the process for the preparation and isolation of the compound of formula (VII) is also another aspect of the invention, comprising: 1 ) reacting the hydrazone of formula (II) with N-amino-piperidine in a suitable solvent to render the compound of formula (VII); and, 2) isolating the obtained compound through a separation with silica gel and a subsequent crystallization.
  • the reaction of hydrazone of formula (II) with N-amino-piperidine according to step a) is carried out in a suitable solvent, preferably by heating and stirring under nitrogen atmosphere.
  • suitable solvents include, but are not limited to, toluene, ethanol, ethylacetate and the like.
  • the suitable temperature is preferably from 60 to 75 0 C, more preferably 70 0 C.
  • the reaction is maintained for a suitable time until starting hydrazone (II) disappears. Reaction time may range from 6 to 12 hours, preferably 6 hours. Disappearance of the hydrazone of formula (II) may be verified by TLC (thin- film chromatography).
  • silica gel and preferably tetrahydrofurane may be added to the solution which has been previously filtered with active carbon at room temperature, the solution may be evaporated, and the residue is chromatographed. Finally, the convenient fraction may be crystallized to yield the compound of formula (VII).
  • the column is a silica gel column and diisopropylether is used as elution solvent.
  • the suitable solvent for the crystallization is preferably selected from methylcyclohexane and toluene or mixtures thereof, preferably methylcyclohexane, according to example 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a new process for the preparation of Rimonabant through the formation of an intermediate compound of formula (VII). The invention further relates to a process for the preparation of the compound of formula (VII).

Description

PROCESS FOR THE PREPARATION OF RIMONABANT
FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of
Rimonabant, to the synthetic intermediate compound and the process for the preparation of said intermediate.
BACKGROUND OF THE INVENTION
Rimonabant is a CB1 receptor antagonist. The CB1 is one of the two receptors located in the endocannabinoid system (or EC system) that plays a fundamental role in the regulation of food ingestion and energy consumption. Thus, Rimonabant acts over the control of appetite and nicotinism. Its chemical name is 5-(p-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-/V- (piperidin-1 -yl)-1 H-pyrazole-3-carboxamide, with the following structure:
Figure imgf000002_0001
Rimonabant
European Patent EP-B1 -656354 discloses Rimonabant and processes for the preparation thereof. The process for the preparation of Rimonabant disclosed in said European Patent is shown in Scheme I and is based on the reaction of N-aminopiperidine with a functional derivative of the acid of formula IV: Scheme I
cyclization Hydrolysis
Figure imgf000003_0001
Figure imgf000003_0002
Figure imgf000003_0003
Rimonabant
There are later publications providing a number of alternative syntheses. Thus, the international patent application WO-A-2006021652 discloses a process for the preparation of Rimonabant characterized by the reaction of a pirazole-3-carbohydrazine derivative of formula Vl with a di-substituted pentane derivative to form the piperidine group, in the presence of a base, and at a temperature comprised between room temperature and the reflux temperature: Scheme 2
Rimonabant
Figure imgf000004_0001
The publication Org. Proc. Res. Dev. 2007, 11 (5), pgs. 910-912 discloses the preparation of Rimonabant, as shown in the following Scheme 3, based on the preparation of the intermediate of formula IV through two synthetic steps starting from 4-chloro-propiophenone:
Scheme 3
Figure imgf000004_0002
H22SOOU.4
Figure imgf000004_0003
Figure imgf000004_0004
Therefore, the preparation of Rimonabant is always carried out through an intermediate compound of formula IV or a derivative thereof. The authors of the present invention have discovered a new alternative process for the preparation of Rimonabant using the hydrazone of formula Il as precursor, without using said intermediate compound of formula IV, characterized in that the process may be carried out in a single reaction pot without the need of isolating the intermediate. Thus, the process of the present invention needs less synthetic steps and provides higher yields than the processes known in the art. The aim of the present invention is to provide a new process for the preparation of Rimonabant through a new intermediate. The process of the present invention proceeds with high yield, is fast, clearly reproducible, and may be readily performed and monitorized.
