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【结 构 式】 
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【分子编号】15853 【品名】tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate 【CA登记号】 |
【 分 子 式 】C14H25NO3 【 分 子 量 】255.35744 【元素组成】C 65.85% H 9.87% N 5.49% O 18.8% |
合成路线1
该中间体在本合成路线中的序号：(VIII)By condensation of N-[3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionyl-L-histidine methyl ester (I) with isopropyl 3(S)-amino-4-cyclohexyl-2(R)-hydroxybutyrate (II) by means of diphenyl phosphoryl azide (DPA) in DMF. The starting products are prepared as follows: The condensation of 3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionic acid (III) and histidine methyl ester (IV) by means of DPA in DMF gives the substituted histidine ester (I). The hydrogenation of N-(tert-butoxycarbonyl)-L-phenylalanine (V) with H2 over Rh/Al2O3 gives N-(tert-butoxycarbonyl)-L-cyclohexylalanine (VI), which is reduced with borane to the corresponding alaninol (VII). Controlled oxidation of (VII) with SO3-pyridine in benzene-DMSO affords N-(tert-butoxycarbonyl)-L-cyclohexylalaninal (VIII), which by treatment with KCN followed by hydrolysis with concentrated HCl yields 3-amino-4-cyclohexyl-2-hydroxybutyric acid (IX). Finally, this compound is esterified with isopropanol and hydrochloric acid to the starting ester (II).
| 【1】 108th Annu Meet Pharm Soc Jpn (April 4-7, Hiroshima) 1988, Abst 5e06 11-3. |
| 【2】 Khandewal, Y.; Rajgopalan, R.; Dohadwalla, A.N.; Rupp, R.H.; De Souza, N.J. (Aventis SA); 7-Acyloxy-6-aminoacyloxypolyoxylabdanes, process for their preparation and their use. DE 3623300; EP 0252482; JP 1988023878 . |
| 【3】 Castaner, J.; Prous, J.; KRI-1314. Drugs Fut 1988, 13, 12, 1042. |
| 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) | 23045 | methyl (2S)-3-(1H-imidazol-4-yl)-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate | C26H30N4O5 | 详情 | 详情 | |
| (II) | 12323 | isopropyl (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoate | C13H25NO3 | 详情 | 详情 | |
| (III) | 12864 | (2R)-4-(4-Morpholinyl)-2-(1-naphthylmethyl)-4-oxobutyric acid | C19H21NO4 | 详情 | 详情 | |
| (IV) | 23048 | methyl (2S)-2-amino-3-(1H-imidazol-4-yl)propanoate | C7H11N3O2 | 详情 | 详情 | |
| (V) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (VI) | 23050 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid | C14H25NO4 | 详情 | 详情 | |
| (VII) | 23051 | tert-butyl (1S)-2-cyclohexyl-1-(hydroxymethyl)ethylcarbamate | C14H27NO3 | 详情 | 详情 | |
| (VIII) | 15853 | tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C14H25NO3 | 详情 | 详情 | |
| (IX) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)By condensation of 2(S)-[N-methyl-N-[2-[N-methyl-N-(morpholinocarbonyl)amino]ethyl]carbamoyloxy]-3-phenylpropanoic acid (I) with protected Nalpha-methyl-L-histidine 1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexylamide (II) by means of oxalyl chloride and DMF in dichloromethane. The starting compounds (I) and (II) are obtained as follows: 1) The reaction of morpholinocarbonyl chloride (III) with N-(tert-butoxycarbonyl)-N,N'-dimethylethylenediamine (IV) by means of triethylamine in dichloromethane gives the monoacylated diamine (V), which is deprotected with trifluoroacetic acid to yield N,N'-dimethyl-N-(morpholinocarbonyl)ethylenediamine (VI). The condensation of (VI) with 2(S)-hydroxy-3-phenylpropanoic acid benzyl ester (VII) by means of trichloromethyl chloroformate in refluxing THF affords 2(S)-[N-methyl-N-[2-[N-methyl-N-(morpholinocarbonyl)amino]ethyl]carbamoyloxy]propanoic acid benzyl ester (VIII), which is finally debenzylated by hydrogenation with H2 over Pd/C to give (I). 2) The Grignard reaction of tert-butoxycarbonyl-(3-cyclohexyl)-L-alaninal (IX) with 3-methylbutylmagnesium bromide (X) in THF gives 2(S)-(tert-butoxycarbonylamino)-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (XI), which is deprotected with trifluoroacetic acid to yield the free amine derivative (XII). The condensation of (XII) with Nalpha-(tert-butoxycarbonyl)-Nalpha-methyl-Ntau-tosyl-L-histidine (XIII) by means of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide (CDI) in dichloromethane affords the corresponding histidinamide (XIV), which is deprotected with trifluoroacetic acid to afford (II).
