4-(chloromethyl)-2-methyl-1,3-thiazole -Drug Synthesis Database

【结构式】

【分子编号】40819

【品名】4-(chloromethyl)-2-methyl-1,3-thiazole

【CA登记号】

【分子式】C₅H₆ClNS

【分子量】147.62808

【元素组成】C 40.68% H 4.1% Cl 24.01% N 9.49% S 21.72%

与该中间体有关的原料药合成路线共 5 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1

该中间体在本合成路线中的序号：(VII)

The silylation of 3(S)-hydroxytetrahydrofuran-2-one (I) with TBDMS-Cl and imidazole gives the silyl ether (II), which is methylated with MeLi in THF yields the 3(S)-(TBDMSO)-5-hydroxy-2-pentanone (IV), through the hemiketal intermediate (III). Simultaneously, the cyclization of 1,3-dichloropropanone (V) with thioacetamide (VI) in refluxing ethanol affords 4-(chloromethyl)-2-methylthiazole (VII), which is treated with tributylphosphine to provide the phosphonium salt (VIII). The condensation of (VIII) with the ketone (IV) gives the unsaturated alcohol (IX), which is oxidized to the corresponding aldehyde (X) by means of oxalyl chloride in DMSO. The condensation of (X) with 2-phosphonopropionic acid triethyl ester (XI) by means of KHMDS gives the dienoic acid ethyl ester (XII), which is reduced with DIBAL in THF yielding the corresponding primary alcohol (XIII). The condensation of (XIII) with the chiral sulfone intermediate (XIV) by means of KHMDS and PPh3 affords the corresponding adduct (XV), which is desulfurized with Na/Hg in THF/methanol giving the silylated diol (XVI). The selective monodesilylation of (XVI) with CSA in methanol/dichloromethane yields the primary alcohol (XVII), which is oxidized with Dess Martin periodinane (DMP) to the aldehyde (XVIII). The condensation of (XVIII) with the intermediate chiral ketone (XIX) by means of LDA in THF affords the hydroxy ketone (XX).

参考文献中间体

合成目标

【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 .

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)	40815	(3S)-3-hydroxydihydro-2(3H)-furanone	19444-84-9	C₄H₆O₃	详情	详情
(II)	40816	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone		C₁₀H₂₀O₃Si	详情	详情
(III)	40817	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol		C₁₁H₂₄O₃Si	详情	详情
(IV)	40818	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone		C₁₁H₂₄O₃Si	详情	详情
(V)	63907	1,3-dichloroacetone		C₃H₄Cl₂O	详情	详情
(VI)	19170	ethanethioamide	62-55-5	C₂H₅NS	详情	详情
(VII)	40819	4-(chloromethyl)-2-methyl-1,3-thiazole		C₅H₆ClNS	详情	详情
(VIII)	40820	tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride		C₁₇H₃₃ClNPS	详情	详情
(IX)	40821	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol		C₁₆H₂₉NO₂SSi	详情	详情
(X)	40822	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal		C₁₆H₂₇NO₂SSi	详情	详情
(XI)	18816	ethyl 2-(diethoxyphosphoryl)propanoate	3699-66-9	C₉H₁₉O₅P	详情	详情
(XII)	40823	ethyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate		C₂₁H₃₅NO₃SSi	详情	详情
(XIII)	40824	(2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol		C₁₉H₃₃NO₂SSi	详情	详情
(XIV)	40825	tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone		C₁₇H₃₀O₃SSi	详情	详情
(XV)	40826	(1R,3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-1-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl phenyl sulfone; 4-[(1E,3S,5Z,8R,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-8-(phenylsulfonyl)-1,5-undecadienyl]-2-methyl-1,3-thiazole		C₃₆H₆₁NO₄S₂Si₂	详情	详情
(XVI)	40827	tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole		C₃₀H₅₇NO₂SSi₂	详情	详情
(XVII)	40828	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol		C₂₄H₄₃NO₂SSi	详情	详情
(XVIII)	40829	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal		C₂₄H₄₁NO₂SSi	详情	详情
(XIX)	40830	(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone		C₂₁H₄₆O₃Si₂	详情	详情
(XX)	40831	(7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one		C₄₅H₈₇NO₅SSi₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The intermediate phosphonium bromide (XVII) is obtained as follows: The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is converted into the unsaturated pyranoside (III). The reductive deoxygenation of (III) with Pd(OAc)2 and NaBH4 affords the acetate (IV), which is treated with NaOMe in methanol to afford the carbinol (V). The oxidation of (V) with oxalyl chloride in DMSO provides the carbaldehyde (VI), which is treated with Me-Mg-Br in THF to give the secondary alcohol (VII). The oxidation of (VII) with oxalyl chloride in DMSO yields the ketone (VIII), which is condensed with the phosphonate (IX) (obtained by reaction of 4-(chloromethyl)-2-methylthiazole (X) with triethyl phosphite (XI) at 165 C) by means of tBu-OK in THF to afford the vinyl-dihydropyran (XII). The opening of the dihydropyran ring of (XII) by means of HOAc in THF/water, followed by reduction of the intermediate aldehyde, provides the unsaturated diol (XIII). The regioselective bromination of (XIII) with CBr4 and PPh3 in acetonitrile gives the bromo derivative (XIV), which is silylated with Tbdms-OTf to yield the silyl ether derivative (XV). Finally, this compound is condensed with methylenetriphenylphosphorane (XVI) in THF to afford the target intermediate, the phosphonium bromide (XVII).

