合成路线1

LY246736 dihydrate is prepared in 12 steps from 1,3-dimethyl-4-piperidone (I) in 6.2% yield as depicted in Scheme 20754901a. Piperidinol (II) can be prepared from (I) using standard methodology. Selective elimination to tetrahydropyridine (IV) is accomplished by the cis-thermal elimination of an ethyl carbonate (III) at 190 C in refluxing Decalin(R). This maintains the stereochemistry at C-3, following resolution of carbonate (III) with di-p-toluoyl-D-tartaric acid ((+)-DDTA), and also enables the trans-stereochemistry of the methyl groups to be established in the next step. Alkylation of the metalloenamine with dimethyl sulfate at -50 C proceeds both regio- and stereospecifically, giving the trans-3,4-dimethyl-gamma-alkylation product (V). Reduction of the enamine with NaBH4 and N,O-didealkylation with phenyl chloroformate followed by HBr/AcOH gives the chiral 3,4-dimethyl-4-arylpiperidine (VII). The benzyl group of the N-substituent is introduced via a nonselective benzylation of the Michael adduct dianion at -20 C followed by a highly efficient crystallization of the (3R,4R,alphaS)-hydrochloride (VIII) from methanol. The undesired diastereomer can be epimerized (LDA, H2O) and recycled to afford additional (VIII). Hydrolysis of the ester with NaOH, DCC coupling of the glycine ester, and hydrolysis of the ester with NaOH in ethanol/water completes the synthesis. The crystalline dihydrate (X) is isolated directly from the saponification reaction mixture upon neutralization with hydrochloric acid (overall yield 6.2% with one recycle of (3R,4R,alphaR)-isomer of (VIII).

合成路线2

Condensation of 1,3-dimethyl-4-piperidone (I) with aniline in the presence of titanium tetraisopropoxide produced imine (II). This was reduced with NaBH4 to give the corresponding amine as a mixture of geometric isomers, from which the desired cis isomer (III) was isolated by column chromatography. Coupling of (III) with 4-fluorobenzoate ester (IV) in the presence of butyllithium yielded the diaryl amine (V). Removal of the 2,6-di-tert-butyl-4-methoxyphenyl ester of (V) was accomplished by transesterification with sodium methoxide, followed by saponification of the methyl ester. The resulting carboxylic acid (VI) was then converted into diethyl amide (VII) using diethylamine and BOP reagent. N-Demethylation of (VII) with phenyl chloroformate furnished the phenyl carbamate (VIII), that was further hydrolyzed and decarboxylated to give piperidine (IX). This was finally alkylated with allyl bromide in the presence of K2CO3.

合成路线3