| 【1】 Hemmi, K.; Neya, M.; Marusawa, H.; Imai, K.; Kayakiri, N.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New amino acid derivs. processes for the preparation thereof and pharmaceutical compsns. containing the same. AU 8818190; EP 0300189; JP 1989019071; US 4921855; US 5223489 . |
| 【2】 Prous, J.; Castaner, J.; FK-906. Drugs Fut 1993, 18, 4, 312. |
| 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) | 15845 | (2S)-2-[[(methyl[2-[methyl(morpholinocarbonyl)amino]ethyl]amino)carbonyl]oxy]-3-phenylpropionic acid | C19H27N3O6 | 详情 | 详情 | |
| (II) | 15846 | (2S)-N-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]-2-(methylamino)-3-[1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl]propanamide | C28H44N4O4S | 详情 | 详情 | |
| (III) | 15847 | 4-morpholinecarbonyl chloride; Morpholine-4-carbonyl chloride | 15159-40-7 | C5H8ClNO2 | 详情 | 详情 |
| (IV) | 15848 | tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate | C9H20N2O2 | 详情 | 详情 | |
| (V) | 15849 | tert-butyl N-methyl-N-[2-[methyl(morpholinocarbonyl)amino]ethyl]carbamate | C14H27N3O4 | 详情 | 详情 | |
| (VI) | 15850 | N-methyl-N-[2-(methylamino)ethyl]-4-morpholinecarboxamide | C9H19N3O2 | 详情 | 详情 | |
| (VII) | 15851 | Benzyl (s)-(-)-2-hydroxy-3-phenylpropionate; benzyl (2S)-2-hydroxy-3-phenylpropanoate | 7622-21-1 | C16H16O3 | 详情 | 详情 |
| (VIII) | 15852 | benzyl (2S)-2-[[(methyl[2-[methyl(morpholinocarbonyl)amino]ethyl]amino)carbonyl]oxy]-3-phenylpropanoate | C26H33N3O6 | 详情 | 详情 | |
| (IX) | 15853 | tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C14H25NO3 | 详情 | 详情 | |
| (X) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (XI) | 15855 | tert-butyl N-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]carbamate | C19H37NO3 | 详情 | 详情 | |
| (XII) | 15856 | (2S,3S)-2-amino-1-cyclohexyl-6-methyl-3-heptanol | C14H29NO | 详情 | 详情 | |
| (XIII) | 15857 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl]propionic acid | C19H25N3O6S | 详情 | 详情 | |
| (XIV) | 15858 | tert-butyl (1S)-2-[[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]amino]-1-([1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl]methyl)-2-oxoethyl(methyl)carbamate | C33H52N4O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)Cyclohexylalanine (XIV) was protected as the Boc derivative (XV) and then coupled with N,O-dimethylhydroxylamine to produce the Weinreb amide (XVI). Reduction of (XVI) with LiAlH4 at -78 C gave aldehyde (XVII) and subsequent addition of tert-butyl isonitrile furnished hydroxy amide (XVIII). After acid hydrolysis of (XVIII), amino acid (XIX) was protected as the N-Boc derivative (XX). This was coupled with benzodioxolylmethyl amine (XXI) yielding amide (XXII). Acid deprotection of the Boc group of (XXII) gave (XXIII), which was further coupled with dipeptide (VII) to generate tripeptide amide (XXIV). Following hydrogenolytic deprotection of the N-nitro group of (XXIV), Swern oxidation of the alcohol group gave rise to the title compound.
| 【1】 Semple, J.E.; et al.; Novel, potent, and selective factor Xa inhibitors featuring a hydrophobic P1-ketoamide moiety. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 193. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIII | 39362 | (3S)-3-amino-N-(1,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxybutanamide | C18H26N2O4 | 详情 | 详情 | |
| (VII) | 39350 | C16H24N6O7S | 详情 | 详情 | ||
| (XIV) | 39357 | (2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine | 27527-05-5 | C9H17NO2 | 详情 | 详情 |
| (XV) | 23050 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid | C14H25NO4 | 详情 | 详情 | |
| (XVI) | 39358 | tert-butyl (1S)-1-(cyclohexylmethyl)-2-[methoxy(methyl)amino]-2-oxoethylcarbamate | C16H30N2O4 | 详情 | 详情 | |
| (XVII) | 15853 | tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C14H25NO3 | 详情 | 详情 | |
| (XVIII) | 39359 | tert-butyl (1S)-3-(tert-butylamino)-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate | C19H36N2O4 | 详情 | 详情 | |
| (XIX) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 | |
| (XX) | 39360 | (3S)-3-[(tert-butoxycarbonyl)amino]-4-cyclohexyl-2-hydroxybutyric acid | C15H27NO5 | 详情 | 详情 | |
| (XXI) | 33669 | 1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine | 2620-50-0 | C8H9NO2 | 详情 | 详情 |
| (XXII) | 39361 | tert-butyl (1S)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate | C23H34N2O6 | 详情 | 详情 | |
| (XXIV) | 39363 | C34H48N8O10S | 详情 | 详情 |