MXPA99005398A - Process for the preparation of nmda antagonists - Google Patents

Abstract

This invention relates to an improved process for the production of known amine compounds of formula (I) which are useful as medicaments, wherein:R1 and R2 are independently phenyl or 4-fluorophenyl;R3 is hydrogen, alkyl C1-4 or methoxycarbonyl;R4 is hydrogen or methyl;which comprises reaction of a compound of formula (II) with a compound of formula (III) in which R5, R6, R7, R8, R9 and R10 are independently C1-6 alkyl followed by deprotection and optionally thereafter forming a pharmaceutically acceptable salt.

Description

PROCESS FOR THE PREPARATION OF NMDA ANTAGONISTS This invention relates to an improved process for the production of known amine compounds that are useful as medicaments.

European Patent EP 279937 describes a group of compounds that are indicated as anticonvulsants. The compound of Example 1, 2-amino-N- (1, 2-diphenyl-1-methylethyl) -aceta ida hydrochloride (having the INN Remacemide hydrochloride), is tested in clinical trials.

The known processes for the production of 2-amino-1 - (1, 2-diphenyl-1-met ilet-il) acetamide and its analogues have the disadvantage of low yields. Example 1 of European Patent EP 279937 provides 2-amino-N- (1, 2-diphenyl-1-methylethyl) acetamide hydrochloride in only 32% yield based on the initiator material 1,2-diphenyl-2-propylamine . The process in question comprises the coupling of Cbz-glycine with 1,2-diphenyl-2-propylamine in the presence of DCC, followed by removal of the Cbz group by hydrogenolysis. Ref.: 30387 In addition, the products of such known processes require considerable purification before being used in pharmaceutical formulations. Now it has surprisingly been found that a different process has the greatly improved performance advantage and, therefore, provides the desired product with good purity.

Therefore in a first aspect the present invention provides a process for the production of a compound of the formula (I) or a pharmaceutically acceptable salt thereof: where R1 and Fr are independently phenyl 4-fluorophenyl; R is hydrogen, C? -4 alkyl or methoxycarbonyl; R 4 is hydrogen or methyl; which comprises the reaction of a compound of formula II: wherein R1, R2, R and R4 are as defined in formula (I), with a compound of formula (III): wherein R5, R6, R7, -R8, R9 and R10 are independently C6-C6 alkyl to give a compound of the formula (IV): (TV) wherein R1, R 'R' R-10 and R are as defined in formula (I), followed by deprotection and then optionally form a pharmaceutically acceptable salt.

The pharmaceutically acceptable salts of the compounds of the formula I include the acid addition salts, in particular hydrochloride salts. Such salts are prepared using standard procedures known in the art.

Suitably R1 and R2 are independently phenyl or 4-fluorophenyl, preferably R1 and R2 are phenyl.

Suitably R is hydrogen, C 1 - or methoxycarbonyl, preferably R 3 'is C 1 -4 alkyl, in particular methyl.

Suitably R4 is hydrogen or methyl, preferably R4 is hydrogen.

More preferably the above process is used to prepare the compound of formula I which is 2-amino-N- (1, 2-diphenyl-1-met ilet-il) acetamide, or a pharmaceutically acceptable salt thereof. Suitable salts include acid addition salts such as hydrohalide salts, preferably the hydrochloride salt.

Suitably R R 'R "R" R "and R are independently C 1-6 alkyl, preferably R 1, R 2, R 3, R 4, R 8, R 9 and R 10 are methyl, such that R 8, R 9 and R 10 are part of a Boc protecting group.

The mixed anhydrides of the formula (III) are prepared by reacting a compound of the formula (V): (V) wherein R5, R6 and R7 are as defined in formula (III) and L is a leaving group with a compound of formula (VI): wherein R8, R9 and R10 are as defined in formula (III). Suitably L is a leaving group, in particular halogen and preferably chlorine. The formation of mixed anhydrides of the formula (III) and their reaction with compounds of the formula (II) is preferably carried out in the temperature range from about -30 to about 10 ° C, preferably at about -10 ° C to about 10 ° C more preferably at about -5 ° C. Preferably the mixed anhydrides of the formula (III) are not isolated but react with compounds of the formula (II) in a one-step process.

