EP2331492A1

EP2331492A1 - Method for preparing the ethyl ester of 4-[trans-4-[(phenylmethyl)amino]cyclohexyl]benzoic acid and the hemifumarate salt thereof

Info

Publication number: EP2331492A1
Application number: EP09737019A
Authority: EP
Inventors: José Ruiz-Montes
Original assignee: Sanofi Aventis France
Current assignee: Sanofi SA
Priority date: 2008-08-21
Filing date: 2009-08-18
Publication date: 2011-06-15
Also published as: JP2012500251A; WO2010020719A1; FR2935141A1; FR2935141B1; US20110190529A1

Abstract

The present invention relates to the compound of formula (I) and to the use thereof as an intermediate for the synthesis of the compound of formula (A) or pharmaceutically acceptable salts thereof: formulae (II).

Description

PROCESS FOR THE PREPARATION OF THE ETHYL ESTER OF A- [TRANS- (t-phenylmethyl) aminyl] cyclohexyl] benzoic acid and

HEMIFUMARATE SALT.

The subject of the present invention is a process for the preparation of the compound of formula (I):

(I) The subject of the present invention is also the hemifumarate of the compound of formula (I), corresponding to formula (IA):

(IA)

The compound of formula (I) is described in patent applications WO03 / 099772, WO03 / 099819 and WO02 / 44139, where it may be used as an intermediate for the preparation of the compound of formula (A) or its pharmaceutically acceptable salts acceptable:

(AT) According to the synthesis method described in the aforementioned patent applications, the compound of formula (I) is synthesized by the action of a compound of formula (II):

(H) on a compound of formula (III):

(III)

A cis / trans mixture is obtained and the compound of formula (I) (trans isomer) is obtained and separated from the cis isomer by chromatography on silica.

It is therefore desirable to provide a new improved process, transferable on an industrial scale, to overcome the silica chromatography step.

It has now been discovered, and it is one of the objects of the present invention that the salification of the crude reaction product resulting from the reaction of the compound (II) with the compound (III) by means of fumaric acid makes it possible to obtain the compound of formula (I), of trans configuration, crystalline with good chemical purity. This process thus makes it possible to easily separate the compound of formula (I) without resorting to the silica chromatography step of the prior art.

According to the present invention, a compound of formula (I) is prepared via the formation of the compound of general formula (IA):

(IA) According to the invention, the process for preparing the compound of formula (IA) comprises the reaction of a compound of formula (II) with a compound of formula (III),

(II) (III) characterized in that:

said reaction is followed by a salification step by addition of fumaric acid.

After the reaction of a compound of formula (II) with the compound of formula (III), the compound of formula (I) in racemic form (mixture of cis / trans isomers) is obtained. The addition of fumaric acid makes it possible to separate the hemifumarate addition salt from the trans form of formula (IA) because it precipitates and can therefore be easily separated from the cis isomer.

Generally, a half-equivalent of fumaric acid is added, based on the compound of formula (II).

According to the invention, the process for preparing the compound of formula (I) comprises the step of adding base to the compound of formula (IA).

When adding base, the compound of formula (IA) is converted into its basic form, that is to say the compound of formula (I).

The reaction of the compound of formula (II) with the compound of formula (III) can be carried out as described in WO 02/44139. This reaction may be carried out in an organic solvent at a temperature between room temperature and the reflux temperature of the solvent. By ambient temperature is meant a temperature of between 18 ° C and 25 ° C. As a solvent, there may be mentioned ethanol or trimethylorthoformate. Advantageously, sodium borohydride (NaBH ₄ ) or a derivative thereof (such as NaBH ₃ CN) is added. The reaction mixture is preferably stirred at a temperature between 0 ^° C. and room temperature. The reaction mixture obtained can be used as it is for the following of the reaction or can be extracted using an organic solvent, such as ethyl acetate, washed, dried and evaporated according to routine methods to be engaged in the subsequent salification step.

Advantageously, the salification step may be carried out in an organic solvent at a temperature between room temperature and the reflux temperature of the solvent. As a solvent, there may be mentioned ethanol.

