|
【结 构 式】 
|
【分子编号】19875 【品名】methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate 【CA登记号】4326-36-7 |
【 分 子 式 】C15H21NO5 【 分 子 量 】295.33548 【元素组成】C 61% H 7.17% N 4.74% O 27.09% |
合成路线1
该中间体在本合成路线中的序号：(I)The methylation of N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (I) with methyl iodide and KOH gives the protected 4-O-methyl-L-tyrosine methyl ester (II), which is deprotected with TFA yielding (III). The Grundke oxidation of (III) affords the N-hydroxy derivative (IV), which is cyclocondensed with cyclohexane-1,4-dione monoethylene ketal (V) and ethyl acrylate (VI) in refluxing toluene to afford the spiroisoxazolidinone (VII). The reductive rearrangement of (VII) with H2 over Pd/C in acetic acid provides the spiropyrrolidinone (VIII), which is treated successively with tosyl chloride and with sodium azide to obtain the azido derivative (IX). The reduction of (IX) with H2 over Pd/C, protection of the resulting amine with Boc2O, and methylation of the resulting carbamate with NaH and methyl iodide affords the N-methylcarbamate (X). The reduction of the methoxycarbonyl group of (X) with LiBH4 in THF gives the carbinol (XI), which is oxidized with Dess-Martin periodinane to the aldehyde (XII). The rearrangement of (XII) by means of potassium tert-butoxide, followed by deprotection of the carbamate group yields the 7,10a-methanopyrrolo[1,2-a]azocin-8-one derivative (XIII), which is reduced at the carbonyl group with LiAlH4 in THF affords the 8(R)-hydroxy derivative (XIV). The protection of the amino group of (XIV) with benzyloxycarbonyl chloride and triethylamine yields the carbamate (XV).
| 【1】 Snider, B.B.; et al.; Total synthesis of (-)-FR901483. J Am Chem Soc 1999, 121, 34, 7778. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (I) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (II) | 32453 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate | C16H23NO5 | 详情 | 详情 | |
| (III) | 32454 | methyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate | C11H15NO3 | 详情 | 详情 | |
| (IV) | 32455 | methyl (2S)-2-(hydroxyamino)-3-(4-methoxyphenyl)propanoate | C11H15NO4 | 详情 | 详情 | |
| (V) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (VI) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (VII) | 32456 | ethyl (3R)-1-[(1S)-2-methoxy-1-(4-methoxybenzyl)-2-oxoethyl]-2,9,12-trioxa-1-azadispiro[4.2.4.2]tetradecane-3-carboxylate | C24H33NO8 | 详情 | 详情 | |
| (VIII) | 32457 | methyl (2S)-2-[(11R)-11-hydroxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate | C22H29NO7 | 详情 | 详情 | |
| (IX) | 32458 | methyl (2S)-2-[(11S)-11-azido-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate | C22H28N4O6 | 详情 | 详情 | |
| (X) | 32459 | methyl (2S)-2-[(11S)-11-[(tert-butoxycarbonyl)(methyl)amino]-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate | C28H40N2O8 | 详情 | 详情 | |
| (XI) | 32460 | tert-butyl (3S)-1-[(1S)-2-hydroxy-1-(4-methoxybenzyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate | C25H36N2O6 | 详情 | 详情 | |
| (XII) | 32461 | tert-butyl (3S)-1-[(1S)-1-formyl-2-(4-methoxyphenyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate | C25H34N2O6 | 详情 | 详情 | |
| (XIII) | 32462 | (1S,3S,6S,7S,8S)-7-hydroxy-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecan-9-one | C20H28N2O3 | 详情 | 详情 | |
| (XIV) | 32463 | (1S,3S,6S,7S,8R,9R)-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecane-7,9-diol | C20H30N2O3 | 详情 | 详情 | |
| (XV) | 32464 | benzyl (1S,3S,6S,7S,8R,9R)-7,9-dihydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C28H36N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Oxazolylethanol (I) was coupled to N-Boc-L-tyrosine methyl ester (II) using Mitsunobu conditions in the presence of PPh3 and DEAD to give ether (III). Subsequent deprotection of the Boc group of (III) with trifluoroacetic acid afforded amine (IV), which was then condensed with methyl cyclohexanone-2-carboxylate (V) in boiling toluene to yield enamine (VI). Further heating of (VI) at 190 C in anisole in the presence of Pd/C resulted in aromatization of the cyclohexene ring to produce the anthranilate derivative (VII). Finally, selective hydrolysis of the aliphatic ester with LiOH under careful conditions provided the target monoester.
| 【1】 Cobb, J.E.; Blanchard, S.G.; Boswell, E.G.; Brown, K.K.; Charifson, P.S.; Cooper, J.P.; Collins, J.L.; Dezube, M.; Henke, B.R.; Hull-Ryde, E.A.; Lake, D.H.; Lenhard, J.M.; Oliver, W. Jr; Oplinger, J.; Pentti, M.; Parks, D.J.; Plunket, K.D.; Tong, W.Q.; N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent. J Med Chem 1998, 41, 25, 5055. |
| 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) | 19874 | 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol | C12H13NO2 | 详情 | 详情 | |
| (II) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (III) | 19876 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanoate | C27H32N2O6 | 详情 | 详情 | |
| (IV) | 19877 | methyl (2S)-2-amino-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanoate | C22H24N2O4 | 详情 | 详情 | |
| (V) | 19878 | methyl 2-oxocyclohexanecarboxylate | 41302-34-5 | C8H12O3 | 详情 | 详情 |
| (VI) | 19879 | methyl 2-[((1S)-2-methoxy-1-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl]-2-oxoethyl)amino]-1-cyclohexene-1-carboxylate | C30H34N2O6 | 详情 | 详情 | |
| (VII) | 19880 | methyl 2-[((1S)-2-methoxy-1-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl]-2-oxoethyl)amino]benzoate | C30H30N2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)In an alternative procedure, N-Boc-L-tyrosine methyl ester (VIII) was treated with trifluoromethanesulfonic anhydride to afford triflate (IX). Suzuki coupling of (IX) with boronic acid (VI) produced biphenyl (X). After deprotection of the Boc group of (X) with trifluoroacetic acid, the resulting aminoester (XI) was acylated with acid chloride (III) to give amide (XII). The title compound was then obtained by hydrolysis of the methyl ester of (XII) with LiOH.