Preferably the formation of the anhydride The mixture of the compounds (V) and (VI) is carried out in the presence of an organic base such as a tertiary organic amine, for example, diisopropylamine, N-methylmorpholine and trialkylamines such as tri-ethylamine and triethylamine. Preferred bases include triethylamine. Preferably the compound of the formula (V) is mixed with the compound of the formula (VI) followed by the addition of the amine. This procedure has been found to reduce the need for the excess reagents to force the reaction of the compounds of the formula (V) and (VI) to be completed.

The compounds of the formula (V) and (VI) are commercially available or can be prepared using the standard procedures. For example, the preferred compound of the formula (V) wherein R5, R6 and R7 are methyl and L is chloro is commercially available pivaloyl chloride. The preferred compound of the formula (VI) wherein R8, R9 and R10 are methyl is commercially available Boc-glycine.

The reaction of the mixed anhydride can be carried out in any appropriate solvent. Examples of Suitable solvents include dimethoxyethane, t-butyl methyl ether, THF, chloroform, xylene, toluene and dichloromethane. Preferably the reaction of the mixed anhydride is carried out using toluene or dichloromethane as the solvent, and more preferably dichloromethane.

Preferably the reaction of the mixed anhydride is carried out under an inert gas atmosphere, preferably under a nitrogen atmosphere.

Preferably the formation of compounds of the formula (IV) is followed by a deprotection etapß in which the protecting group is removed by any appropriate means. Preferably when the protecting group is a Boc group it is removed by acid hydrolysis. This can be carried out in an appropriate solvent such as isopropanol. The products of the process are then of such purity that they could be used in pharmaceutical formulations without further purification. Alternatively the product can be purified by conventional means, for example by recrystallization from an appropriate solvent system such as methanol / IPA. Therefore in a further aspect the invention provides a process as described above including recrystallization of the compound of the formula (I) or a salt thereof.

New intermediaries also form an aspect of the invention. Therefore the invention provides a compound of the formula (III), as defined above.

The compounds of the formula (II) can be prepared by the methods described in European Patent EP 279937. The compound of the formula (III) can be prepared by methods well known to those skilled in the art as illustrated below.

