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【结 构 式】 
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【分子编号】12324 【品名】methyl (2R)-2-amino-3-phenylpropanoate 【CA登记号】21685-51-8 |
【 分 子 式 】C10H13NO2 【 分 子 量 】179.21876 【元素组成】C 67.02% H 7.31% N 7.82% O 17.85% |
合成路线1
该中间体在本合成路线中的序号：(XIII)2) Synthesis of (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester (II): Phenylalanine methyl ester (XIII) is protected with isopropyl chloroformate and triethylamine in THF to give N-(isopropoxycarbonyl)phenylalanine methyl ester (XIV), which is reduced with NaBH4 - LiCl in THF - ethanol, yielding N-(isopropoxycarbonyl)phenylalaninol (XV). The hydrogenation of (XV) with H2 over Rh/Al2O3 in methanol affords N-(isopropoxycarbonyl)cyclohexylalaninol (XVI), which is oxidized with pyridine - SO3 in DMSO to the corresponding aldehyde (XVII). The reaction of (XVII) with NaCN - HCl in CHCl3 - water affords (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid (XVIII), which is finally esterified with isopropanol - HCl to give (II). 3) Synthesis of KRY-1314: By condensation of N(tau)-tert-butoxycarbonyl-N(alpha)-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine (I) with (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester (II) by means of dicyclohexylcarbodiimide (DCC) and N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) in acetonitrile - triethylamine.
| 【1】 Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.; Kamijo, T.; Kiso, Y.; Iizuka, K.; Hirata, K.; A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-[N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naaphthyl)propionyl]-L-histidyl]aminobutyrate. J Chem Soc - Perkins Trans I 1990, 9, 2497-500. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 | |
| (I) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (II) | 12323 | isopropyl (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoate | C13H25NO3 | 详情 | 详情 | |
| (XIII) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (XIV) | 12325 | methyl (2S)-2-[(isopropoxycarbonyl)amino]-3-phenylpropanoate | C14H19NO4 | 详情 | 详情 | |
| (XV) | 12326 | isopropyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate | C13H19NO3 | 详情 | 详情 | |
| (XVI) | 12327 | isopropyl N-[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]carbamate | C13H25NO3 | 详情 | 详情 | |
| (XVII) | 12328 | isopropyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C13H23NO3 | 详情 | 详情 | |
| (XVIII) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(V)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：(III)In a different strategy, N-Cbz-p-fluorophenylalanine (I) is activated as the mixed anhydride (II) employing isobutyl chloroformate and N-methylmorpholine. Coupling of anhydride (II) with phenylalanine methyl ester (III) leads to the dipeptide ester (IV), which is further treated with methanolic ammonia to produce amide (V). The dipeptide amide (V) is alternatively obtained by direct coupling of mixed anhydride (II) with phenylalanine amide (VI). Hydrogenolysis of the N-Cbz group of (V) in the presence of Pd/C furnishes the deprotected dipeptide (VII).
| 【1】 Franzen, H.M.; Bessidskaia, G.; Abedi, V.; Nilsson, A.; Nilsson, M.; Olsson, L.; Frakefamide, an analgesic tetrapeptide: Development of a pilot-plant-scale process. Org Process Res Dev 2002, 6, 6, 788. |
| 【2】 Franzen, H. (AstraZeneca plc); Process for the preparation of a tetrapeptide. WO 9947548 . |
| 【3】 Nilsson, M.; Ellburg, M.; Franzen, H. (AstraZeneca AB); A process for the preparation of H-Tyr-D-Ala-Phe(F)-Phe-NH2. EP 1212350; JP 2003509437; WO 0119849 . |
| 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) | 61047 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-fluorophenyl)propanoic acid | C17H16FNO4 | 详情 | 详情 | |
| (II) | 61048 | C22H24FNO6 | 详情 | 详情 | ||
| (III) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (IV) | 61049 | methyl (2S)-2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-fluorophenyl)propanoyl]amino}-3-phenylpropanoate | C27H27FN2O5 | 详情 | 详情 | |
| (V) | 61050 | benzyl (1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethylcarbamate | C26H26FN3O4 | 详情 | 详情 | |
| (VI) | 19032 | (2S)-2-amino-3-phenylpropanamide | 5241-58-7 | C9H12N2O | 详情 | 详情 |
| (VII) | 61044 | (2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-(4-fluorophenyl)propanamide | C18H20FN3O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The reaction of L-phenylalanine methyl ester (I) with phosgene and pyridine in dichloromethane gives the isocyanate (II) (1), which is condensed with 5-amino-1,3,4-thiadiazol-2(3H)-thione (III) in THF to yield the urea (IV). Finally, this compound is treated with methylamine in ethanol to affords the target compound.
