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【结 构 式】 
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【分子编号】14505 【品名】(2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine 【CA登记号】1161-13-3 |
【 分 子 式 】C17H17NO4 【 分 子 量 】299.32632 【元素组成】C 68.22% H 5.72% N 4.68% O 21.38% |
合成路线1
该中间体在本合成路线中的序号：(XVI)The reduction of N-(benzyloxycarbonyl)-L-phenylalanine (XVI) gives the corresponding aldehyde (XVII), which is cyclized with 2-sulfanylethylamine (XVIII) to yield the thiazolidine (XIX). The dehydrogenation of (XIX) by means of MnO2 affords the thiazole derivative (XX). Finally, the amino group of (XX) is deprotected with HBr to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XXI). Alternatively, N-(benzyloxycarbonyl)-L-phenylalanine (XVI) can be converted into the corresponding amide (XXII), which is treated with the Lawesson's reagent to yield the thioamide (XXIII). Finally, the cyclization of (XXIII) with 2-bromoacetaldehyde (XXIV) gives already reported thiazole derivative (XX) (partial racemization occurs during the synthetic process). Enantiomeric separation takes place in a later stage.
| 【1】 Roux, F.; et al.; Synthesis of dolastatin-10 and [R-Doe]-dolastatin-10. Tetrahedron 1994, 50, 18, 5345. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 54607 | (1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine | C11H12N2S | 详情 | 详情 | ||
| (XVI) | 14505 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine | 1161-13-3 | C17H17NO4 | 详情 | 详情 |
| (XVII) | 16586 | benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C17H17NO3 | 详情 | 详情 | |
| (XVIII) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (XX) | 54604 | benzyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate | C19H22N2O2S | 详情 | 详情 | |
| (XXI) | 24802 | 2-bromoacetaldehyde | C2H3BrO | 详情 | 详情 | |
| (XXII) | 54603 | benzyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate | 4801-80-3 | C17H18N2O3 | 详情 | 详情 |
| (XXIII) | 54605 | benzyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate | C19H18N2O2S | 详情 | 详情 | |
| (XXIV) | 54606 | benzyl (1S)-2-amino-1-benzyl-2-thioxoethylcarbamate | C17H18N2O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(Ia)Various new routes for the large-scale synthesis of Ro-31-8959 have been described: 1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III), which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV). The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI), which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII). The treatment of (VII) with oxalyl chloride, mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII), which, without isolation, is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX). The reaction of (IX) with KOH in methanol yields the epoxide (X), which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI), yielding the protected condensation product (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII), which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way, giving the protected peptide (XV). The deprotection of (XV) as before yields compound (XVI), with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.
| 【1】 Parkes, K.E.B.; Bushnell, D.J.; Crackett, P.H.; et al.; Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J Org Chem 1994, 59, 13, 3656. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (Ib) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (IIIb) | 12876 | ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate | C18H25NO5 | 详情 | 详情 | |
| (Ia) | 14505 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine | 1161-13-3 | C17H17NO4 | 详情 | 详情 |
| (IIIa) | 14508 | ethyl (4S)-4-[[(benzyloxy)carbonyl]amino]-3-oxo-5-phenylpentanoate | C21H23NO5 | 详情 | 详情 | |
| (IVa) | 14510 | ethyl (3R,4S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-phenylpentanoate | C21H25NO5 | 详情 | 详情 | |
| (VIa) | 14514 | benzyl (4S,5R)-4-benzyl-5-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-1,3-oxazolane-3-carboxylate | C24H29NO5 | 详情 | 详情 | |
