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【结 构 式】 
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【分子编号】11123 【品名】Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride 【CA登记号】111-64-8 |
【 分 子 式 】C8H15ClO 【 分 子 量 】162.6592 【元素组成】C 59.07% H 9.29% Cl 21.8% O 9.84% |
合成路线1
该中间体在本合成路线中的序号：(LXVI)The esterification of optical active (-)-N-methylephedrine (LXV) with octanoyl chloride (LXVI) in tert-butyl methyl ether gives the corresponding ester (LXVII), which is treated with trimethylsilyl chloride and butyllithium-diisopropylamine in THF to yield the enolic trimethylsilyl ether (LXVIII). The condensation of (LXVIII) with the previously obtained aldehyde, 3(R)-(benzyloxy)tetradecanal (XI) (scheme 11082301a), by means of TiCl4 in dichloromethane affords, after chromatography, (2S,3S,5R)-5-(benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid 2(S)-(dimethylamino)-1(R)-phenylpropyl ester (LXIX), which is finally hydrolyzed with methanolic KOH to (2S,3S,5R)-5-(benzyloxy)-2-hexyl-3-hydroxy-hexadecanoic acid (XIX), obtained in scheme 11082301a. The previously obtained 3(R)-(benzyloxy)tetradecanal (XI) can also be obtained by benzylation of 3(R)-hydroxytetradecanoic acid methyl ester (LXX) as usual, to the protected (LXXI), which is then reduced with DIBAL as before. Tetrahydrolipstatin can also be obtained from natural lipstatin by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Barbier, P.; Widmer, U.; Schneider, F.; Stereoselective syntheses of tetrahydrolipstatin and of an analogue, potent pancreatic-lipase inhibitors containing a beta-lactone moiety. Helv Chim Acta 1987, 70, 1412-8. |
| 【2】 Prous, J.; Mealy, N.; Castaner, J.; Orlistat. Drugs Fut 1994, 19, 11, 1003. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LXV) | 11122 | (1S,2R)-2-(Dimethylamino)-1-phenyl-1-propanol | C11H17NO | 详情 | 详情 | |
| (LXVI) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (LXVII) | 11124 | (1S,2R)-2-(dimethylamino)-1-phenylpropyl octanoate | C19H31NO2 | 详情 | 详情 | |
| (LXVIII) | 11125 | (1S,2R)-1-([(Z)-1-[(Dimethylsilyl)oxy]-1-octenyl]oxy)-N,N-dimethyl-1-phenyl-2-propanamine; N-[(1R,2S)-2-([(Z)-1-[(Dimethylsilyl)oxy]-1-octenyl]oxy)-1-methyl-2-phenylethyl]-N,N-dimethylamine | C21H37NO2Si | 详情 | 详情 | |
| (LXX) | 11127 | methyl (3R)-3-hydroxytetradecanoate | C15H30O3 | 详情 | 详情 | |
| (LXXI) | 11128 | methyl (3R)-3-(benzyloxy)tetradecanoate | C22H36O3 | 详情 | 详情 | |
| (LXXIX) | 11126 | (1S,2R)-2-(dimethylamino)-1-phenylpropyl (2S,3S,5R)-5-(benzyloxy)-2-hexyl-3-hydroxyhexadecanoate | C40H65NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)2,2',3,3'-Tetra-O-benzyl-alpha,alpha-trehalose (III) was prepared by condensation of trehalose (I) with benzaldehyde, followed by alkylation of the resulting bisbenzylidene derivative (II) with benzyl chloride and then acid hydrolysis of the benzylidene ketal. Acylation of (III) with octanoyl chloride (IV) in the presence of pyridine provided diester (V). Finally, catalytic hydrogenolysis of the benzyl protecting groups yielded the title compound.
