tert-butyl 2-chloroacetate -Drug Synthesis Database

【结构式】

【分子编号】40664

【品名】tert-butyl 2-chloroacetate

【CA登记号】107-59-5

【分子式】C₆H₁₁ClO₂

【分子量】150.60484

【元素组成】C 47.85% H 7.36% Cl 23.54% O 21.25%

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：(II)

The condensation of sodium saccharin (I) with tert-butyl chloroacetate (II) in hot DMF gives the benzoisothiazolin-acetic ester (III), which is rearranged by means of potassium tert-butoxide in THF to yield 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid tert-butyl ester 1,1-dioxide (IV). The methylation of (IV) with dimethyl sulfate and NaOH in water affords the 2-methyl derivative (V), which is acylated with cinnamoyl chloride (VI) and TEA in DMF to provide the 4-cinnamoyloxy derivative (VII). The cleavage of the tert-butyl group of (VII) by means of Tms-Cl, NaI and sodium thiosulfate gives the expected free acid (VIII), which is finally condensed with 2-aminopyridine (IX), previous activation with Cl2SO or ethyl chloroformate, and TEA in chloroform or dichloromethane to give rise to the target amide.

参考文献中间体

合成目标

【1】 Montserrat Vidal, C.; Serra Masia, J. (Laboratorios Salvat SA); 4-Cinnamoyloxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, process for obtaining it and intermediates for its preparation. ES 2053395 .

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)	33704	1,1-Dioxide-1,2-benzisothiazol-3(2H)-one, sodium salt; 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt (1:1)	38279-26-4	C₇H₄NNaO₃S	详情	详情
(II)	40664	tert-butyl 2-chloroacetate	107-59-5	C₆H₁₁ClO₂	详情	详情
(III)	50875	tert-butyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate		C₁₃H₁₅NO₅S	详情	详情
(IV)	50876	tert-butyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate		C₁₃H₁₅NO₅S	详情	详情
(V)	50877	tert-butyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate		C₁₄H₁₇NO₅S	详情	详情
(VI)	11303	(E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride	102-92-1	C₉H₇ClO	详情	详情
(VII)	50878	tert-butyl 2-methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate		C₂₃H₂₃NO₆S	详情	详情
(VIII)	50879	2-methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic acid		C₁₉H₁₅NO₆S	详情	详情
(IX)	11305	2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine	504-29-0	C₅H₆N₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III), which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V). The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI), which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII). The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX), which by treatment with HCl in methanol and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X). Finally, this compound is hydrolyzed with NaOH in methanol to afford the target acetic acid derivative.

参考文献中间体

合成目标

【1】 Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Müller, T.; Weisenberger, J.; Linz, G.; Krüger, G. (Dr. Karl Thomae GmbH); Cyclic imino derivs., process for their preparation and drugs containing them. DE 4035961; EP 0483667; JP 1992264068; US 5591769 .
【2】 Himmelsbach, F.; Austel, V.; Pieper, H.; Linz, G.; Wisenberger, J.; Muller, T. (Dr. Karl Thomae GmbH); Cyclic imino derivs., medicaments containing these cpds. and processes for the production thereof. DE 4213919; EP 0567966; JP 1994073001 .

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)	48730	(S)-(+)-5-(Trityloxymethyl)-2-pyrrolidinone		C₂₄H₂₃NO₂	详情	详情
(II)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(III)	48731	benzyl (5S)-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate		C₃₂H₂₉NO₄	详情	详情
(IV)	40664	tert-butyl 2-chloroacetate	107-59-5	C₆H₁₁ClO₂	详情	详情
(V)	48732	benzyl (3S,5S)-3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate		C₃₈H₃₉NO₆	详情	详情
(VI)	48733	tert-butyl 2-[(3S,5S)-5-(hydroxymethyl)-2-oxopyrrolidinyl]acetate		C₁₁H₁₉NO₄	详情	详情
(VII)	48734	tert-butyl 2-((3S,5S)-5-[[(methylsulfonyl)oxy]methyl]-2-oxopyrrolidinyl)acetate		C₁₂H₂₁NO₆S	详情	详情
(VIII)	48735	4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile	19812-93-2	C₁₃H₉NO	详情	详情
(IX)	48736	tert-butyl 2-((3S,5S)-5-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-2-oxopyrrolidinyl)acetate		C₂₄H₂₆N₂O₄	详情	详情
(X)	48737	methyl 2-[(3S,5S)-5-[([4'-[amino(imino)methyl][1,1'-biphenyl]-4-yl]oxy)methyl]-2-oxopyrrolidinyl]acetate		C₂₁H₂₃N₃O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III), which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V). The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI), which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII). The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX), which by treatment with HCl in methanol, and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X). Finally, this compound is condensed with methyl chloroformate (XI) by means of NaOH in dichloromethane to afford the target compound.

参考文献中间体

合成目标

【1】 Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Müller, T.; Weisenberger, J.; Linz, G.; Krüger, G. (Dr. Karl Thomae GmbH); Cyclic imino derivs., process for their preparation and drugs containing them. DE 4035961; EP 0483667; JP 1992264068; US 5591769 .
【2】 Himmelsbach, F.; Austel, V.; Pieper, H.; Linz, G.; Wisenberger, J.; Muller, T. (Dr. Karl Thomae GmbH); Cyclic imino derivs., medicaments containing these cpds. and processes for the production thereof. DE 4213919; EP 0567966; JP 1994073001 .

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)	48730	(S)-(+)-5-(Trityloxymethyl)-2-pyrrolidinone		C₂₄H₂₃NO₂	详情	详情
(II)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(III)	48731	benzyl (5S)-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate		C₃₂H₂₉NO₄	详情	详情
(IV)	40664	tert-butyl 2-chloroacetate	107-59-5	C₆H₁₁ClO₂	详情	详情
(V)	48732	benzyl (3S,5S)-3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate		C₃₈H₃₉NO₆	详情	详情
(VI)	48733	tert-butyl 2-[(3S,5S)-5-(hydroxymethyl)-2-oxopyrrolidinyl]acetate		C₁₁H₁₉NO₄	详情	详情
(VII)	48734	tert-butyl 2-((3S,5S)-5-[[(methylsulfonyl)oxy]methyl]-2-oxopyrrolidinyl)acetate		C₁₂H₂₁NO₆S	详情	详情
(VIII)	48735	4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile	19812-93-2	C₁₃H₉NO	详情	详情
(IX)	48736	tert-butyl 2-((3S,5S)-5-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-2-oxopyrrolidinyl)acetate		C₂₄H₂₆N₂O₄	详情	详情
(X)	48737	methyl 2-[(3S,5S)-5-[([4'-[amino(imino)methyl][1,1'-biphenyl]-4-yl]oxy)methyl]-2-oxopyrrolidinyl]acetate		C₂₁H₂₃N₃O₄	详情	详情
(XI)	10257	methyl 2-chloroacetate; methyl chloroacetate	96-34-4	C₃H₅ClO₂	详情	详情

Extended Information