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【结 构 式】 
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【分子编号】22613 【品名】(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid 【CA登记号】2900-27-8 |
【 分 子 式 】C13H17NO4 【 分 子 量 】251.28232 【元素组成】C 62.14% H 6.82% N 5.57% O 25.47% |
合成路线1
该中间体在本合成路线中的序号：(IX)An alternative synthesis starting from the chiral precursor N-Boc-(R)-phenylglycine (IX) was reported. Borane reduction of (IX) provided the N-Boc aminoalcohol (X), which was activated as the mesylate (XI) by reaction with methanesulfonyl chloride in pyridine, yielding (XI). Displacement of the mesylate group of (XI) with NaCN furnished the Boc-aminonitrile (XII). Hydrolysis of the nitrile group of (XII) with concomitant N-Boc group cleavage under acidic conditions gave aminoacid (XIII). This was reduced to amino alcohol (XIV) using borane in THF. Eschweiler-Clarke methylation of aminoalcohol (XIV) yielded the dimethyl amine (XV). This was finally condensed with 1-fluoronaphthalene (VIII) to produce the title naphthyl ether. The [14C]-labeled compound was similarly prepared employing 14C-sodium cyanide.
| 【1】 Wheeler, W.J.; O'Bannon, D.D.; A chiral synthesis of dapoxetine hydrochloride, a serotonin reuptake inhibitor, and its 14C isotopomer. J Label Compd Radiopharm 1992, 31, 4, 305. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 40503 | 1-fluoronaphthalene | 321-38-0 | C10H7F | 详情 | 详情 |
| (IX) | 22613 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid | 2900-27-8 | C13H17NO4 | 详情 | 详情 |
| (X) | 59225 | (R)-N-(tert-Butoxycarbonyl)-phenylglycinol; N-t-BOC-D-phenylglycinol | 102089-74-7 | C13H19NO3 | 详情 | 详情 |
| (XI) | 59226 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate | C14H21NO5S | 详情 | 详情 | |
| (XII) | 59227 | tert-butyl (1S)-2-cyano-1-phenylethylcarbamate | C14H18N2O2 | 详情 | 详情 | |
| (XIII) | 56272 | (3R)-3-amino-3-phenylpropanoic acid | C9H11NO2 | 详情 | 详情 | |
| (XIV) | 59228 | (R)-3-Amino-3-phenylpropan-1-ol | C9H13NO | 详情 | 详情 | |
| (XV) | 59229 | (3S)-3-(dimethylamino)-3-phenyl-1-propanol | C11H17NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Reduction of the phenyl ring of N-(tert-butoxycarbonyl)-(R)-phenylglycine (VI) with H2 over Rh/Al2O3 in methanol gives the protected (R)-cyclohexylglycine (VII), which is condensed with azetidine (VIII) by means of EDC in acetonitrile to yield the dipeptide (IX). Hydrolysis of the ester group of (IX) affords the carboxylic acid (X), which is condensed with the amino group of the previous intermediate (V) by means of EDC and DMAP in acetonitrile or ethyl acetate/acetonitrile to provide adduct (XI). Cleavage of the Boc-protecting group of (XI) with HCl or methanesulfonic acid gives (XII) with a terminal amino group that is condensed with benzyl 2-(2-nitrophenylsulfonyloxy)acetate (XIII) or benzyl 2-bromoacetate (XIV) by means of K2CO3 in the same solvent to yield the melagatran precursor (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155. |
| 【2】 Antonsson, K.T.; Bylund, R.E.; Gustafsson, N.D.; Nilsson, N.O.I. (AstraZeneca plc); New peptide derivs.. EP 0701568; JP 1996511018; JP 2001322974; US 5602253; US 5723444; WO 9429336 . |
| 【3】 Hedstrom, L.; Lundblad, A.; Nagard, S. (AstraZeneca AB); A substantially crystalline form of melagatran. WO 0102426 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 50386 | benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate | C16H17N3O2 | 详情 | 详情 | |
