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【结 构 式】 
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【分子编号】23159 【品名】(2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid 【CA登记号】 |
【 分 子 式 】C19H28N2O6 【 分 子 量 】380.4412 【元素组成】C 59.99% H 7.42% N 7.36% O 25.23% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of N6-(benzyloxycarbonyl)-N2--(tert-butoxycarbonyl)-L-lysine (I) with 1H-tetrazol-5-amine (II) by means of BOP and DIEA or NMM in DMF gives the corresponding amide (III), which is hydrogenolyzed with H2 over Pd/C in etyhanol/HOAc to yield N2-(tert-butoxycarbonyl)-N1-(1H-tetrazol-5-yl)-L-lysine (IV). The reaction of (IV) with methyl acetimidate (V) by means of TEA in DMF (or ethyl acetimidate (VI) and NaOH in ethanol) affords the iminomethyl derivative (VII), which is finally deprotected with HCl in dioxane.
| 【1】 Hallinan, E.A.; Tsymbalov, S.; Dorn, C.R.; Pitzele, B.S.; Hansen, D.W. Jr.; Synthesis and biological characterization of L-N6-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor. J Med Chem 2002, 45, 8, 1686. |
| 【2】 Hallinan, E.A.; Hansen, D.W. Jr.; Tsymbalov, S. (Pharmacia Corp.); Aminotetrazole derivs. useful as nitric oxide synthase inhibitors. EP 0790987; EP 1113011; JP 1998508847; US 5684008; WO 9615120 . |
| 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) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (II) | 14092 | 1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole | 4418-61-5 | CH3N5 | 详情 | 详情 |
| (III) | 54697 | benzyl (5S)-5-[(tert-butoxycarbonyl)amino]-6-oxo-6-(1H-1,2,3,4-tetraazol-5-ylamino)hexylcarbamate | C20H29N7O5 | 详情 | 详情 | |
| (IV) | 54698 | tert-butyl (1S)-5-amino-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C12H23N7O3 | 详情 | 详情 | |
| (V) | 54699 | Methyl ethanimidoate; Methyl acetimidate | C3H7NO | 详情 | 详情 | |
| (VI) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (VII) | 54700 | tert-butyl (1S)-5-(ethanimidoylamino)-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C14H26N8O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The N-tetrazolyl lysinamide derivative (III) was obtained by acylation of 5-aminotetrazole (II) with Boc-L-lysine(Cbz) (I) using BOP as the coupling reagent. The N-benzyloxycarbonyl protecting group of (III) was then removed by hydrogenation over Pd/C to afford amine (IV), which was subsequently condensed with methyl acetimidate (V) producing amidine (VI). The target compound was finally obtained by N-Boc group cleavage in (VI) under acidic conditions
| 【1】 Hallinan, E.A.; Tsymbalov, S.; Dorn, C.R.; Pitzele, B.S.; Hansen, D.W. Jr.; Synthesis and biological characterization of L-N6-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor. J Med Chem 2002, 45, 8, 1686. |
| 【2】 Hallinan, E.A.; Hansen, D.W. Jr.; Tsymbalov, S. (Pharmacia Corp.); Aminotetrazole derivs. useful as nitric oxide synthase inhibitors. EP 0790987; EP 1113011; JP 1998508847; US 5684008; WO 9615120 . |
| 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) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (II) | 14092 | 1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole | 4418-61-5 | CH3N5 | 详情 | 详情 |
| (III) | 54697 | benzyl (5S)-5-[(tert-butoxycarbonyl)amino]-6-oxo-6-(1H-1,2,3,4-tetraazol-5-ylamino)hexylcarbamate | C20H29N7O5 | 详情 | 详情 | |
| (IV) | 54698 | tert-butyl (1S)-5-amino-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C12H23N7O3 | 详情 | 详情 | |
| (V) | 54699 | Methyl ethanimidoate; Methyl acetimidate | C3H7NO | 详情 | 详情 | |
| (VI) | 54700 | tert-butyl (1S)-5-(ethanimidoylamino)-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C14H26N8O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Treatment of protected lysine (I) with N,O-dimethyl hydroxylamine and (benzotriazolyl)tetramethyluronium fluoborate afforded hydroxamate (II). This was condensed with organolithium reagent (IV) (prepared from 2-bromothiazole (III) and butyllithium), to yield thiazolyl ketone (V). Acid deprotection of the N-Boc group of (V) provided amine (VI), which was then coupled with the mixed anhydride obtained from dipeptide (VII) and isobutyl chloroformate. The resulting compound (VIII) was finally deprotected using TFA and thioanisole.