| 【1】 Fukushi, K. (SSP Co., Ltd.); Antitumor formulation containing lipopolysaccharide with trehalose derivs.. US 4612304 . |
| 【2】 Kukita, K.; Shibata, A.; Katori, T.; Nishikawa, Y.; Yoshimoto, K. (SSP Co., Ltd.); alphaalpha-Trehalose-6,6'-middle chained aliphatic acid diester and a pharmaceutical agent containing the same. DE 3241199; FR 2534259; GB 2133399 . |
| 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) | 33680 | (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-[[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]tetrahydro-2H-pyran-3,4,5-triol | C12H22O11 | 详情 | 详情 | |
| (II) | 33681 | (4aR,6R,7R,8R,8aS)-6-[[(4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol | C26H30O11 | 详情 | 详情 | |
| (III) | 33682 | (2R,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-[[(2R,3R,4S,5S,6R)-3,4-bis(benzyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol | C40H46O11 | 详情 | 详情 | |
| (IV) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (V) | 33683 | [(2R,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-([(2R,3R,4S,5S,6R)-3,4-bis(benzyloxy)-5-hydroxy-6-[(octanoyloxy)methyl]tetrahydro-2H-pyran-2-yl]oxy)-3-hydroxytetrahydro-2H-pyran-2-yl]methyl octanoate | C56H74O13 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The Friedel-Crafts condensation of phenethyl acetate (I) with octanoyl chloride (II) by means of AlCl3 in dichloroethane gives 2-(4-octanoylphenyl)ethyl acetate (III), which is reduced with triethylsilane in TFA to afford 2-(4-octylphenyl)ethyl acetate (IV). The deprotection of (IV) with sodium ethoxide in ethanol gives 2-(4-octylphenyl)ethanol (V), which is treated with methanesulfonyl chloride followed by sodium iodide in refluxing 2-butanone yielding 2-(4-octylphenyl)ethyl iodide (VI). The condensation of (VI) with diethylacetamidomalonate (VII) by means of sodium ethoxide in ethanol/THF gives diethyl 2-acetamido-2-[2-(4-octylphenyl)ethyl]malonate (VIII), which is reduced with LiAlH4 in THF and treated with acetic anhydride in pyridine to afford 2-acetamido-2-(acetoxymethyl)-4-(4-octylphenyl)butyl acetate (IX). The hydrolysis of (IX) with lithium hydroxide in refluxing methanol/water gives 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (X), which is finally treated with HCl in diethyl ether.
| 【1】 Chiba, K.; Adachi, K.; FTY720. Drugs Fut 1997, 22, 1, 18. |
| 【2】 Fujita, T.; Sasaki, S.; Yoneta, M.; Mishina, T.; Adachi, K.; Chiba, K. (Taito Co., Ltd.; Welfide Corporation); 2-Amino-1,3-propanediol compound and immunosuppressant. EP 0627406; JP 1994509845; US 5719176; WO 9408943 . |
| 【3】 Kiuchi, M.; Adachi, K.; Kohara, T.; et al.; Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. J Med Chem 2000, 43, 15, 2946. |
| 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) | 16704 | phenethyl acetate; Phenylethyl-(2) Acetate | 103-45-7 | C10H12O2 | 详情 | 详情 |
| (II) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (III) | 16706 | 4-octanoylphenethyl acetate | C18H26O3 | 详情 | 详情 | |
| (IV) | 16707 | 4-octylphenethyl acetate | C18H28O2 | 详情 | 详情 | |
| (V) | 16708 | 2-(4-octylphenyl)-1-ethanol | C16H26O | 详情 | 详情 | |
| (VI) | 16709 | 1-[4-(2-iodoethyl)phenyl]octane | C16H25I | 详情 | 详情 | |
| (VII) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (VIII) | 16711 | diethyl 2-(acetamido)-2-(4-octylphenethyl)malonate | C25H39NO5 | 详情 | 详情 | |
| (IX) | 16712 | 2-(acetamido)-2-[(acetoxy)methyl]-4-(4-octylphenyl)butyl acetate | C25H39NO5 | 详情 | 详情 | |
| (X) | 16713 | 2-amino-2-(4-octylphenethyl)-1,3-propanediol | 162359-55-9 | C19H33NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The acylation of (-)-2,10-camphorsultam (II) with octanoyl chloride (I) provides the N-octanoyl sultam (III). Diastereoselective alkylation of the lithium enolate of (III) with allyl bromide (IV) gives rise to the (2S)-2-propenoyloctanoyl sultam (V). Hydrolysis of the N-acyl sultam (V) to furnish acid (VI) is then effected by treatment with hydrogen peroxide-tetrabutylammonium hydroxide. Finally, catalytic hydrogenation of the unsaturated acid (VI) in the presence of either Pd/C or Pt/C yields the required (R)-2-propyloctanoic acid. Alternatively, the title compound is obtained by hydrogenation of the N-acyl sultam (V) to the saturated derivative (VII), followed by hydrolytic removal of the camphorsultam moiety.