| (VIb) | 14515 | ethyl 2-[(4S,5R)-4-benzyl-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolan-5-yl]acetate | C21H31NO5 | 详情 | 详情 | |
| (VIIa) | 14516 | 2-[(4S,5R)-4-benzyl-3-[(benzyloxy)carbonyl]-2,2-dimethyl-1,3-oxazolan-5-yl]acetic acid | C22H25NO5 | 详情 | 详情 | |
| (VIIb) | 14517 | 2-[(4S,5R)-4-benzyl-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolan-5-yl]acetic acid | C19H27NO5 | 详情 | 详情 | |
| (VIIIa) | 14518 | benzyl (4S,5S)-4-benzyl-5-(bromomethyl)-2,2-dimethyl-1,3-oxazolane-3-carboxylate | C21H24BrNO3 | 详情 | 详情 | |
| (VIIIb) | 14519 | (4S,5S)-4-benzyl-5-(bromomethyl)-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolane | C18H26BrNO3 | 详情 | 详情 | |
| (IXa) | 14520 | benzyl N-[(1S,2S)-1-benzyl-3-bromo-2-hydroxypropyl]carbamate | C18H20BrNO3 | 详情 | 详情 | |
| (IXb) | 14521 | (2S,3S)-1-bromo-3-[[(2,2-dimethylpropanoyl)oxy]amino]-4-phenyl-2-butanol | C15H22BrNO3 | 详情 | 详情 | |
| (Xa) | 14522 | benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate | C18H19NO3 | 详情 | 详情 | |
| (XIIa) | 14526 | benzyl (1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropylcarbamate | C32H45N3O4 | 详情 | 详情 | |
| (XIIb) | 14527 | (3S,4aS,8aS)-N-(tert-butyl)-2-((2R,3S)-3-[[(2,2-dimethylpropanoyl)oxy]amino]-2-hydroxy-4-phenylbutyl)decahydro-3-isoquinolinecarboxamide | C29H47N3O4 | 详情 | 详情 | |
| (IXb) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (IVb) | 25725 | 2-[(4S,5R)-4-benzyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin-5-yl]acetic acid | C17H23NO5 | 详情 | 详情 | |
| (II) | 14507 | Malonic acid monoethyl ester magnesium salt | C5H6MgO4 | 详情 | 详情 | |
| (XI) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XIII) | 14528 | (3S,4aS,8aS)-2-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2 | 详情 | 详情 | |
| (XIV) | 14529 | (2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 2304-96-3 | C12H14N2O5 | 详情 | 详情 |
| (XV) | 14530 | benzyl (1S)-1-[([(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]amino)carbonyl]-3-amino-3-oxopropylcarbamate | C36H51N5O6 | 详情 | 详情 | |
| (XVI) | 14531 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 | |
| (XVII) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIV)The chiral indolines (XIX) and (XX) have been obtained as follows: The condensation of racemic 5-bromo-2-methylindoline (XXIII) with N-(benzyloxycarbonyl)-L-phenylalanine (XXIV) by means of DIC and triethylamine in THF gives the diastereomeric mixture of indolines (XXV), which is separated by column chromatography, yielding the pure enantiomer (XXVI). The cleavage of (XXVI) with 6N HCl affords 5-bromo-1(R)-methylisoindoline (XXVII), which is treated with trityl chloride and triethylamine in dichloromethane to give indoline (XIX), or with benzyl chloroformate and triethylamine to give indoline (XX).
| 【1】 Castañer, J.; Rabasseda, X.; Graul, A.; T-3811ME. Drugs Fut 1999, 24, 12, 1324. |
| 【2】 Todo, Y.; Hayashi, K.; Takahata, M.; Watanabe, Y.; Narita, H. (Toyama Chemical Co., Ltd.); Quinolonecarboxylic acid derivs. or salts thereof.. EP 0882725; US 6025370; WO 9729102 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 30634 | (1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole | C28H24BrN | 详情 | 详情 | |
| (XX) | 30635 | benzyl (1R)-5-bromo-1-methyl-1,3-dihydro-2H-isoindole-2-carboxylate | C17H16BrNO2 | 详情 | 详情 | |
| (XXIII) | 30638 | 5-bromo-1-methylisoindoline | C9H10BrN | 详情 | 详情 | |
| (XXIV) | 14505 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine | 1161-13-3 | C17H17NO4 | 详情 | 详情 |
| (XXV) | 30639 | benzyl (1S)-1-benzyl-2-(5-bromo-1-methyl-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethylcarbamate | C26H25BrN2O3 | 详情 | 详情 | |
| (XXVI) | 30640 | benzyl (1S)-1-benzyl-2-[(1R)-5-bromo-1-methyl-1,3-dihydro-2H-isoindol-2-yl]-2-oxoethylcarbamate | C26H25BrN2O3 | 详情 | 详情 | |
| (XXVII) | 30641 | (1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindole | C9H10BrN | 详情 | 详情 |