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【结 构 式】 
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【分子编号】40585 【品名】1-[diazo(phenyl)methyl]benzene 【CA登记号】 |
【 分 子 式 】C13H10N2 【 分 子 量 】194.23588 【元素组成】C 80.39% H 5.19% N 14.42% |
合成路线1
该中间体在本合成路线中的序号：(II)The partial hydrolysis of 7-(phenylacetamido) cephalosporanic acid (I) followed by esterification with diphenyldyazomethane (II) gives benzhydryl 3-(hydroxymethyl)-7-(phenylacetamido)-3-cephem-4-carboxylate (III), which by reaction with PCl5 affords benzhydryl 7-amino-3-(chloromethyl)-3- cephem-4-carboxylate (IV). The condensation of (IV) with N-(tert-butoxycarbonyl)-2(R)-(4-hydroxyphenyl) glycine (V) by means of dicyclohexylcarbodiimide (DCC) yields benzhydryl 7-[(R)-2-(tert-butoxycarbonylamino)-2-(4-hydroxypheny) acetamido]-3-(chloro-methyl)-3-cephem-4-carboxylate (VI), which by reaction with NaI in acetone is converted to the corresponding iodomethyl derivative (VII).The reaction of (VII) with triphenylphosphine in ethyl acetate affords the phosphonium salt (VIII), which is submitted to a Wittig condensation with acetaldehyde to yield benzhydryl 7-[(R)-2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetamido]-3-(propenyl)-3-cephem-4-carboxylate (IX). Finally this compound is deprotected by a treatment with trifluoroacetic acid.
| 【1】 Winocour, P.; Vezina, M.; Kornbrust, D.; Sullivan, T.; Durkin, J.; Synthesis and structure-activity relationsships of a new oral cephalosporin, BMY-28100 and related compounds. J Antibiot 1987, 40, 7, 991. |
| 【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; CEFPROZIL. Drugs Fut 1989, 14, 6, 507. |
| 【3】 Hoshi, H.; Okumura, J.; Naito, T.; Abe, Y.; Abukari, S. (Bristol-Myers Squibb Co.); Substituted vinyl cephalosporins. DE 3402642; US 4520022 . |
| 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) | 59721 | (6R,7R)-3-[(acetyloxy)methyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H17N2O6S | 详情 | 详情 | |
| (II) | 40585 | 1-[diazo(phenyl)methyl]benzene | C13H10N2 | 详情 | 详情 | |
| (III) | 59722 | benzhydryl (6R,7R)-3-(hydroxymethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H26N2O5S | 详情 | 详情 | |
| (IV) | 31135 | benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C21H19ClN2O3S | 详情 | 详情 | |
| (V) | 59723 | (2R)-2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)ethanoic acid | C13H17NO5 | 详情 | 详情 | |
| (VI) | 59724 | diphenylmethyl 3-(chloromethyl)-7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C34H34ClN3O7S | 详情 | 详情 | |
| (VII) | 59725 | diphenylmethyl 7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C34H34IN3O7S | 详情 | 详情 | |
| (VIII) | 59726 | [(7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-2-{[(diphenylmethyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl](triphenyl)phosphonium | C52H49N3O7PS | 详情 | 详情 | |
| (IX) | 59727 | diphenylmethyl 7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-8-oxo-3-(1-propenyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C36H37N3O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The intermediate stannane derivative (XVI) has been obtained as follows: The esterification of propynoic acid (XII) with diphenyldiazomethane (XIII) in benzene gives the corresponding ester (XIV), which is then condensed with Me3Sn-Cu(CN)Li (XV) in THF/methanol to yield the desired intermediate (XVI). 3-Hydroxy-2(S)-methylpropionic acid methyl ester (I) is converted into the chiral tosylate (II) by conventional methods. The condensation of (II) with 4-pentenylmagnesium bromide (III) in THF gives the chiral tetrahydropyranyl ether (IV), which is condensed with the phosphonate (V) by means of KHMDS in THF/toluene yielding the chiral nonenoic ester (VI). The reduction of (VI) with DIBAL in the same solvent, followed by protection of the resulting alcohol with TBDPSCl and TEA in dichloromethane affords the protected diol (VII). The selective elimination of the THP protecting group, followed by reaction with TsCl and TEA in dichloromethane affords the tosylate (VIII), which is condensed with lithium acetylide (IX) in DMSO to provide the terminal acetylene (X). The deprotection of (X) with TBAF, followed by reaction with Me3Al, Cp2ZrCl2, and I2 in THF gives the omega iodoundecadienol (XI), which is condensed with the stannane derivative (XVI) by means of PdCl2 in DMF yielding the tetradecatrienoic diphenylmethyl ester (XVII). The chiral epoxidation of (XVII) with Ti(OiPr)4, BuOOH and (R,R)(+)-diisopropyl tartrate (DIPT) in dichloroethane affords the hydroxymethyl-oxirane (XVIII), which is oxidized with tetrapropylammonium perruthenate (TPAP) to provide the oxirane carbaldehyde (XIX).
