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).

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).

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).

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).

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).