新产品编号:783599

Chemical Name: 3-Cyclopropyl-2(R)-[3(S)-[4-[3,3-difluoro-3-(4-fluorophenyl)propyl]piperidin-1-ylmethyl]-4(S)-(3-fluorophenyl)pyrrolidin-1-yl]propionic acid
CAS No. 301183-74-4
项目整合开发状态: Preclinical
项目研究机构: Merck & Co. (Originator)
合成路线:m-Fluorocinnamic acid (I) is coupled to (S)-4-benzyloxazolidin-2-one (II),via the corresponding mixed anhydride with pivaloyl chloride,to furnish the N-cinnamoyl oxazolidinone (III).Cycloaddition of (III) with N-methoxymethyl-N-trimethylsilylmethyl benzylamine (IV) in the presence of trifluoroacetic acid produces a mixture of the diastereoisomeric pyrrolidines (V) and (VI),separable by column chromatography.The desired isomer (V) is then reduced by means of LiAlH4 to the primary alcohol (VII),which is further protected by silylation with t-butyldimethylsilyl chloride.The resultant silyl ether (VIII) is then subjected to benzyl group cleavage under transfer hydrogenation conditions,producing pyrrolidine (IX) (1).

合成路线:Diazotization of L-cyclopropylalanine (X) with NaNO2/H2SO4 gives rise to the chiral hydroxy acid (XI).Subsequent treatment of hydroxyacid (XI) with p-methoxybenzyl chloride (XII) in the presence of Et3N furnishes the corresponding p-methoxybenzyl ester (XIII).Hydroxy ester (XIII) is then converted to triflate (XIV),which is further condensed with pyrrolidine (IX) to yield amino ester (XV).Desilylation of (XV) with tetrabutylammonium fluoride affords alcohol (XVI).This is then subjected to Swern oxidation to provide aldehyde (XVII) (1).

合成路线:4-(Hydroxymethyl)piperidine (XVIII) is protected as the N-Boc derivative (XIX) with Boc2O in CH2Cl2.Conversion of alcohol (XIX) into the corresponding mesylate,followed by treatment with NaI in acetone,furnishes the alkyl iodide (XX).Quaternization of triphenylphosphine with iodide (XX) in refluxing acetonitrile gives rise to the phosphonium salt (XXI).

合成路线:Addition of 4-fluorophenylmagnesium bromide (XXII) to dimethyl oxalate (XXIII) leads to methyl 4-fluorobenzoylformate (XXIV).Subsequent fluorination of (XXIV) employing diethylaminosulfur trifluoride affords the gem-difluoro ester (XXV).Reduction of ester (XXV) with NaBH4 in cold MeOH gives rise to the aldehyde hemiacetal (XXVI).Then,Wittig condensation of hemiacetal (XXVI) with the ylide generated from phosphonium salt (XXI) provides olefin (XXVII).This is partly reduced to the saturated compound (XXVIII) by treatment with in situ generated diimide,and completely reduced to (XXVIII) by catalytic hydrogenation over iridium black.Cleavage of the N-Boc protecting group of (XXVIII) to furnish piperidine (XXIX) is accomplished by means of iodotrimethylsilane in CHCl3.

合成路线:Reductive condensation between piperidine (XXIX) and aldehyde (XVII) in the presence of NaBH(OAc)3 leads to adduct (XXXVIII).The p-methoxybenzyl ester group of (XXXVIII) is then removed by hydrogenolysis over Pearlman's catalyst to provide the title carboxylic acid.