Benexate cyclodextrin, TKG01 clathrate cpd., TA-903, Lonmiel, Ulgut

Chemical Name: trans-4-(Guanidinomethyl)cyclohexanecarboxylic acid 2-(benzyloxycarbonyl)phenyl ester hydrochloride 1:1 complex with beta-cyclodextrin; trans-2-[4-(Guanidinomethyl)cyclohexylcarbonyloxy]benzoic acid benzyl ester hydrochloride 1:1 complex with beta-cyclodextrin; trans-2-O-[4-(Guanidinomethyl)cyclohexylcarbonyl]salicylic acid benzyl ester hydrochloride 1:1 complex with beta-cyclodextrin
CAS No. 86157-91-7
项目整合开发状态: Launched-1987
项目研究机构: Nagase (Originator), Nippon Chemiphar (Originator), Shionogi (Originator), Teikoku Chemical (Originator)
合成路线:The condensation of S-methylisothiourea (I) with trans-4-(aminomethyl)cyclohexanecarboxylic acid (II) by means of NaOH in water gives trans-4-(guanidinomethyl)cyclohexanecarboxylic acid (III) (I),which is esterified with benzyl salicylate (IV) by means of dicyclohexylcarbodiimide (DCC) or SOCl2 yielding 2-benzyloxycarbonylphenyl trans-4-(guanidinomethyl)cyclohexanecarboxylate (V).Finally,this compound is treated with cyclodextrin in aqueous solution to afford the corresponding complex.

合成路线:1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.

合成路线:2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V),which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI).Finally,cornpound (VI) is treated with ethyl chloroformate (II) in toluene.

合成路线:Alcoholysis of 3-methylpyridine-2-carbonitrile (I) with hot tert-butanol and H2SO4 gives the N-tert-butylcarboxamide (II),which is alkylated with 3-chlorobenzyl chloride (III) and BuLi in THF,yielding N-tert-butyl-3-[2-(3-chlorophenyl)ethyl]pyridine-2-carboxamide (IV).The reaction of (IV) with refluxing POCl3 and then with NaOH affords the corresponding nitrile (V),which is condensed with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF to give the ketone (VII).Cyclization of (VII) by means of either BF3 in HF or trifluoromethanesulfonic acid yields 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII),which is reacted with cyanogen bromide in benzene to give the N-cyano compound (IX).Finally,this compound is treated with HCl in refluxing acetic acid/water.Alternatively,8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII) is treated with ethyl chloroformate in hot toluene,affording the carbamate (X) (2),which is finally decarboxylated with KOH or NaOH in refluxing ethanol/water.