参考文献中间体

合成目标

【1】 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895.

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)	54335	(1aR,2S,3aR,6R,7aS,7bS)-2-methoxy-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxine; (1aR,2S,3aR,6R,7aS,7bS)-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxin-2-yl methyl ether	n/a	C₁₄H₁₆O₅	详情	详情
(II)	54336	(2R,4aR,6S,7S,8S,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol	n/a	C₁₅H₂₀O₅	详情	详情
(III)	54337	[(2R,3S,6S)-3-(acetyloxy)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]methyl acetate	n/a	C₁₂H₁₈O₆	详情	详情
(IV)	54338	[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]methyl acetate	n/a	C₁₀H₁₆O₄	详情	详情
(V)	54339	[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]methanol	n/a	C₈H₁₄O₃	详情	详情
(VI)	54340	(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde	n/a	C₈H₁₂O₃	详情	详情
(VII)	54341	(1R)-1-[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]-1-ethanol	n/a	C₉H₁₆O₃	详情	详情
(VIII)	54342	1-[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]-1-ethanone	n/a	C₉H₁₄O₃	详情	详情
(IX)	44442	diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate		C₉H₁₆NO₃PS	详情	详情
(X)	40819	4-(chloromethyl)-2-methyl-1,3-thiazole		C₅H₆ClNS	详情	详情
(XII)	54343	4-{(E)-2-[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]-1-propenyl}-2-methyl-1,3-thiazole; methyl (2S,6S)-3-methyl-6-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,6-dihydro-2H-pyran-2-yl ether	n/a	C₁₄H₁₉NO₂S	详情	详情
(XIII)	54344	(2Z,5S,6E)-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadiene-1,5-diol	n/a	C₁₃H₁₉NO₂S	详情	详情
(XIV)	54345	(1E,3S,5Z)-7-bromo-2,6-dimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol	n/a	C₁₃H₁₈BrNOS	详情	详情
(XV)	46147	4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether		C₁₉H₃₂BrNOSSi	详情	详情
(XVI)	27301	methylene(triphenyl)phosphorane		C₁₉H₁₇P	详情	详情
(XVII)	46148	[(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide		C₃₈H₄₉BrNOPSSi	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 intermediate phosphonate (X) has been obtained as follows. The cyclization of thioacetamide (IV) with ethyl 3-bromopiruvate (V) in ethanol gives 2-methylthiazole-4-carboxylic acid ethyl ester (VI), which is reduced by means of LiAlH4 in ethyl ether to yield the carbinol (VII). The bromination of (VII) with CBr4 and PPh3 in CCl4 affords the 4-bromomethyl-2-methylthiazole (VIII), which is finally condensed with triethyl phosphite (IX) to provide the target phosphonate intermediate (X). Alternatively, the cyclization of thioacetamide (IV) with 1,3-dichloroacetone (XI) gives 4-(chloromethyl)-2-methylthiazole (XII), which is condensed with triethyl phosphite (IX) to also provide the target phosphonate intermediate (X).

参考文献中间体

合成目标

【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	19170	ethanethioamide	62-55-5	C₂H₅NS	详情	详情
(V)	63904	propyl 3-bromo-2-oxopropanoate		C₆H₉BrO₃	详情	详情
(VI)	63905	propyl 2-methyl-1,3-thiazole-4-carboxylate		C₈H₁₁NO₂S	详情	详情
(VII)	63906	(2-methyl-1,3-thiazol-4-yl)methanol		C₅H₇NOS	详情	详情
(VIII)	63909	4-(bromomethyl)-2-methyl-1,3-thiazole		C₅H₆BrNS	详情	详情
(IX)	15487	triethyl phosphite	122-52-1	C₆H₁₅O₃P	详情	详情
(X)	63908	dipropyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate		C₁₁H₂₀NO₃PS	详情	详情
(XI)	63907	1,3-dichloroacetone		C₃H₄Cl₂O	详情	详情
(XII)	40819	4-(chloromethyl)-2-methyl-1,3-thiazole		C₅H₆ClNS	详情	详情