| 【1】 Rewinkel, J.B.M.; Smit, M.J.; Noach, A.B.J.; van Dinther, T.G.; Grootenhuis, P.D.J.; Peters, J.A.M.; Kelser, J.; Visser, A.; van Boeckel, C.A.A.; Vogel, G.M.T.; van Aelst, S.F.; Adang, A.E.P.; A polar pharmacophore for oral bioavailability in thrombin inhibitors. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.157. |
| 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) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (II) | 23160 | benzyl (5S)-5-[(tert-butoxycarbonyl)amino]-6-[methoxy(methyl)amino]-6-oxohexylcarbamate | C21H33N3O6 | 详情 | 详情 | |
| (III) | 23161 | 2-bromo-1,3-thiazole | 3034-53-5 | C3H2BrNS | 详情 | 详情 |
| (IV) | 23162 | 1,3-thiazol-2-yllithium | C3H2LiNS | 详情 | 详情 | |
| (V) | 23163 | benzyl (5S)-5-[(tert-butoxycarbonyl)amino]-6-oxo-6-(1,3-thiazol-2-yl)hexylcarbamate | C22H29N3O5S | 详情 | 详情 | |
| (VI) | 23164 | benzyl (5S)-5-amino-6-oxo-6-(1,3-thiazol-2-yl)hexylcarbamate | C17H21N3O3S | 详情 | 详情 | |
| (VII) | 23165 | (2S)-1-((2R)-2-[(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino]-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid | C25H42N2O7 | 详情 | 详情 | |
| (VIII) | 23166 | tert-butyl 2-[[(1R)-2-[(2S)-2-([[(1S)-5-[[(benzyloxy)carbonyl]amino]-1-(1,3-thiazol-2-ylcarbonyl)pentyl]amino]carbonyl)pyrrolidinyl]-1-(cyclohexylmethyl)-2-oxoethyl](tert-butoxycarbonyl)amino]acetate | C42H61N5O9S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXIV)The peptidic chain is elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Arg(Tos)-OH (XXII), Boc-Lys(COOCH2Ph)-OH (XXIV)) with BOP/DIEA, providing derivative (XXIV). (Scheme 28946801c).
| 【1】 Bedos, P.; Daffix, I.; Amblard, M.; et al.; Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J Med Chem 1999, 42, 20, 4185. |
| 【2】 Amblard, M.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 43255 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben | C49H59N7O12S | 详情 | 详情 | |
| (XXII) | 43256 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoic acid | C18H28N4O7S | 详情 | 详情 | |
| (XXIII) | 43257 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-((2S)-2-[(tert-butoxycarbonyl)amino]-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]- | C62H77N11O16S2 | 详情 | 详情 | |
| (XXIV) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (XXV) | 43258 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-((2S)-2-([(2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoyl]amino)-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoyl)pyrrolidinyl]carbon | C76H95N13O19S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXIV)The peptidic chain is elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc Arg(Tos)-OH (XXII), and Boc-Lys(COOCH2Ph)-OH (XXIV)) with BOP/DIEA, providing derivative (XXV)(Scheme 28947001c).
| 【1】 Bedos, P.; Daffix, I.; Amblard, M.; et al.; Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J Med Chem 1999, 42, 20, 4185. |
| 【2】 Amblard, M.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 43255 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben | C49H59N7O12S | 详情 | 详情 | |
| (XXII) | 43256 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoic acid | C18H28N4O7S | 详情 | 详情 | |
| (XXIII) | 43257 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-((2S)-2-[(tert-butoxycarbonyl)amino]-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]- | C62H77N11O16S2 | 详情 | 详情 | |
| (XXIV) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (XXV) | 43258 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-((2S)-2-([(2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoyl]amino)-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoyl)pyrrolidinyl]carbon | C76H95N13O19S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXIV)The peptidic chain is elongated by deprotection with TFA/EDT and coupling of protected amino acid (Boc-Lys(COOCH2Ph)-OH (XXIV)) with BOP/DIEA, providing derivative (XXVI), which is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole (Scheme 28947001d).
| 【1】 Bedos, P.; Daffix, I.; Amblard, M.; et al.; Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J Med Chem 1999, 42, 20, 4185. |
| 【2】 Amblard, M.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (XXV) | 43258 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-((2S)-2-([(2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoyl]amino)-5-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]pentanoyl)pyrrolidinyl]carbon | C76H95N13O19S2 | 详情 | 详情 | |
| (XXVI) | 43259 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[[2-([[(2R,4S)-1-([(2R)-1-[(2S,5S,8S)-5-(4-[[(benzyloxy)carbonyl]amino]butyl)-8-[(tert-butoxycarbonyl)amino]-2-(3-[[imino([[(4-methylphenyl)sulfonyl]oxy]amino)methyl]amino]propyl)-4,7,14-trioxo-16-phenyl-15- | C90H113N15O22S2 | 详情 | 详情 |