| 【1】 Sircar, I.; et al.; Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035, a dual alpha4beta7/alpha4beta1 integrin antagonist. Bioorg Med Chem 2002, 10, 6, 2051. |
| 【2】 Hattfield, L.D.; Sircar, I.; McNutly, A.; Naubauer, B.; Discovery of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 59. |
| 【3】 Sircar, I.; Liang, J.T.; Martin, R.; et al.; SAR of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (VI) | 32549 | 2,6-dimethoxyphenylboronic acid | 23112-96-1 | C8H11BO4 | 详情 | 详情 |
| (VIII) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (IX) | 32551 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(trifluoromethyl)sulfonyl]oxy]phenyl)propanoate | C16H20F3NO7S | 详情 | 详情 | |
| (X) | 32552 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C23H29NO6 | 详情 | 详情 | |
| (XI) | 32553 | methyl (2S)-2-amino-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C11H16N2O4S | 详情 | 详情 | |
| (XII) | 32554 | methyl (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C25H23Cl2NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)N-Boc-L-Tyrosine methyl ester (I) was alkylated with either 3-(dimethylamino)-1-propanol (II) under Mitsunobu conditions or with N,N-dimethyl-3-chloropropylamine (III) in the presence of K2CO3 to afford N-Boc-L-4-(3-dimethylaminopropoxy)phenylalanine methyl ester (IV). Subsequent acidic cleavage of the N-Boc protecting group of (IV) gave amino ester (V). N-Tosyl-L-5,5-dimethylthiaproline (VII) was obtained by treatment of L-5,5-dimethylthiaproline (VI) with p-toluenesulfonyl chloride in the presence of NaOH. Acid (VII) was then coupled to amino ester (V) using EDC and HOBt to furnish amide (VIII). Finally, basic hydrolysis of the methyl ester group of (VIII) yielded the title compound.
| 【1】 Grant, F.S.; Dressen, D.B.; Dappen, M.S.; et al.; CT747: A very potent and highly selective small molecule inhibitor of VLA4 that is metabolically stable. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 135. |
| 【2】 Ashwell, S.; Konradi, A.W.; Lombardo, L.J.; Dappen, M.S.; Baudy, R.B.; Kreft, A.; Grant, F.S.; Sarantakis, D.; Pleiss, M.A.; Semko, C.M.; Dressen, D.B.; Thorsett, E.D. (American Home Products Corp.; Athena Neurosciences, Inc.); Substd. phenylalanine type cpds. which inhibit leukocyte adhesion mediated by VLA-4. WO 9906431 . |
| 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) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (II) | 37173 | 3-(dimethylamino)-1-propanol | 3179-63-3 | C5H13NO | 详情 | 详情 |
| (III) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (IV) | 45680 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[3-(dimethylamino)propoxy]phenyl]propanoate | C20H32N2O5 | 详情 | 详情 | |
| (V) | 45681 | methyl (2S)-2-amino-3-[4-[3-(dimethylamino)propoxy]phenyl]propanoate | C15H24N2O3 | 详情 | 详情 | |
| (VI) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (VII) | 45682 | (4R)-5,5-dimethyl-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidine-4-carboxylic acid | C13H17NO4S2 | 详情 | 详情 | |
| (VIII) | 45683 | methyl (2S)-3-[4-[3-(dimethylamino)propoxy]phenyl]-2-[([(4R)-5,5-dimethyl-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidin-4-yl]carbonyl)amino]propanoate | C28H39N3O6S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)N-Boc-L-Tyrosine (I) methyl ester is treated with methanolic ammonia to provide amide (II). Protection of the phenolic hydroxyl of (II) with t-butyldimethylsilyl chloride leads to the silyl ether (III), which is further reacted with di-t-butyl dicarbonate in the presence of DMAP to furnish the tri-Boc derivative (IV). Subsequent desilylation of (IV) by means of tetrabutylammonium fluoride affords the tri-Boc-tyrosinamide (V).
| 【1】 Peyrottes, S.; Coussot, G.; Lefebvre, I.; Imbach, J.-L.; Gosselin, G.; Aubertin, A.-M.; Perigaud, C.; S-acyl-2-thioethyl aryl phosphotriester derivatives of AZT: Synthesis, antiviral activity, and stability study. J Med Chem 2003, 46, 5, 782. |
| 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) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (II) | 64278 | tert-butyl (1S)-2-amino-1-(4-hydroxybenzyl)-2-oxoethylcarbamate | C14H20N2O4 | 详情 | 详情 | |
| (III) | 64279 | tert-butyl (1S)-2-amino-1-(4-{[tert-butyl(dimethyl)silyl]oxy}benzyl)-2-oxoethylcarbamate | C20H34N2O4Si | 详情 | 详情 | |
| (IV) | 64280 | C25H38N2O8 | 详情 | 详情 | ||
| (V) | 64281 | (7S)-5-(tert-butoxycarbonyl)-7-(4-{[tert-butyl(dimethyl)silyl]oxy}benzyl)-2,2,11,11-tetramethyl-4,6,9-trioxo-3,10-dioxa-5,8-diazadodecane | C30H50N2O8Si | 详情 | 详情 |