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【结 构 式】 
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【分子编号】22668 【品名】benzyl 2-(triphenylphosphoranylidene)acetate 【CA登记号】 |
【 分 子 式 】C27H23O2P 【 分 子 量 】410.452182 【元素组成】C 79.01% H 5.65% O 7.8% P 7.55% |
合成路线1
该中间体在本合成路线中的序号：(VI)The esterification of bromoacetic acid (I) with benzyl alcohol (II) gives the corresponding ester (III), which by reaction with triphenylphosphine (IV) in hot toluene yields the phosphonium bromide (V). The reaction of (V) with NaOH in water-dichloromethane affords benzyl(triphenylphosphoranylidene) acetate (VI), which is submitted to a Wittig condensation with 5-(hydroxymethyl)-2-pyrrolidone (VII) in the presence of Dess-Martin periodinane (DMPI) giving benzyl 3-(5-oxo-2-pyrrolidinyl)-2(E) propenoate (VIII). The acylation of (VIII) with 4-methoxybenzoyl chloride (IX) by means of triethylamine in hot toluene yields the corresponding amide (X), which is finally hydrogenated and deprotected with H2 over Pd/C in THF.
| 【1】 Huang, C.C.; Synthesis of carbon-14 labeled 1-(4-methoxybenzoyl. J Label Compd Radiopharm 1987, 24, 6, 675. |
| 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) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (II) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (III) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (IV) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
| (V) | 22667 | [2-(benzyloxy)-2-oxoethyl](triphenyl)phosphonium bromide | C27H24BrO2P | 详情 | 详情 | |
| (VI) | 22668 | benzyl 2-(triphenylphosphoranylidene)acetate | C27H23O2P | 详情 | 详情 | |
| (VII) | 10079 | 5-(Hydroxymethyl)-2-pyrrolidinone | 62400-75-3 | C5H9NO2 | 详情 | 详情 |
| (VIII) | 22670 | benzyl (E)-3-(5-oxo-2-pyrrolidinyl)-2-propenoate | C14H15NO3 | 详情 | 详情 | |
| (IX) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (X) | 22672 | benzyl (E)-3-[1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinyl]-2-propenoate | C22H21NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)Synthesis of intermediate (I): 1c) The bromination of diketene (XIII) followed by reaction with diphenylmethanol gives diphenylmethyl 4-bromoacetoacetate (XIV), which by cyclization with thiourea by means of K2CO3 yields diphenylmethyl 2-(2-aminothiazol-4-yl)acetate (XV). The reaction of (XV) with benzyloxycarbonyl chloride and pyridine affords the protected compound (XVI), which is formylated with diphenyl methyl formiate (XVII) and NaH to afford diphenyl methyl 2-(2-benzyloxycarbonylamino)thiazol-4-yl-3-hydroxyacrylate (XVIII) The Wittig condensation of (XVIII) with benzyl triphenylphosphoranylidene acetate (XIX) gives diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4-(benzyloxycarbonyl)-2-butenoate (XX), which is selectively hydrolyzed with trifluoroacetic acid and anisole lo acid.
| 【1】 Yoshioka, M.; Synthetic studies related to oral beta-lactam antibiotics. Pure Appl Chem 1987, 59, 8, 1041. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 | |
| (I) | 22689 | (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid | C23H20N2O6S | 详情 | 详情 | |
| (XIII) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (XIV) | 22715 | benzhydryl 4-bromo-3-oxobutanoate | C17H15BrO3 | 详情 | 详情 | |
| (XV) | 22716 | benzhydryl 2-amino-1,3-thiazole-4-carboxylate | C17H14N2O2S | 详情 | 详情 | |
| (XVI) | 22717 | benzhydryl 2-[[(benzyloxy)carbonyl]amino]-1,3-thiazole-4-carboxylate | C25H20N2O4S | 详情 | 详情 | |
| (XVII) | 22718 | benzhydryl formate | C14H12O2 | 详情 | 详情 | |
| (XVIII) | 22719 | benzhydryl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-3-hydroxy-2-propenoate | C27H22N2O5S | 详情 | 详情 | |
| (XIX) | 22668 | benzyl 2-(triphenylphosphoranylidene)acetate | C27H23O2P | 详情 | 详情 | |
| (XX) | 22721 | 1-benzhydryl 5-benzyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate | C36H30N2O6S | 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 Wittig condensation of diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4 yl-2-formyl acetate with benzyloxycarbonylmethylene triphenylphosphorane (II) in toluene or dioxane gives 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4 (benzyloxycarbonyl)-2-butenoic acid diphenylmethyl ester (III), which is hydrolyzed partiaily wth trifluoroacetic acid and anisole to the 2-butenoic acid (IV). The condensation of (IV) with 7-beta-amino-3-cephem-4-carboxylic acid benzyl ester (V) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane affords the protected final product (VI), which is finally debenzylated by means of AlCl3 and anisole in methylene chloride.