After adding fumaric acid, the solubility of the reaction medium is generally observed, while heating, and the formation of a precipitate during cooling. The crystals obtained correspond to the hemifumarate salt of the compound of formula (I), trans (compound (IA)).

The compound of formula (I) can be obtained according to the methods known to those skilled in the art, for example by addition of base, in an organic solvent.

As a base, mention may in particular be made of organic bases such as a solution of ammonia or NH ₄ OH. As organic solvent, there may be mentioned (C1-C4) alkyl acetates, esters, aromatic solvents such as toluene, ethers such as isopropyl-ether or tert-butyl-methyl-ether (TBME) dichloromethane, methyl tetrahydrofuran (THF) and methoxycyclopropane.

The compound of formula (I) thus obtained can be engaged in the subsequent steps of the preparation process leading to the product of formula (A) according to the methods described in WO 02/44139.

The process for preparing the compound of formula (I) may be carried out directly or may comprise the step of separating the compound of formula (IA) after the salification and before the addition of base. This separation can be carried out by any technique known per se, such as filtration, and optionally washing the precipitate with a suitable solvent, wherein the compound of formula (IA) is not soluble. It is thus possible to use the solvent used for the salification step.

Thus, according to another of its objects, the present invention also relates to the compound of formula (IA):

(IA)

This compound is useful as an intermediate in the preparation of the compound of formula (A), by application or adaptation of the methods described in WO 02/44139, WO 03/099819 and WO 03/099772.

According to another object, the present application also relates to a process for the preparation of the compound of formula (A) or a pharmaceutically acceptable salt thereof, comprising the preparation of the compound of formula (I) from the compound of formula (IA) as described above.

Preferentially, the process for preparing the compound of formula (A) or a pharmaceutically acceptable salt thereof also comprises the step of preparing the compound of formula (IA) as described above.

The process for preparing the compound of formula (A) further comprises the following steps:

coupling of the compound of formula (I) thus obtained from the compound of formula (IA) with the compound of formula (IV):

(IV) in which :

Pg represents a protecting group of the alcohol function; Pg 'represents a hydrogen atom or an amino function protecting group; deprotection of the protective groups present in the compc obtained so as to obtain the compound of formula (A); then, optionally - salification, more particularly with hydrochloric acid, so as to obtain the hydrochloride of the desired compound of formula (A).

Preferentially, Pg represents benzyl; preferably, I represents H or a group -C (= O) (OR) where R represents a group (C1- (alkyl), more particularly tert-butyl.

The process for preparing the compound of formula (A) is shown in the scheme below:

(III) (IV)

hydrogenation

Diagram 1 The present invention also relates to the use of the compound of formula (IA) for the preparation of the compound of formula (A) or a pharmaceutically acceptable salt thereof.

In the foregoing, the term "protecting group" is intended to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the reactive function. intact at the end of synthesis. Examples of protecting groups and methods of protection and deprotection are given in Protective Groups in Organic Synthesis, Green et al., ^2nd Edition (John Wiley & Sons, Inc., New York).

The following examples illustrate the invention without limiting it. In these examples and in the description, the following abbreviations are used:

DCM: dichloromethane.

The mass spectra are measured in the so-called Electrospray (ES) ionization mode.

The proton nuclear magnetic resonance spectra ( ¹ H NMR) are recorded at 200 MHz or at 300 MHz in DMSO-dβ or in CDCl3. The chemical shifts δ are expressed in parts per million (ppm).

The signals observed in NMR are expressed as follows: s: singlet; it is: widened singlet; d: doublet; d.d: double doublet; t: triplet; td: split triplet; q: quadruplet; m: massive; mt: multiplet.

* = not integrable due to interference with a wide water-based peak.

Mass spectra were obtained using a Thermoelectron LCQ DecaXP MCX ion trap spectrometer equipped with an ESI source.

¹ L HPLC was performed using a Thermoelectron Surveyor system equipped with a diode bar detector.

