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【结 构 式】 
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【分子编号】26616 【品名】N-(tert-butoxycarbonyl)-beta-alanine 【CA登记号】3303-84-2 |
【 分 子 式 】C8H15NO4 【 分 子 量 】189.21144 【元素组成】C 50.78% H 7.99% N 7.4% O 33.82% |
合成路线1
该中间体在本合成路线中的序号：(I)Activation of N-Boc-beta-alanine (I) as the mixed anhydride (II) with isobutyl chloroformate, followed by condensation with triethanolamine (III), furnished the [bis(2-hydroxyethyl)amino]ethyl ester (IV). Silylation of the free hydroxyl groups of (IV) by means of tert-butyldimethylsilyl chloride and imidazole afforded the bis-silylether (V). The N-Boc protecting group of (V) was then selectively removed upon treatment with trifluoroacetic acid to give amino ester (VI). This was subsequently coupled with 9-methoxyacridine (VII), yielding adduct (VIII), which was further desilylated with HF/pyridine. The resultant bis(hydroxyethyl) derivative (IX) was finally converted to the target dichloro compound by treatment with thionyl chloride.
| 【1】 Wollowitz, S.; Rapoport, H.; Cook, D.; Merritt, J.; Neiro, A.; Stassinopoulos, A.; Matejovic, J. (Cerus Corp.); Frangible cpds. for pathogen inactivation. WO 9830545 . |
| 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) | 26616 | N-(tert-butoxycarbonyl)-beta-alanine | 3303-84-2 | C8H15NO4 | 详情 | 详情 |
| (II) | 52945 | n/a | C13H23NO6 | 详情 | 详情 | |
| (III) | 28168 | 2-[bis(2-hydroxyethyl)amino]-1-ethanol | 102-71-6 | C6H15NO3 | 详情 | 详情 |
| (IV) | 52946 | 2-[bis(2-hydroxyethyl)amino]ethyl 3-[(tert-butoxycarbonyl)amino]propanoate | n/a | C14H28N2O6 | 详情 | 详情 |
| (V) | 52947 | 2-[bis(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl 3-[(tert-butoxycarbonyl)amino]propanoate | n/a | C26H56N2O6Si2 | 详情 | 详情 |
| (VI) | 52948 | 2-[bis(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl 3-aminopropanoate | n/a | C21H48N2O4Si2 | 详情 | 详情 |
| (VII) | 52949 | 9-acridinyl methyl ether; 9-methoxyacridine | n/a | C14H11NO | 详情 | 详情 |
| (VIII) | 52950 | 2-[bis(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl 3-(9-acridinylamino)propanoate | n/a | C34H55N3O4Si2 | 详情 | 详情 |
| (IX) | 52951 | 2-[bis(2-hydroxyethyl)amino]ethyl 3-(9-acridinylamino)propanoate | n/a | C22H27N3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The reaction of N-(benzyloxycarbonyl)-L-asparagine (I) with bis(trifluoroacetyl)iodobenzene (BTI) in DMF/water gives 3-amino-2(S)-(benzyloxycarbonylamino)propionic acid (II), wehich is protected at the amino group with tert-butoxycarbonyl anhydride yielding carbamate (III). The esterification of (III) with ethanol WSC and DMAP affords the expected ethyl ester (IV), which is selectively deprotected with methanesulfonic acid in acetonitrile providing 3-amino-2-(benzyloxycarbonylamino)propionic acid ethyl ester (V). The condensation of (V) with N-(tert-butoxycarbonyl)-beta-alanine (VI) by means of HOBT, WSC and triethylamine in DMF gives the protected propionamidopropionic ester (VII), which is selectively deprotected by hydrogenation with H2 over Pd/C in ethanol/ethyl acetate giving the 2-aminopropionic ester (VIII). The condensation of (VIII) with 4-ethylbenzenesulfonyl chloride (IX) by means of triethylamine in dichloromethane yields the sulfonamide (X), which is deprotected with methanesulfonic acid as before afording intermediate (XI) with a free amino group, which is condensed with 4-(tert-butoxycarbonylamino)benzoic acid (XII) by means of HOBT and WSC in DMF providing the fully protected target compound (XIII).
