Diphenyldiazomethane -Drug Synthesis Database

【结构式】

【分子编号】23003

【品名】Diphenyldiazomethane

【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%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(A)

The condensation of 2-(tert-butoxycarbonylmethoxyimino)-2-(4 thiazolyl)acetic acid (I) with 7-amino 3-cephem-4-carboxylic acid (II) by means of the Vusmejer reagent (POCl3 and dimethylformamide) in ethyl acetate gives 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (III), which is then de protected with trifluoroacetic acid and anisole in methylene chloride. The starting acetic acid derivative (I) can be obtained by several different ways: 1) The partial hydrolysis of 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4yl) acetic acid (IV) with concentrated HCl in methanol gives 2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid (V), which is then deaminated with tert butyl nitrite in refluxing THF. 2) The preceding deamination of (IV) can be performed in a similar way with previous esterification with diphenyldiazomethane, through compounds (VI), (VII) and (VIII). Compound (VIII) is submitted to a partial hydrolysis with trifluoroacetic acid. 3) Compound (I) can also be obtained by condensation of 2-(4-thiazolylglyoxylic acid (IX) with tert-butyl-2-(aminooxy)acetate (X) by means of NaHCO3 in ethyl acetate.

参考文献中间体

合成目标

【1】 Takaya, T.; Takasugi, H.; Yamanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Cephem compounds. EP 0071891; US 4515788; US 4649136; US 4736039 .
【2】 Prous, J.; Castaner, J.; FK-089. Drugs Fut 1986, 11, 2, 103.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	23767	Methoxybenzene; Methyl phenyl ether; Anisole	100-66-3	C₇H₈O	详情	详情
(A)	23003	Diphenyldiazomethane		C₁₃H₁₀N₂	详情	详情
(I)	24081	2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetic acid		C₁₁H₁₄N₂O₅S	详情	详情
(II)	24082	7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₇H₈N₂O₃S	详情	详情
(III)	24083	7-[[2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₈H₂₀N₄O₇S₂	详情	详情
(IV)	24084	2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetic acid		C₁₂H₁₅N₃O₆S	详情	详情
(V)	24085	2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetic acid		C₁₁H₁₅N₃O₅S	详情	详情
(VI)	24086	benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetate		C₂₅H₂₅N₃O₆S	详情	详情
(VII)	24087	benzhydryl 2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetate		C₂₄H₂₅N₃O₅S	详情	详情
(VIII)	24088	benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetate		C₂₄H₂₄N₂O₅S	详情	详情
(IX)	24089	2-oxo-2-(1,3-thiazol-4-yl)acetic acid		C₅H₃NO₃S	详情	详情
(X)	24090	tert-butyl 2-(aminooxy)acetate		C₆H₁₃NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The bromination of 3,4-diacetoxyphenylacetic acid with N-bromosuccinimide (NBS) and SOCl2 gives the corresponding bromoacetic acid (II), which is esterified with diphenyldiazomethane (III) in acetone affording the diphenylmethyl ester (IV). The reaction of (IV) with N-hydroxyphthalimide (V) by means of triethylamine in acetonitrile yields diphenylmethyl-2-phthalimidooxy-2-(3,4-diacetoxy phenyl)acetate (VI), which is treated witb methyl hydrazine in dichloromethane to give diphenylmethyl-2-aminooxy-2-(3,4-diacetoxyphenyl)acetate (VII). The condensation of (VII) with (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid (VIII) in methanol affords 2-(2-triphenylmethylamino-4-thiazolyl)-2-[(Z)-(diphenyl)methoxyimino]acetic acid (IX), which is condensed with 7beta-amino-3-[2-(diphenylmethoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (X) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane giving the protected final product (XI). Finally, this compound is deprotected by treatment first with trifluoroacetic acid and then with NaHCO3 in water.

参考文献中间体

合成目标

【1】 Ohnishi, H.; Kosuzume, H.; Mizota, M.; Suzuki, Y.; Mochida, E. (Mochida Pharmaceutical Co., Ltd.); Cephalosporin derivs.. AU 8654876; AU 8655860; EP 0197409; EP 0359291; JP 1987077392; JP 1987161793; JP 1987167784; US 4840945; US 5001121; WO 8605786 .
【2】 Prous, J.; Castaner, J.; M-14659. Drugs Fut 1988, 13, 12, 1047.
【3】 Kusakabe, S.; Kosuzume, H.; Kato, K.; Shiihara, T.; Murakami, K.; Yamada, H.; Ishigura, J.; Oikawa, Y.; Mochizuki, H.; Antibacterial and pharmacokinetic properties of M1. J Antibiot 1988, 41, 3, 377.

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)	23001	2-[3,4-bis(acetoxy)phenyl]acetic acid		C₁₂H₁₂O₆	详情	详情
(II)	23002	2-[3,4-bis(acetoxy)phenyl]-2-bromoacetic acid		C₁₂H₁₁BrO₆	详情	详情
(III)	23003	Diphenyldiazomethane		C₁₃H₁₀N₂	详情	详情
(IV)	23004	benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-bromoacetate		C₂₅H₂₁BrO₆	详情	详情
(V)	13505	N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione	524-38-9	C₈H₅NO₃	详情	详情
(VI)	23006	benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetate		C₃₃H₂₅NO₉	详情	详情
(VII)	23007	benzhydryl 2-(aminooxy)-2-[3,4-bis(acetoxy)phenyl]acetate		C₂₅H₂₃NO₇	详情	详情
(VIII)	23008	2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid		C₂₄H₁₈N₂O₃S	详情	详情
(IX)	23009	2-([2-(benzhydryloxy)-1-[3,4-bis(acetoxy)phenyl]-2-oxoethoxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid		C₄₉H₃₉N₃O₉S	详情	详情

Extended Information