2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol -Drug Synthesis Database

【结构式】

【分子编号】16338

【品名】2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol

【CA登记号】

【分子式】C₁₂H₁₄F₂O₂

【分子量】228.2387664

【元素组成】C 63.15% H 6.18% F 16.65% O 14.02%

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：(V)

An alternative synthesis of the key intermediate (II) in the synthesis of Sch-51048 published in the original monograph has been reported:The reaction of 2-(2,4-difluorophenyl)allyl alcohol (I) with PBr3 in dichloromethane gives the corresponding allyl bromide (II), which is condensed with sodium diethyl malonate (III), yielding the diester (IV). The reduction of (VI) with NaBH4 in ethanol affords the diol (V), which is submitted to an asymmetric acetylation with vinyl acetate catalyzed by the enzyme Novo SP435, giving the chiral monoester (VI). The cyclization of (VI) with I2 and NaHCO3 in acetonitrile affords the tetrahydrofuran derivative (VII), which is allowed to react with the sodium salt of 1,2,4-triazole (VIII) in DMF, yielding the corresponding condensation product (IX). Hydrolysis of (IX) with NaOH in methanol gives the alcohol (X), which is tosylated with tosyl chloride in pyridine.

参考文献中间体

合成目标

【1】 Puar, M.S.; Girijavallabhan, V.M.; Saksena, A.K.; Lovey, R.G.; Ganguly, A.K.; Pike, R.E.; Wang, H.Y.; Zaks, A.; Morgan, B.; Highly stereoselective access to novel 2,2,4-trisubstituted tetrahydrofurans by halocyclization: Practical chemoenzymatic synthesis of SCH 51048, a broad-spectrum orally active antifungal agent. Tetrahedron Lett 1995, 36, 11, 1787.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	24543	vinyl acetate	108-05-4	C₄H₆O₂	详情	详情
(I)	15491	2-(2,4-difluorophenyl)-2-propen-1-ol		C₉H₈F₂O	详情	详情
(II)	16335	1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene		C₉H₇BrF₂	详情	详情
(III)	16336	[2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium		C₇H₁₁NaO₄	详情	详情
(IV)	16337	diethyl 2-[2-(2,4-difluorophenyl)-2-propenyl]malonate		C₁₆H₁₈F₂O₄	详情	详情
(V)	16338	2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol		C₁₂H₁₄F₂O₂	详情	详情
(VI)	16339	(2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenyl acetate		C₁₄H₁₆F₂O₃	详情	详情
(VII)	16340	[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl acetate		C₁₄H₁₅F₂IO₃	详情	详情
(VIII)	16341	1H-1,2,4-triazol-1-ylsodium		C₂H₂N₃Na	详情	详情
(IX)	16342	[(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl acetate		C₁₆H₁₇F₂N₃O₃	详情	详情
(X)	16343	[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol		C₁₄H₁₅F₂N₃O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXVIII)

2) The 2-(2,4-difluorophenyl)-2-propen-1-ol (IV) is converted into the corresponding propenyl bromide (XXVI), which is condensed with diethyl malonate (X) to afford the malonyl derivative (XXVII). The reduction of (XXVII) with NaBH4 and LiCl yields the 1,3-propanediol derivative (XXVIII), which is enantioselectively acetylated with vinyl acetate and Novozyme 435 in acetonitrile yielding the isomeric (S)-monoacetate (XXIX). The cyclization of (XXIX) with iodine and NaHCO3 in acetonitrile affords (5R-cis)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-methanol acetate ester (XXX), which is condensed with sodium 1,2,4-triazole (XXXI) to give (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol acetate ester (XXXII). The hydrolysis of (XXXII) with NaOH yields the corresponding methanol (XXXIII), which is finally tosylated to the tosyl ester (XIV), already obtained previously.

参考文献中间体

合成目标

【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Bennett, F.; Pike, R.E.; Wang, H.; Pinto, P.; Liu, Y.T.; Patel, N.; Ganguly, A.K.; Novel analogs of SCH 51048: Synthesis and preliminary structure activity relationships. 35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995, Abst F83..
【2】 Fromtling, R.A.; Castañer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	24543	vinyl acetate	108-05-4	C₄H₆O₂	详情	详情
(IV)	15491	2-(2,4-difluorophenyl)-2-propen-1-ol		C₉H₈F₂O	详情	详情
(X)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(XXVI)	16335	1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene		C₉H₇BrF₂	详情	详情
(XXVII)	16337	diethyl 2-[2-(2,4-difluorophenyl)-2-propenyl]malonate		C₁₆H₁₈F₂O₄	详情	详情
(XXVIII)	16338	2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol		C₁₂H₁₄F₂O₂	详情	详情
(XXIX)	16339	(2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenyl acetate		C₁₄H₁₆F₂O₃	详情	详情
(XXX)	16340	[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl acetate		C₁₄H₁₅F₂IO₃	详情	详情
(XXXI)	13104	1,2,4-Triazole, sodium derivative	41253-21-8	C₂H₂N₃Na	详情	详情
(XXXII)	16342	[(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl acetate		C₁₆H₁₇F₂N₃O₃	详情	详情
(XXXIII)	16343	[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol		C₁₄H₁₅F₂N₃O₂	详情	详情

Extended Information