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【结 构 式】 
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【分子编号】36775 【品名】tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate 【CA登记号】 |
【 分 子 式 】C16H23N3O3 【 分 子 量 】305.37704 【元素组成】C 62.93% H 7.59% N 13.76% O 15.72% |
合成路线1
该中间体在本合成路线中的序号：(VII)Condensation of L-phenylalanine methyl ester (I) with benzaldehyde gave aldimine (II). Then, alkylation of (II) with allyl bromide in the presence of LDA, and subsequent imine hydrolysis afforded the racemic alpha-allylphenylalanine methyl ester (III), which was protected as the N-Boc derivative (IV) upon treatment with Boc2O. Ozonolysis of the olefin group of (IV), followed by reductive workup with Me2S yielded the aldehyde ester (V). This was cyclized with hydrazine, affording pyridazinone (VI), which was further hydrogenated over PtO2 to give (VII). The 1,3-dipolar cycloaddition of the iminium ion (VIII), formed by treatment of (VII) with formaldehyde, with boiling ethyl acrylate furnished a mixture of pyrazolopyridazines (IXa-b). After chromatographic isolation of the racemic cis amino ester, hydrolysis with LiOH yielded carboxylic acid (X), which was activated as the mixed anhydride (XI) with isobutyl chloroformate. Coupling of racemic anhydride (XI) with the L-arginine analogue (XII) provided a diastereomeric mixture of amides, from which the desired isomer (XIII) was isolated by column chromatography. Finally, deprotection of (XIII) by means of trifluoroacetic acid furnished the title compound.
| 【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 | |
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| (IXa) | 36777 | methyl (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate | C21H29N3O5 | 详情 | 详情 | |
| (IXb) | 36778 | methyl (1R,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate | C21H29N3O5 | 详情 | 详情 | |
| (I) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (II) | 36770 | methyl (2S)-3-phenyl-2-[[(E)-benzylidene]amino]propanoate | C17H17NO2 | 详情 | 详情 | |
| (III) | 36771 | methyl 2-amino-2-benzyl-4-pentenoate | C13H17NO2 | 详情 | 详情 | |
| (IV) | 36772 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-pentenoate | C18H25NO4 | 详情 | 详情 | |
| (V) | 36773 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate | C17H23NO5 | 详情 | 详情 | |
| (VI) | 36774 | tert-butyl 4-benzyl-3-oxo-2,3,4,5-tetrahydro-4-pyridazinylcarbamate | C16H21N3O3 | 详情 | 详情 | |
| (VII) | 36775 | tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate | C16H23N3O3 | 详情 | 详情 | |
| (VIII) | 36776 | 4-benzyl-4-[(tert-butoxycarbonyl)amino]-1-methylene-3-oxohexahydropyridazin-1-ium | C17H24N3O3 | 详情 | 详情 | |
| (X) | 36779 | (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylic acid | C20H27N3O5 | 详情 | 详情 | |
| (XI) | 36780 | C25H35N3O7 | 详情 | 详情 | ||
| (XII) | 36781 | [[[[(4S)-4-amino-6-chloro-5-oxohexyl]amino](imino)methyl]amino](4-methoxy-2,3,6-trimethylphenyl)dioxo-lambda(6)-sulfane | C17H27ClN4O4S | 详情 | 详情 | |
| (XIII) | 36782 | C38H52ClN7O10S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The reaction of phenylalanine methyl ester (I) with benzaldehyde (II) and TEA in dichloromethane gives the aldimine (III), which is condensed with allyl bromide (IV) by means of n-BuLi in THF yielding the adduct (V). Treatment of (V) with HCl in methanol cleaves the benzylidene protecting group to afford the alpha-allylphenylalanine methyl ester (VI), which is reprotected with Boc2O and NaHCO3 in THF providing the carbamate (VII). The ozonolysis of (VII) with O3 in MeOH/CH2Cl2 gives the aldehyde (VIII), which is cyclized with hydrazine in refluxing THF yielding the tetrahydropyridazinone (IX). Hydrogenation of (IX) with H2 over PtO2 in methanol affords the hexahydropyridazinone (X), which is cyclocondensed with ethyl acrylate (XI) and formaldehyde to furnish the pyrazolopyridazine (XII). Hydrolysis of the ester group of (XII) with LiOH in THF/water gives the acid (XIII), which is finally condensed with N-omega(4-methoxytrityl)-L-arginylchloromethane (XIV) by means of isobutyl chloroformate and NMM in THF yielding, after working up, a diastereomeric mixture of amides, from which the target diastereomer is obtained by column chromatography.
