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【结 构 式】

【分子编号】26656

【品名】methyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate

【CA登记号】

【 分 子 式 】C13H12F2O4

【 分 子 量 】270.2326864

【元素组成】C 57.78% H 4.48% F 14.06% O 23.68%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III), which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V). The optical resolution of dihydropyrimidine (V) can also be performed as follows: Dihydropyrimidine (V) is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP giving the 4-nitrophenyl ester (VII), which is treated with (R)-(+)-alpha-methylbenzylamine [(R)-MBA] yielding amide (VIII) as mixture of diastereomers that is separated by column chromatography. The (+) isomer was then treated with DBU in hot toluene to provide the dihydropyrimidine (+)(IX), already reported. The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.

1 Nagarathnam, D.; et al.; Design, synthesis and evaluation of dihydropyrimidinones as alpha-1A selective antagonists: 7. Modification of the piperidine moiety into 4-aminocyclohexane; identification and structure-activity relationship of SNAP 6991 analogs. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 110.
2 Nagarathnam, D.; Wong, W.C.; Miao, S.W.; Patane, M.A.; Gluchowski, C. (Merck & Co., Inc.; Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 0866708; JP 2000500470; WO 9717969 .
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) 26654 3,4-difluorobenzaldehyde 34036-07-2 C7H4F2O 详情 详情
(II) 26655 methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate 41051-15-4 C6H10O4 详情 详情
(III) 26656 methyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate C13H12F2O4 详情 详情
(IV) 26657 O-methyl isourea; [Amino(imino)methoxy]methane 52328-05-9 C2H6N2O 详情 详情
(V) 26658 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate C15H16F2N2O4 详情 详情
(VI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(VII) 26659 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate C22H19F2N3O8 详情 详情
(VIII) 26660 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1-[[(1-phenylethyl)amino]carbonyl]-1,6-dihydro-5-pyrimidinecarboxylate C24H25F2N3O5 详情 详情
(IX) 26658 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate C15H16F2N2O4 详情 详情
(X) 16606 Isobutyramide; 2-methylpropanamide 563-83-7 C4H9NO 详情 详情
(XI) 26659 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate C22H19F2N3O8 详情 详情
(XII) 26661 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate C21H17F2N3O8 详情 详情
(XIII) 26662 4-[(2-aminoethyl)amino]-1-phenylcyclohexanecarbonitrile C15H21N3 详情 详情
(XIV) 26663 4-oxo-1-phenylcyclohexanecarbonitrile 25115-74-6 C13H13NO 详情 详情
(XV) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine;1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(III)

The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III), which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V). The optical resolution of (V) by chiral chromatography affords the (+)(IX) isomer, which is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP in dichloromethane giving the active 4-nitrophenyl ester (+)(X). The hydrolysis of the enol methyl ether of (X) with HCl in ether/dichloromethane yields the pyrimidinone (+)(XI), which is finally condensed with 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) in dichloromethane. The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.

1 Nagarathnam, D.; et al.; Design, synthesis and evaluation of dihydropyrimidinones as alpha-1A selective antagonists: 7. Modification of the piperidine moiety into 4-aminocyclohexane; identification and structure-activity relationship of SNAP 6991 analogs. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 110.
2 Nagarathnam, D.; Wong, W.C.; Miao, S.W.; Patane, M.A.; Gluchowski, C. (Merck & Co., Inc.; Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 0866708; JP 2000500470; WO 9717969 .
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) 26654 3,4-difluorobenzaldehyde 34036-07-2 C7H4F2O 详情 详情
(II) 26655 methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate 41051-15-4 C6H10O4 详情 详情
(III) 26656 methyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate C13H12F2O4 详情 详情
(IV) 26657 O-methyl isourea; [Amino(imino)methoxy]methane 52328-05-9 C2H6N2O 详情 详情
(V) 26658 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate C15H16F2N2O4 详情 详情
(IX) 26658 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate C15H16F2N2O4 详情 详情
(X) 16606 Isobutyramide; 2-methylpropanamide 563-83-7 C4H9NO 详情 详情
(XI) 26659 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate C22H19F2N3O8 详情 详情
(XII) 26661 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate C21H17F2N3O8 详情 详情
(XIII) 26662 4-[(2-aminoethyl)amino]-1-phenylcyclohexanecarbonitrile C15H21N3 详情 详情
(XIV) 26663 4-oxo-1-phenylcyclohexanecarbonitrile 25115-74-6 C13H13NO 详情 详情
(XV) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine;1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情
Extended Information