SUMMARY OF THE INVENTION
The object of present invention is to provide a new one-pot process for the preparation of Rimonabant employing a new intermediate compound, wherein yield is significantly improved and the number of synthetic steps is reduced.
The synthetic intermediate is a further object of the invention. Thus, the process for the preparation and isolation of the intermediate is also an object of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
A first aspect of the invention relates to a one-pot process for the preparation of Rimonabant of the following formula:
Figure imgf000005_0001
which comprises a) the reaction of the hydrazone of formula (II) with N-amino-piperidine, in a suitable solvent, to render an intermediate compound of formula (VII), and b) further reacting said intermediate compound of formula (VII), without being isolated, with anhydrous zinc chloride to obtain Rimonabant. The process may be schematized as follows:
Figure imgf000006_0001
Figure imgf000006_0002
Rimonabant
Starting compound (II) can be prepared according to the methods known in the state of the art, e.g. Preparation 2B-1 ) of EP-B1 -656354.
The process of the present invention is a one-pot process, i.e. all reactions are carried out in the same reaction pot without isolating the intermediate, adding successively the reacting agents, and, therefore, the process can be carried out in a continuous way.
The process of the invention starts with the reaction of the hydrazone of formula (II) with N-amino-piperidine in a suitable solvent, preferably heated and stirred under nitrogen atmosphere. Examples of suitable solvents include, but are not limited to, toluene, ethanol, ethylacetate, and the like. The suitable temperature is comprised in a range between 60 and 75 0C, preferably at 70 0C. The reaction is continued for a suitable time until the starting hydrazone (II) disappears. The reaction time may be comprised between 6 and 12 hours, preferably 6 hours. The disappearance of the hydrazone of formula (II) may be verified by TLC (Thin-Layer Chromatography).
The intermediate compound (VII) obtained, which is not isolated, is reacted with anhydrous zinc chloride, which is a dehydrating agent capable to induce the cyclization and the formation of the pyrazole group. This reaction is carried out in the same solvent, maintaining the same temperature, for additional 6 to 12 hours, until the complete transformation of compound (VII) into Rimonabant. The disappearance of intermediate (VII) may be verified by TLC (Thin-Layer Chromatography).
Once the reaction is complete, water is added and a residue may be obtained after filtration, decantation and concentration. The residue is preferably crystallized in a solvent to render Rimonabant. Preferably, the solvent is isopropyl ether, toluene and methylcyclohexane or mixtures thereof.
Surprisingly, a new process has been found which allows obtaining Rimonabant with a high yield starting from precursor compound (II), without the need of isolating the intermediate as disclosed. Thus, it has been observed that the global yield is comprised between 60 and 70%, and therefore it is noticed that the developed process is advantageous over the processes disclosed by EP-B1 -656354 and Org. Proc. Res. Dev. 2007, 11 (5), p. 910-912, which reported lower yields, respectively 43 and 50%.
In other aspect of the invention, compound of formula (VII) obtained in the first synthetic step, as described above, is isolated from the reaction medium.
Thus, the process for the preparation and isolation of the compound of formula (VII) is also another aspect of the invention, comprising: 1 ) reacting the hydrazone of formula (II) with N-amino-piperidine in a suitable solvent to render the compound of formula (VII); and, 2) isolating the obtained compound through a separation with silica gel and a subsequent crystallization.
The reaction of hydrazone of formula (II) with N-amino-piperidine according to step a) is carried out in a suitable solvent, preferably by heating and stirring under nitrogen atmosphere. Examples of suitable solvents include, but are not limited to, toluene, ethanol, ethylacetate and the like. The suitable temperature is preferably from 60 to 75 0C, more preferably 70 0C. The reaction is maintained for a suitable time until starting hydrazone (II) disappears. Reaction time may range from 6 to 12 hours, preferably 6 hours. Disappearance of the hydrazone of formula (II) may be verified by TLC (thin- film chromatography).
