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【结 构 式】 
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【分子编号】26655 【品名】methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate 【CA登记号】41051-15-4 |
【 分 子 式 】C6H10O4 【 分 子 量 】146.143 【元素组成】C 49.31% H 6.9% O 43.79% |
合成路线1
该中间体在本合成路线中的序号：(II)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：(II)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 |
合成路线3
该中间体在本合成路线中的序号：(IX)The cyclization between 3,4-difluorobenzaldehyde (VIII), methyl 4-methoxyacetoacetate (IX) and urea (X) in the presence of cuprous oxide and boron trifluoride etherate gave rise to racemic pyrimidinone (XI). Optical resolution of (XI) by means of chiral HPLC furnished the desired (-)-enantiomer (XII), which was then hydrolyzed to carboxylic acid (XIII). Alternatively, kinetic resolution of (XI) by enzymatic hydrolysis using subtilistin furnished the desired (-)-carboxylic acid (XIII), which was then separated from the unreacted (+)-ester. Finally, coupling of carboxylic acid (XIII) with amine (V) using EDC and HOBt yielded the title amide.
| 【1】 Rittle, K.; et al.; Dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 90. |
| 【2】 Selnick, H.G.; Barrow, J.C.; Nanterment, P.G.; et al.; In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists for the treatment of benign prostatic hyperplasia. J Med Chem 2000, 43, 14, 2703. |
| 【3】 Selnick, H.G.; Nantermet, P.G.; Barrow, J.C. (Merck & Co., Inc.); alpha1a Adrenergic receptor antagonists. WO 0006565 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 39302 | 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine | C14H21FN2 | 详情 | 详情 | |
| (VIII) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (IX) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (X) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (XI) | 39303 | methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XII) | 39304 | methyl (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XIII) | 39305 | (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid | C13H12F2N2O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)Methyl 4-methoxyacetoacetate (XIV) was transesterified with 3-hydroxypropionitrile (XV) at 180 C to yield the 2-cyanoethyl ester (XVI). Subsequent condensation between 3,4-difluorobenzaldehyde (XVII) and ketoester (XVI) in the presence of piperidine acetate furnished the benzylidene derivative (XVIII), which was cyclized with O-methylisourea hemisulfate (XIX) to produce the racemic pyrimidine (XX). Resolution of (XX) was achieved via conversion to the 4-nitrophenyl carbamate (XXI), which was then condensed with (R)-1-phenylethylamine (XXII) to afford a separable mixture of diastereoisomeric amides. The desired isomer (XXIII) was treated with DBU in hot toluene to give the (+)-pyrimidine (XXIV). This was again converted to the corresponding 4-nitrophenyl carbamate (XXV) by reaction with 4-nitrophenyl chloroformate and DMAP.
| 【1】 Wong, W.C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 1021185; JP 2000506904; WO 9742956 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (XV) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XVI) | 48390 | 2-cyanoethyl 4-methoxy-3-oxobutanoate | C8H11NO4 | 详情 | 详情 | |
| (XVII) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (XVIII) | 48391 | 2-cyanoethyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate | C15H13F2NO4 | 详情 | 详情 | |
| (XIX) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (XX) | 48392 | 2-cyanoethyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C17H17F2N3O4 | 详情 | 详情 | |
| (XXI) | 48393 | 5-(2-cyanoethyl) 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C24H20F2N4O8 | 详情 | 详情 | |
| (XXII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXIII) | 48394 | 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1-([[(1R)-1-phenylethyl]amino]carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate | C26H26F2N4O5 | 详情 | 详情 | |
| (XXIV) | 48395 | 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C17H17F2N3O4 | 详情 | 详情 | |
| (XXV) | 48396 | 5-(2-cyanoethyl) 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C24H20F2N4O8 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIV)In a related synthetic method, condensation between 4-methoxyacetoacetate (XIV), 3,4-difluorobenzaldehyde (XVII) and urea (XXIX) in the presence of copper acetate and boron trifluoride etherate furnished the racemic pyrimidinone (XXX). Enzymatic resolution of (XXX) by incubation with subtilisin yielded a separable mixture of the (R)-acid (XXXII) and the unreacted (S)-ester (XXXI). Alternatively, the (S)-enantiomer (XXXI) was isolated by chiral preparative HPLC. Pyrimidinone (XXXI) was activated by conversion to either aryl carbamate (XXXIII) using 4-nitrophenyl chloroformate or to imidazolide (XXXIV) with carbonyl diimidazole. Finally, coupling of the intermediate amine (X) with either the carbamate (XXXIII) or the imidazolide (XXXIV) furnished the title compound.
