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【结 构 式】 
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【分子编号】18319 【品名】Chloro(methoxy)methane; Chloromethyl methyl ether 【CA登记号】107-30-2 |
【 分 子 式 】C2H5ClO 【 分 子 量 】80.5138 【元素组成】C 29.84% H 6.26% Cl 44.03% O 19.87% |
合成路线1
该中间体在本合成路线中的序号：(H)Fermentation of Streptomyces lactamdurans NRRL-3802 produces sodium 7beta-(D-5-amino-S-carboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylate (XXXIII), which is tosylated as usual to the N-tosyl derivative (XXXIV). The esterification of (XXXIV) with methyl chloromethyl ether (H) in CH2Cl2 yields the methoxymethyl ester (XXXV), which is finally treated first with 2-thienylcarbonyl chloride (E) on a 4-angstrom molecular sieve in dichloroethane, and then with HCl methanol.
| 【1】 Weinstock, L.M.; Preparation of 7-acylaminocephalosporin derivatives. DE 2456528; FR 2253022; GB 1480757; JP 50105687 . |
| 【2】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (H) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (XXXIII) | 39846 | (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-[(5-amino-5-carboxypentanoyl)amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C16H22N4O9S | 详情 | 详情 | |
| (XXXIV) | 39847 | (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-[(5-carboxy-5-[[(4-methylphenyl)sulfonyl]amino]pentanoyl)amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C23H28N4O11S2 | 详情 | 详情 | |
| (XXXV) | 39848 | methoxymethyl (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-7-[(6-(methoxymethoxy)-5-[[(4-methylphenyl)sulfonyl]amino]-6-oxohexanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H36N4O13S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)The esterification of potassium phenoxymethylpenicillanate (I) with chloromethyl methyl ether (A) in methylene chloride-THF gives the methoxymethyl ester of penicilline V (II), which is then treated with dimethylaniline (B) in CH2Cl2 to afford methoxymethyl 6-aminopenicillanate (III). Finally, this product is condensed with phenylglycyl chloride (C) hydrochloride and acetone (D) by means of NaOH.
| 【1】 Sleezer, P.D.; Johnson, D.A. (Bristol-Myers Squibb Co.); Antibacterial agents. DE 2244915; ES 406644; FR 2154488; GB 1400584; JP 48036186 . |
| 【2】 Playle, A.C.; Castaner, J.; Sarpicillin. Drugs Fut 1977, 2, 7, 478. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 17036 | N,N-dimethyl-N-phenylamine; N,N-dimethylbenzenamine; N,N-dimethylaniline | 121-69-7 | C8H11N | 详情 | 详情 |
| (A) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (D) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (I) | 40163 | potassium (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2-phenoxyacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | 132-98-9 | C16H17KN2O5S | 详情 | 详情 |
| (II) | 40164 | methoxymethyl (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2-phenoxyacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C18H22N2O6S | 详情 | 详情 | |
| (III) | 40165 | methoxymethyl (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C10H16N2O4S | 详情 | 详情 | |
| (IV) | 40166 | methoxymethyl (2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C18H23N3O5S | 详情 | 详情 | |
| (C) | 40055 | (2R)-2-amino-2-phenylethanoyl chloride | C8H8ClNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)By reaction of sodium phenobarbital (I) with 2 mols of methyl chloromethyl ether (A) in DMF. It can also be obtained by reaction of phenobarbital (II), 2 mols of NaH, LiH, KH, LiOH or t-BuOK and 2 moles of methyl chloromethyl ether (A) in DMF.
| 【1】 Samour, C.M.; et al.; Anticonvulsants.1. Alkoxymethyl derivatives of barbiturates and diphenylhydantoin. J Med Chem 1971, 14, 3, 187. |
| 【2】 Vida, J.A. (The Kendall Company); Verfahren zur Herstellung von 5,5-disubstituierten N,N'-Dialkyloxyalkyl- oder N,N'-Dibenzyloxyalkylverbindugen der Barbitusaure. DE 2005108; FR 2033950; GB 1276387 . |
| 【3】 Samour, C.M.; et al. (The Kendall Company); Krampflosende Verbindungen. DE 1939787; ES 370220; FR 2015091; GB 1276386 . |
| 【4】 Castaner, J.; Playle, A.C.; Eterobarb. Drugs Fut 1976, 1, 6, 286. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (I) | 40324 | sodium 5-ethyl-4,6-dioxo-5-phenyl-1,4,5,6-tetrahydro-2-pyrimidinolate | 57-30-7 | C12H11N2NaO3 | 详情 | 详情 |
| (II) | 40323 | 5-ethyl-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione | 50-06-6 | C12H12N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which then reacts with benzoyl chloride (VIII) in pyridine to furnish (IX). Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (+)-(XV) is obtained by HPLC chromatography of (XIV) on a chiral stationary phase. Treatment of (+)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (+)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.