| 【1】 Mitchell, M.A.; Hendges, S.K.; Jacobsen, E.J.; et al.; Synthesis of a series of stromelysin-selective thiadiazole urea matrix metalloproteinase inhibitors. J Med Chem 1999, 42, 9, 1525. |
| 【2】 Jacobsen, E.J.; Mitchell, M.A.; Schostarez, H.J.; Harper, D.E. (Pharmacia & Upjohn AB); Thiadiazolyl(thio)ureas useful as matrix metalloprotease inhibitors. EP 0900211; JP 2000509039; WO 9740031 . |
| 【3】 Mitchell, M.A.; Schostarez, H.J.; Harper, D.E.; Jacobsen, E.J. (Pharmacia Corp.); Thiadiazole derivs. useful for the treatment of diseases related to connective tissue degradation. US 5847148 . |
| 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) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (II) | 38888 | methyl (2S)-2-isocyanato-3-phenylpropanoate | 40203-94-9 | C11H11NO3 | 详情 | 详情 |
| (III) | 24397 | 5-amino-1,3,4-thiadiazole-2(3H)-thione | 2349-67-9 | C2H3N3S2 | 详情 | 详情 |
| (IV) | 38889 | methyl (2S)-3-phenyl-2-([[(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)amino]carbonyl]amino)propanoate | C13H14N4O3S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The cyclization between 5-bromoisatoic anhydride (I) and D-phenylalanine methyl ester (II) in the presence of DMAP in refluxing pyridine produced the benzodiazepindione (III), which was further reduced to the benzodiazepine (IV) by treatment with borane in THF. Displacement of the bromide group of (IV) with cuprous cyanide in hot N-methylpyrrolidone furnished nitrile (V). Acylation of the aliphatic nitrogen of (V) with 2-thienylsulfonyl chloride (VI) gave rise to sulfonamide (VII). Finally, the title compound was obtained by reductive alkylation of (VII) with 4-formylimidazole (VIII) by means of either treatment with sodium triacetoxyborohydride or, in an improved procedure, using triethylsilane in the presence of trifluoroacetic acid.
| 【1】 Chen, B.C.; et al.; Novel triethylsilane mediated reductive N-alkylation of amines: Improved synthesis of 1-(4-imidazolyl)methyl-4-sulfonylbenzodiazepines new farnesyltransferase inhibitors. Tetrahedron Lett 2001, 42, 7, 1245. |
| 【3】 Ding, C.Z.; Hunt, J.T.; Kim, S.-H.; Mitt, T.; Bhide, R.; Leftheris, K. (Bristol-Myers Squibb Co.); Inhibitors of farnesyl protein transferase. EP 0892797; JP 2000502356; US 6011029; WO 9730992 . |
| 【2】 Batorsky, R.; Hunt, J.T.; Ding, C.Z.; et al.; Discovery of (R)-7-cyano-2,3,4,5-tetrahydro-1-(1-H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity. J Med Chem 2000, 43, 20, 3557. |
| 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) | 47112 | 6-bromo-2H-3,1-benzoxazine-2,4(1H)-dione | C8H4BrNO3 | 详情 | 详情 | |
| (II) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (III) | 47113 | (3R)-3-benzyl-7-bromo-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione | C16H13BrN2O2 | 详情 | 详情 | |
| (IV) | 47114 | (3R)-3-benzyl-7-bromo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine | C16H17BrN2 | 详情 | 详情 | |
| (V) | 47115 | (3R)-3-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carbonitrile | C17H17N3 | 详情 | 详情 | |
| (VI) | 40760 | 2-thiophenesulfonyl chloride | 16629-19-9 | C4H3ClO2S2 | 详情 | 详情 |
| (VII) | 47116 | (3R)-3-benzyl-4-(2-thienylsulfonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carbonitrile | C21H19N3O2S2 | 详情 | 详情 | |
| (VIII) | 41951 | 1H-imidazole-5-carbaldehyde | 3034-50-2 | C4H4N2O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)The reaction of 4-acetyldiphenylsulfide (I) with carbon disulfide by means of sodium tert-amyloxide in benzene gives 4-phenylthiobenzoyldithioacetic acid (II), which is cyclized with o-phenylenediamine (III) in refluxing toluene yielding 4-(p-phenylthiophenyl)-1,3-dihydro-2H-1,5-benzodiazepine-2-thione (IV). The condensation of (IV) with diethylaminoethyl chloride (V) by means of NaH in refluxing benzene affords 2-[beta-(N-diethylamino)ethylthio]-4-(p-phenylthio)phenyl-3H-1,5-benzodiazepine (VI), which is finally quaternized with methyl iodide in isopropanol. (1,2)