| 【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367. |
| 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) | 40419 | methyl 2-amino-3-phenylpropanoate | 5619-07-8 | C10H13NO2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 40420 | methyl 3-phenyl-2-[[(E)-benzylidene]amino]propanoate | C17H17NO2 | 详情 | 详情 | |
| (IV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (V) | 40416 | methyl 2-benzyl-2-[[(E)-benzylidene]amino]-4-pentenoate | C20H21NO2 | 详情 | 详情 | |
| (VI) | 36771 | methyl 2-amino-2-benzyl-4-pentenoate | C13H17NO2 | 详情 | 详情 | |
| (VII) | 36772 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-pentenoate | C18H25NO4 | 详情 | 详情 | |
| (VIII) | 36773 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate | C17H23NO5 | 详情 | 详情 | |
| (IX) | 36774 | tert-butyl 4-benzyl-3-oxo-2,3,4,5-tetrahydro-4-pyridazinylcarbamate | C16H21N3O3 | 详情 | 详情 | |
| (X) | 36775 | tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate | C16H23N3O3 | 详情 | 详情 | |
| (XI) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XII) | 40417 | ethyl (1S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate | C22H31N3O5 | 详情 | 详情 | |
| (XIII) | 36779 | (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylic acid | C20H27N3O5 | 详情 | 详情 | |
| (XIV) | 40418 | N-[(4S)-4-amino-6-chloro-5-oxohexyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C27H31ClN4O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)Condensation of L-phenylalanine methyl ester (V) with benzaldehyde gave aldimine (VI). Then, alkylation of (VI) with allyl bromide in the presence of LDA, and subsequent imine hydrolysis afforded the racemic alpha-allylphenylalanine methyl ester (VII), which was protected as the N-Boc derivative (VIII) upon treatment with Boc2O. Ozonolysis of the olefin group of (VIII), followed by reductive workup with Me2S yielded the aldehyde ester (IX). This was cyclized with hydrazine, affording pyridazinone (X), which was further hydrogenated over PtO2 to give (XI). The 1,3-dipolar cycloaddition of the iminium ion (XII), formed by treatment of (XI) with formaldehyde, and boiling ethyl acrylate furnished a mixture of pyrazolopyridazines (XIIIa-b). After chromatographic isolation of the racemic cis amino ester, its hydrolysis with LiOH yielded carboxylic acid (XIV). Coupling of (XIV) with aminoalcohol (IVa-b) using EDC and HOBt provided the corresponding amide (XVa-d) as a mixture of 4 diastereomers. Oxidation of the secondary alcohol of (XVa-d) with Dess-Martin periodinane gave the diastereomeric ketones (XVIa-b). Then, deprotection of (XVIa-b) by means of trifluoroacetic acid, followed by separation of the isomers by HPLC furnished the title compound.
| 【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 | |
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| (XIIIa) | 36777 | methyl (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate | C21H29N3O5 | 详情 | 详情 | |
| (XIIIb) | 36778 | methyl (1R,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate | C21H29N3O5 | 详情 | 详情 | |
| (IVa) | 36787 | 2-[(1S,2S)-2-amino-1-hydroxy-5-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]pentyl]-1,3-benzothiazole | C23H31N5O4S2 | 详情 | 详情 | |
| (IVb) | 36788 | 2-[(1R,2S)-2-amino-1-hydroxy-5-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]pentyl]-1,3-benzothiazole | C23H31N5O4S2 | 详情 | 详情 | |
| (XVa) | 36789 | tert-butyl (3S,6S)-3-[([(1S)-1-[(S)-1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate | C43H56N8O8S2 | 详情 | 详情 | |
| (XVb) | 36790 | tert-butyl (3S,6S)-3-[([(1S)-1-[(R)-1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate | C43H56N8O8S2 | 详情 | 详情 | |
| (XVc) | 36791 | tert-butyl (3S,6S)-3-[([(1R)-1-[(R)-1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate | C43H56N8O8S2 | 详情 | 详情 | |
| (XVd) | 36792 | tert-butyl (3S,6S)-3-[([(1R)-1-[(S)-1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate | C43H56N8O8S2 | 详情 | 详情 | |
| (XVIa) | 36793 | tert-butyl (3S,6S)-3-[([(1S)-1-(1,3-benzothiazol-2-ylcarbonyl)-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate | C43H54N8O8S2 | 详情 | 详情 | |