| 【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 . |
| 【2】 Kise, M.; Amimoto, I.; Kitano, M.; Segawa, J.; Tomii, Y.; Matsuoka, M.; Masui, Y.; Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives. Chem Pharm Bull 1999, 47, 12, 1765. |
| 【3】 Segawa, J.; Kitano, M.; Kazuno, K.; Matsuoka, M.; Shirahase, I.; Ozaki, M.; Matsuda, M.; Tomii, Y.; Kise, M.; Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3, 2-a]quinoline-3-carboxylic acids. J Med Chem 1992, 35, 25, 4727. |
| 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) | 13451 | 3,4-Difluoroaniline; 3,4-Difluorophenylamine | 3863-11-4 | C6H5F2N | 详情 | 详情 |
| (II) | 42953 | 3,4-difluorophenylcarbamodithioic acid | C7H5F2NS2 | 详情 | 详情 | |
| (III) | 13453 | 1,2-Difluoro-4-isothiocyanatobenzene; 3,4-difluorophenyl isothiocyanate | 113028-75-4 | C7H3F2NS | 详情 | 详情 |
| (IV) | 42954 | potassium 1-(3,4-difluoroanilino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propene-1-thiolate | C14H14F2KNO4S | 详情 | 详情 | |
| (V) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (VI) | 13455 | diethyl 2-[(3,4-difluoroanilino)[(methoxymethyl)sulfanyl]methylene]malonate | C16H19F2NO5S | 详情 | 详情 | |
| (VII) | 13456 | ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate | C14H13F2NO4S | 详情 | 详情 | |
| (VIII) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (IX) | 42955 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate | C21H17F2NO5S | 详情 | 详情 | |
| (X) | 42956 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate | C19H13F2NO4S | 详情 | 详情 | |
| (XI) | 28769 | 1-bromo-2-fluoroethane | 762-49-2 | C2H4BrF | 详情 | 详情 |
| (XII) | 42957 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(2-fluoroethyl)sulfanyl]-3-quinolinecarboxylate | C21H16F3NO4S | 详情 | 详情 | |
| (XIII) | 42958 | ethyl 4-(benzoyloxy)-2-[(1-chloro-2-fluoroethyl)sulfanyl]-6,7-difluoro-3-quinolinecarboxylate | C21H15ClF3NO4S | 详情 | 详情 | |
| (XIV) | 42959 | ethyl 6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C14H10F3NO3S | 详情 | 详情 | |
| (XV) | 42960 | ethyl (1R)-6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C14H10F3NO3S | 详情 | 详情 | |
| (XVI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XVII) | 42961 | ethyl (1R)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H21F2N3O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane, and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which is then converted into (IX) by means of benzoyl chloride (VIII) in pyridine. Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (-)-(XV) is then obtained by HPLC chromatography on a chiral stationary phase. Treatment of (-)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (-)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.