Next, silica gel and preferably tetrahydrofurane may be added to the solution which has been previously filtered with active carbon at room temperature, the solution may be evaporated, and the residue is chromatographed. Finally, the convenient fraction may be crystallized to yield the compound of formula (VII). Preferably, the column is a silica gel column and diisopropylether is used as elution solvent. The suitable solvent for the crystallization is preferably selected from methylcyclohexane and toluene or mixtures thereof, preferably methylcyclohexane, according to example 1.
Compound of formula VII obtained was characterized by NMR (Nuclear Magnetic Resonance) and EI-MS (Electronic Impact Mass Spectrum). The reaction was monitored by a Merck 5554 TLC (thin-film chromatography) system of silica gel plates, revealed at UV 254 nm, solvent: diisopropylethentoluene 2:1.
The following examples are provided by means of illustration only, without being intended to be limitative of the objects defined in the attached claims.
EXAMPLE 1
Preparation of intermediate of formula VII (4-(4-chlorophenyl)-2[(2,4- dichlorophenvDhydrazonoi-S-methyl^-oxo-N-piperidin-i -yl-butiramide)
(4-(4-chlorophenyl)-2[(2,4-dichlorophenyl)hydrazono]-3-methyl-4-oxo ethyl butirate (Hidrazone II, 8 gr, 18.7 mM) is dissolved in toluene (35 ml) and N-aminopiperidine is added (10 gr, 100 mM). The reaction mixture is heated to 75 0C under nitrogen distilling 1/3 of the volume thereof for about 6 hours. Monitoring is performed by TLC targeting the disappearance of Hydrazone Il (Rf: 0.69) and the rising of a new spot (Rf: 0.57). Then, the reaction mixture is cooled until room temperature and treated for 15 min with activated carbon, then the solution is filtered and 10 ml of tetrahydrofuran and 25 g of chromatographic silica are added. The resulting product is vacuum-evaporated until dry and the residue is loaded to be subjected to chromatography in a silica gel column using diisopropylether as eluting solvent and collecting the fractions containing the product showing an Rf: 0.57, the eluted fractions being monitored by TLC. Said fractions are concentrated by vacuum in a rotary vacuum drier and the residue is crystallized in methylcyclohexane. Crystals with mp 153.5/154.5 0C are obtained. The obtained product with formula VII shows the following physical and chemistry features:
1H-NMR and 13C-NMR: [Instrumentation: Bruker Avance Il 400] Consistent with the proposed structure. The assignments were carried out including 2D tests (COSY, HSQC, and HMBC).
MS: [Instrumentation: Shimadzu QP5050A MSD Ionization: El, 70 eV] 480/482/484 (M+) (2.97%/2.56%/0.61 %); 380/382/384 (4.21 %/2.65%/0.80%); 353/355/357 (0.67%/0.52%/nd); 341/343 (4.54%/3.33%); 320/322 (1.98%/0.51 %); 160/162 (15.26%/8.48%); 139/141 (35.21 %/10.84%); 1 1 1/1 13 (20.07%/6.29%); 99 (88.57%); 84 (50.70%).
EXAMPLE 2
One-pot preparation of Rimonabant from the hvdrazone of formula Il
A mixture of the hydrazone of formula Il (4 g, 9.36 mM), toluene (20 ml) and N-aminopiperidine (2,4 g, 24 mM), is heated to 75 0C under stirring and nitrogen, distilling 1/3 of the volume thereof for 6 hours. Disappearance of the starting hydrazone and the formation of the new product, the hydrazone amide VII characterized in Example 1 , are verified by TLC.
Then, anhydrous ZnCI2 is added (2.5 g, 18.3 mM) and the temperature is maintained at 75 0C for about 8-10 h, monitoring by TLC the disappearance of intermediate VII.