| (XVIb) | 36794 | tert-butyl (3R,6S)-3-[([(1S)-1-(1,3-benzothiazol-2-ylcarbonyl)-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate | C43H54N8O8S2 | 详情 | 详情 | |
| (V) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (VI) | 36770 | methyl (2S)-3-phenyl-2-[[(E)-benzylidene]amino]propanoate | C17H17NO2 | 详情 | 详情 | |
| (VII) | 36771 | methyl 2-amino-2-benzyl-4-pentenoate | C13H17NO2 | 详情 | 详情 | |
| (VIII) | 36772 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-pentenoate | C18H25NO4 | 详情 | 详情 | |
| (IX) | 36773 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate | C17H23NO5 | 详情 | 详情 | |
| (X) | 36774 | tert-butyl 4-benzyl-3-oxo-2,3,4,5-tetrahydro-4-pyridazinylcarbamate | C16H21N3O3 | 详情 | 详情 | |
| (XI) | 36775 | tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate | C16H23N3O3 | 详情 | 详情 | |
| (XII) | 36776 | 4-benzyl-4-[(tert-butoxycarbonyl)amino]-1-methylene-3-oxohexahydropyridazin-1-ium | C17H24N3O3 | 详情 | 详情 | |
| (XIV) | 36779 | (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylic acid | C20H27N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)The reaction of phenylalanine methyl ester (I) with benzaldehyde (II) and TEA in dichloromethane gives the aldimine (III), which is condensed with allyl bromide (IV) by means of n-BuLi in THF yielding the adduct (V). Treatment of (V) with HCl in methanol cleaves the benzylidene protecting group to afford the alpha-allylphenylalanine methyl ester (VI), which is reprotected with Boc2O and NaHCO3 in THF providing the carbamate (VII). The ozonolysis of (VII) with O3 in MeOH/CH2Cl2 gives the aldehyde (VIII), which is cyclized with hydrazine in refluxing THF yielding the tetrahydropyridazinone (IX). Hydrogenation of (IX) with H2 over PtO2 in methanol affords the hexahydropyridazinone (X), which is cyclocondensed with ethyl acrylate (XI) and formaldehyde to furnish the pyrazolopyridazine (XII). Hydrolysis of the ester group of (XII) with LiOH in THF/water gives the acid (XIII), which is finally condensed with the argininol derivative (XIV) by means of EDC, HOBT and DIEA in THF yielding the corresponding amide (XV). Finally, the secondary alcohol of (XV) is oxidized with Dess Martin periodinane (DMP) to afford, after working up, a diastereomeric mixture of amides, from which the target diastereomer is obtained by HPLC chromatography.
| 【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367. |
| 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) | 40419 | methyl 2-amino-3-phenylpropanoate | 5619-07-8 | C10H13NO2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 40420 | methyl 3-phenyl-2-[[(E)-benzylidene]amino]propanoate | C17H17NO2 | 详情 | 详情 | |
| (IV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (V) | 40416 | methyl 2-benzyl-2-[[(E)-benzylidene]amino]-4-pentenoate | C20H21NO2 | 详情 | 详情 | |
| (VI) | 36771 | methyl 2-amino-2-benzyl-4-pentenoate | C13H17NO2 | 详情 | 详情 | |
| (VII) | 36772 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-pentenoate | C18H25NO4 | 详情 | 详情 | |
| (VIII) | 36773 | methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate | C17H23NO5 | 详情 | 详情 | |
| (IX) | 36774 | tert-butyl 4-benzyl-3-oxo-2,3,4,5-tetrahydro-4-pyridazinylcarbamate | C16H21N3O3 | 详情 | 详情 | |
| (X) | 36775 | tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate | C16H23N3O3 | 详情 | 详情 | |
| (XI) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XII) | 40417 | ethyl (1S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate | C22H31N3O5 | 详情 | 详情 | |
| (XIII) | 36779 | (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylic acid | C20H27N3O5 | 详情 | 详情 | |
| (XIV) | 40421 | N-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-hydroxypentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C33H35N5O2S | 详情 | 详情 | |
| (XV) | 40422 | (1S)-7-amino-N-[(1S)-4-[[amino(imino)methyl]amino]-1-[1,3-benzothiazol-2-yl(hydroxy)methyl]butyl]-7-benzyl-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxamide | C28H36N8O3S | 详情 | 详情 |