| 【1】 O'Malley, S.S.; Chen, T.-B.; Chang, R.S.L.; et al.; In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist. Eur J Pharmacol 2000, 409, 3, 301. |
| 【2】 Broten, T.P.; Nichtberger, S.A.; Siegl, P.K.S. (Merck & Co., Inc.); Combination therapy for the treatment of benign prostatic hyperplasia. WO 9948530 . |
| 【3】 Evans, B.; Dunn, M.; Lagu, B.; Kari, H.P.; Nagarathnam, D.; Vyas, K.P.; Cui, D.; Davis, M.R.; Zhang, K. (Merck & Co., Inc.; Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. WO 0037026 . |
| 【4】 Ikemoto, N.; Taylor, C.S.; Sidler, D.R.; Chartrain, M.; Bills, G.F.; Roberge, C.M.; Li, W.; Larsen, R.D. (Merck & Co., Inc.); alpha 1a Adrenergic receptor antagonist. WO 9907695 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 48387 | 3-[4-(2-pyridinyl)-1-piperidinyl]propylamine; 3-[4-(2-pyridinyl)-1-piperidinyl]-1-propanamine | C13H21N3 | 详情 | 详情 | |
| (XIV) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (XVII) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (XXIX) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (XXX) | 39303 | methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XXXI) | 48402 | methyl (4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XXXII) | 39304 | methyl (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (XXXIII) | 48400 | 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate | C21H17F2N3O8 | 详情 | 详情 | |
| (XXXIV) | 48401 | methyl (4S)-4-(3,4-difluorophenyl)-3-(1H-imidazol-1-ylcarbonyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C18H16F2N4O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)3,4-Difluorobenzaldehyde (I) is condensed with methyl 4-methoxyacetoacetate (II) and urea in the presence of boron trifluoride etherate and copper (I) oxide to produce the dihydropyrimidinone adduct (III). After isolation of the desired enantiomer by means of chiral HPLC, reaction with p-nitrophenyl chloroformate leads to the nitrophenyl carbamate (IV). Then, condensation of (IV) with 3 bromoproylamine (V) furnishes the N-bromopropyl urea derivative (VI).
| 【1】 Gluchowski, C.; Chiu, G.; Marzabadi, M.R.; Nagarathnam, D.; Lagu, B.; Noble, S.; Wetzel, J.; Deleon, J.E. (Synaptic Pharmaceutical Corp.); Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof. EP 1299362; WO 0206245 . |
| 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) | 39303 | methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (IV) | 48400 | 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate | C21H17F2N3O8 | 详情 | 详情 | |
| (V) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (VI) | 60991 | methyl (4S)-3-{[(3-bromopropyl)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C18H20BrF2N3O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XLIII)Condensation of methyl 4-methoxyacetoacetate (XLIII) with N,N-dimethylformamide dimethyl acetal (XXXII) produces methyl 3-(dimethylamino)-2-(methoxyacetyl)-2-propenoate (XLIV), which by reaction with 2,2-dimethoxyethylamine (XXVI) in MeOH affords the N-(dimethyoxyethyl)enamine (XLV). Cyclization of enaminoketone (XLV) with dimethyl oxalate (XXXVI) by means of LiH at 40 °C gives the dimethyl pyridone-dicarboxylate (XLVI), which by selective hydrolysis with LiOH yields the monocarboxylic acid (XLVII). Hydrolysis of acetal (XLVII) with MsOH and AcOH in acetonitrile at 58-65 °C followed by in situ cyclization of the resulting aldehyde (XLVIII) with 3(R)-amino-1-butanol (XI) in acetonitrile at 64 °C affords the pyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XLIX). Activation of acid (XLIX) with CDI in DME at 80 °C and subsequent coupling with 2,4-difluorobenzylamine (XIV) gives amide (L), which is finally O-demethylated with either MgBr2 in hot acetonitrile or LiBr in refluxing THF .
| 【1】 Wang, H., Goodman, S.N., Mans, D., Kowalski, M. (GlaxoSmithKline, Inc.). Process for preparing carbamoylpyridone derivatives and intermediates. WO 2011119566. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 详情 | 详情 |
| (XIV) | 68578 | 2,4-difluorobenzylamine | 72235-52-0 | C7H7F2N | 详情 | 详情 |
| (XV) | 68579 | (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide | C27H25F2N3O5 | 详情 | 详情 | |
| (XXVI) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XXXII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XXXVI) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
| (XLIII) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (XLIV) | 68600 | methyl 3-(dimethylamino)-2-(methoxyacetyl)-2-propenoate;(Z)-methyl 2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate | C9H15NO4 | 详情 | 详情 | |
| (XLV) | 68601 | (Z)-methyl 2-(((2,2-dimethoxyethyl)amino)methylene)-4-methoxy-3-oxobutanoate | C11H19NO6 | 详情 | 详情 | |
| (XLVI) | 68602 | dimethyl 1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C14H19NO8 | 详情 | 详情 | |
| (XLVII) | 68603 | 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid | C13H17NO8 | 详情 | 详情 | |
| (XLVIII) | 68604 | 5-methoxy-6-(methoxycarbonyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid | C11H11NO7 | 详情 | 详情 | |
| (XLIX) | 68606 | (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid | C14H16N2O6 | 详情 | 详情 | |
| (L) | 68605 | (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide | C21H21F2N3O5 | 详情 | 详情 |