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【结 构 式】 
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【分子编号】25065 【品名】[[2-[[(4-methoxybenzyl)oxy]carbonyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl](triphenyl)phosphonium iodide 【CA登记号】 |
【 分 子 式 】C59H51IN5O6PS2 【 分 子 量 】1148.094272 【元素组成】C 61.72% H 4.48% I 11.05% N 6.1% O 8.36% P 2.7% S 5.59% |
合成路线1
该中间体在本合成路线中的序号：(IVb)The cephalosporin was synthesized following the reaction pathway depicted in Scheme 25490101a: Protected 2-(2-aminothiazol-4-yl)-2-(alkoxy)iminoacetic acid ((Ia-c) was reacted with p-methoxybenzyl 7-amino-3-chloromethyl-cephaslosporonate (II) by a conventional method (POCl3, pyr / CH2Cl2. -5 C) to give the acylated product (IIIa-c). Product (IIIa-c) was then coverted to a phosponium salt (Iva-c) (PPh3, NaI / acetone, r.t.), followed by the reaction (NaHCO3(2N) / CH2Cl2, 0 C - r.t.) with a substituted isoxazole aldehyde (V) to afford the protected final product (Via-c). The aldehyde (V) was prepared by the sequential reduction-oxidation of the 1,3-dipolar cycloaddition product of methyl propiolate and the corresponding aldoxime. Deprotection, sodium salt formation and purification by reverse phase column chromatography (LiChrosorb(R) RP-18, 25% aq. MeOH) followed by frezee drying gave the final product as an amorphous white solid.
| 【1】 Choi, K.I.; Discovery of novel 3-isoxazolylvinylcephalosporins. Drugs Fut 1999, 24, 3, 287. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 25057 | 2-[2-(tritylamino)-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetic acid | C43H33N3O3S | 详情 | 详情 | |
| (Ib) | 25058 | 2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | 64485-90-1 | C25H21N3O3S | 详情 | 详情 |
| (Ic) | 25059 | 2-[(cyclopentyloxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C29H27N3O3S | 详情 | 详情 | |
| (IIIa) | 25061 | 4-methoxybenzyl 3-(chloromethyl)-8-oxo-7-([2-[2-(tritylamino)-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C59H48ClN5O6S2 | 详情 | 详情 | |
| (IIIb) | 25062 | 4-methoxybenzyl 3-(chloromethyl)-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C41H36ClN5O6S2 | 详情 | 详情 | |
| (IIIc) | 25063 | 4-methoxybenzyl 3-(chloromethyl)-7-([2-[(cyclopentyloxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C45H42ClN5O6S2 | 详情 | 详情 | |
| (IVa) | 25064 | [[2-[[(4-methoxybenzyl)oxy]carbonyl]-8-oxo-7-([2-[2-(tritylamino)-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl](triphenyl)phosphonium iodide | C77H63IN5O6PS2 | 详情 | 详情 | |
| (IVb) | 25065 | [[2-[[(4-methoxybenzyl)oxy]carbonyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl](triphenyl)phosphonium iodide | C59H51IN5O6PS2 | 详情 | 详情 | |
| (IVc) | 25066 | [(7-([2-[(cyclopentyloxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-2-[[(4-methoxybenzyl)oxy]carbonyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl](triphenyl)phosphonium iodide | C63H57IN5O6PS2 | 详情 | 详情 | |
| (VIa) | 25068 | 4-methoxybenzyl 3-[(E)-2-(3-chloro-5-isoxazolyl)ethenyl]-8-oxo-7-([2-[2-(tritylamino)-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C63H49ClN6O7S2 | 详情 | 详情 | |
| (VIb) | 25069 | 4-methoxybenzyl 3-[(E)-2-(3-chloro-5-isoxazolyl)ethenyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C45H37ClN6O7S2 | 详情 | 详情 | |
| (VIc) | 25070 | 4-methoxybenzyl 3-[(E)-2-(3-chloro-5-isoxazolyl)ethenyl]-7-([2-[(cyclopentyloxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C49H43ClN6O7S2 | 详情 | 详情 | |
| (II) | 25060 | 4-methoxybenzyl 3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H16ClNO4S | 详情 | 详情 | |
| (V) | 25067 | 3-chloro-5-isoxazolecarbaldehyde | C4H2ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IVb)The cephalosporin was synthesized following the reaction pathway depicted in Scheme 25490201a: Protected 2-(2-aminothiazol-4-yl)-2-(alkoxy)iminoacetic acid ((Ia-c) was reacted with p-methoxybenzyl 7-amino-3-chloromethyl-cephaslosporonate (II) by a conventional method (POCl3, pyr / CH2Cl2. -5 C) to give the acylated product (IIIa-c). Product (IIIa-c) was then coverted to a phosponium salt (Iva-c) (PPh3, NaI / acetone, r.t.), followed by the reaction (NaHCO3(2N) / CH2Cl2, 0 C - r.t.) with a substituted isoxazole aldehyde (V) to afford the protected final product (Via-c). The aldehyde (V) was prepared by the sequential reduction-oxidation of the 1,3-dipolar cycloaddition product of methyl propiolate and the corresponding aldoxime. Deprotection, sodium salt formation and purification by reverse phase column chromatography (LiChrosorb(R) RP-18, 25% aq. MeOH) followed by frezee drying gave the final product as an amorphous white solid.
