|
【结 构 式】 
|
【分子编号】39365 【品名】(2S)-2-(acetamido)-3-sulfanylpropionic acid 【CA登记号】616-91-1 |
【 分 子 式 】C5H9NO3S 【 分 子 量 】163.1974 【元素组成】C 36.8% H 5.56% N 8.58% O 29.41% S 19.65% |
合成路线1
该中间体在本合成路线中的序号：(II)The title compound may be prepared either by acetylation of L-cystine (I) or by oxidative dimerization of N-acetylcysteine (II).
| 【1】 Andersson, C.-M.A.; Bergstrand, S.H.A.; Hallberg, A.R.; Särnstrand, B.O.; Tunek, P.A.S. (AstraZeneca plc); The pharmacological use of certain cystine derivs.. EP 0463514; EP 0532595; EP 0727207; JP 1992230359; JP 1993507705; US 5441976; US 5780508; WO 9118594 . |
合成路线2
该中间体在本合成路线中的序号：(I)Alkylation of N-acetyl-D-cysteine (I) with 1-fluoro-5-methyl-2-nitrobenzene (II) gave adduct (III). After hydrolysis of the acetamido group of (III) with aqueous sulfuric acid, the resulting amine (IV) was protected as the benzyl carbamate (V). Reduction of the nitro group of (V) provided amino acid (VI), which was cyclized to the benzothiazepinone (VII) using EDC. Subsequent alkylation of (VII) with ethyl bromoacetate under phase-transfer conditions yielded (VIII) (1). Cleavage of both N-Cbz group and ethyl ester by HBr in AcOH, followed by introduction of the N-Boc group afforded intermediate (X) (2). Optionally, hydrogenolysis of the N-Cbz group of (VIII) provided amino lactam (XI). This was coupled with N-Boc-O-benzylserine (XII) to give amide (XIII). Then, basic hydrolysis of the ethyl ester produced carboxylic acid (XIV).
| 【1】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 . |
| 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 | |
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| (I) | 39365 | (2S)-2-(acetamido)-3-sulfanylpropionic acid | 616-91-1 | C5H9NO3S | 详情 | 详情 |
| (II) | 39366 | 2-fluoro-4-methyl-1-nitrobenzene | 446-34-4 | C7H6FNO2 | 详情 | 详情 |
| (III) | 39367 | (2S)-2-(acetamido)-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid | C12H14N2O5S | 详情 | 详情 | |
| (IV) | 39368 | (2S)-2-amino-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid | C10H12N2O4S | 详情 | 详情 | |
| (V) | 39369 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid | C18H18N2O6S | 详情 | 详情 | |
| (VI) | 39370 | (2S)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid | C18H20N2O4S | 详情 | 详情 | |
| (VII) | 39371 | benzyl (3S)-8-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate | C18H18N2O3S | 详情 | 详情 | |
| (VIII) | 39372 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C22H24N2O5S | 详情 | 详情 | |
| (IX) | 39376 | 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C12H14N2O3S | 详情 | 详情 | |
| (X) | 39377 | 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C17H22N2O5S | 详情 | 详情 | |
| (XI) | 39373 | ethyl 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C14H18N2O3S | 详情 | 详情 | |
| (XII) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (XIII) | 39374 | ethyl 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C29H37N3O7S | 详情 | 详情 | |
| (XIV) | 39375 | 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C27H33N3O7S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)o-Fluoronitrobenzene (I) is converted into (III) by an aromatic nucleophilic substitution with N-Ac-Cysteine (II) in EtOH in the presence of NaHCO3. Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and in the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (Scheme 28946801a).
| 【1】 Slade, J.; Mazzegna, G.C.; Ben-David, D.; Stanton, J.L.; Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives. J Med Chem 1985, 28, 1517-1521. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 39365 | (2S)-2-(acetamido)-3-sulfanylpropionic acid | 616-91-1 | C5H9NO3S | 详情 | 详情 |
| (III) | 43244 | (2S)-2-(acetamido)-3-[(2-nitrophenyl)sulfanyl]propionic acid | C11H12N2O5S | 详情 | 详情 | |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 43245 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-nitrophenyl)sulfanyl]propionic acid | C17H16N2O6S | 详情 | 详情 | |
| (VI) | 43246 | (2S)-3-[(2-aminophenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid | C17H18N2O4S | 详情 | 详情 | |
| (VII) | 43247 | benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate | C17H16N2O3S | 详情 | 详情 | |
| (VIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IX) | 43248 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C21H22N2O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Aromatic nucleophilic substitution of o-fluoronitrobenzene (I) with N-Ac-cysteine (II) in EtOH in the presence of NaHCO3 yields (III). Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (1) (Scheme 28947001a). Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in AcOH, followed by introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH, Boc-Gly-OH, Boc-Hyp-OH, Boc-Pro-OH, Boc Arg(Tos)-OH, Boc-Lys(COOCH2Ph)-OH (x2)) with BOP/DIEA, providing derivative (XIV), which is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole (2,3) (Scheme 28947001[b-d]).
| 【1】 Slade, J.; Mazzegna, G.C.; Ben-David, D.; Stanton, J.L.; Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives. J Med Chem 1985, 28, 1517-1521. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 39365 | (2S)-2-(acetamido)-3-sulfanylpropionic acid | 616-91-1 | C5H9NO3S | 详情 | 详情 |
| (III) | 43244 | (2S)-2-(acetamido)-3-[(2-nitrophenyl)sulfanyl]propionic acid | C11H12N2O5S | 详情 | 详情 | |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 43245 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-nitrophenyl)sulfanyl]propionic acid | C17H16N2O6S | 详情 | 详情 | |
| (VI) | 43246 | (2S)-3-[(2-aminophenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid | C17H18N2O4S | 详情 | 详情 | |
| (VII) | 43247 | benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate | C17H16N2O3S | 详情 | 详情 | |
| (VIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IX) | 43248 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C21H22N2O5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Coupling of ibuprofen (I) with N-acetylcysteine (II) via activation with carbonyl diimidazole produced the thioester adduct (III). Reaction of the free carboxyl group of (III) with tetrahydrofuran in the presence of triphenylphosphine and carbon tetrabromide gave rise to the bromobutyl ester (IV). The bromide group of (IV) was finally displaced with silver nitrate to produce the title nitrate ester.
| 【1】 Del Soldato, P. (NicOx SA); Pharmaceutical cpds.. EP 1169294; WO 0061537 . |
| 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) | 52312 | 2-(4-Isobutylphenyl)propionic acid; Ibuprofen | 15687-27-1 | C13H18O2 | 详情 | 详情 |
| (II) | 39365 | (2S)-2-(acetamido)-3-sulfanylpropionic acid | 616-91-1 | C5H9NO3S | 详情 | 详情 |
| (III) | 52313 | N-acetyl{2-[4-(2-methylpropyl)phenyl]propanoyl}cysteine | C18H25NO4S | 详情 | 详情 | |
| (IV) | 52314 | 4-bromobutyl 2-(acetylamino)-3-({2-[4-(2-methylpropyl)phenyl]propanoyl}sulfanyl)propanoate | C22H32BrNO4S | 详情 | 详情 |