| 【1】 Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E.; Iguchi, Y.; Yonekawa, Y.; Okamoto, M.; Ohta, C.; Hashimoto, S.; Ohuchida, S.; Process development of ONO-2506: A therapeutic agent for stroke and Alzheimer's disease. Org Process Res Dev 2003, 7, 2, 168. |
| 【2】 Hasegawa, T.; Yamamoto, H.; A practical synthesis of optically active (R)-2-propyloctanoic acid: Therapeutic agent for Alzheimer's disease. Bull Chem Soc Jpn 2000, 73, 2, 423. |
| 【3】 Hasegawa, T.; Yamamoto, H.; A practical removal method of camphorsultam. Synlett 1998, 8, 882. |
| 【4】 Yamamoto, H. (Ono Pharmaceutical Co., Ltd.); Novel intermediates and processes for the preparation of optically active octanoic acid derivs.. EP 1078921; US 6333415; WO 9958513 . |
| 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) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (II) | 58242 | (1S,5R,7R)-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C10H17NO2S | 详情 | 详情 | |
| (III) | 58243 | (1S,5R,7R)-10,10-dimethyl-4-octanoyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C18H31NO3S | 详情 | 详情 | |
| (IV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (V) | 58244 | (1S,5R,7R)-4-[(2S)-2-hexyl-4-pentenoyl]-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C21H35NO3S | 详情 | 详情 | |
| (VI) | 58245 | (1S,5R,7R)-10,10-dimethyl-4-[(2R)-2-propyloctanoyl]-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C21H37NO3S | 详情 | 详情 | |
| (VII) | 58246 | (2S)-2-hexyl-4-pentenoic acid | C11H20O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Sordarin (I) was isolated from culture broths of Sordaria araneosa. Protection of the carboxyl group of (I) as the benzhydryl ester (II) was effected by treatment with diphenyl diazomethane. The 2'-hydroxyl group of (II) was subsequently blocked as the carbonate ester (III) by selective acylation with benzyl chloroformate in the presence of DMAP. Subsequent esterification of the 3'-hydroxyl of (III) with octanoyl chloride (IV) furnished the octanoate ester (V). The benzhydryl ester and benzyl carbonate protecting groups of (V) were finally removed by catalytic hydrogenation over Pd/C.
| 【1】 Fraile, M.T.; Ruiz, J.R.; Gómez de las Heras, F.; García-Ochoa, S.; Arribas, E.M.; Castro, J.; Clemens, I.R.; Cuevas, J.C.; Chicharro, J.; Antifungal sordarins. Synthesis and structure-activity relationships of 3'-O-substituted derivatives. Bioorg Med Chem Lett 2002, 12, 2, 117. |
| 【2】 Hayes, M.; Wildman, H.; Dawson, M.; Chalk, P.; Hall, R.; Ruiz Gomez, J.R. (GlaxoSmithKline plc); Antifungal sordarin derivs.. EP 0711783; EP 0791007; JP 1999502188; US 6054478; WO 9614327 . |
| 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) | 59613 | (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylic acid | C27H40O8 | 详情 | 详情 | |
| (II) | 59614 | benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate | C40H50O8 | 详情 | 详情 | |
| (III) | 59615 | benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-{[((2R,3S,4R,5S,6R)-3-{[(benzyloxy)carbonyl]oxy}-4-hydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy]methyl}-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate | C48H56O10 | 详情 | 详情 | |
| (IV) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (V) | 59616 | benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4R,5R,6R)-3-{[(benzyloxy)carbonyl]oxy}-5-methoxy-6-methyl-4-(octanoyloxy)tetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate | C56H70O11 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VIII)Condensation of amine (I) with N,N’-di-Boc-thiourea (II) using HgCl2 and Et3N in DMF (1) or with di-Boc-amidinopyrazole (III) in THF gives the protected guanidine derivative (IV), which by deacetylation with methanolic sodium methoxide followed by saponification of the deacylated methyl pyranosoate (V) leads to the carboxylic acid (VI). Alternatively, acid (VI) is prepared by direct hydrolysis of compound (IV) by means of aqueous NaOH or K2CO3 in H2O/MeOH. After conversion of acid (VI) to the corresponding benzhydryl ester (VII) by treatment with diphenyldiazomethane and BF3·Et2O, selective acylation of the primary hydroxyl group with octanoyl chloride (VIII) and Et3N in CH2Cl2 yields the 9-octanoate ester (IX) (1). Finally, compound (IX) is deprotected by removal of N-Boc and O-benzhydryl protecting groups by treatment with trifluoroacetic acid in CH2Cl2, followed by basification of the obtained TFA salt with NaHCO3 (2-8). Scheme 1.
