KC-12615

Chemical Name: 2-[3(S)-[1-[2(R)-Carboxy-4-phenylbutyl]cyclopentan-1-ylcarboxamido]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid
CAS No. 182821-29-0, 204781-69-1 (diNa salt), 182561-00-8 (racemate), 204781-61-3 (stereoisomer), 182560-86-7 (undefined stereoch.)
项目整合开发状态: Phase II
项目研究机构: Solvay (Originator)
合成路线:1) The acylation of the chiral amine (I) with the chiral cyclopentanecarboxylic aid (II) by means of N-methylmorphline (NMM),hydroxybenzotriazole (HOBT) and N-(dimethylaminopropyl)-N'-ethylcarbodiimide (EDT) in dichloromethane gives the amide (III),which is then treated with trifluoroacetic acid to elimnate the tert-butyl ester groups.

合成路线:2) The chiral intermediates the amine (I) and the acid (II) have been obtained as follows: 2a) The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V),which is treated with hydroxylamine yielding the corresponding oximae (VI).The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII),which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX).The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI),which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I).Finally,this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).

合成路线:2b) The alkylation of 2-(dimethoxyphosphoryl)acetic acid tert-butyl ester (XII) with 2-phenylethyl bromide (XIII) by means of potassium tert-butoxide in DMF gives 2-(dimethoxyphosphoryl)-4-phenylbutyric acid tert-butyl ester (XIV),which is allowed to react with formaldehyde/potasium tert-butoxide in THF to afford the tert-butyl acrylate (XV).The condensation of (XV) with cyclopentanecarboxylic acid (XVI) by means of butyllithium/diisopropylamine in THF affords racemic (II),which is finally submitted to optical resolution with L-(-)-alpha-methylbenzylamine to afford the chiral (R)-intermediate (II).

合成路线:1) The acylation of the chiral amine (I) with the chiral cyclopentanecarboxylic aid (II) by means of N-methylmorphline (NMM),hydroxybenzotriazole (HOBT) and N-(dimethylaminopropyl)-N'-ethylcarbodiimide (EDT) in dichloromethane gives the amide (III),which is then treated with trifluoroacetic aid to elimnate the tert-butyl ester group.

合成路线:2a) The chiral intermediate amine (I) has been obtained as follows:The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V),which is treated with hydroxylamine yielding the corresponding oximae (VI).The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII),which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX).The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI),which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I).Finally,this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).

合成路线:2b) The chiral intermediate acid (II) has been obtained as follows:The alkylation of diethyl malonate (XII) with 2-phenylethyl bromide (XIII) by means of potassium tert-butoxide in DMF gives diethyl 2-(2-phenylethyl)malonate (XIV),which is treated with KOH in ice-cooled water to afford the corresponding monoester monoacid (XV).The reacction of (XV) with formaldehyde in piperidine/water gives teh acrylate (XVI),which is condensed with cyclopentanecarboxylic acid (XVII) by meansof butyllithium/diisopropylamine in THF to afford racemic (II).Finally,this racemate is submitted to optical resolution with L-(-)-alpha-methylbenzylamine to afford the chiral (R)-intermediate (II).