methyl 2-hydroxy-2-methoxyacetate -Drug Synthesis Database

【结构式】

【分子编号】22764

【品名】methyl 2-hydroxy-2-methoxyacetate

【CA登记号】19757-97-2

【分子式】C₄H₈O₄

【分子量】120.10512

【元素组成】C 40% H 6.71% O 53.28%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(IV)

A new synthesis of (-)-15-deoxyspergualin has been reported: The hydrolysis of 7-bromoheptanenitrile (I) with HCl gives the corresponding amide (II), which by reaction with sodium azide yields 7-azidoheptanamide (III). The condensation of (III) with 2-hydroxy-2-methoxyacetic acid methyl ester (IV) affords the alpha-hydroxyglycine derivative (V), which is condensed with 1(S)-(2-naphthyl)ethanol (VI) by means of SO2Cl2 and triethylamine in dichloromethane providing the diastereomeric mixture (VII). Hydrolysis of the ester group of (VII) with NaOH yields the corresponding free acid (VIII), which is condensed with the diprotected triamine (IX) by means of DCC and HOBt in dichloromethane affording a diastereomeric mixture of diamides. This mixture is separated by flash chromatography giving the desired diastereomer (X). The condensation of (X) with the protected isothiourea (XI) by means of triphenylphosphine in THF/water provides the proteted guanidino derivative (XII), which is finally deprotected by hydrogenation with H2 over Pd/C in methanol/acetic acid.

参考文献中间体

合成目标

【1】 Durand, P.; et al.; (-)-15-Deoxyspergualin: A new and efficient enantioselective synthesis which allows the definitive assignment of the absolute configuration. J Org Chem 1998, 63, 26, 9723.

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)	32852	7-bromoheptanenitrile	20965-27-9	C₇H₁₂BrN	详情	详情
(II)	32853	7-bromoheptanamide		C₇H₁₄BrNO	详情	详情
(III)	32854	7-azidoheptanamide		C₇H₁₄N₄O	详情	详情
(IV)	22764	methyl 2-hydroxy-2-methoxyacetate	19757-97-2	C₄H₈O₄	详情	详情
(V)	32855	methyl 2-[(7-azidoheptanoyl)amino]-2-hydroxyacetate		C₁₀H₁₈N₄O₄	详情	详情
(VI)	32856	(1S)-1-(2-naphthyl)-1-ethanol; 1(S)-(2-naphthyl)ethanol	7228-47-9	C₁₂H₁₂O	详情	详情
(VII)	32857	methyl 2-[(7-azidoheptanoyl)amino]-2-[[(1S)-1-(2-naphthyl)ethyl]oxy]acetate		C₂₂H₂₈N₄O₄	详情	详情
(VIII)	32858	2-[(7-azidoheptanoyl)amino]-2-[[(1S)-1-(2-naphthyl)ethyl]oxy]acetic acid		C₂₁H₂₆N₄O₄	详情	详情
(IX)	32859	benzyl 4-aminobutyl(3-[[(benzyloxy)carbonyl]amino]propyl)carbamate		C₂₃H₃₁N₃O₄	详情	详情
(X)	32860	benzyl 4-[((2S)-2-[(7-azidoheptanoyl)amino]-2-[[(1S)-1-(2-naphthyl)ethyl]oxy]ethanoyl)amino]butyl(3-[[(benzyloxy)carbonyl]amino]propyl)carbamate		C₄₄H₅₅N₇O₇	详情	详情
(XI)	32861	benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate		C₁₈H₁₈N₂O₄S	详情	详情
(XII)	32862	benzyl (7S,17Z)-17-[[(benzyloxy)carbonyl]amino]-7-[[(1S)-1-(2-naphthyl)ethyl]oxy]-6,9,19-trioxo-21-phenyl-20-oxa-5,8,16,18-tetraaza-17-henicosen-1-yl(3-[[(benzyloxy)carbonyl]amino]propyl)carbamate		C₆₁H₇₁N₇O₁₁	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 hydrolysis of 7-bromoheptanenitrile (I) with HCl gives the corresponding amide (II), which is treated with Na-N3 in hot DMSO to yield 7-azidoheptanamide (III) (1). The condensation of (III) with 2-hydroxy-2-methoxyacetic acid methyl ester (IV) in hot dichloromethane affords the alpha-hydroxyglycine (V), which is treated with SOCl2 in the same solvent to provide the alpha-chloroglycine (VI). The reaction of (VI) with benzyl alcohol and TEA in dichloromethane furnishes the benzyloxy derivative (VII), which is hydrolyzed at the ester group by means of NaOH in DME to give the carboxylic acid (VIII). The condensation of (VIII) with N1,N4-bis(benzyloxycarbonyl)spermidine (IX) by means of DCC and HOBt in dichloromethane yields the corresponding amide (X), which is reduced at the terminal azido group by means of PPh3 in THF/water, affording the expected primary amine (XI). The condensation of (XI) with the protected isothiourea (XII) in THF affords the protected guanidine derivative (XIII), which is finally deprotected by hydrogenolysis with H2 over Pd(OH)2 in methanol/acetic acid to provide the target compound.