Thin layer chromatography was performed on Merck Silica gel 60 silica gel TLC plates. Silica gel for flash column chromatography is commercially available from Biotage. All solvents used are of purity "reagent grade" or "HPLC grade".

Example 1

Step 1: Synthesis of the compound of formula (IA)

In a reactor, 3 g (12.18 mmol) of 4- (4-ethoxycarbonylphenyl) -cyclohexanone are introduced into 36 ml of trimethylorthoformate then 1.56 g (14.61 mmol., 1.2 eq.). N-benzylamine.

The reaction medium is heated under nitrogen for 12 hours, then it is returned to ambient temperature and then evaporated with the rotavapor until an oil is obtained. The residue is engaged as such in the next step.

The imine formed is taken up in 50 ml of ethanol. It is cooled to 5 ° C. and 0.460 g (12.18 mmol, 1 eq) of sodium borohydride are added under nitrogen for 15 minutes. The reaction medium is left stirring for 2 hours at 5 ° C. 15 ml of water are then added, the mixture is stirred for 15 minutes and then extracted with ethyl acetate (50 ml). The organic phase is washed with 15 ml of water and then with 15 ml of a saturated solution of sodium chloride. It is dried over magnesium sulphate, filtered and then evaporated with a rotavapor. The oily residue (trans / cis mixture in an 85/15 ratio of the two amines) is used as it is in the salification step. The crude reaction product is taken up in 50 ml of ethanol. It is heated to 50 ^° C. 0.710 g (0.5 eq) of fumaric acid are added. The medium becomes soluble and is allowed to return to ambient temperature. The precipitate obtained is cooled to 5 ° C. The mixture is filtered and the crystals are washed with 2 times 5 ml of ice-cold ethanol. It is dried under vacuum at 50 ^° C. 2.40 g is obtained 4- [trans-4 - [(phenylmethyl) amino] cyclohexyl] benzoic acid ethyl ester fumarate salt.

Step 2: Synthesis of the compound of formula (I) ethyl ester of the acid

4- [trans-4 - [(phenylmethyl) amino] cyclohexyn benzoic:

In a 100 ml three-necked flask, 2 g (5.06 mmol) of the 4- [trans-4- [(phenylmethyl) amino] cyclohexyl] benzoic acid ethyl fumarate salt are introduced into 50 ml. dichloromethane. 10 ml of a 28% ammonia solution are then added and the mixture is stirred at room temperature for 30 minutes. The two phases are left to settle, then the organic phase is washed with water and then dried with magnesium sulfate. The solution is filtered and evaporated with a rotavapor. 1.60 g of 4- [trans-4 - [(phenylmethyl) amino] cyclohexyl] benzoic acid ethyl ester are obtained in the form of a white solid, ie a yield of 95%. Melting point = 74-76 ° C, TLC: (CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5): R _f trans = 0.40.

The compound thus obtained can be used to prepare the compound of formula (A) by application or adaptation of the methodologies described in WO 02/44139, WO 03/099772 and WO 03/099819, or according to the following steps 3 and 4.

Step 3: Synthesis of 4-Trans-4- (phenylmethyl) - (2S) -3- (4-benzyloxy-3-methanesulfonylamino-phenoxy) -2-hydroxy-propyl-amino-cyclohexyl-4-ethyl ester benzoic:

A mixture of N- [2-Benzyloxy-5 - ((S) -1-oxiranylmethoxy) -phenyl] methanesulfonamide (9.4 kg), ethyl ester of 4- [trans-4- [ phenylmethyl) amino] cyclohexyl] benzoic acid (7.05 kg) and Li-triflate (lithium trifluoromethanesulfonate) (330 g) in a solution of toluene (90 L) is refluxed for 8 h. Allowed to warm to room temperature, then the mixture is diluted in toluene (60 L) and extracted with water (15 L). The organic phase is concentrated under vacuum to a volume of 55 L. Crystallization of the product begins when the concentrate is returned to room temperature. The crystallized mixture was stirred at 5 ⁰ C for 90 minutes, the product was filtered, washed with toluene (6 L) and dried in vacuo at 50 ⁰ C. Yield: 12.84 kg, colorless crystals, Melting point: 99- 100 ⁰ C.