| 【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 . |
| 【2】 Kise, M.; Amimoto, I.; Kitano, M.; Segawa, J.; Tomii, Y.; Matsuoka, M.; Masui, Y.; Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives. Chem Pharm Bull 1999, 47, 12, 1765. |
| 【3】 Segawa, J.; Kitano, M.; Kazuno, K.; Matsuoka, M.; Shirahase, I.; Ozaki, M.; Matsuda, M.; Tomii, Y.; Kise, M.; Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3, 2-a]quinoline-3-carboxylic acids. J Med Chem 1992, 35, 25, 4727. |
| 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) | 13451 | 3,4-Difluoroaniline; 3,4-Difluorophenylamine | 3863-11-4 | C6H5F2N | 详情 | 详情 |
| (II) | 42953 | 3,4-difluorophenylcarbamodithioic acid | C7H5F2NS2 | 详情 | 详情 | |
| (III) | 13453 | 1,2-Difluoro-4-isothiocyanatobenzene; 3,4-difluorophenyl isothiocyanate | 113028-75-4 | C7H3F2NS | 详情 | 详情 |
| (IV) | 42954 | potassium 1-(3,4-difluoroanilino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propene-1-thiolate | C14H14F2KNO4S | 详情 | 详情 | |
| (V) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (VI) | 13455 | diethyl 2-[(3,4-difluoroanilino)[(methoxymethyl)sulfanyl]methylene]malonate | C16H19F2NO5S | 详情 | 详情 | |
| (VII) | 13456 | ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate | C14H13F2NO4S | 详情 | 详情 | |
| (VIII) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (IX) | 42955 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate | C21H17F2NO5S | 详情 | 详情 | |
| (X) | 42956 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate | C19H13F2NO4S | 详情 | 详情 | |
| (XI) | 28769 | 1-bromo-2-fluoroethane | 762-49-2 | C2H4BrF | 详情 | 详情 |
| (XII) | 42957 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(2-fluoroethyl)sulfanyl]-3-quinolinecarboxylate | C21H16F3NO4S | 详情 | 详情 | |
| (XIII) | 42958 | ethyl 4-(benzoyloxy)-2-[(1-chloro-2-fluoroethyl)sulfanyl]-6,7-difluoro-3-quinolinecarboxylate | C21H15ClF3NO4S | 详情 | 详情 | |
| (XIV) | 42959 | ethyl 6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C14H10F3NO3S | 详情 | 详情 | |
| (XV) | 42971 | octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
| (XVI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XVII) | 42975 | ethyl (1S)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H21F2N3O3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：2) The esterification of Shikimic acid (XIV) with MeOH/TsOH gives the methyl ester (XV), which is treated with 2,2-dimethoxypropane (II) and TsOH to yield the acetonide (XVI). The mesylation of (XVI) with mesyl chloride and TEA in dichloromethane gives the mesylated acetonide (XVII), which is hydrolyzed with HCl, yielding the dihydroxy ester (XVIII). The epoxidation of (XVIII) with DBU in THF affords the epoxide (XIX), which is protected with methyl chloromethyl ether to give compound (XX). The reaction of (XX) with sodium azide in refluxing methanol/water provides the hydroxy azide (XXI), which is acylated with mesyl chloride to the mesylate (XXII). The cyclization of (XXII) by means of triphenylphosphine in THF affords the aziridine (XXIII), which is treated with sodium azide in hot DMF to give the amino azide (XXIV). The deprotection of (XXIV) with HCl followed by tritylation of the free amino group with trityl chloride and TEA yields compound (XXV), which is cyclized by means of mesyl chloride and TEA to afford the tritylaziridine (XXVI). The cleavage of the aziridine ring of (XXVI) with 3-pentanol, followed by acetylation of the resulting amino group, affords the acetamido aziridine (XXVII), which is hydrolyzed at the ester group with KOH in THF/water to give the carboxylic acid (XXVIII). The esterification of (XXVIII) with ethanol, DCC and DMAP in dichloromethane affords the azido ester (XIII), which is finally reduced with triphenylphosphine in hot THF/water.
| 【1】 Castañer, J.; Leeson, P.A.; Graul, A.; Oseltamivir Phosphate. Drugs Fut 1999, 24, 11, 1189. |
| 【2】 Bischofberger, N.W.; Kim, C.U.; Lew, W.; Liu, H.; Williams, M.A. (Gilead Sciences Inc.); Novel selective inhibitors of viral or bacterial neuraminidases. EP 0759917; EP 0976734; JP 1999501908; WO 9626933 . |
| 【3】 Bischofberger, N.W.; Kim, C.U.; Williams, M.A.; Lew, W.; Liu, H. (Gilead Sciences Inc.); Carbocyclic cpds.. US 5763483 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 | |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XIII) | 29906 | ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C16H26N4O4 | 详情 | 详情 | |
| (XIV) | 29907 | (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid; Shikimic acid | 138-59-0 | C7H10O5 | 详情 | 详情 |
| (XV) | 29908 | methyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate | C8H12O5 | 详情 | 详情 | |
| (XVI) | 29909 | methyl (3aR,7R,7aS)-7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C11H16O5 | 详情 | 详情 | |