参考文献中间体

合成目标

【1】 Durand, P.; et al.; A new efficient synthesis of the immunosuppressive agent (±)-15-deoxyspergualin. Tetrahedron 2001, 57, 14, 2757.
【2】 Durand, P.; et al.; (-)-15-Deoxyspergualin: A new and efficient enantioselective synthesis which allows the definitive assignment of the absolute configuration. J Org Chem 1998, 63, 26, 9723.

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)	32852	7-bromoheptanenitrile	20965-27-9	C₇H₁₂BrN	详情	详情
(II)	32853	7-bromoheptanamide		C₇H₁₄BrNO	详情	详情
(III)	32854	7-azidoheptanamide		C₇H₁₄N₄O	详情	详情
(IV)	22764	methyl 2-hydroxy-2-methoxyacetate	19757-97-2	C₄H₈O₄	详情	详情
(V)	32855	methyl 2-[(7-azidoheptanoyl)amino]-2-hydroxyacetate		C₁₀H₁₈N₄O₄	详情	详情
(VI)	55499	methyl 2-[(7-azidoheptanoyl)amino]-2-chloroacetate		C₁₀H₁₇ClN₄O₃	详情	详情
(VII)	55500	methyl 2-[(7-azidoheptanoyl)amino]-2-(benzyloxy)acetate		C₁₇H₂₄N₄O₄	详情	详情
(VIII)	55501	2-[(7-azidoheptanoyl)amino]-2-(benzyloxy)acetic acid		C₁₆H₂₂N₄O₄	详情	详情
(IX)	32859	benzyl 4-aminobutyl(3-[[(benzyloxy)carbonyl]amino]propyl)carbamate		C₂₃H₃₁N₃O₄	详情	详情
(X)	55502	benzyl 4-{[2-[(7-azidoheptanoyl)amino]-2-(benzyloxy)acetyl]amino}butyl(3-{[(benzyloxy)carbonyl]amino}propyl)carbamate		C₃₉H₅₁N₇O₇	详情	详情
(XI)	55503	benzyl 4-{[2-[(7-aminoheptanoyl)amino]-2-(benzyloxy)acetyl]amino}butyl(3-{[(benzyloxy)carbonyl]amino}propyl)carbamate		C₃₉H₅₃N₅O₇	详情	详情
(XII)	32861	benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate		C₁₈H₁₈N₂O₄S	详情	详情
(XIII)	55504	benzyl (Z)-7-(benzyloxy)-17-{[(benzyloxy)carbonyl]amino}-6,9,19-trioxo-21-phenyl-20-oxa-5,8,16,18-tetraaza-17-henicosen-1-yl(3-{[(benzyloxy)carbonyl]amino}propyl)carbamate		C₅₆H₆₇N₇O₁₁	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIII)

In a further procedure, 3,5-dimethoxybenzoic acid (X) was converted to the acetophenone (XI) using methyllithium. Treatment of (XI) with phenyltrimethylammonium tribromide provided the dibromoacetophenone (XII) which, upon reaction with morpholine at 55 C, followed by hydrolysis with aqueous HCl, gave the phenylglyoxal (VIII). Alternatively, (VIII) was prepared directly by treating acetophenone (XI) with DMSO and HBr or by oxidation with SeO2. Condensation of the phenylglyoxal (VIII) with methyl glyoxylate hemiacetal (XIII) and ammonium acetate produced the phenylimidazole (XIV), which was protected as the tetrahydrofuranyl derivative (XVI) with dihydrofuran and catalytic p-TsOH. Reduction of the protected imidazole ester (XVI) with LiBH4 provided alcohol (XVII), and then reaction of (XVII) with trichloroacetonitrile in the presence of DBU furnished the acetimidate (XVIII). Finally, the target compound was obtained by reaction of ascomycin (I) with trichloroacetimidate (XVIII) in the presence of fluoboric acid etherate, followed by hydrolytic deprotection.

