2-chloro-1-methylpyridinium iodide -Drug Synthesis Database

【结构式】

【分子编号】34696

【品名】2-chloro-1-methylpyridinium iodide

【CA登记号】14338-32-0

【分子式】C₆H₇ClIN

【分子量】255.48549

【元素组成】C 28.21% H 2.76% Cl 13.88% I 49.67% N 5.48%

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：

(LX) is treated successively with H2O2 and LiOH, with triethylsilyl trifluoromethylsulfonate and with water to afford acid (LXI). Cyclization of (LXI) with 2-chloro-N-methylpyridinium iodide and triethylamine in dichloromethane yields the cyclic derivative (LXII), which is treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to eliminate the 4-methoxybenzyl protecting group, so yielding alcohol (LXIII). A new partial deprotection of (LXIII) with trifluoroacetic acid affords the glycol (LXIV), which is oxidized with oxalyl chloride in DMSO to the vicinal triketone (LXV). Treatment of (LXV) with HF in acetonitrile gives the epoxy derivative (LXVI) with some free hydroxyl groups which are protected with triethylsilyl chloride, affording the compound (LXVII) with only one free hydroxy group. Oxidation of (LXVII) with Dess-Martin periodinane (DMP) in dichloromethane yields protected FK-506 (LXVIII), which is finally deprotected with HF in acetonitrile.

参考文献中间体

合成目标

【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	34696	2-chloro-1-methylpyridinium iodide	14338-32-0	C₆H₇ClIN	详情	详情
(LX)	11559	2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R,17R)-6-allyl-19-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-12,14-dimethoxy-18-[(4-methoxybenzyl)oxy]-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-19-oxo-3-[(triisopropylsilyl)oxy]-7-nonadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate		C₉₇H₁₇₀N₂O₁₇Si₄	详情	详情
(LXI)	11560	(2S,3R,4R,6S,7R,8S,10S,12E,14R,15S,17S,18S,19S,20E)-14-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,10,12,18,20-pentamethyl-19-[[(2S)piperidinylcarbonyl]oxy]-3-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoic acid		C₈₈H₁₆₇NO₁₄Si₅	详情	详情
(LXII)	11561	(3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,19R,20S,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-20-[(4-methoxybenzyl)oxy]-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione		C₈₈H₁₆₅NO₁₃Si₅	详情	详情
(LXIII)	11562	(3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,19R,20S,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-20-hydroxy-14,16-dimethoxy-3-((E)-2-[(1R,3R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione		C₈₀H₁₅₇NO₁₂Si₅	详情	详情
(LXIV)	11563	(3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,19R,20S,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-19,20-dihydroxy-14,16-dimethoxy-3-((E)-2-[(1R,3R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione		C₇₄H₁₄₃NO₁₂Si₄	详情	详情
(LXV)	11564	(3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,20,21(4H,23H)-tetrone		C₇₄H₁₃₉NO₁₂Si₄	详情	详情
(LXVI)	11565	(1R,9S,12S,13S,14S,16R,17R,21S,23S,24R,25S,27R)-17-Allyl-1,16-dihydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10-trione		C₄₄H₇₁NO₁₂	详情	详情
(LXVII)	11566	(1R,9S,12S,13S,14S,16R,17R,21S,23S,24R,25S,27R)-17-Allyl-1,16-dihydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10-trione		C₅₆H₉₉NO₁₂Si₂	详情	详情
(LXVIII)	11567	(1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-1-hydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone		C₅₆H₉₇NO₁₂Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(A)

The title compound was synthesized starting from the described intermediate (I). Hydrogenation of the olefinic double bond in the presence of PtO2 afforded (II). After protection of the free hydroxyl group of (II) as the corresponding silyl ether (III) with tert-butyldimethylsilyl chloride and imidazole, hydrolysis of the acetate ester of (III) by means of K2CO3 in MeOH furnished alcohol (IV). Further protection of (IV) employing dihydropyran and camphorsulfonic acid gave tetrahydropyranyl ether (V). Reduction of the lactone function of (V) with DIBAL in toluene at -78 C produced lactol (VI), which was submitted to a Wittig reaction with the ylide resulting from phosphonium salt (VII) and t-BuOK to yield the cis olefin (VIII). Esterification of (VIII) with isopropanol in the presence of 2-chloro-1-methylpyridinium iodide gave isopropyl ester (IX). Inversion of the configuration of the 9beta-hydroxyl group of (IX) was then achieved by Mitsunobu coupling with formic acid to give the 9beta-formate ester (X). Subsequent hydrolysis of the formate ester of (X) with K2CO3 in hot isopropanol, followed by acid deprotection of the tetrahydropyranyl and silyl groups yielded the title compound.

参考文献中间体

合成目标

【1】 Miyazaki, T.; Kawakura, M.; Shirasawa, E. (Ono Pharmaceutical Co., Ltd.); 13,14-Dihydro-PGF2BETA and its isopropyl ester. CA 2125804; EP 0628545; JP 1995061965 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	34696	2-chloro-1-methylpyridinium iodide	14338-32-0	C₆H₇ClIN	详情	详情
(I)	34689	(3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-1-octenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl acetate		C₁₇H₂₆O₅	详情	详情
(II)	34690	(3aR,4R,5R,6aS)-4-[(3S)-3-hydroxyoctyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl acetate		C₁₇H₂₈O₅	详情	详情
(III)	34691	(3aR,4R,5R,6aS)-4-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl acetate		C₂₃H₄₂O₅Si	详情	详情
(IV)	34692	(3aR,4R,5R,6aS)-4-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one		C₂₁H₄₀O₄Si	详情	详情
(V)	34693	(3aR,4R,5R,6aS)-4-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one		C₂₆H₄₈O₅Si	详情	详情
(VI)	34694	(3aR,4R,5R,6aS)-4-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol		C₂₆H₅₀O₅Si	详情	详情
(VII)	13616	(4-Carboxybutyl)triphenylphosphonium bromide	17814-85-6	C₂₃H₂₄BrO₂P	详情	详情
(VIII)	34695	(Z)-7-[(1R,2R,3R,5S)-2-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid		C₃₁H₅₈O₆Si	详情	详情
(IX)	34697	isopropyl (Z)-7-[(1R,2R,3R,5S)-2-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate		C₃₄H₆₄O₆Si	详情	详情
(X)	34698	isopropyl (Z)-7-[(1R,2R,3R,5R)-2-((3S)-3-[[tert-butyl(dimethyl)silyl]oxy]octyl)-5-formyl-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate		C₃₅H₆₄O₆Si	详情	详情

Extended Information