| 摘要 |
#CMT# #/CMT# Preparation of (3-chloro-4-fluorophenyl)-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)amino]methyl}piperidinyl-1-yl)methanone (2) by reacting 5-methylpyrimidine-2-methylamine (1) with 1-(4-fluoro-3-chlorobenzoyl)-4-fluoro-4-(hydroxycyanomethyl)piperidine (3). #CMT# : #/CMT# Preparation of (3-chloro-4-fluorophenyl)-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)amino]methyl}piperidinyl-1-yl)methanone (2) by reacting 5-methylpyrimidine-2-methylamine (1) with 1-(4-fluoro-3-chlorobenzoyl)-4-fluoro-4-(hydroxycyanomethyl)piperidine (3). Independent claims are included for the following: (1) 5-methylpyrimidine-2-methylamine (1) as new; and (2) three pyrimidine derivatives of formula (4) as new compounds. one or R 1and R 2H and the other is tert-butoxycarbonyl or benzyloxycarbonyl, or R 1and R 2together complete phthalimido. #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# None given. #CMT#MECHANISM OF ACTION : #/CMT# 5-Hydroxytryptamine agonist. #CMT#USE : #/CMT# (2) is known () as a selective agonist of serotoninergic receptors of subtype 5-HT 1A, potentially useful for treating disorders of the serotoninergic system. #CMT#ADVANTAGE : #/CMT# The new method provides a yield of (2) of over 50% (compare below 30% for the known method), also the amount of effluents generated and costs are reduced and purification of (2) is simplified. #CMT#ORGANIC CHEMISTRY : #/CMT# Preferred Process: This is done in presence of a water-scavenging agent, especially a molecular sieve. Starting Materials: (1) (1) is prepared from compounds (4), themselves prepared by reacting R-CH=CHMe-CHO (A) and NH 2-C(=NH)-NR 1>R 2>(B). (2) (1) may also be prepared from a protected compound (4-1), similar to (4) but with NH 2replaced by NR 4>R 5>, and (4-1) are prepared by essentially the same methods as (4), using the corresponding protected version of (B). R : OEt, NH 2, NMe 2or a releasable group, particularly MeO. #CMT#EXAMPLE : #/CMT# A mixture of 5-methylpyrimidine-2-methylamine dihydrochloride (8.31 g); 1-(4-fluoro-3-chlorobenzoyl)-4-fluoro-4-(hydroxycyanomethyl)-piperidine (13.2 g); 1,4-diazabicyclo[2,2,2]octane (14.7 g); sodium cyanoborohydride (2.7 g), 4A molecular sieve (13 g) and methanol (250 ml) was stirred at 50[deg]C for 6 hours. Insolubles were filtered off, the filtrate concentrated under reduced pressure, and the residue taken up in water for extraction with dichloromethane (DCM). The combined organic phases were extracted with 2N HCl and combined aqueous phases washed with ethyl acetate, then made basic and extracted with DCM. The DCM extracts were dried and concentrated in vacuo to give 11.87 g (71%) of (3-chloro-4-fluorophenyl)-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)amino]methyl}piperidinyl-1-yl)methanone (2), m. pt. of the fumarate 105[deg]C (decomposition). |