| 【1】 Castaner, J.; de Angelis, L.; Tibezonium Iodide. Drugs Fut 1978, 3, 2, 152. |
| 【2】 Nardi, D.; et al.; New 2-methyldialkylammoniumalkylthio-4-p-substituted phenyl-3-H-1,5-benzodiazepine iodides with antibacterial activity. II Farmaco (ed. sc.) 1975, 30, Suppl. 3, 248. |
| 【3】 Degen, L. (Recordati S.A. Chem Pharm. Co.); AT 321922; CH 555347; GB 1412008; GB 1412009; US 3993793 . |
| 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) | 60710 | 1-[4-(phenylsulfanyl)phenyl]-1-ethanone | C14H12OS | 详情 | 详情 | |
| (II) | 60711 | 3-oxo-3-[4-(phenylsulfanyl)phenyl]propanedithioic acid | C15H12OS3 | 详情 | 详情 | |
| (III) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (IV) | 60712 | 4-[4-(phenylsulfanyl)phenyl]-1,3-dihydro-2H-1,5-benzodiazepine-2-thione | C21H16N2S2 | 详情 | 详情 | |
| (V) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (VI) | 60713 | N,N-diethyl-2-({4-[4-(phenylsulfanyl)phenyl]-3H-1,5-benzodiazepin-2-yl}sulfanyl)-1-ethanamine; N,N-diethyl-N-[2-({4-[4-(phenylsulfanyl)phenyl]-3H-1,5-benzodiazepin-2-yl}sulfanyl)ethyl]amine | C27H29N3S2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)In an alternative method, L-phenylalanine (I) is esterified employing SOCl2 in MeOH. The resultant phenylalanine methyl ester (II) is then acylated with the sulfonyl proline derivative (III) by means of PyBOP to furnish the sulfonyl dipeptide (IV). Finally, saponification of the methyl ester group of (IV) with LiOH leads to the title compound
| 【1】 Kopka, I.E.; Young, D.N.; Lin, L.S.; et al.; Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists. Bioorg Med Chem Lett 2002, 12, 4, 637. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (III) | 60842 | (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methyl-2-pyrrolidinecarboxylic acid | C12H13Cl2NO4S | 详情 | 详情 | |
| (IV) | 60843 | methyl (2S)-2-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methylpyrrolidinyl}carbonyl)amino]-3-phenylpropanoate | C22H24Cl2N2O5S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XI)Condensation of N-Boc-L-leucine (X) with L-phenylalanine methyl ester (XI) in the presence of DIEA, HOBt and BOP in DMF gives the protected dipeptide (XII). Dipeptide (XII) is then deprotected by means of TFA in CH2Cl2 to yield L-Leu-L-Phe-OMe trifluoroacetate salt (XIII), which without isolation is then condensed with N-Boc-Lhomophenylalanine (XIV) in the presence of DIEA, HOBt and BOP in acetonitrile to yield the protected tripeptide (XV) . Then, N-deprotection of peptide (XV) by means of TFA in CH2Cl2 gives tripeptide (XVI), which is finally coupled with chloroacetyl chloride (XVII) in the presence of DIEA in DMF .
| 【1】 Phiasivongsa, P., Sehl, L.C., Fuller, W.D., Laidig, G.J. (Proteolix, Inc.). Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides. WO 2009045497. |
| 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) | 69390 | (R)-methyl 2-((S)-2-((R)-2-(2-chloroacetamido)-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate | C28H36ClN3O5 | 详情 | 详情 | |
| (X) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XI) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (XII) | 69398 | L-Phenylalanine,N-[(1,1-dimethylethoxy)carbonyl]-L-leucyl-, methyl ester;tert-butyloxycarbonyl-leucylphenylalanine methyl ester;(R)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-phenylpropanoate | 5874-73-7 | C21H32N2O5 | 详情 | 详情 |
| (XIII) | 69399 | (R)-methyl 2-((S)-2-amino-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate;L-Leu-L-Phe-OMe trifluoroacetate salt | C16H24N2O3.C2HF3O2 | 详情 | 详情 | |
| (XIV) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XV) | 69400 | (6S,9S,12R)-methyl 12-benzyl-9-isobutyl-2,2-dimethyl-4,7,10-trioxo-6-phenethyl-3-oxa-5,8,11-triazatridecan-13-oate | C31H43N3O6 | 详情 | 详情 | |
| (XVI) | 69401 | (R)-methyl 2-((S)-2-((R)-2-amino-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate | C26H35N3O4.C2HF3O2 | 详情 | 详情 | |
| (XVII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |