|
【结 构 式】 
|
【分子编号】25725 【品名】2-[(4S,5R)-4-benzyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin-5-yl]acetic acid 【CA登记号】 |
【 分 子 式 】C17H23NO5 【 分 子 量 】321.37336 【元素组成】C 63.54% H 7.21% N 4.36% O 24.89% |
合成路线1
该中间体在本合成路线中的序号：(IVb)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2
该中间体在本合成路线中的序号：(XV)Treatment of N-Boc-L-phenylalanine (XI) with carbonyl diimidazole, followed by condensation with the lithium enolate of ethyl acetate provided the beta-ketoester (XII). Then, reduction with NaBH4 in EtOH at -78 C furnished the anti aminoalcohol (XIII) as the major isomer. Subsequent reaction with formaldehyde in the presence of p-toluenesulfonic acid in boiling toluene produced the cis oxazolidine (XIV). Basic hydrolis of the ester group yielded carboxylic acid (XV) which, after activation as the mixed anhydride with 2,4,6-trichlorobenzoyl chloride (VI), was coupled to hydroxyester (X) to give triester (XVI). Reduction of the oxazolidine with NaBH3CN in the presence of trifluoroacetic acid afforded the N-methylated derivative (XVII). Then, hydrogenolysis of the benzyl ester in the presence of Pd/C produced acid (XVIII), which was finally cyclized using DPPA.
| 【1】 Wagner, B.; et al.; Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin. Bioorg Med Chem 1999, 7, 5, 737. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (X) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 详情 | 详情 | |
| (XI) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XII) | 12876 | ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate | C18H25NO5 | 详情 | 详情 | |
| (XIII) | 25723 | ethyl (3R,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenylpentanoate | C18H27NO5 | 详情 | 详情 | |
| (XIV) | 25724 | tert-butyl (4S,5R)-4-benzyl-5-(2-ethoxy-2-oxoethyl)-1,3-oxazolidine-3-carboxylate | C19H27NO5 | 详情 | 详情 | |
| (XV) | 25725 | 2-[(4S,5R)-4-benzyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin-5-yl]acetic acid | C17H23NO5 | 详情 | 详情 | |
| (XVI) | 25726 | tert-butyl (4S,5R)-4-benzyl-5-[2-([(1S)-1-[(1S)-2-([(1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl]oxy)-1-methyl-2-oxoethyl]octyl]oxy)-2-oxoethyl]-1,3-oxazolidine-3-carboxylate | C40H57NO9 | 详情 | 详情 | |
| (XVII) | 25727 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3S)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoate | C35H51NO7 | 详情 | 详情 | |
| (XVIII) | 25728 | (2S)-2-[((2S,3S)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoyl)oxy]-3-methylbutyric acid | C28H45NO7 | 详情 | 详情 |