| 【1】 Bates, R.W.; et al.; Total synthesis of the cholesterol biosynthesis inhibitor 1233A via a (Pi-allyl)tricarbonyliron lactone complex. J Chem Soc - Perkins Trans I 1999, 14, 1917. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 41854 | (2S)-2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl 4-methylbenzenesulfonate | C17H26O5S | 详情 | 详情 | |
| (III) | 39424 | bromo(4-pentenyl)magnesium | C5H9BrMg | 详情 | 详情 | |
| (IV) | 41855 | (3R)-3-methyl-8-nonenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(3R)-3-methyl-8-nonenyl]oxy]tetrahydro-2H-pyran | C15H28O2 | 详情 | 详情 | |
| (V) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (VI) | 41857 | methyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenoate | C17H30O4 | 详情 | 详情 | |
| (VII) | 41858 | tert-butyl[[(Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl ether | C32H48O3Si | 详情 | 详情 | |
| (VIII) | 41859 | (2R,7Z)-9-[[tert-butyl(diphenyl)silyl]oxy]-2-methyl-7-nonenyl 4-methylbenzenesulfonate | C33H44O4SSi | 详情 | 详情 | |
| (IX) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 | |
| (X) | 41860 | tert-butyl[[(Z,8R)-8-methyl-2-undecen-10-ynyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-2-undecen-10-ynyl ether | C28H38OSi | 详情 | 详情 | |
| (XI) | 41861 | (2Z,8R,10E)-11-iodo-8,10-dimethyl-2,10-undecadien-1-ol | C13H23IO | 详情 | 详情 | |
| (XII) | 10398 | 2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether | C13H19IO2 | 详情 | 详情 | |
| (XIII) | 40585 | 1-[diazo(phenyl)methyl]benzene | C13H10N2 | 详情 | 详情 | |
| (XIV) | 41862 | benzhydryl 2-butynoate | C17H14O2 | 详情 | 详情 | |
| (XVI) | 41863 | benzhydryl (E)-3-(trimethylstannyl)-2-butenoate | C20H24O2Sn | 详情 | 详情 | |
| (XVII) | 41864 | benzhydryl (2E,4E,7R,12Z)-14-hydroxy-3,5,7-trimethyl-2,4,12-tetradecatrienoate | C30H38O3 | 详情 | 详情 | |
| (XVIII) | 41865 | benzhydryl (2E,4E,7R)-11-[(2R,3S)-3-(hydroxymethyl)oxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H38O4 | 详情 | 详情 | |
| (XIX) | 41866 | benzhydryl (2E,4E,7R)-11-[(2R,3R)-3-formyloxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H36O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：A new efficient process for the synthesis of the key intermediate (XII) has been reported. Cyclization of L-alpha-aminoadipic acid in either refluxing AcOH or in DMSO at 130 C provided (S)-6-oxopipecolic acid (II), which was converted to the benzhydryl ester (III) upon treatment with diphenyldiazomethane. Further protection of (III) with benzyl chloroformate produced the N-benzyloxycarbonyl derivative (IV). Methylation of (IV) using iodomethane and lithium hexamethyldisilazide at -78 C produced a 4:1 mixture of the desired trans compound (V) and the cis isomer (VI). The diastereomer specific reduction of the mixture (V+VI) with LiAlH(O-t-Bu)3 yielded the trans cyclic aminal (VII) along with the unreacted cis isomer (VI). Subsequent condensation of aminal (VII) with L-cysteine methyl ester - HCl (VIII) produced the required thiazolidine (IX) as a diastereomeric mixture while leaving the unchanged lactam (VI). Then, acid cleavage of the benzhydryl esters of (VI) and (IXa, IXb) allowed the separation of the HCl-soluble thiazolidine acid (Xa, Xb) from the ether-soluble cis lactam.
| 【1】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor.II. Stereoselective synthesis of peptidomimetic [5.7]-bycyclic compounds. Chem Pharm Bull 1999, 47, 11, 1532. |
| 【2】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor. I. Diastereoselective alkylation of protected 6-oxopipecolic acid esters. Chem Pharm Bull 1999, 47, 11, 1525. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 40585 | 1-[diazo(phenyl)methyl]benzene | C13H10N2 | 详情 | 详情 | ||
| (IXa) | 35115 | methyl (2S,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate | C32H36N2O6S | 详情 | 详情 | |
| (IXb) | 35116 | methyl (2R,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate | C32H36N2O6S | 详情 | 详情 | |
| (Xa) | 35117 | (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2R,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid | C19H26N2O6S | 详情 | 详情 | |
| (Xb) | 35118 | (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2S,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid | C19H26N2O6S | 详情 | 详情 | |
| (I) | 35109 | (2S)-2-aminohexanedioic acid | 1118-90-7 | C6H11NO4 | 详情 | 详情 |
| (II) | 22661 | (2S)-6-oxo-2-piperidinecarboxylic acid | C6H9NO3 | 详情 | 详情 | |
| (III) | 35110 | benzhydryl (2S)-6-oxo-2-piperidinecarboxylate | C19H19NO3 | 详情 | 详情 | |
| (IV) | 35111 | 2-benzhydryl 1-benzyl (2S)-6-oxo-1,2-piperidinedicarboxylate | C27H25NO5 | 详情 | 详情 | |
| (V) | 35112 | 2-benzhydryl 1-benzyl (2S,5R)-5-methyl-6-oxo-1,2-piperidinedicarboxylate | C28H27NO5 | 详情 | 详情 | |
| (VI) | 35113 | 2-benzhydryl 1-benzyl (2S,5S)-5-methyl-6-oxo-1,2-piperidinedicarboxylate | C28H27NO5 | 详情 | 详情 | |
| (VII) | 35114 | 2-benzhydryl 1-benzyl (2S,5R)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate | C28H29NO5 | 详情 | 详情 | |
| (VIII) | 27413 | methyl (2R)-2-amino-3-sulfanylpropanoate | C4H9NO2S | 详情 | 详情 |