| (VI) | 22613 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid | 2900-27-8 | C13H17NO4 | 详情 | 详情 |
| (VII) | 35619 | (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid | C13H23NO4 | 详情 | 详情 | |
| (VIII) | 50387 | methyl (2S)-2-azetidinecarboxylate | C5H9NO2 | 详情 | 详情 | |
| (IX) | 50388 | tert-butyl (1R)-1-cyclohexyl-2-[(2S)-2-[(methylamino)carbonyl]azetidinyl]-2-oxoethylcarbamate | C18H31N3O4 | 详情 | 详情 | |
| (X) | 50389 | (2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]-2-azetidinecarboxylic acid | C17H28N2O5 | 详情 | 详情 | |
| (XI) | 50376 | benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate | C33H43N5O6 | 详情 | 详情 | |
| (XII) | 50390 | benzyl (4-[[([(2S)-1-[(2R)-2-amino-2-cyclohexylethanoyl]azetidinyl]carbonyl)amino]methyl]phenyl)(imino)methylcarbamate | C28H35N5O4 | 详情 | 详情 | |
| (XIII) | 50391 | benzyl 2-[[(2-nitrophenyl)sulfonyl]oxy]acetate | C15H13NO7S | 详情 | 详情 | |
| (XIV) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XV) | 50392 | benzyl 2-[((1R)-2-[(2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]azetidinyl]-1-cyclohexyl-2-oxoethyl)amino]acetate | C37H43N5O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Acylation of sarcosine methyl ester (I) with 3,5-dichlorobenzoyl chloride (II) produced the corresponding amide (III). Claisen condensation of (III) with the dianion of 3,4-dichlorophenylacetic acid (IV), generated in the presence of lithium hexamethyldisilazide, gave, after acid decarboxylation, ketone (V). The lithium enolate of ketone (V) was then alkylated with 1-bromo-3-methyl-2-butene (VI) to afford (VII). Treatment of ketone (VII) with hydroxylamine produced a geometric mixture of oximes from which the desired (E)-isomer (VIII) was isolated by column chromatography. Resolution of the racemic (VIII) was achieved by coupling with N-Boc-D-phenylglycine (IX) followed by fractional crystallization of the desired diastereoisomer (X). Hydrazinolysis of the oxime ester then furnished the chiral intermediate (XI).
| 【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 . |
| 【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 . |
| 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) | 10430 | methyl 2-(methylamino)acetate; methyl N-methylglycinate | 5473-12-1 | C4H9NO2 | 详情 | 详情 |
| (II) | 27769 | 3,5-dichlorobenzoyl chloride | 2905-62-6 | C7H3Cl3O | 详情 | 详情 |
| (III) | 44268 | methyl 2-[(3,5-dichlorobenzoyl)(methyl)amino]acetate | C11H11Cl2NO3 | 详情 | 详情 | |
| (IV) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (V) | 44269 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-oxopropyl]-N-methylbenzamide | C17H13Cl4NO2 | 详情 | 详情 | |
| (VI) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (VII) | 44270 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-6-methyl-2-oxo-5-heptenyl]-N-methylbenzamide | C22H21Cl4NO2 | 详情 | 详情 | |
| (VIII) | 44271 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide | C22H22Cl4N2O2 | 详情 | 详情 | |
| (IX) | 22613 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid | 2900-27-8 | C13H17NO4 | 详情 | 详情 |
| (X) | 44272 | tert-butyl (1R)-2-([[(Z,2R)-1-[[(3,5-dichlorobenzoyl)(methyl)amino]methyl]-2-(3,4-dichlorophenyl)-5-methyl-4-hexenylidene]amino]oxy)-2-oxo-1-phenylethylcarbamate | C35H37Cl4N3O5 | 详情 | 详情 | |
| (XI) | 44273 | 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide | C22H22Cl4N2O2 | 详情 | 详情 |