Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1998-02-24
2000-05-16
O'Sullivan, Peter
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
560 41, 560157, 560160, 564196, C07C23114, C07C23102, C07C23112
Patent
active
060639628
DESCRIPTION:
BRIEF SUMMARY
This invention relates to an improved process for the production of known amine compounds which are useful as medicaments.
European Patent EP 279937 describes a group of compounds which are indicated as anticonvulsants. The compound of Example 1, 2-amino-N-(1,2-diphenyl-1-methylethyl)acetamide hydrochloride (which has the INN Remacemide hydrochloride), is undergoing clinical trials.
Known processes for the production 2-amino-N-(1,2-diphenyl-1-methylethyl)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 1,2-diphenyl-2-propylamine starting material. The process in question comprises coupling of Cbz-glycine with 1,2-diphenyl-2-propylamine in the presence of DCC, followed by removal of the Cbz group by hydrogenolysis.
In addition, the products of such known processes require considerable purification before they can be used in pharmaceutical formulations. It has now surprisingly been found that a different process has the advantage of greatly improved yield and, furthermore, provides the desired product with good purity.
In a first aspect the present invention therefore provides a process for the production of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR1## wherein: R.sup.1 and R.sup.2 are independently phenyl or 4-fluorophenyl; ##STR2## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in formula (I), with a compound of formula (III): ##STR3## in which R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are independently C.sub.1-6 alkyl to give a compound of formula (IV): ##STR4## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.8, R.sup.9 and R.sup.10 are as defined in formula (I), followed by deprotection and optionally thereafter forming a pharmaceutically acceptable salt.
Pharmaceutically acceptable salts of the compounds of formula I include acid addition salts, in particular hydrochloride salts. Such salts are prepared using standard procedures known in the art.
Suitably R.sup.1 and R.sup.2 are independently phenyl or 4-fluorophenyl, preferably R.sup.1 and R.sup.2 are both phenyl.
Suitably R.sup.3 is hydrogen, C.sub.1-4 alkyl or methoxycarbonyl, preferably R.sup.3 is C.sub.1-4 alkyl, in particular methyl.
Suitably R.sup.4 is hydrogen or methyl, preferably R.sup.4 is hydrogen.
Most preferably the above process is used to prepare the compound of formula I which is 2-amino-N-(1,2-diphenyl-1-methylethyl)acetamide, or a pharmaceutically acceptable salt thereof. Suitable salts include acid addition salts such as hydrohalide salts, preferably the hydrochloride salt.
Suitably R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.8, R.sup.9 and R.sup.10 are independently C.sub.1-6 alkyl, preferably R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.8, R.sup.9 and R.sup.10 are all methyl, such that R.sup.8, R.sup.9 and R.sup.10 forms part of a Boc protecting group.
The mixed anhydrides of formula (III) are prepared by reacting a compound of formula (V): ##STR5## in which R.sup.5, R.sup.6 and R.sup.7 are as defined in formula (III) and L is a leaving group with a compound of formula (VI): ##STR6## in which R.sup.8, R.sup.9 and R.sup.10 are as defined in formula (III). Suitably L is a leaving group, in particular halogen and preferably chloro. The formation of mixed anhydrides of formula (III) and their reaction with compounds of formula (II) is preferably carried out in the temperature range of about -30 to about 10.degree. C., preferably at about -10.degree. C. to about 10.degree. C. more preferably at about -5.degree. C. Preferably the mixed anhydrides of formula (III) are not isolated but are reacted with compounds of formula (II) in a one-pot procedure.
Preferably the formation of the mixed anhydride from 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 trimethylamine and triethylamine. Prefe
REFERENCES:
Wender et al, "The Intramolecular Addition of Silylated Alkynes to Aldehydes: Methodology . . . ," Tetrahedron Letters, vol. 36, No. 2, pp. 209-212 (1995).
Astra Pharmaceuticals Limited
O'Sullivan Peter
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