| 【1】 Ikeda, Y.; Ueki, Y.; Kishimoto, H.; Nishihara, T.; Kamikawa, Y. (Sumitomo Pharmaceuticals Co., Ltd.); 2,3-Diaminopropionic acid deriv.. US 5707994; US 6048854; WO 9511228 . |
| 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) | 14529 | (2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 2304-96-3 | C12H14N2O5 | 详情 | 详情 |
| (II) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (III) | 26613 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propionic acid | C16H22N2O6 | 详情 | 详情 | |
| (IV) | 26614 | ethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C18H26N2O6 | 详情 | 详情 | |
| (V) | 26615 | ethyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C13H18N2O4 | 详情 | 详情 | |
| (VI) | 26616 | N-(tert-butoxycarbonyl)-beta-alanine | 3303-84-2 | C8H15NO4 | 详情 | 详情 |
| (VII) | 26617 | ethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)propanoate | C21H31N3O7 | 详情 | 详情 | |
| (VIII) | 26618 | ethyl (2S)-2-amino-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)propanoate | C13H25N3O5 | 详情 | 详情 | |
| (IX) | 26619 | 4-ethylbenzenesulfonyl chloride | 16712-69-9 | C8H9ClO2S | 详情 | 详情 |
| (X) | 26620 | ethyl (2S)-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C21H33N3O7S | 详情 | 详情 | |
| (XI) | 26621 | ethyl (2S)-3-[(3-aminopropanoyl)amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C16H25N3O5S | 详情 | 详情 | |
| (XII) | 26622 | 4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoic acid | C13H16N2O4 | 详情 | 详情 | |
| (XIII) | 26623 | ethyl (2S)-3-[[3-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)propanoyl]amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C29H39N5O8S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The reaction of disulfide (I) with sodium azide in DMSO gives the bis azido derivative (II), which is finally reduced with PPh3 in THF/water to afford the target beta-alanine derivative. Alternatively, the condensation of N-(tert-butoxycarbonyl)-beta-alanine (III) with S-acetyl-cysteamine (IV) by means of DCC in ethyl acetate gives the bet-alaninamide (V), which is deacetylated by means of NaOMe in methanol to yield N-[N-(tert-butoxycarbonyl)-beta-alanyl]cysteamine (VI). The dimerization of (VI) by means of I2 in Ac-OH affords the protected cystamine derivative (VII), which is finally deprotected by means of TFA.
| 【1】 Oiry, J.; et al.; Synthesis and radioprotective activity of new cysteamine and cystamine derivatives. J Med Chem 1986, 29, 11, 2217. |
| 【2】 Vogel, K.W.; et al.; Investigating the role of the geminal dimethyl groups of coenzyme A: Synthesis and studies of a didemethyl analogue. Bioorg Med Chem 2000, 8, 10, 2451. |
| 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) | 54379 | 3-chloro-N-[2-({2-[(3-chloropropanoyl)amino]ethyl}disulfanyl)ethyl]propanamide | C10H18Cl2N2O2S2 | 详情 | 详情 | |
| (II) | 54380 | 3-azido-N-[2-({2-[(3-azidopropanoyl)amino]ethyl}disulfanyl)ethyl]propanamide | C10H18N8O2S2 | 详情 | 详情 | |
| (III) | 26616 | N-(tert-butoxycarbonyl)-beta-alanine | 3303-84-2 | C8H15NO4 | 详情 | 详情 |
| (IV) | 54381 | S-(2-aminoethyl) ethanethioate | C4H9NOS | 详情 | 详情 | |
| (V) | 54382 | S-[2-({3-[(tert-butoxycarbonyl)amino]propanoyl}amino)ethyl] ethanethioate | C12H22N2O4S | 详情 | 详情 | |
| (VI) | 54383 | tert-butyl 3-oxo-3-[(2-sulfanylethyl)amino]propylcarbamate | C10H20N2O3S | 详情 | 详情 | |
| (VII) | 54384 | tert-butyl 18,18-dimethyl-3,12,16-trioxo-17-oxa-7,8-dithia-4,11,15-triazanonadec-1-ylcarbamate | C20H38N4O6S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The condensation of 3-aminno-4-phenylsulfonyl fluoride (II) with 3,4,5-trimethoxyphenol (I) in the presence of triethylamine furnished the sulfonate ester (III). The amino group of (III) was then acylated with N-Boc-beta-alanine (IV) using EDC and HOBt to yield amide (V). Finally, acid cleavage of the N-Boc protecting group of (V) provided the title aminopropionamide.