| 【1】 Yoshida, T.; Synthesis and biological properties of 7Beta-[(Z)-2-(2-amino-4-thiazoyl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxilic acid (7432-S), a new oral cephem antibiotic. J Antibiot 1987, 40, 10, 1468. |
| 【2】 Hamashima, Y. (Shionogi & Co. Ltd.); 7-Carboxyalkenoylamido-3-cephem-4-carboxylic acid derivs.. EP 0136721; ES 8604602; ES 8605278; ES 8700222; GB 2154580; GB 2198727; JP 1985078987; JP 1985163884; JP 1985246388; US 4634697; US 4748170 . |
| 【3】 Castaner, J.; Prous, J.; 7432-S. Drugs Fut 1987, 12, 12, 1117. |
| 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) | 24153 | benzhydryl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-3-oxopropanoate | C27H22N2O5S | 详情 | 详情 | |
| (II) | 22668 | benzyl 2-(triphenylphosphoranylidene)acetate | C27H23O2P | 详情 | 详情 | |
| (III) | 22721 | 1-benzhydryl 5-benzyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate | C36H30N2O6S | 详情 | 详情 | |
| (IV) | 22689 | (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid | C23H20N2O6S | 详情 | 详情 | |
| (V) | 24157 | benzyl (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H14N2O3S | 详情 | 详情 | |
| (VI) | 24158 | benzyl (6R,7R)-7-[[(Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C37H32N4O8S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Saponification of ethyl adamantyloxyacetate (I), followed by treatment of the resultant carboxylic acid (II) with oxalyl chloride gives rise to acid chloride (III). This is then condensed with benzyl (triphenylphosphoranylidene)acetate (IV) to produce the phosphoranylidene keto ester (V). Subsequent oxidative cleavage of phosphorane (V) with oxone under phase transfer conditions leads to diketo ester (VI). Cyclization between diketo ester (VI), cyclohexanecarboxaldehyde (VII) and ammonium acetate in hot AcOH affords imidazole (VIII). The benzyl ester group of (VIII) is removed by catalytic hydrogenolysis, yielding acid (IX), which is further coupled with benzyl 3-aminobenzoate (X) to furnish amide (XI). Finally, benzyl ester hydrogenolysis in the presence of Pd/C provides the target compound (1,2).
| 【1】 Gastrin and cholecystokinin receptor ligands. JP 2002529455; US 6479531; WO 0027823 . |
| 【2】 Kalindjian, S.B.; Mesens, J.L.; Black, J.W.; Hull, R.A.D.; Shankley, N.P.; Andries, L.J. (James Black Foundation Ltd.; Janssen Pharmaceutica NV); Pharmaceutical compsns. comprising proton pump inhibitors and gastrin/cholecystokinin receptor ligands. WO 0185167 . |
| 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) | 64427 | ethyl 2-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)acetate | C14H22O3 | 详情 | 详情 | |
| (II) | 64428 | 2-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)acetic acid | C12H18O3 | 详情 | 详情 | |
| (III) | 64429 | 2-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)acetyl chloride | C12H17ClO2 | 详情 | 详情 | |
| (IV) | 22668 | benzyl 2-(triphenylphosphoranylidene)acetate | C27H23O2P | 详情 | 详情 | |
| (V) | 64430 | phenylmethyl 3-oxo-4-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)-2-(triphenyl-lambda~5~-phosphanylidene)butanoate | C39H39O4P | 详情 | 详情 | |
| (VI) | 64449 | phenylmethyl 2,3-dioxo-4-(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)butanoate | C21H24O5 | 详情 | 详情 | |
| (VII) | 33694 | cyclohexanecarbaldehyde | 2043-61-0 | C7H12O | 详情 | 详情 |
| (VIII) | 64450 | phenylmethyl 2-cyclohexyl-5-[(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)methyl]-1H-imidazole-4-carboxylate | C28H36N2O3 | 详情 | 详情 | |
| (IX) | 64461 | 2-cyclohexyl-5-[(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)methyl]-1H-imidazole-4-carboxylic acid | C21H30N2O3 | 详情 | 详情 | |
| (X) | 64462 | phenylmethyl 3-aminobenzoate | C14H13NO2 | 详情 | 详情 | |
| (XI) | 64463 | phenylmethyl 3-[({2-cyclohexyl-5-[(tricyclo[3.3.1.1~3,7~]dec-1-yloxy)methyl]-1H-imidazol-4-yl}carbonyl)amino]benzoate | C35H41N3O4 | 详情 | 详情 |