The following conventional abbreviations used in this application will be well known to those skilled in the art: Cbz benzyloxycnyl Boc terbutyloxycnyl DCC dicyclohexylcdii ida The invention is illustrated by the following examples. Example 1 Preparation of 2-amino-iV- (1, 2-diphenyl-1-meleyl) acetamide hydrochloride (a) 2- (erbutyloxycnylamino) -N- (1, 2-diphenyl-1-methylethyl) acetamide A reaction vessel was charged with dichloromethane (360 1) and Boc-glycine (32.6 kg, 186.3 mol). Triethylamine (18.8 kg, 186.1 mol) was cautiously added maintaining the temperature below 25 ° C. The mixture was cooled to below -5 ° C and pivaloyl chloride (trimethylacetyl chloride, 22.4 kg, 185.9 mol) in dichloromethane (40 1) was added at such a rate as to maintain the temperature below -5 ° C. This was washed with dichloromethane (2 1). After the mixture was stirred below -5 ° C for 2-2.5 h and then 1,2-diphenyl-2-r-ropylamine hydrochloride (40 kg, 161.1 mole, estimated dry weight, current weight including wet 42.94 kg was added) ) as a solid through the orifice keeping the temperature below -5 ° C. Then triethylamine (28.4 kg, 281.2 mol) was added keeping the temperature below -5 ° C. This was washed with dichloromethane (2 1). The mixture was stirred below -5 ° C for 2.75-3.25 h, water (400 1) was added and the mixture was stirred for at least 15 min. The organic layer was separated and washed with dilute hydrochloric acid made from concentrated hydrochloric acid (40 1) and water (400 1). The organic layer was separated again and then approximately 80% (360 1) of the dichloromethane was removed by distillation. Then, isopropyl alcohol (140 1) was charged and the distillation was continued until the head temperature reached 80 ° C. The solution was then cooled and isopropyl alcohol was added to make a total weight of 200 kg. Then this solution was divided into two by weight and each half was used directly in the next stage. (b) 2-amino-iV- (1, 2-diphenyl-1-methylethyl) acetamide hydrochloride A reaction vessel was charged with half the product of step (a) in the propan-2-ol solution of the previous reaction (100 kg total gypsum), plus propan-2-ol (179.4 kg) and methanol (61.2) 1) . He The vessel was purged with nitrogen and then concentrated hydrochloric acid (15.8 kg) was added to the solution. The solution was refluxed for 2-3 h, and then filtered through a line filter in a second vessel. The first reaction vessel and the filter were washed with methanol (8 kg) in the second vessel. Then the vessel was heated and the solvent was distilled to remove excess methanol. The distillation was continued until 125 kg of distillate (a mixture of methanol and propan-2-ol) was removed. The vessel was cooled to -5 ° C for about 2 h and the final product was filtered and washed with cold propan-2-ol (-5 ° C) (25 1). The product was dried in a vacuum vessel to give the final product as an almost white solid (21.4 kg, 87% overall yield of 1,2-diphenyl-2-propylamine hydrochloride).

The product was sufficiently pure to be used in the pharmaceutical formulations without further purification.

Example 2 Preparation of 2-amino-N- (1, 2-diphenyl-1-methylethyl) acetamide hydrochloride (Remacemide hydrochloride) (a) A mixture of 1,2-diphenyl-2-propylamine hydrochloride (40 g, 0.1507 mol) and toluene (100 ml) was stirred at room temperature under a nitrogen atmosphere. Triethylamine (46.1 ml, 0.3315 mol) was added as a single portion and stirring of the resulting mixture was continued. (b) A mixture of BOC-glycine (30.3 g, 0.1733 mol) and toluene (486 ml) was stirred under a nitrogen atmosphere. Pivaloyl chloride (21.3 ml, 0.1733 mol) was added in a single portion. Immediately after the addition, the contents of the reactor were cooled to -5 ° C. Triethylamine (17.5 g, 0.1733 mol) was added for one hour with the contents of the vessel maintained at -5 ° C. After the addition was complete the reaction mixture was stirred for 2 hours. The suspension of 1,2-diphenyl-2-propylamine hydrochloride prepared in (A) was added for 30 minutes at the temperature of the container maintained at -5 ° C. After this addition was complete, the reaction mixture was stirred for an additional 3 hours and then water (250 ml) was added and the internal temperature was allowed to warm to 20 ° C. The mixture was stirred for 45 minutes and then the toluene layer was separated. The HPLC analysis showed 96.4% conversion to the required BOC-Remacemide. This solution was used directly in the deprotection step. (c) A toluene solution of BOC-remacemide (containing an estimated 0.3013 mol of BOC-remacemide) was stirred at 65 ° C. Hydrochloric acid (52 ml) was added for 10 minutes and then the mixture was stirred at 65 ° C for 1.5 hours, a solid precipitated during this time.

The mixture was heated to reflux and the solvent was collected by distillation. 310 ml of solvent was collected and the head temperature of the distillation had reached 98 ° C. The mixture was cooled to -5 ° C then filtered and the reaction flask was washed with toluene (2 x 30 mL). The wet mass was 127.7 g. The filtered residue was dried in va cuo at 80 ° C to give 88. 2 g of crude remacemide hydrochloride which represents a yield of 96.1% with respect to 1,2-diphenyl-2-propylamine hydrochloride.