| 【1】 Choi, K.I.; Discovery of novel 3-isoxazolylvinylcephalosporins. Drugs Fut 1999, 24, 3, 287. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 25057 | 2-[2-(tritylamino)-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetic acid | C43H33N3O3S | 详情 | 详情 | |
| (Ib) | 25058 | 2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | 64485-90-1 | C25H21N3O3S | 详情 | 详情 |
| (Ic) | 25059 | 2-[(cyclopentyloxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C29H27N3O3S | 详情 | 详情 | |
| (IIIa) | 25061 | 4-methoxybenzyl 3-(chloromethyl)-8-oxo-7-([2-[2-(tritylamino)-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C59H48ClN5O6S2 | 详情 | 详情 | |
| (IIIb) | 25062 | 4-methoxybenzyl 3-(chloromethyl)-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C41H36ClN5O6S2 | 详情 | 详情 | |
| (IIIc) | 25063 | 4-methoxybenzyl 3-(chloromethyl)-7-([2-[(cyclopentyloxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C45H42ClN5O6S2 | 详情 | 详情 | |
| (IVa) | 25064 | [[2-[[(4-methoxybenzyl)oxy]carbonyl]-8-oxo-7-([2-[2-(tritylamino)-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl](triphenyl)phosphonium iodide | C77H63IN5O6PS2 | 详情 | 详情 | |
| (IVb) | 25065 | [[2-[[(4-methoxybenzyl)oxy]carbonyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl](triphenyl)phosphonium iodide | C59H51IN5O6PS2 | 详情 | 详情 | |
| (IVc) | 25066 | [(7-([2-[(cyclopentyloxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-2-[[(4-methoxybenzyl)oxy]carbonyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl](triphenyl)phosphonium iodide | C63H57IN5O6PS2 | 详情 | 详情 | |
| (VIa) | 25072 | 4-methoxybenzyl 3-[(E)-2-(3-methoxy-5-isoxazolyl)ethenyl]-8-oxo-7-([2-[2-(tritylamino)-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C64H52N6O8S2 | 详情 | 详情 | |
| (VIb) | 25073 | 4-methoxybenzyl 7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-3-[(E)-2-(3-methoxy-5-isoxazolyl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C46H40N6O8S2 | 详情 | 详情 | |
| (VIc) | 25074 | 4-methoxybenzyl 7-([2-[(cyclopentyloxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-3-[(E)-2-(3-methoxy-5-isoxazolyl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C50H46N6O8S2 | 详情 | 详情 | |
| (II) | 25060 | 4-methoxybenzyl 3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H16ClNO4S | 详情 | 详情 | |
| (V) | 25071 | 3-methoxy-5-isoxazolecarbaldehyde | C5H5NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Trityl protected 2-(2-aminothiazol-4-yl)-2-(methoxy)iminoacetic acid (I) was coupled to 7-amino-3-(chloromethyl)cephalosporanic acid p-methoxybenzyl ester (II) using POCl3 and pyridine to give amide (III). This was converted to phosphonium salt (IV) upon treatment with triphenylphosphine and NaI. Subsequent Wittig reaction of (IV) with 3-chloroisoxazole-5-carbaldehyde (V) produced the corresponding vinyl isoxazole as a mixture of geometrical isomers, from which the major trans isomer (VI) was separated by flash column chromatography. Finally, deprotection of both trityl and p-methoxybenzyl groups of (VI) by means of trifluoroacetic acid afforded the title compound, which was isolated as the sodium salt.
| 【1】 Cho, Y.S.; Pae, A.N.; Cha, J.H.; Choi, K.I.; Chang, M.H.; Koh, H.Y.; Studies on novel 3-isoxazolylvinylcephalosporins: I. Synthesis and biological activity of 7-[2-(2-aminothiazol-4-yl)-2-(alkoxy)iminoacetamido] derivatives. J Antibiot 1998, 51, 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) | 25058 | 2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | 64485-90-1 | C25H21N3O3S | 详情 | 详情 |
| (II) | 26869 | 4-methoxybenzyl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H17ClN2O4S | 详情 | 详情 | |
| (III) | 25062 | 4-methoxybenzyl 3-(chloromethyl)-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C41H36ClN5O6S2 | 详情 | 详情 | |
| (IV) | 25065 | [[2-[[(4-methoxybenzyl)oxy]carbonyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl](triphenyl)phosphonium iodide | C59H51IN5O6PS2 | 详情 | 详情 | |
| (V) | 25067 | 3-chloro-5-isoxazolecarbaldehyde | C4H2ClNO2 | 详情 | 详情 | |
| (VI) | 26870 | 4-methoxybenzyl 3-[(E)-2-(3-chloro-5-isoxazolyl)ethenyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C45H37ClN6O7S2 | 详情 | 详情 |