Water (20 ml) and toluene (20 ml) are added. Then, the solution is stirred and decanted and the phases are separated. The upper toluene phase is washed with water (20 ml), dried (anhydrous sodium sulphate) and vacuum-evaporated (until dry).
The residue is crystallized in isopropyl ether and 3.0 g of Rimonabant are obtained, m.p. 156.5 0C. Yield: 69% MS: [Instrumentation: GC-MS Agilent 6890N-5973N. Ionization: El: 70 eV] 462/464/466 (M+) (0.71 %/0.99%/0.17%); 380/382/384 (9.76%/8.43%/2.91 %); 363/365/367 (53.16%/50.22%/16.23%); 99 (25.77%); 84 (100.00%).

Claims

1. Process for the preparation of Rimonabant, characterized in that it is carried out in one pot, a) the reaction of compound of formula (II)
Figure imgf000011_0001
with N-aminopiperidine in a suitable solvent, for obtaining the intermediate compound of formula (VII), and
Figure imgf000011_0002
b) further reacting said intermediate compound of formula (VII), without being isolated, with anhydrous zinc chloride, to render Rimonabant.
2. The process according to claim 1 , characterized in that said suitable solvent is selected from the group consisting of toluene, ethanol and ethyl acetate.
3. The process according to claim 1 , characterized in that the process is carried out at a temperature between 60 and 75 0C.
4. The process according to claim 3, wherein the temperature of the process is 70 0C.
5. The process according to claim 1 , characterized in that the reaction time of the first step of the process for the preparation of intermediate VII ranges from 6 to 12 hours.
6. The process according to claim 1 , characterized in that the reaction time of the second step of the process for the preparation of Rimonabant ranges from 6 to 12 hours.
7. Compound of formula (VII).
Figure imgf000012_0001
VII
8. Process for the preparation of the compound of formula (VII) comprising: 1 ) reacting the compound of formula (II)
Figure imgf000012_0002
with N-aminopiperidine in a suitable solvent, for the preparation of the compound of formula (VII),
Figure imgf000013_0001
2) isolating said compound (VII) by a separation in a silica gel column and a subsequent crystallization.
9. The process according to claim 8, characterized in that said suitable solvent of step 1 ) is selected from the group consisting of toluene, ethanol and ethyl acetate.
10. The process according to claim 8, characterized in that step 1 ) is carried out at temperatures between 60 and 75 0C.
11. The process according to claim 10, wherein the temperature is 70 0C.
12. The process according to claim 8, characterized in that the reaction time of step 1 ) ranges from 6 to 12 hours.
13. The process according to claim 8, characterized in that the elution solvent used in step 2) is diisopropyl ether.
14. The process according to claim 8, characterized in that the suitable solvent of step 2) is selected from the group consisting of methylcyclohexane, toluene and mixtures thereof.
15. The process according to claim 14, wherein the solvent is methylcyclohexane.
PCT/EP2008/052636 2008-03-04 2008-03-04 Process for the preparation of rimonabant WO2009109222A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656354A1 (en) * 1993-12-02 1995-06-07 Sanofi Substituted N-piperidino 3-pyrazolecarboxamide
WO2006021652A1 (en) * 2004-07-22 2006-03-02 Sanofi-Aventis Method for preparing n-piperidino-1,5-diphenylpyrazole-3-carboxamide derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656354A1 (en) * 1993-12-02 1995-06-07 Sanofi Substituted N-piperidino 3-pyrazolecarboxamide
WO2006021652A1 (en) * 2004-07-22 2006-03-02 Sanofi-Aventis Method for preparing n-piperidino-1,5-diphenylpyrazole-3-carboxamide derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KOTAGIRI V K ET AL: "AN IMPROVED SYNTHESIS OF RIMONABANT: ANTI-OBESITY DRUG", ORGANIC PROCESS RESEARCH AND DEVELOPMENT,, vol. 11, no. 5, 1 January 2007 (2007-01-01), pages 910 - 912, XP002491303 *

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