合成路线4

该中间体在本合成路线中的序号：(X)

The intermediate phosphonium bromide (XVII) is obtained as follows: The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is converted into the unsaturated pyranoside (III). The reductive deoxygenation of (III) with Pd(OAc)2 and NaBH4 affords the acetate (IV), which is treated with NaOMe in methanol to afford the carbinol (V). The oxidation of (V) with oxalyl chloride in DMSO provides the carbaldehyde (VI), which is treated with Me-Mg-Br in THF to give the secondary alcohol (VII). The oxidation of (VII) with oxalyl chloride in DMSO yields the ketone (VIII), which is condensed with the phosphonate (IX) (obtained by reaction of 4-(chloromethyl)-2-methylthiazole (X) with triethyl phosphite (XI) at 165 C) by means of tBu-OK in THF to afford the vinyl-dihydropyran (XII). The opening of the dihydropyran ring of (XII) by means of AcOH in THF/water, followed by reduction of the intermediate aldehyde, provides the unsaturated diol (XIII). The regioselective bromination of (XIII) with CBr4 and PPh3 in acetonitrile gives the bromo derivative (XIV), which is silylated with Tbdms-OTf to yield the silyl ether derivative (XV). Finally, this compound is condensed with methylenetriphenylphosphorane (XVI) in THF to afford the target intermediate, the phosphonium bromide (XVII).

参考文献中间体

合成目标

【1】 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895.

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)	54335	(1aR,2S,3aR,6R,7aS,7bS)-2-methoxy-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxine; (1aR,2S,3aR,6R,7aS,7bS)-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxin-2-yl methyl ether	n/a	C₁₄H₁₆O₅	详情	详情
(II)	54336	(2R,4aR,6S,7S,8S,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol	n/a	C₁₅H₂₀O₅	详情	详情
(III)	54337	[(2R,3S,6S)-3-(acetyloxy)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]methyl acetate	n/a	C₁₂H₁₈O₆	详情	详情
(IV)	54338	[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]methyl acetate	n/a	C₁₀H₁₆O₄	详情	详情
(V)	54339	[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]methanol	n/a	C₈H₁₄O₃	详情	详情
(VI)	54340	(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde	n/a	C₈H₁₂O₃	详情	详情
(VII)	54341	(1R)-1-[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]-1-ethanol	n/a	C₉H₁₆O₃	详情	详情
(VIII)	54342	1-[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]-1-ethanone	n/a	C₉H₁₄O₃	详情	详情
(IX)	44442	diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate		C₉H₁₆NO₃PS	详情	详情
(X)	40819	4-(chloromethyl)-2-methyl-1,3-thiazole		C₅H₆ClNS	详情	详情
(XII)	54343	4-{(E)-2-[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]-1-propenyl}-2-methyl-1,3-thiazole; methyl (2S,6S)-3-methyl-6-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,6-dihydro-2H-pyran-2-yl ether	n/a	C₁₄H₁₉NO₂S	详情	详情
(XIII)	54344	(2Z,5S,6E)-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadiene-1,5-diol	n/a	C₁₃H₁₉NO₂S	详情	详情
(XIV)	54345	(1E,3S,5Z)-7-bromo-2,6-dimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol	n/a	C₁₃H₁₈BrNOS	详情	详情
(XV)	46147	4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether		C₁₉H₃₂BrNOSSi	详情	详情
(XVI)	27301	methylene(triphenyl)phosphorane		C₁₉H₁₇P	详情	详情
(XVII)	46148	[(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide		C₃₈H₄₉BrNOPSSi	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XII)

参考文献中间体

合成目标

【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	19170	ethanethioamide	62-55-5	C₂H₅NS	详情	详情
(V)	63904	propyl 3-bromo-2-oxopropanoate		C₆H₉BrO₃	详情	详情
(VI)	63905	propyl 2-methyl-1,3-thiazole-4-carboxylate		C₈H₁₁NO₂S	详情	详情
(VII)	63906	(2-methyl-1,3-thiazol-4-yl)methanol		C₅H₇NOS	详情	详情
(VIII)	63909	4-(bromomethyl)-2-methyl-1,3-thiazole		C₅H₆BrNS	详情	详情
(IX)	15487	triethyl phosphite	122-52-1	C₆H₁₅O₃P	详情	详情
(X)	63908	dipropyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate		C₁₁H₂₀NO₃PS	详情	详情
(XI)	63907	1,3-dichloroacetone		C₃H₄Cl₂O	详情	详情
(XII)	40819	4-(chloromethyl)-2-methyl-1,3-thiazole		C₅H₆ClNS	详情	详情

Extended Information