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【结 构 式】 
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【分子编号】15341 【品名】(2S)-2-amino-3-(4-nitrophenyl)propionic acid; 4-nitro-L-phenylalanine 【CA登记号】949-99-5 |
【 分 子 式 】C9H10N2O4 【 分 子 量 】210.18948 【元素组成】C 51.43% H 4.8% N 13.33% O 30.45% |
合成路线1
该中间体在本合成路线中的序号：(I)Zolmitriptan can be obtained by several related ways: 1) The esterification of L-4-nitrophenylalanine (I) with SOCl2 and methanol gives the corresponding methyl ester (II), which is reduced with NaBH4 in ethanol/water yielding (S)-2-amino-3-(4-nitrophenyl)-1-propanol (III). The cyclization of (III) with phosgene and KOH affords (S)-4-(4-nitrobenzyl)oxazolidin-2-one (IV), which is reduced with H2 over Pd/C in ethanol/water to the corresponding amino derivative (V). The diazotation of (V) with NaNO2.HCl, followed by reduction with SnCl2 in water affords the expected hydrazino derivative (VI), which is cyclized with 4-chlorobutanal diethylacetal (VII) in refluxing ethanol/water to give (S)-4-[3-(2-aminoethyl)-1H-indol-5-ylmethyl]oxazolidin-2-one (VIII). Finally, this compound is methylated with formaldehyde/sodium cyanoborohydride in methanol. 2) The reduction of L-4-nitrophenylalanine (I) to the propanol (III) can also be performed directly by treatment of (I) first with BF3.(Et)2O, followed by reduction with BH3.(CH3)2S complex in hot dimethoxyethane. 3) The cyclization of propanol (III) to oxazolidinone (IV) can also be performed with trichloromethyl chloroformate and NaOH in dichloromethane. 4) The cyclization of hydrazino derivative (VI) with 4-(dimethylamino)butanal diethylacetal (IX) in refluxing acetic acid/water directly yields zolmitriptan. 5) The condensation of hydrazino derivative (VI) with 3-cyanopropanal diethylacetal (X) in aqueous HCl gives (S)-4-[4-(N2-(3-cyanopropylidene)hydrazino]benzyl]oxazolidin-2-one (XI), which is cyclized with polyphosphate ester (PPE) in refluxing chloroform to yield (S)-4-[3-(cyanomethyl)-1H-indol-5-ylmethyl]oxazolidin-2-one (XII). Finally, this compound is reduced with H2 over Pd/C in 30% w/w ethanolic dimethylamine to afford zolmitriptan.
| 【1】 Ngo, J.; Mealy, N.; Castaner, J.; Zolmitriptan. Drugs Fut 1997, 22, 3, 260. |
| 【2】 Glen, R.C.; Martin, G.R.; Hill, A.P.; Hyde, R.M.; Woollard, P.M.; Salmon, J.A.; Buckingham, J.; Robertson, A.D.; Computer-aided design and synthesis of 5-substituted tryptamines and their pharmacology at the 5-HT1D receptor: Discovery of compounds with potential anti-migraine properties. J Med Chem 1995, 38, 18, 3566. |
| 【3】 Robertson, A.D.; Hill, A.P.; Glen, R.C.; Martin, G.R. (Glaxo Wellcome plc); Therapeutic heterocyclic cpds.. EP 0486666; EP 0636623; JP 1993502679; US 5399574; US 5466699; WO 9118897 . |
