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【结 构 式】

【分子编号】14517

【品名】2-[(4S,5R)-4-benzyl-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolan-5-yl]acetic acid

【CA登记号】

【 分 子 式 】C19H27NO5

【 分 子 量 】349.42712

【元素组成】C 65.31% H 7.79% N 4.01% O 22.89%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VIIb)

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
Extended Information