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【结 构 式】

【分子编号】43247

【品名】benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate

【CA登记号】

【 分 子 式 】C17H16N2O3S

【 分 子 量 】328.39172

【元素组成】C 62.18% H 4.91% N 8.53% O 14.62% S 9.76%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VII)

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2

该中间体在本合成路线中的序号:(VII)

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
Extended Information