| (XVII) | 29910 | methyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C12H18O7S | 详情 | 详情 | |
| (XVIII) | 29911 | methyl (3R,4R,5R)-3,4-dihydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C9H14O7S | 详情 | 详情 | |
| (XIX) | 29912 | methyl (1S,5R,6R)-5-hydroxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C8H10O4 | 详情 | 详情 | |
| (XX) | 29913 | methyl (1S,5R,6S)-5-(methoxymethoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H14O5 | 详情 | 详情 | |
| (XXI) | 29914 | methyl (3R,4S,5R)-5-azido-4-hydroxy-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H15N3O5 | 详情 | 详情 | |
| (XXII) | 29915 | methyl (3R,4S,5R)-5-azido-3-(methoxymethoxy)-4-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C11H17N3O7S | 详情 | 详情 | |
| (XXIII) | 29916 | methyl (1R,5R,6R)-5-(methoxymethoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H15NO4 | 详情 | 详情 | |
| (XXIV) | 29917 | methyl (3R,4R,5S)-4-amino-5-azido-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H16N4O4 | 详情 | 详情 | |
| (XXV) | 29918 | methyl (3R,4R,5S)-5-azido-3-hydroxy-4-(tritylamino)-1-cyclohexene-1-carboxylate | C27H26N4O3 | 详情 | 详情 | |
| (XXVI) | 29919 | methyl (1S,5S,6S)-5-azido-7-trityl-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate | C27H24N4O2 | 详情 | 详情 | |
| (XXVII) | 29920 | methyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C15H24N4O4 | 详情 | 详情 | |
| (XXVIII) | 29921 | (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid | C14H22N4O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XI)Thiophene (III) was obtained by condensation of (4-methoxyphenyl)acetone (I) with ethyl cyanoacetate (II) in the presence of NH4OAc and AcOH, followed by treatment with sulfur and diethylamine. Subsequent reaction of (III) with ethyl isocyanato-acetate (IV) in pyridine at 45 C and further cyclization with ethanolic NaOEt provided the thienopyrimidine (V). Cleavage of the methyl ether was performed by treatment with AlCl3 and dimethyl disulfide in CH2Cl2 at r.t. to afford phenol (VI), which was then acetylated with Ac2O in pyridine to give ester (VII). N-Alkylation with 2-(methylsulfanyl)benzyl chloride (VIII) in the presence of K2CO3 in DMF yielded (IX), and then the acetate ester was hydrolyzed with K2CO3 in a mixture of H2O/MeOH/THF. The resulting phenol (X) was alkylated with chloromethyl methyl ether (XI) in the presence of NaH to provide (XII).
| 【1】 Cho, N.; Nara, Y.; Harada, M.; Sugo, T.; Masuda, Y.; Abe, A.; Kusumoto, K.; Itoh, Y.; Ohtaki, T.; Watanabe, T.; Furuya, S.; Thieno[2,3-d]pyrimidine-3-acetic acids a new class of nonpeptide endothelin receptor antagonists. Chem Pharm Bull 1998, 46, 11, 1724. |
| 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) | 10038 | 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone | 122-84-9 | C10H12O2 | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 18311 | ethyl 2-amino-5-(4-methoxyphenyl)-4-methyl-3-thiophenecarboxylate | C15H17NO3S | 详情 | 详情 | |
| (IV) | 18312 | ETHYL ISOCYANATOACETATE; ethyl 2-isocyanatoacetate | 2949-22-6 | C5H7NO3 | 详情 | 详情 |
| (V) | 18313 | ethyl 2-[6-(4-methoxyphenyl)-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate | C18H18N2O5S | 详情 | 详情 | |
| (VI) | 18314 | ethyl 2-[6-(4-hydroxyphenyl)-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate | C17H16N2O5S | 详情 | 详情 | |
| (VII) | 18315 | ethyl 2-[6-[4-(acetoxy)phenyl]-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate | C19H18N2O6S | 详情 | 详情 | |
| (VIII) | 18316 | 1-(chloromethyl)-2-(methylsulfanyl)benzene; 2-(chloromethyl)phenyl methyl sulfide | C8H9ClS | 详情 | 详情 | |
| (IX) | 18317 | ethyl 2-[6-[4-(acetoxy)phenyl]-5-methyl-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate | C27H26N2O6S2 | 详情 | 详情 | |
| (X) | 18318 | ethyl 2-[6-(4-hydroxyphenyl)-5-methyl-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate | C25H24N2O5S2 | 详情 | 详情 | |
| (XI) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (XII) | 18320 | ethyl 2-[6-[4-(methoxymethoxy)phenyl]-5-methyl-1-[2-(methylsulfanyl)benzyl]-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]acetate | C27H28N2O6S2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)In an alternative procedure, the known hydroxynaphthalene dicarboxylate (I) is protected as the methoxymethyl ether (III) using chloromethyl methyl ether (II) and diisopropyl ethylamine. Subsequent partial hydrolysis of diester (III) with KOH leads to acid (IV). Removal of the methoxymethyl protecting group of (IV) to produce naphthol (V) is accomplished by treatment with in situ generated iodotrimethylsilane. Hydroxy acid (V) is then converted to the dioxinone derivative (VI) employing diiodomethane and CsF in hot DMF. Finally, addition of the Grignard reagent (VII) to the lactone function of (VI) yields the desired 2-ethylbutyl ketone.
