2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid -Drug Synthesis Database

【结构式】

【分子编号】24737

【品名】2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid

【CA登记号】65872-41-5

【分子式】C₆H₇N₃O₃S

【分子量】201.206

【元素组成】C 35.82% H 3.51% N 20.88% O 23.86% S 15.94%

与该中间体有关的原料药合成路线共 6 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(VI)

The protection of 7-aminocephalosporanic acid (I) with di-tert-butyl dicarbonate gives 7-(tert-butoxycarbonylamino)cephalosporanic acid (II), which is condensed with 2,3-cyclopentenopyridine (III) by means of KI and NaHCO3 in hot water affording 7-(tert-butoxycarbonylamino)-3-[(2,3-cyclopenteno-1-pyridinium)methyl]ceph-3-em-4-carboxylate (IV). Deprotection of (IV) with trifluoroacetic acid anisole gives 7-amino-3-[(2,3-cyclopenteno-1-pyridinium)methyl]ceph-3-em-4-carboxylate (V), which is finally condensed with 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid (VI) by means of phosgene in toluene.

参考文献中间体

合成目标

【1】 Klesel, N.; Seibert, G.; Lattrell, R.; Wieduwilt, M.; Durckheimer, W.; Kirrstetter, R.; HR-810, a new parenteral cephalosporin. I. Chemistry and physical properties. Int Con Chemother 1983, PS 4.2/11-1.
【2】 Klesel, N.; Dürckheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K.H.; Wieduwilt, M.; Schwab, W.; Ross, B.C.; Limbert, M.; Winkler, I.; Seibert, G.; Mencke, B.; Kirrstetter, R.; Seeger, K.; Schrinner, E.; Fleischmann, K.; HR-810, a new parenteral cephalosporin with a broad antibacterial spectrum. Arzneim-Forsch Drug Res 1983, 33, 8, 1084-1086.
【3】 Lattrell, R.; Wieduwilt, M.; Duerckheimer, W.; Blumbach, J.; Seeger, K. (Aventis SA); Cephalosporin derivatives. EP 0064740; FR 2511682; FR 2515654; GB 2098216; JP 57192394; US 5071979 .
【4】 Castaner, J.; Serradell, M.N.; Cefpirome. Drugs Fut 1984, 9, 4, 252.

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)	22747	(6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₀H₁₂N₂O₅S	详情	详情
(II)	30507	(6R,7R)-3-[(acetoxy)methyl]-7-[(tert-butoxycarbonyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₅H₂₀N₂O₇S	详情	详情
(III)	30508	6,7-dihydro-5H-cyclopenta[b]pyridine	533-37-9	C₈H₉N	详情	详情
(IV)	30509	(6R,7R)-7-[(tert-butoxycarbonyl)amino]-3-(6,7-dihydro-5H-cyclopenta[b]pyridinium-1-ylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₁H₂₅N₃O₅S	详情	详情
(V)	30510	(6R,7R)-7-amino-3-(6,7-dihydro-5H-cyclopenta[b]pyridinium-1-ylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₁₆H₁₇N₃O₃S	详情	详情
(VI)	24737	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid	65872-41-5	C₆H₇N₃O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Displacement of the acetate group of 7-aminocephalosporanic acid (I) with the mercapto thiazole (II) yielded thioether (III). This was then acylated with 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (IV) in the presence of DCC and HOBt to furnish the corresponding amide.

参考文献中间体

合成目标

【1】 Wolff, S.; et al.; Results of a multicenter phase III trial of magnetic resonance angiography (MRA) with MS-325 for the detection of peripheral vascular disease in the aortolliac region. Circulation 2002, 106, 19, Suppl. 2, Abst 3408.

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)	15672	7-Aminocephalosporanic acid; 3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ACA		C₁₀H₁₂N₂O₅S	详情	详情
(II)	19846	2-(4-methyl-2-sulfanyl-1,3-thiazol-5-yl)acetic acid	34272-64-5	C₆H₇NO₂S₂	详情	详情
(III)	56514	7-amino-3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₅N₃O₅S₃	详情	详情
(IV)	24737	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid	65872-41-5	C₆H₇N₃O₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

In a further procedure, 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (IV) was activated as the mixed anhydride (V) by treatment with tosyl chloride and triethylamine. After protection of the cephem thioether (III) by silylation with either chlorotrimethylsilane or with bis(trimethylsilyl)acetamide, coupling with the mixed anhydride (V) gave rise to the title compound.

参考文献中间体

合成目标

【1】 Wagner, H.; Jaenicke, O.; Worm, M. (Aventis Pharma AG); Process for the preparation of cefodizime. EP 0226093 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	56514	7-amino-3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₅N₃O₅S₃	详情	详情
(IV)	24737	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid	65872-41-5	C₆H₇N₃O₃S	详情	详情
(V)	56515	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl 4-methylbenzenesulfonate		C₁₃H₁₃N₃O₅S₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

Using a different protection strategy, aminoacid (IV) was protected as the N-phenylacetyl derivative (VII) by treatment with acid chloride (VI). Subsequent DCC-mediated coupling with the cephem derivative (III) furnished (VIII). The N-phenylacetyl group was then selectively removed by enzymatic hydrolysis with penicillin G amidase.