| 【1】 Barr, K.J.; Gwaltney, S.L. II; Imade, H.M.; et al.; Novel sulfonate derivatives: Potent antimitotic agents. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 135. |
| 【2】 Barr, K.J.; Steiner, B.A.; Qun, L.; Rosenberg, S.; Sham, H.; Gwaltney, S.L. II; Imade, H.M.; Woods, K.W. (Abbott Laboratories Inc.); Cell proliferation inhibitors. WO 0073264 . |
| 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) | 37163 | 3,4,5-trimethoxyphenol | C9H12O4 | 详情 | 详情 | |
| (II) | 51178 | 4-Methoxymetanilyl fluoride; 3-Amino-4-methoxybenzenesulfonyl fluoride | 498-74-8 | C7H8FNO3S | 详情 | 详情 |
| (III) | 51179 | 3,4,5-trimethoxyphenyl 3-amino-4-methoxybenzenesulfonate | C16H19NO7S | 详情 | 详情 | |
| (IV) | 26616 | N-(tert-butoxycarbonyl)-beta-alanine | 3303-84-2 | C8H15NO4 | 详情 | 详情 |
| (V) | 51180 | 3,4,5-trimethoxyphenyl 3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)-4-methoxybenzenesulfonate | C24H32N2O10S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Treatment of N-Boc-beta-alanine (I) with bromochloromethane gives the chloromethyl ester (II), which is further converted to the iodomethyl analogue (III) under the Finkelstein halide exchange reaction conditions. Condensation of iodomethyl ester (III) with 6-mercaptopurine (IV) provides adduct (V). The N-Boc group of (V) is then removed employing trifluoroacetic acid to furnish the amine compound (VI). Finally, EDC-mediated coupling of amine (VI) with the polyethyleneglycol-bound aspartic acid (VII) affords the title mercaptopurine prodrug.
| 【1】 Choe, Y.H.; et al.; PEG prodrugs of 6-mercaptopurine (6-MP) - I: Synthesis and in vitro studies. Proc Am Assoc Cancer Res 2002, 43. |
| 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) | 26616 | N-(tert-butoxycarbonyl)-beta-alanine | 3303-84-2 | C8H15NO4 | 详情 | 详情 |
| (II) | 57758 | chloromethyl 3-[(tert-butoxycarbonyl)amino]propanoate | C9H16ClNO4 | 详情 | 详情 | |
| (III) | 57759 | iodomethyl 3-[(tert-butoxycarbonyl)amino]propanoate | C9H16INO4 | 详情 | 详情 | |
| (IV) | 11711 | 9H-Purine-6-thiol; 9H-Purin-6-ylhydrosulfide; 6-Mercaptopurine | 50-44-2 | C5H4N4S | 详情 | 详情 |
| (V) | 57760 | (9H-purin-6-ylsulfanyl)methyl 3-[(tert-butoxycarbonyl)amino]propanoate | C14H19N5O4S | 详情 | 详情 | |
| (VI) | 57761 | (9H-purin-6-ylsulfanyl)methyl 3-aminopropanoate | C9H11N5O2S | 详情 | 详情 | |
| (VII) | 65174 | C9H14NO7 | 详情 | 详情 |