| 【1】 Mori, S.; Takechi, S.; Kida, S.; Mizui, T.; Ichihashi, T. (Shionogi & Co. Ltd.); Lignan analog, production thereof, and hypolipidemic drug. EP 0597107; EP 0701991; JP 1993310634; US 5731455; WO 9308155 . |
| 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) | 57436 | dimethyl 4-(3,4-dimethoxyphenyl)-1-hydroxy-5,6,7-trimethoxy-2,3-naphthalenedicarboxylate | C25H26O10 | 详情 | 详情 | |
| (II) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (III) | 57437 | dimethyl 4-(3,4-dimethoxyphenyl)-5,6,7-trimethoxy-1-(methoxymethoxy)-2,3-naphthalenedicarboxylate | C27H30O11 | 详情 | 详情 | |
| (IV) | 57438 | 4-(3,4-dimethoxyphenyl)-5,6,7-trimethoxy-3-(methoxycarbonyl)-1-(methoxymethoxy)-2-naphthoic acid | C26H28O11 | 详情 | 详情 | |
| (V) | 57439 | 4-(3,4-dimethoxyphenyl)-1-hydroxy-5,6,7-trimethoxy-3-(methoxycarbonyl)-2-naphthoic acid | C24H24O10 | 详情 | 详情 | |
| (VI) | 57440 | methyl 6-(3,4-dimethoxyphenyl)-7,8,9-trimethoxy-4-oxo-4H-naphtho[1,2-d][1,3]dioxine-5-carboxylate | C25H24O10 | 详情 | 详情 | |
| (VII) | 57441 | bromo(2-ethylbutyl)magnesium | C6H13BrMg | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(-)-Quinic acid (I) is converted into the acetonide (II) in the usual way and its secondary alcohol is converted into the tosylate (III) by reaction with tosyl chloride and DMAP in pyridine. The dehydration of (III) with SOCl2 and pyridine in methanol yields the cyclohexenecarboxylate (IV), which is epoxidized by means of DBU inb THF affording the epoxide (V). The protection of the free hydroxy group of (V) with methoxymethyl chloride and DIPEA in dichloromethane gives the ether (VI), which is treated with sodium azide in methanol yielding the azido alcohol (VII). The reaction of (VII) with methanesulfonyl chloride and triethylamine in dichloromethane affords the mesylate (VIII), which is submitted to a reductocyclization with triphenylphosphine in in THF providing the aziridine (IX). The cleavage of the aziridine group of (IX) with sodium azide in DMF gives the amino azide (X), which is deprotected at the methoxymethyl ether by a treatment with HCl in methanol to afford the alcohol (XI). The acetylation of (XI) with acetic anhydride in pyridine gives the N,O-diacetyl derivative (XII), which is condensed with N-(1-ethylpropyl)-N-methylamine (XIII) by means of palladium tetrakis(triphenylphosphine) in THF yielding the tertiary amine (XIV). The azido group of (XIV) in then reduced with triphenylphosphine in THF/water providing the amino intermediate (XV), which is finally hydrolyzed with KOH in aqueous THF.