| 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) | 15341 | (2S)-2-amino-3-(4-nitrophenyl)propionic acid; 4-nitro-L-phenylalanine | 949-99-5 | C9H10N2O4 | 详情 | 详情 |
| (II) | 15342 | methyl (2S)-2-amino-3-(4-nitrophenyl)propanoate | C10H12N2O4 | 详情 | 详情 | |
| (III) | 15343 | (2S)-2-amino-3-(4-nitrophenyl)-1-propanol | C9H12N2O3 | 详情 | 详情 | |
| (IV) | 15344 | (4S)-4-(4-nitrobenzyl)-1,3-oxazolan-2-one | C10H10N2O4 | 详情 | 详情 | |
| (V) | 15345 | (4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one | C10H12N2O2 | 详情 | 详情 | |
| (VI) | 15346 | (4S)-4-(4-hydrazinobenzyl)-1,3-oxazolan-2-one | C10H13N3O2 | 详情 | 详情 | |
| (VII) | 15347 | 4-Chloro-1-ethoxybutyl ethyl ether; 4-Chloro-1,1-diethoxybutane; 4-Chlorobutyraldehyde diethyl acetal | 6139-83-9 | C8H17ClO2 | 详情 | 详情 |
| (VIII) | 15348 | (4S)-4-[[3-(2-aminoethyl)-1H-indol-5-yl]methyl]-1,3-oxazolan-2-one | C14H17N3O2 | 详情 | 详情 | |
| (IX) | 15349 | N-(4,4-diethoxybutyl)-N,N-dimethylamine; 4,4-diethoxy-N,N-dimethyl-1-butanamine | C10H23NO2 | 详情 | 详情 | |
| (X) | 15350 | 4,4-diethoxybutanenitrile; 4,4-diethoxy-butanenitrile | 18381-45-8 | C8H15NO2 | 详情 | 详情 |
| (XI) | 15351 | 4-[(E)-2-(4-[[(4S)-2-oxo-1,3-oxazolan-4-yl]methyl]phenyl)hydrazono]butanenitrile | C14H16N4O2 | 详情 | 详情 | |
| (XII) | 15352 | 2-(5-[[(4S)-2-oxo-1,3-oxazolan-4-yl]methyl]-1H-indol-3-yl)acetonitrile | C14H13N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)6) The cyclization of L-4-nitrophenylalanine (I) with benzyl isocyanate (XIII) in hot water gives (S)-5-(4-nitrobenzyl)imidazolidine-2,4-dione (XIV), which is reduced with H2 over Pd/C in ethanol/water to the corresponding amino derivative (XV). The diazotation of (XV) with NaNO2.HCl, followed by reduction with SnCl2 in water affords the expected hydrazino derivative (XVI), which is cyclized with 4-chlorobutanal diethylacetal (VII) in refluxing ethanol/water to give (S)-5-[3-(2-aminoethyl)-1H-indol-5-ylmethyl]imidazolidine-2,4-dione (XVII). The reductive methylation of (XVII) with formaldehyde and sodium cyanoborohydride yields (S)-5-[3-[2-(dimethylamino)ethyl]-1H-indol-3-yl]alanine (XIX). The esterification of (XIX) with SOCl2 and methanol affords the corresponding methyl ester (XX), which is reduced with NaBH4 in ethanol/water giving the 2(S)-aminopropanol derivative (XXI). Finally, this compound is cyclized with diethyl carbonate and potassium carbonate at 130 C. 7) The cyclization of hydrazino derivative (XVI) with 4-(dimethylamino)butanal diethylacetal (IX) in refluxing acetic acid/water directly yields (S)-5-[3-[2-(dimethylamino)ethyl]-1H-indol-5-ylmethyl]imidazolidine-2,4-dione (XVIII), already reported.