Example 3 Crystallization of remacemide hydrochloride A mixture of remacemide hydrochloride (50 g) and methanol (200 ml) was stirred and heated to reflux to form a solution. This was the minimum volume of methanol required to form a solution. The solution was filtered through 0.2m and then washed with methanol (12ml).

The solution was re-heated to reflux and the solvent was removed by distillation, with 50 ml of the distillate that was collected. Then, isopropanol (400 ml) was added, which initiated the precipitation. The distillation was continued with another 410 ml of the distillate that was collected. The mixture was cooled to -5 ° C, diluted with isopropanol (100 ml) and the purified remacemide hydrochloride was collected by filtration then dried in vacuo at 65 ° C. The mass of the material dry purified was 46.05 g (92% recovered).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (18)

1. A process for the production of a compound of the formula (I) or a pharmaceutically acceptable salt thereof: where : R1 and R2 are independently phenyl or -fluorophenyl; R3 is hydrogen, C4-4 alkyl or methoxycarbonyl; R 4 is hydrogen or methyl; which process is characterized in that it comprises the reaction of a compound ae to formula II. wherein R1, R2, R3 and R4 are as defined in formula (I), with a compound of formula (III): wherein R5, R6, R7, R8, R9 and R10 are independently C6_6 alkyl to give a compound of the formula (IV): wherein R1, R2, R3, R4, R8, R9 and R10 are as defined in formula (I), followed by deprotection and then optionally forming a pharmaceutically acceptable salt.

2. A process as claimed in claim 1, characterized in that R1 and R2 are phenyl.

3. A process as claimed in claim 1 or 2, characterized in that R3 is C? -4 alkyl.

4. A process as claimed in any of claims 1 to 3, characterized in that R4 is hydrogen.

5. A process according to any of claims 1 to 4, characterized in that R1, R2, R3, R8, R9 and R10 are methyl.

6. A process according to any one of claims 1 to 5, cross-linked because the compound of the formula I is 2-amino-N- (1, 2-diphenyl- 1-methylethyl) acetamide, or a pharmaceutically acceptable salt thereof.

7. A process according to any of claims 1 to 6, characterized in that the reaction of the mixed anhydride is carried out in a temperature range from about -30 to about 10 ° C.

8. A process according to any of claims 1 to 6, characterized in that the reaction of the mixed anhydride is carried out at about -5 ° C.

9. A process according to any of claims 1 to 8, characterized in that the reaction of the mixed anhydride is carried out using dichloromethane as the solvent.

10. A process according to claims 1 to 9, characterized in that the reaction of the mixed anhydride is carried out under a nitrogen atmosphere.

11. A process according to any of claims 1 to 10, characterized in that the compound of the formula (III) is prepared by mixing a compound of the formula (V): wherein R5, R6 and R7 are as defined in formula (III) and L is a leaving group with a compound of formula (VI): wherein R8, R9 and R10 are as defined in formula (III) followed by the addition of an organic amine.

12. A process according to claim 11, characterized in that the organic amine is triethylamine.

13. A process according to any of claims 1 to 12, characterized in that the reaction of the mixed anhydride is followed by the removal of the protecting group of the compound of the formula (IV) by acid hydrolysis.

14. A process according to any of claims 1 to 13, characterized in that it further comprises recrystallization of the compound of the formula (I) or a salt thereof.

15. A process according to claim 14, characterized in that the recrystallization is carried out using methanol / IPA.

16. A process of agreement.:. Claim 14 or 15, characterized in that the compound of the formula (I) is 2-amino-N- (1, 2-diphenyl-1-methylethyl) acetamide hydrochloride.

17. 2-amino-N- (1, 2-diphenyl-1-methylethyl) acetamide, or a pharmaceutically acceptable salt thereof, characterized in that it is prepared by a process as defined in any of claims 1 to 16.

18. A compound of the formula (III), * characterized in that it is co-defined in the claim. 1 .