参考文献中间体

合成目标

【1】 Zenoni, M.; Fuganti, C.; A method for the acylation of the 7-amino group of the cephalosporanic ring. EP 0582102 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	56514	7-amino-3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₅N₃O₅S₃	详情	详情
(IV)	24737	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid	65872-41-5	C₆H₇N₃O₃S	详情	详情
(VI)	25890	2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride	103-80-0	C₈H₇ClO	详情	详情
(VII)	56516	2-(methoxyimino)-2-{2-[(2-phenylacetyl)amino]-1,3-thiazol-4-yl}acetic acid		C₁₄H₁₃N₃O₄S	详情	详情
(VIII)	56517	3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-7-[(2-(methoxyimino)-2-{2-[(2-phenylacetyl)amino]-1,3-thiazol-4-yl}acetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₂₈H₂₆N₆O₈S₄	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VI)

The condensation of 7-aminocephalosporanic acid (I) with 5-methyltetrazole (II) by means of BF3 ethyl ether in sulfolane gives 7-amino-3-(5-methyl-1,2,3,4-tetrazol-2-ylmethyl)-3-cephem-4-carboxylic acid (III), which is esterified with pivaloyloxymethyl iodide (IV) by means of triethylamine in DMF yielding the corresponding ester (V). Finally, this compound it condensed with 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (VI) by means of POCl3 and dimethylacetamide in CH2Cl2.

参考文献中间体

合成目标

【1】 Hirakawa, T.; Imaizumi, H.; Inaba, T.; Konishi, Y.; Narita, H.; Sadaki, H.; Saikawa, I.; Tai, M.; Taki, H.; Watanabe, Y. (Toyama Chemical Co., Ltd.); Cephalosporins. AU 8549860; AU 8549863; DE 3137854; US 4489072 .
【2】 Serradell, M.N.; Castaner, J.; Cefteram. Drugs Fut 1986, 11, 9, 732.

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)	15672	7-Aminocephalosporanic acid; 3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ACA		C₁₀H₁₂N₂O₅S	详情	详情
(II)	24726	5-methyl-2H-1,2,3,4-tetraazole	4076-36-2	C₂H₄N₄	详情	详情
(III)	24727	7-amino-3-[(5-methyl-2H-1,2,3,4-tetraazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₀H₁₂N₆O₃S	详情	详情
(IV)	24735	tert-Butyl 2-iodoacetate		C₆H₁₁IO₂	详情	详情
(V)	24736	[(2,2-dimethylpropanoyl)oxy]methyl 7-amino-3-[(5-methyl-2H-1,2,3,4-tetraazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₁₆H₂₂N₆O₅S	详情	详情
(VI)	24737	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid	65872-41-5	C₆H₇N₃O₃S	详情	详情

合成路线6

该中间体在本合成路线中的序号：(XI)

Coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) and methoxyimino acetic acid derivative (XI) by means of POCl3 and pyridine in CH2Cl2 gives compound (XII) (alternatively (XII) can be obtained by condensation of ceftizoxime (CZX) (XIII) with iodomethyl pivalate (X) in N,N-dimethylacetamide (DMAc) in the presence of dicyclohexylamine). Coupling of (XII) with Boc-L-alanine (II) by means of EDC and DMAP in CH2Cl2 gives intermediate (VII), whose Boc protecting group is removed by treatment with either HCl/isopropanol in formic acid or TFA and anisole in CH2Cl2. Yet another strategy can be followed, involving the coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) with derivative (XIV) by means of Et3N in N,N-dimethylacetamide.

参考文献中间体

合成目标

【1】 Shirahase, H.; Hatano, S.; Yoshimi, A.; Kitagawa, M.; Kasai, M.; Nishimura, K.; Kakeya, N.; AS-924, a novel bifunctional prodrug of ceftizoxime. J Antibiot 1999, 52, 5, 491.
【2】 Kasai, M.; et al.; AS-924, a novel orally active bifunctional prodrug of ceftizoxime. Synthesis and relationship between physicochemical properties and oral absorption. Chem Pharm Bull 1999, 47, 8, 1081.
【3】 Muro, H.; Kasai, M.; Hatano, s.; Nishimura, K.-I.; Nishizawa, S.; Kakeya, N. (Kyoto Pharmaceutical Industries, Ltd.); Cephalosporin cpds. and production thereof. EP 0497978; JP 1991204883; US 5389625; WO 9106549 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	26450	Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid	15761-38-3	C₈H₁₅NO₄	详情	详情
(VI)	49510	[(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₁₃H₁₈N₂O₅S	详情	详情
(VII)	49511	[(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-[[2-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₇H₃₆N₆O₁₀S₂	详情	详情
(X)	11159	iodomethyl pivalate		C₆H₁₁IO₂	详情	详情
(XI)	24737	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid	65872-41-5	C₆H₇N₃O₃S	详情	详情
(XII)	49514	[(2,2-dimethylpropanoyl)oxy]methyl (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₁₉H₂₃N₅O₇S₂	详情	详情
(XIII)	49515	(6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₃H₁₃N₅O₅S₂	详情	详情
(XIV)	49516	2-(2-[[(2S)-2-aminopropanoyl]amino]-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl chloride		C₉H₁₁ClN₄O₃S	详情	详情

Extended Information