| 【1】 Ngo, J.; Mealy, N.; Castaner, J.; Zolmitriptan. Drugs Fut 1997, 22, 3, 260. |
| 【2】 Robertson, A.D.; Hill, A.P.; Glen, R.C.; Martin, G.R. (Glaxo Wellcome plc); Therapeutic heterocyclic cpds.. EP 0486666; EP 0636623; JP 1993502679; US 5399574; US 5466699; WO 9118897 . |
| 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) | 15341 | (2S)-2-amino-3-(4-nitrophenyl)propionic acid; 4-nitro-L-phenylalanine | 949-99-5 | C9H10N2O4 | 详情 | 详情 |
| (VII) | 15347 | 4-Chloro-1-ethoxybutyl ethyl ether; 4-Chloro-1,1-diethoxybutane; 4-Chlorobutyraldehyde diethyl acetal | 6139-83-9 | C8H17ClO2 | 详情 | 详情 |
| (IX) | 15349 | N-(4,4-diethoxybutyl)-N,N-dimethylamine; 4,4-diethoxy-N,N-dimethyl-1-butanamine | C10H23NO2 | 详情 | 详情 | |
| (XIV) | 15353 | (5S)-5-(4-nitrobenzyl)-1H-imidazole-2,4(3H,5H)-dione | C10H9N3O4 | 详情 | 详情 | |
| (XV) | 15354 | (5S)-5-(4-aminobenzyl)-1H-imidazole-2,4(3H,5H)-dione | C10H11N3O2 | 详情 | 详情 | |
| (XVI) | 15355 | (5S)-5-(4-hydrazinobenzyl)-1H-imidazole-2,4(3H,5H)-dione | C10H12N4O2 | 详情 | 详情 | |
| (XVII) | 15356 | (5S)-5-[[3-(2-aminoethyl)-1H-indol-5-yl]methyl]-1H-imidazole-2,4(3H,5H)-dione | C14H16N4O2 | 详情 | 详情 | |
| (XVIII) | 15357 | (5S)-5-([3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl)-1H-imidazole-2,4(3H,5H)-dione | C16H20N4O2 | 详情 | 详情 | |
| (XIX) | 15358 | (2S)-2-amino-3-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]propionic acid | C15H21N3O2 | 详情 | 详情 | |
| (XX) | 15359 | methyl (2S)-2-amino-3-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]propanoate | C16H23N3O2 | 详情 | 详情 | |
| (XXI) | 15360 | (2S)-2-amino-3-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-1-propanol | C15H23N3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Fischer esterification of L-4-nitrophenylalanine (V) afforded nitrophenylalanine methyl ester (VI), which was then protected as the tert-butyl carbamate (VII) using (Boc)2O. Reduction of the nitro group of (VII) by catalytic hydrogenation gave aniline (VIII). Subsequent coupling of (VIII) with 2,6-dichlorobenzoyl chloride (IX) generated amide (X). Deprotection of the Boc group of (X) using HCl in dioxan provided aminoester (XI), which was coupled with camphoric acid derivative (IV) in the presence of benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (BOP) to yield amide (XII). Deprotection of the tert-butyl ester group of (XII) by means of trifluoroacetic acid gave acid (XIII). Finally, the methyl ester group of (XIII) was hydrolyzed with LiOH to furnish the title compound.
| 【1】 Rishton, G.; Chrusciel, R.A.; Yamagishi, M.; Polinsky, A.; Thomas, E.W.; Lobl, T.J.; Tanis, S.P.; Teegarden, B.; Fisher, J.F. (Pharmacia Corp.; Tanabe Seiyaku Co., Ltd.); Inhibitors of alpha4beta1 mediated cell adhesion. EP 0991619; WO 9858902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 32572 | (1S,3R)-3-(tert-butoxycarbonyl)-2,2,3-trimethylcyclopentanecarboxylic acid | C14H24O4 | 详情 | 详情 | |
| (V) | 15341 | (2S)-2-amino-3-(4-nitrophenyl)propionic acid; 4-nitro-L-phenylalanine | 949-99-5 | C9H10N2O4 | 详情 | 详情 |
| (VI) | 15342 | methyl (2S)-2-amino-3-(4-nitrophenyl)propanoate | C10H12N2O4 | 详情 | 详情 | |
| (VII) | 32574 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propanoate | C15H20N2O6 | 详情 | 详情 | |
| (VIII) | 32575 | methyl (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate | C15H22N2O4 | 详情 | 详情 | |
| (IX) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (X) | 32576 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[(2,6-dichlorobenzoyl)amino]phenyl]propanoate | C22H24Cl2N2O5 | 详情 | 详情 | |
