2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide -Drug Synthesis Database

【结构式】

【分子编号】21859

【品名】2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide

【CA登记号】

【分子式】C₆H₁₂F₃NOSi

【分子量】199.2481296

【元素组成】C 36.17% H 6.07% F 28.61% N 7.03% O 8.03% Si 14.1%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：

The reaction of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(methoxyimino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (I) with N-methyl-N-(trimethylsilyl)trifluoroacetamide and then with iodotrimethylsilane in dichloromethane gives the corresponding silylated 3-iodomethyl derivative (II), which is then treated with 4-carbamoylquinuclidine (III) in acetonitrile.

参考文献中间体

合成目标

【1】 Kamiya, T.; Machida, Y.; Negi, S.; Nomoto, S.; Saito, I.; Sugiyama, I.; Yamauchi, H. (Eisai Co., Ltd.); Cephem cpds. having at the 3-position a (1,4-methylene-1-piperidinio)methyl group or a (1-quinuclidinio)methyl group. AU 8652240; EP 0188255; ES 8703885; JP 1987030786; JP 1987123189; US 4748171; US 5010188 .
【2】 Prous, J.; Castaner, J.; E-1040. Drugs Fut 1988, 13, 2, 117.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	21859	2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide	C₆H₁₂F₃NOSi	详情	详情
(I)	21858	(7R)-3-[(acetoxy)methyl]-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid	C₁₅H₁₆N₆O₇S₂	详情	详情
(II)	21860	trimethylsilyl (7R)-3-(iodomethyl)-7-[(2-(methoxyimino)-2-[5-[(trimethylsilyl)amino]-1,2,4-thiadiazol-3-yl]acetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₁₉H₂₉IN₆O₅S₂Si₂	详情	详情
(III)	11766	4-Quinuclidinecarboxamide	C₈H₁₄N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：

The hydrogenation of the double bond of (XVIII) with H2 and Lindlar catalyst affords the corresponding saturated aldehyde (XIX), which is condensed with the diazophosphonate (XX) giving the acetylenic derivative (XXI). The bromination of (XXI) with N-bromosuccinimide (NBS) and AgNO3 yields the bromoacetylenic compound (XXII), which is desilylated with HF and TBAF affording the dihydroxy derivative (XXIII). The resilylation of (XXIII) with CF3CO-N(Me)-Tms gives the bis(trimethylsilyl) derivative (XXIV), which is finally converted into the desired intermediate, the stannane (XXV) by reaction with tributyltin hydride, PPh3 and Pd dibenzylideneacetone complex.

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of sanglifehrin A. Angew Chem. Int Ed Engl 1999, 38, 16, 2447.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	21859	2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide	C₆H₁₂F₃NOSi	详情	详情
(XVIII)	32430	(E,4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-4-methyl-2-hexenal	C₃₃H₆₃NO₅Si₂	详情	详情
(XIX)	32431	(4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-4-methylhexanal	C₃₃H₆₅NO₅Si₂	详情	详情
(XX)	32432	1-Diazo-2-oxopropylphosphonic acid dimethyl ester	C₅H₉N₂O₄P	详情	详情
(XXI)	32433	(2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₄H₆₅NO₄Si₂	详情	详情
(XXII)	32434	(2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-7-bromo-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₄H₆₄BrNO₄Si₂	详情	详情
(XXIII)	32435	(2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₂H₃₆BrNO₄	详情	详情
(XXIV)	32436	(2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-3-methyl-2-[(trimethylsilyl)methyl]-6-heptynyl]-9-ethyl-3,5,11-trimethyl-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₀H₅₆BrNO₂Si₂	详情	详情
(XXV)	32437	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-2-[(2S,3S,6E)-3-methyl-7-(tributylstannyl)-2-[(trimethylsilyl)methyl]-6-heptenyl]-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undecan-8-one	C₄₂H₈₅NO₂Si₂Sn	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XII)

The reduction of 3,4-dinitrobenzoic acid amide (I) with H2 over Pd/C in methanol gives 3,4-diaminobenzoic acid (II), which is cyclized with 3-ethoxy-3-iminopropionic acid ethyl ester (IV) (obtained by reaction of cyanacetic acid ethyl ester (III) with ethanolic HCl) in hot acetic acid to yield 2-(5-carbamoyl-1H-benzimidazol-2-yl)acetic acid ethyl ester (V). The reaction of 3-methoxy-4-nitrobenzoic acid (VII) with aqueous methylamine in a sealed tube at 100 C gives 3-(methylamino)-4-nitrobenzoic acid (VIII), which is reduced with H2 over Pd/C in methanol/THF to yield 4-amino-3-(methylamino)benzoic acid (VI). The cyclization of (VI) with (V) by means of 1,3-dimethylperhydropyrimidin-2-one (DMPU) at 190 C affords the substituted bis-benzimidazolylmethyl (IX). The reaction of (IX) with 2-amino-3-phosponopropionic acid tris-trimethylsilyl ester (X) (prepared by esterification of 2-amino-3-phosphonopropionic acid (XI) with N-methyl-N-(trimethylsilyl)trifluoroacetamide (XII)) by means of (PyBroP) in DMF provides the carboxamide (XIII). Finally, the cleavage of the trimethylsilyl ester groups by means of TFA furnishes the target phosphonic acid.

参考文献中间体

合成目标

【1】 Rice, K.; Wang, V.R.; Hataye, J.M.; Shelton, E.J.; Spender, J.R. (Celera Genomics); Novel cpds. and compsns. for treating hepatitis C infections. WO 0020400 .

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)	55559	3,4-dinitrobenzamide		C₇H₅N₃O₅	详情	详情
(II)	55560	3,4-diaminobenzamide		C₇H₉N₃O	详情	详情
(III)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(IV)	17929	ethyl 3-ethoxy-3-iminopropanoate	2318-25-4	C₇H₁₃NO₃	详情	详情
(V)	55561	ethyl 2-[5-(aminocarbonyl)-1H-benzimidazol-2-yl]acetate		C₁₂H₁₃N₃O₃	详情	详情
(VI)	14729	4-amino-3-(methylamino)benzoic acid		C₈H₁₀N₂O₂	详情	详情
(VII)	21085	3-methoxy-4-nitrobenzoic acid；4-Nitro-3-methoxybenzoic acid	5081-36-7	C₈H₇NO₅	详情	详情
(VIII)	14728	3-(methylamino)-4-nitrobenzoic acid		C₈H₈N₂O₄	详情	详情
(IX)	55562	2-{[5-(aminocarbonyl)-1H-benzimidazol-2-yl]methyl}-1-methyl-1H-benzimidazole-6-carboxylic acid		C₁₈H₁₅N₅O₃	详情	详情
(X)	55563	3-{bis[(trimethylsilyl)oxy]phosphoryl}alanine		C₉H₂₄NO₅PSi₂	详情	详情
(XI)	55565	DL-2-Amino-3-phosphonopropionic acid; 2-Amino-3-phosphonopropionic acid	20263-06-3	C₃H₈NO₅P	详情	详情
(XII)	21859	2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide		C₆H₁₂F₃NOSi	详情	详情
(XIII)	55564	N-[(2-{[5-(aminocarbonyl)-1H-benzimidazol-2-yl]methyl}-1-methyl-1H-benzimidazol-6-yl)carbonyl]-3-{bis[(trimethylsilyl)oxy]phosphoryl}alanine		C₂₇H₃₇N₆O₇PSi₂	详情	详情

Extended Information