| 【1】 Lew, W.; Wu, H.; Mendel, D.B.; Escarpe, P.A.; Chen, X.; Laver, W.G.; Graves, B.J.; Kim, C.U.; A new series of C3-aza carbocyclic influenza neuraminidase inhibitors: Synthesis and inhibitory activity. Bioorg Med Chem Lett 1998, 8, 23, 3321. |
| 【2】 Williams, M.A.; Lew, W.; Kim, C.U.; et al.; Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: Design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 1997, 119, 4, 681. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 | |
| (I) | 30978 | methyl (3R,5R)-1,3,4,5-tetrahydroxycyclohexanecarboxylate | C8H14O6 | 详情 | 详情 | |
| (II) | 30979 | methyl (3aR,5R,7R,7aS)-5,7-dihydroxy-2,2-dimethylhexahydro-1,3-benzodioxole-5-carboxylate | C11H18O6 | 详情 | 详情 | |
| (III) | 30980 | methyl (3aR,5S,7R,7aR)-5-hydroxy-2,2-dimethyl-7-[[(4-methylphenyl)sulfonyl]oxy]hexahydro-1,3-benzodioxole-5-carboxylate | C18H24O8S | 详情 | 详情 | |
| (IV) | 30981 | methyl (3R,4R,5R)-3,4-dihydroxy-5-[[(4-methylphenyl)sulfonyl]oxy]-1-cyclohexene-1-carboxylate | C15H18O7S | 详情 | 详情 | |
| (V) | 29912 | methyl (1S,5R,6R)-5-hydroxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C8H10O4 | 详情 | 详情 | |
| (VI) | 29913 | methyl (1S,5R,6S)-5-(methoxymethoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H14O5 | 详情 | 详情 | |
| (VII) | 29914 | methyl (3R,4S,5R)-5-azido-4-hydroxy-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H15N3O5 | 详情 | 详情 | |
| (VIII) | 30982 | methyl (3R,4S,5R)-5-azido-3-(methoxymethoxy)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-cyclohexene-1-carboxylate | C13H21N3O5S | 详情 | 详情 | |
| (IX) | 29916 | methyl (1R,5R,6R)-5-(methoxymethoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H15NO4 | 详情 | 详情 | |
| (X) | 29917 | methyl (3R,4R,5S)-4-amino-5-azido-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H16N4O4 | 详情 | 详情 | |
| (XI) | 30983 | methyl (3R,4R,5S)-4-amino-5-azido-3-hydroxy-1-cyclohexene-1-carboxylate | C8H12N4O3 | 详情 | 详情 | |
| (XII) | 30984 | methyl (3R,4R,5S)-4-(acetamido)-3-(acetoxy)-5-azido-1-cyclohexene-1-carboxylate | C12H16N4O5 | 详情 | 详情 | |
| (XIII) | 30985 | N-methyl-3-pentanamine; N-(1-ethylpropyl)-N-methylamine | C6H15N | 详情 | 详情 | |
| (XIV) | 30986 | methyl (3R,4S,5S)-4-(acetamido)-5-azido-3-[(1-ethylpropyl)(methyl)amino]-1-cyclohexene-1-carboxylate | C16H27N5O3 | 详情 | 详情 | |
| (XV) | 30987 | methyl (3R,4R,5S)-4-(acetamido)-5-amino-3-[(1-ethylpropyl)(methyl)amino]-1-cyclohexene-1-carboxylate | C16H29N3O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)Alternatively, benzylic alcohol (VI) can be protected as the methoxymethyl ether (IX) by treatment with chloromethyl methyl ether (VIII) and DIEA in CH2Cl2. Finally, aryl bromide (IX) is metalated with t-BuLi or n-BuLi, followed by borylation with B(OMe)3 in THF and subsequent treatment with HCl in H2O/MeOH .
| 【1】 Baker, S.J., AkamA, T., Bellinger-Kawahara, C. et al. (Anacor Pharmaceuticals, Inc.). Boron-containing small molecules. CN 101914109, EP 1853251, EP 2343304, JP 2008535781, JP 2010248265, KR 2010105869, KR 2013095330, KR 2013100019, US 20062334981, US 7582621, US 8039451, US 2011319361, US 2012289686, US 2013059802, US 2013059803, US 2013064783, US 8440642, US 2013210770, US 2013244980, US 8722917, US 2014142064, WO 2013210770. |
| 【2】 Baker, S.J., Sanders, V. Akama, T. et al. (Anacor Pharmaceuticals, Inc.). Boron-containing small molecules as anti-inflammatory agents. CN 103479654, EP 2719388, JP 2009531292, KR 2013120552, KR 2014082842, US 8168614, US 2012264714, US 8501712, US 2013316979, WO 2007095638. |
| 【3】 Akama, T., Zhang, Y.-K., Ding, C.Z. et al. (Anacor Pharmaceuticals, Inc.). Boron-containing small molecules as anti-inflammatory agents. US 2009291917, US 8039450. |