| (XI) | 32578 | methyl (2S)-2-amino-3-[4-[(2,6-dichlorobenzoyl)amino]phenyl]propanoate | C17H16Cl2N2O3 | 详情 | 详情 | |
| (XII) | 32573 | tert-butyl (1R,3S)-3-[[((1S)-1-[4-[(2,6-dichlorobenzoyl)amino]benzyl]-2-methoxy-2-oxoethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylate | C31H38Cl2N2O6 | 详情 | 详情 | |
| (XIII) | 32577 | (1R,3S)-3-[[((1S)-1-[4-[(2,6-dichlorobenzoyl)amino]benzyl]-2-methoxy-2-oxoethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylic acid | C27H30Cl2N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Partial esterification of (1R,3S)-camphoric acid (I) with MeOH and HCl produced mono methyl ester (II). Further esterification of (II) with isobutylene in the presence of H2SO4 yielded the corresponding methyl tert-butyl ester, which was selectively hydrolyzed with LiOH to provide camphoric acid mono tert-butyl ester (III). From this, intermediate (X) was synthesized by two related methods. Fischer esterification of L-4-nitrophenylalanine (IV) afforded nitrophenylalanine methyl ester (V), which was then coupled with camphoric acid derivative (IV) in the presence of benzotriazolyloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) to yield amide (VI). Then, reduction of the nitro group of (VI) by catalytic hydrogenation gave aniline (X). In an alternative procedure, N-Boc-4-(carbobenzoxyamino)-L-phenylalanine (VII) was deprotected and esterified with MeOH and HCl to provide 4-(carbobenzoxyamino)phenylalanine methyl ester (VIII). Coupling of (VIII) with camphoric acid derivative (III) as above produced amide (IX). Then, hydrogenolytic removal of the carbobenzoxy group of (IX) yielded aniline (X).
| 【1】 Teegarden, B.R.; Rishton, G.M.; Yamagishi, M.; et al.; Discovery of TR-9109: A novel small molecule inhibitor of alpha4beta1 integrin mediated cell adhesion. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 58. |
| 【2】 Rishton, G.; Chrusciel, R.A.; Yamagishi, M.; Polinsky, A.; Thomas, E.W.; Lobl, T.J.; Tanis, S.P.; Teegarden, B.; Fisher, J.F. (Pharmacia Corp.; Tanabe Seiyaku Co., Ltd.); Inhibitors of alpha4beta1 mediated cell adhesion. EP 0991619; WO 9858902 . |
| 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) | 32569 | (1R,3S)-1,2,2-trimethyl-1,3-cyclopentanedicarboxylic acid; (+)-Camphoric acid | 124-83-4 | C10H16O4 | 详情 | 详情 |
| (II) | 32570 | (1R,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid | C11H18O4 | 详情 | 详情 | |
| (III) | 32572 | (1S,3R)-3-(tert-butoxycarbonyl)-2,2,3-trimethylcyclopentanecarboxylic acid | C14H24O4 | 详情 | 详情 | |
| (IV) | 15341 | (2S)-2-amino-3-(4-nitrophenyl)propionic acid; 4-nitro-L-phenylalanine | 949-99-5 | C9H10N2O4 | 详情 | 详情 |
| (V) | 15342 | methyl (2S)-2-amino-3-(4-nitrophenyl)propanoate | C10H12N2O4 | 详情 | 详情 | |
| (VI) | 32579 | tert-butyl (1R,3S)-3-([[(1S)-2-methoxy-1-(4-nitrobenzyl)-2-oxoethyl]amino]carbonyl)-1,2,2-trimethylcyclopentanecarboxylate | C24H34N2O7 | 详情 | 详情 | |
| (VII) | 32580 | (2S)-3-(4-[[(benzyloxy)carbonyl]amino]phenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid | C22H26N2O6 | 详情 | 详情 | |
| (VIII) | 32581 | methyl (2S)-2-amino-3-(4-[[(benzyloxy)carbonyl]amino]phenyl)propanoate | C18H20N2O4 | 详情 | 详情 | |
| (IX) | 32582 | tert-butyl (1R,3S)-3-([[(1S)-1-(4-[[(benzyloxy)carbonyl]amino]benzyl)-2-methoxy-2-oxoethyl]amino]carbonyl)-1,2,2-trimethylcyclopentanecarboxylate | C32H42N2O7 | 详情 | 详情 | |
| (X) | 32583 | tert-butyl (1R,3S)-3-([[(1S)-1-(4-aminobenzyl)-2-methoxy-2-oxoethyl]amino]carbonyl)-1,2,2-trimethylcyclopentanecarboxylate | C24H36N2O5 | 详情 | 详情 |