J-104871, -Drug Synthesis Database

【结构式】

【药物名称】J-104871

【化学名称】5(S)-[N-[2(R)-(1,3-Benzodioxol-5-yl)-5-(2-benzoxazolyl)-1(R)-methyl-4(E)-pentenyl]-N-(2-naphthylmethyl)carbamoyl]-1,3-dioxolane-2,2,4(R)-tricarboxylic acid

【CA登记号】191088-19-4

【分子式】C₃₈H₃₂N₂O₁₂

【分子量】708.68494

【开发单位】Banyu (Originator)

【药理作用】Farnesyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways

合成路线1 合成路线2

合成路线1

Intermediate amine (X) was prepared as follows: Alkylation of 3,4-(methylenedioxy)phenylacetone (I) with iodoacetaldehyde diethyl acetal (II) provided racemic ketone (III), which was diastereoselectively reduced to alcohol (IV) with L-Selectride. Resolution was effected by esterification with (R)-alpha-methoxyphenylacetic acid, followed by chromatographic separation of the diastereoisomeric esters. The required isomer (V) was hydrolyzed under alkaline conditions and the resulting alcohol was converted to mesylate (VI) by treatment with methanesulfonyl chloride and Et3N. Displacement of the mesylate group of (VI) with NaN3 with inversion of the configuration yielded azide (VII), which was reduced to amine (VIII) using PPh3. Then, reductive condensation of (VIII) with 2-naphthalenecarboxaldehyde in the presence of NaBH4 afforded the secondary amine (X).

参考文献中间体

【1】 Aoyama, T.; et al.; A new class of highly potent farnesyl diphosphate-competitive inhibitors of farnesyltransferase. J Med Chem 1998, 41, 2, 143.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	28466	1-(1,3-benzodioxol-5-yl)acetone	4676-39-5	C₁₀H₁₀O₃	详情	详情
(II)	28467	1,1-diethoxy-2-iodoethane		C₆H₁₃IO₂	详情	详情
(III)	28468	3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-2-pentanone		C₁₆H₂₂O₅	详情	详情
(IV)	28469	(2S,3R)-3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-2-pentanol		C₁₆H₂₄O₅	详情	详情
(V)	28470	(1S,2R)-2-(1,3-benzodioxol-5-yl)-4,4-diethoxy-1-methylbutyl (2R)-2-methoxy-2-phenylethanoate		C₂₅H₃₂O₇	详情	详情
(VI)	28471	(1S,2R)-2-(1,3-benzodioxol-5-yl)-4,4-diethoxy-1-methylbutyl methanesulfonate		C₁₇H₂₆O₇S	详情	详情
(VII)	28472	5-[(1R)-1-[(1R)-1-azidoethyl]-3,3-diethoxypropyl]-1,3-benzodioxole		C₁₆H₂₃N₃O₄	详情	详情
(VIII)	28473	(1R,2R)-2-(1,3-benzodioxol-5-yl)-4,4-diethoxy-1-methylbutylamine		C₁₆H₂₅NO₄	详情	详情
(IX)	28474	2-Naphthaldehyde	66-99-9	C₁₁H₈O	详情	详情
(X)	28475	(2R,3R)-3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-N-(2-naphthylmethyl)-2-pentanamine		C₂₇H₃₃NO₄	详情	详情

合成路线2

Partial hydrolysis of dimethyl D-tartrate (XI), followed by esterification with diphenyldiazomethane provided benzhydryl methyl tartrate (XII). Subsequent condensation of (XII) with diethyl dibromomalonate in the presence of NaH produced dioxolane (XIII). Hydrogenolytic removal of the benzhydryl ester of (XIII) using Pd/C gave carboxylic acid (XIV), which was coupled with the intermediate amine (X) by means of 2-chloro-1,3-dimethylimidazolium chloride (DMC) to furnish amide (XV). Acid hydrolysis of the diethyl acetal of (XV) gave aldehyde (XVI). This was condensed with the benzoxazolylmethyl phosphonium salt (XVII) in the presence of NaH to yield the trans olefin (XVIII). Finally, hydrolysis of the ester groups of (XVIII) with LiOH provided the title tricarboxylic acid.

参考文献中间体

【1】 Aoyama, T.; et al.; A new class of highly potent farnesyl diphosphate-competitive inhibitors of farnesyltransferase. J Med Chem 1998, 41, 2, 143.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	28475	(2R,3R)-3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-N-(2-naphthylmethyl)-2-pentanamine	C₂₇H₃₃NO₄	详情	详情
(XI)	28476	dimethyl (2S,3S)-2,3-dimethylbutanedioate	C₆H₁₀O₆	详情	详情
(XII)	28477	1-benzhydryl 4-methyl (2S,3S)-2,3-dimethylbutanedioate	C₁₈H₁₈O₆	详情	详情
(XIII)	28478	4-benzhydryl 2,2-diethyl 5-methyl (4S,5R)-1,3-dioxolane-2,2,4,5-tetracarboxylate	C₂₅H₂₆O₁₀	详情	详情
(XIV)	28479	(4S,5R)-2,2-bis(ethoxycarbonyl)-5-(methoxycarbonyl)-1,3-dioxolane-4-carboxylic acid	C₁₂H₁₆O₁₀	详情	详情
(XV)	28480	2,2-diethyl 4-methyl (4R,5S)-5-[[[(1R,2R)-2-(1,3-benzodioxol-5-yl)-4,4-diethoxy-1-methylbutyl](2-naphthylmethyl)amino]carbonyl]-1,3-dioxolane-2,2,4-tricarboxylate	C₃₉H₄₇NO₁₃	详情	详情
(XVI)	28481	2,2-diethyl 4-methyl (4R,5S)-5-[[[(1R,2R)-2-(1,3-benzodioxol-5-yl)-1-methyl-4-oxobutyl](2-naphthylmethyl)amino]carbonyl]-1,3-dioxolane-2,2,4-tricarboxylate	C₃₅H₃₇NO₁₂	详情	详情
(XVII)	28482	(1,3-benzoxazol-2-ylmethyl)(triphenyl)phosphonium chloride	C₂₆H₂₁ClNOP	详情	详情
(XVIII)	28483	2,2-diethyl 4-methyl (4R,5S)-5-[[[(1R,2R,4E)-2-(1,3-benzodioxol-5-yl)-5-(1,3-benzoxazol-2-yl)-1-methyl-4-pentenyl](2-naphthylmethyl)amino]carbonyl]-1,3-dioxolane-2,2,4-tricarboxylate	C₄₃H₄₂N₂O₁₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)