参考文献中间体

合成目标

【1】 Mathre, D.J.; Sohar, P.; Shuman, R.F.; Song, Z. (Merck & Co., Inc.); Process for the preparation of imidazolyl macrolide immunosuppressants. JP 1999512096; US 5777105; WO 9708182 .

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)	14951	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron		C₄₃H₆₉NO₁₂	详情	详情
(VIII)	22759	1-(3,5-dimethoxyphenyl)-2,2-dihydroxy-1-ethanone		C₁₀H₁₂O₅	详情	详情
(X)	22761	3,5-dimethoxybenzoic acid	1132-21-4	C₉H₁₀O₄	详情	详情
(XI)	22762	1-(3,5-dimethoxyphenyl)-1-ethanone	39151-19-4	C₁₀H₁₂O₃	详情	详情
(XII)	22763	2,2-dibromo-1-(3,5-dimethoxyphenyl)-1-ethanone		C₁₀H₁₀Br₂O₃	详情	详情
(XIII)	22764	methyl 2-hydroxy-2-methoxyacetate	19757-97-2	C₄H₈O₄	详情	详情
(XIV)	22765	methyl 4-(3,5-dimethoxyphenyl)-1H-imidazole-2-carboxylate		C₁₃H₁₄N₂O₄	详情	详情
(XV)	22766	2,3-dihydrofuran	1191-99-7	C₄H₆O	详情	详情
(XVI)	22767	methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate		C₁₇H₂₀N₂O₅	详情	详情
(XVI)	22768	[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol		C₁₆H₂₀N₂O₄	详情	详情
(XVIII)	22769	[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate		C₁₈H₂₀Cl₃N₃O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

The cyclization of 2-(3,5-dimethoxyphenyl)glyoxal monohydrate (I) with methyl glyoxylate hemiacetal (II) and ammonium acetate in acetonitrile gives the imidazole derivative (III), which is protected with dihydrofuran (IV) and TsOH, yielding compound (V). The reduction of the ester group of (V) with LiBH4 affords the carbinol (VI), which is esterified with trichloroacetonitrile (VII) to provide the trichloroacetimidate (VIII). The condensation of (VIII) with ascomycin (IX) by means of CF3SO3H in N,N-dimethylpivalamide gives the adduct (X), which is finally deprotected with hot aqueous CF3SO3H.

参考文献中间体

合成目标

【1】 Song, Z.; et al.; Highly chemoselective trichloroacetimidate-mediated alkylation of ascomycin: A convergent, practical synthesis of the immunosuppressant L-733,725. J Org Chem 1999, 64, 6, 1859.

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)	22759	1-(3,5-dimethoxyphenyl)-2,2-dihydroxy-1-ethanone		C₁₀H₁₂O₅	详情	详情
(II)	22764	methyl 2-hydroxy-2-methoxyacetate	19757-97-2	C₄H₈O₄	详情	详情
(III)	22765	methyl 4-(3,5-dimethoxyphenyl)-1H-imidazole-2-carboxylate		C₁₃H₁₄N₂O₄	详情	详情
(IV)	22766	2,3-dihydrofuran	1191-99-7	C₄H₆O	详情	详情
(V)	22767	methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate		C₁₇H₂₀N₂O₅	详情	详情
(VI)	22768	[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol		C₁₆H₂₀N₂O₄	详情	详情
(VII)	42279	2,2,2-trichloroacetonitrile; Trichloromethylcyanide	545-06-2	C₂Cl₃N	详情	详情
(VIII)	22769	[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate		C₁₈H₂₀Cl₃N₃O₄	详情	详情
(IX)	14951	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron		C₄₃H₆₉NO₁₂	详情	详情
(X)	42280	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-((1R,3R,4R)-4-[[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methoxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,2		C₅₉H₈₇N₃O₁₅	详情	详情

Extended Information