Step 4: Synthesis of the hydrochloride of the compound of formula (A) (4-Ftrans-4 - [(S) -2-Hydroxy-3- (4-hydroxy-3-methanesulfonylamino) ethyl ester hydrochloride phenoxy) -propylaminol-cyclohexyl benzoic acid):

A mixture of 4- (4 - {- phenylmethyl - [(2S) -3- (4-benzyloxy-3-methanesulfonylamino-phenoxy) -2-hydroxy-propyl] -amino trans-ethyl ester cyclohexyl) -benzoic acid (10 kg), Pd (OH) ₂ 20% on carbon (Degussa E101 NE / W, 0.52 kg) and acetic acid (48 kg) is hydrogenated in an autoclave at 50 ^° C./8 bar for 2 hours then the mixture is allowed to come to room temperature overnight under pressure. The mixture is filtered twice and the equipment is rinsed with acetic acid (25 kg). The filtrates are concentrated almost to dryness under vacuum, then ethanol (45 kg) is added, followed by 30% HCl (2 kg). After addition of crystal seeds, the mixture is stirred at 45 ^° C. for 3 h and at 0 ^° C. for 14 h. The crystals are filtered, washed with ethanol (12 kg) and dried under vacuum at 40 ^° C. Yield: 7.58 kg, colorless crystals, mp: 192-193 ^° C.

Claims

1. Process for preparing the compound of formula (IA)

comprising reacting a compound of formula (II) with a compound of formula (III),

(II) (III) characterized in that:

said reaction is followed by a salification step by addition of fumaric acid.

2. The method of claim 1 such that the reaction of the compound of formula (II) and the compound of formula (III) is carried out in the presence of NaBH ₄ or NaBH ₃ CN.

3. Process according to claim 1, wherein the reaction of the compound of formula (II) and of the compound of formula (III) is carried out in ethanol and / or trimethylorthoformate.

4. Process according to any one of the preceding claims, such that the salification is carried out by adding a half-equivalent of fumaric acid, based on the compound of formula (II).

5. Process according to claim 1, 2 or 3, such that the reaction of the compound of formula (II) and of the compound of formula (III) leads to the formation of the compound of formula (I):

as a cis / trans mixture.

6. Method according to any one of the preceding claims, such that it comprises the step of separating the compound of formula (IA) at the end of the salification.

7. The method of claim 6 such that the separation is carried out by filtration.

8. Process for preparing the compound of formula (I)

(I) from the compound of formula (IA):

by adding base.

9. The method of claim 8 wherein said base is ammonia or NH ₄ OH.

10. Process according to any one of the preceding claims, such that it comprises the isolation of the compound obtained.

11. Compound of general formula (IA):

12. Process for preparing a compound of formula (A):

or a pharmaceutically acceptable salt thereof, comprising preparing the compound of formula (I):

(I) from the compound of formula (IA)

according to claim 8 or 9.

A process for preparing a compound of formula (A) according to claim 12, comprising preparing the compound of formula (IA) according to any one of claims 1 to 7.

A process for preparing a compound of formula (A) according to claim 12 or 13, comprising the subsequent steps of:

coupling of the compound of formula (I) and the compound of formula (IV);

(IV) wherein:

Pg represents a protecting group of the alcohol function;

Pg 'represents a hydrogen atom or a group protecting the amine function;

deprotection of the protective groups present in the compound obtained so as to obtain the compound of formula (A); then, eventually

salification, so as to obtain the salt of the compound of formula (A) desired.

15. The process of claim 14 wherein Pg is benzyl.

16. The process of claim 14 or 15 wherein Pg is H or -C (= O) (OR) where R is (C1-C4) alkyl.

17. Use of the compound of formula (IA):

for the preparation of a compound of formula (A)

or a pharmaceutically acceptable salt thereof.