Alternatively, reaction of the 4-amino-5,6-dihydropyran derivative (X) with di-Boc-amidinopyrazole (III) provides the corresponding 4-guanidinodihydropyran, which is hydrolyzed with K2CO3 in MeOH/H2O to give carboxylic acid (VI). In an alternative strategy, carboxylic acid (VI) is prepared by hydrolysis of the 4-amino-5,6-dihydropyrancarboxylate ester (X) with NaOH followed by reaction with the amidinopyrazole derivative (III). Deprotection of di-Boc intermediate (VI) by stirring at 80 °C in MeOH gives laninamivir (XI), which is finally selectively acylated with trimethyl orthooctanoate (XII) in the presence of methanolic HCl. Laninamivir (XI) can also be obtained by hydrolysis of intermediate (X) with NaOH followed by reaction of the resulting free amine (XIII) with pyrazole-1-carboxamidine HCl (XIV) or, alternatively, by treatment of 4-amino-5,6-dihydropyran (X) with pyrazole-1-carboxamidine HCl (XIV), and then hydrolysis of the methyl ester with K2CO3 in MeOH (3). Scheme 1.
| 【1】 Honda, T., Kobayashi, Y., Masuda, T., Yamashita, M., Arai, M. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. EP 0823428, JP 1998330373, JP 1999279059, JP 199927968. |
| 【2】 Murakami, M., Yamaoka, M., Honda, T., Watanabe, M. (Daiichi Sankyo Co., Ltd.). Hydrates and crystals of a neuraminic acid compound. EP 1277759, US 2003105158, US 6844363, WO 200108131. |
| 【3】 Nakamura, Y., Murakami, M., Yamaoka, M., Wakayama, M., Umeo, K. (Daiichi Sankyo Co., Ltd.). Method for manufacturing neuraminic acid derivatives. EP 2132191, JP 2010523472, WO 2008126943. |
| 【4】 Honda, T., Kubo, S., Masuda, T., Arai, M., Kobayashi, Y., Yamashita, M. Synthesis and in vivo influenza-inhibitory effect of ester prodrug of 4-guanadino-7-O-methyl-Neu5Ac2en. Bioorg Med Chem Lett 2009, 19(11): 2938-40. |
| 【5】 Honda, T., Masuda, T. Synthesis of 4-guanidino-7-modified-neu5Ac2en derivatives and their biological activities as influenza sialidase inhibitors. J Synth Org Chem Jpn 2009, 67(11): 1105. |
| 【6】 Yamashita, M., Kawaoka, Y. (University of Tokyo; Daiichi Sankyo Co., Ltd.). Drug for treatment of influenza. EP 2123271, WO 2008108323. |
| 【7】 Honda, T., Arai, M., Yamashita, M., Masuda, T., Kobayashi, Y. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. US 6340702. |
| 【8】 Kobayashi, Y., Honda, T., Yamashita, M. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. US 2002137791, US 6451766. |
| 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) | 65992 | C17H26N2O9 | 详情 | 详情 | ||
| (II) | 21843 | tert-butyl [(tert-butoxycarbonyl)amino]carbothioylcarbamate | 145013-05-4 | C11H20N2O4S | 详情 | 详情 |
| (III) | 29482 | N,N-bis-Boc-1-guanylpyrazole; tert-butyl (E)-[(tert-butoxycarbonyl)amino](1H-pyrazol-1-yl)methylidenecarbamate | 152120-54-2 | C14H22N4O4 | 详情 | 详情 |
| (IV) | 65993 | C27H44N4O13 | 详情 | 详情 | ||
| (V) | 65994 | C23H40N4O11 | 详情 | 详情 | ||
| (VI) | 65995 | C22H38N4O11 | 详情 | 详情 | ||
| (VII) | 65996 | C35H48N4O11 | 详情 | 详情 | ||
| (VIII) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (IX) | 65997 | C43H62N4O12 | 详情 | 详情 | ||
| (X) | 65998 | C14H20N2O8 | 详情 | 详情 | ||
| (XI) | 65999 | Laninamivir; (4S,5R,6R)-5-Acetamido-4-guanidino-6-((1R,2R)-2,3-dihydroxy-1-methoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid | 203120-17-6 | C13H22N4O7 | 详情 | 详情 |
| (XII) | 66000 | trimethyl orthooctanoate; 1,1,1-Trimethoxyoctane | 161838-87-5 | C11H24O3 | 详情 | 详情 |
| (XIII) | 66001 | (4S,5R,6R)-5-acetylamino-4-amino-6-[(1R,2R)-2,3-dihydroxy-1-methoxy-propyl]-5,6-dihydro-4H-pyran-2-carboxylic acid | 475483-21-7 | C12H20N2O7 | 详情 | 详情 |
| (XIV) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIII)Reaction of bromoacetyl bromide (I) with phenol at 80 °C gives the phenyl ester (II) , which by cyclization with (S)-(+)-phenylglycinol (III), previously treated with DIEA, in acetonitrile provides 5(S)-phenylmorpholin-2-one (IV) . Treatment of compound (IV) with HCl affords the corresponding HCl salt (V), which is reacted with NaHCO3 followed by coupling with benzodioxane-6-carboxaldehyde (VI) in refluxing EtOAc/toluene to yield the oxazine adduct (VII). Oxazine derivative (VII) can also be obtained by direct coupling of 5(S)-phenylmorpholin-2-one (IV) with aldehyde (VI) in refluxing toluene. Opening of adduct (VII) with pyrrolidine (VIII) in CH2Cl2, CHCl3 or refluxing THF followed by addition of HCl in refluxing MeOH leads to 3-(1,4-benzodioxan-6-yl)-3(R)-hydroxy-2(R)-(2-hydroxy-1-phenylethylamino)-1-(pyrrolidin-1-yl)propanone (IX), which is reduced with LiAlH4 in refluxing THF to give diol (X). Cleavage of diol (X) by means of H2 and Pd(OH)2 in the presence of either CF3COOH or HCl in MeOH or EtOH/H2O provides amine (XI), which is finally coupled with octanoic acid N-hydroxysuccinimide ester (XII) in CH2Cl2 . Ester (XII) is prepared by condensation of octanoyl chloride (XIII) with N-hydroxysuccinimide (XIV) by means of Et3N in CH2Cl2 .
| 【1】 Dellaria, J.F. Jr., Santarsiero, B.D. Enantioselective synthesis of alphaamino acid derivatives via the stereoselective alkylation of a homochiral glycine enolate synthon. J Org Chem 1989, 54(16): 3916-26. |
| 【2】 Siegel, C., Hirth, B.H. (Genzyme Corp.). Synthesis of UDP-glucose:N-acylsphingosine glucosyltransferase inhibitors. CA 2453978, EP 1409467, EP 2067775, JP 2005255686, JP 2005502635, JP 2010095546, US 2003050299, US 6855830, WO 2003008399. |
| 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) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (II) | 69187 | phenyl 2-bromoacetate;Phenyl bromoacetate;alpha-Phenyl Bromoacetate;Phenyl a-bromoacetate;bromoacetic acidphenyl ester | 620-72-4 | C8H7BrO2 | 详情 | 详情 |
| (III) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (IV) | 61798 | (5S)-5-phenyl-2-morpholinone;5(S)-phenylmorpholin-2-one;(5S)-3,4,5,6-Tetrahydro-5-phenyl-4(H)-1,4-oxazin-2-one | 144896-92-4 | C10H11NO2 | 详情 | 详情 |
| (V) | 69188 | 5(S)-phenylmorpholin-2-one hydrochloride | C10H11NO2.HCl | 详情 | 详情 | |
| (VI) | 61797 | 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde; 1,4-Benzodioxan-6-carboxaldehyde; 3,4-ethylenedioxybenzaldehyde ;benzodioxane-6-carboxaldehyde | 29668-44-8 | C9H8O3 | 详情 | 详情 |
| (VII) | 61799 | (1S,3S,5S)-1,3-di(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyltetrahydro-8H-[1,3]oxazolo[4,3-c][1,4]oxazin-8-one | C28H25NO7 | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IX) | 61800 | (2R,3R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-2-[(2-hydroxy-1-phenylethyl)amino]-1-(1-pyrrolidinyl)-1-propanone | C23H28N2O5 | 详情 | 详情 | |
| (X) | 61801 | (1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-3-(1-pyrrolidinyl)-1-propanol | C23H30N2O4 | 详情 | 详情 | |
| (XI) | 61802 | (1R,2R)-2-amino-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1-pyrrolidinyl)-1-propanol | C15H22N2O3 | 详情 | 详情 | |
| (XII) | 69189 | octanoic acid N-hydroxysuccinimide ester;2,5-Dioxopyrrolidin-1-yl octanoate;Caprylic acid N-hydroxysuccinimide ester;N-(Octanoyloxy)succinimide;N-Hydroxysuccinimidyl caprylate | 14464-30-3 | C12H19NO4 | 详情 | 详情 |
| (XIII) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (XIV) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |