3,4-difluorophenol -Drug Synthesis Database

【结构式】

【分子编号】16739

【品名】3,4-difluorophenol

【CA登记号】2713-33-9

【分子式】C₆H₄F₂O

【分子量】130.0939664

【元素组成】C 55.4% H 3.1% F 29.21% O 12.3%

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：(I)

The reaction of 3,4-difluorophenol (I) with (S)-oxiranylmethyl p-toluenesulfonate ester (II) by means of NaH in DMF gives (S)-(3,4-difluorophenoxymethyl)oxirane (III), which is then condensed with N-(2-benzothiazolyl)-N-methyl-N-(4-piperidyl)amine (IV) by means of Na2CO3 in refluxing isopropanol or butanol/water.

参考文献中间体

合成目标

【1】 Graul, A.; Castañer, J.; Lubeluzole. Drugs Fut 1997, 22, 6, 629.
【2】 Stokbroekx, R.A.; Grauwels, G.A.J. (Janssen Pharmaceutica NV); 4-[(2-Benzothiazolyl)methylamino]-alpha-[(3,4-difluorophenoxy)methyl]-1-piperidineethanol. EP 0501552; EP 0573473; JP 1994505012; US 5434168; WO 9214731 .

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)	16739	3,4-difluorophenol	2713-33-9	C₆H₄F₂O	详情	详情
(II)	16740	(2S)-(+)-Glycidyl tosylate; (2S)oxiranylmethyl 4-methylbenzenesulfonate	70987-78-9	C₁₀H₁₂O₄S	详情	详情
(III)	16741	(2S)-2-[(3,4-difluorophenoxy)methyl]oxirane; 3,4-difluorophenyl (2S)oxiranylmethyl ether		C₉H₈F₂O₂	详情	详情
(IV)	16742	N-(1,3-benzothiazol-2-yl)-N-methyl-N-(4-piperidinyl)amine; N-methyl-N-(4-piperidinyl)-1,3-benzothiazol-2-amine		C₁₃H₁₇N₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

A new synthesis of lubeluzole has been reported: The condensation of 3,4-difluorophenol (I) with racemic glycidol (II) by means of PPh3 and DEAD in THF gives 2-(3,4-difluorophenoxymethyl)oxirane (III), which is opened by means of Li2CuCl4 in THF yielding racemic 1-chloro-3-(3,4-difluorophenoxy)-2-propanol (IV). Racemic compound (IV) is kinetically resolved by transesterification with vinyl butyrate using Rhizomucor miehei lipase (RML) as catalyst, providing a mixture of (R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol (V) and the (S)-butyrate (VI). This mixture is easily separated by column chromatography. Finally, the (R)-alcohol (V) is condensed with N-methyl-N-(piperidin-4-yl)benzothiazol-2-amine (VII) by means of NaHCO3 in hot DMF. The key intermediate N-methyl-N-(piperidin-4-yl)benzothiazol-2-amine (VII) has been obtained as follows: Reductive amination of 4-oxopiperidine-1-carboxylic acid ethyl ester (VIII) with methylamine and borane/pyridine complex in methanol gives 4-(methylamino)piperidine-1-carboxylic acid ethyl ester (IX), which is condensed with isothiocyanatobenzene (X) in isopropyl ether to yield the thiourea (XI). Cyclization of compound (XI) by means of Br2 in refluxing CCl4 affords the benzothiazole derivative (V), which is finally decarboxylated by means of HBr in refluxing water, followed by treatment with NaOH.

参考文献中间体

合成目标

【1】 Liu, H.L.; Helgehoff, B.; Berg, T.C.; Anthonsen, T.; Synthesis of the antistroke drug lubeluzole and its enantiomer. Lipase-catalyzed resolution of chiral building block. Chirality 2001, 13, 3, 135.

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)	16739	3,4-difluorophenol	2713-33-9	C₆H₄F₂O	详情	详情
(II)	29648	2-oxiranylmethanol	556-52-5	C₃H₆O₂	详情	详情
(III)	47537	2-[(3,4-difluorophenoxy)methyl]oxirane; 3,4-difluorophenyl 2-oxiranylmethyl ether		C₉H₈F₂O₂	详情	详情
(IV)	47534	1-chloro-3-(3,4-difluorophenoxy)-2-propanol		C₉H₉ClF₂O₂	详情	详情
(V)	47535	(1S)-2-chloro-1-[(3,4-difluorophenoxy)methyl]ethyl butyrate		C₁₃H₁₅ClF₂O₃	详情	详情
(VI)	47536	(2R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol		C₉H₉ClF₂O₂	详情	详情
(VII)	13486	Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone	29976-53-2	C₈H₁₃NO₃	详情	详情
(VIII)	22145	ethyl 4-(methylamino)-1-piperidinecarboxylate		C₉H₁₈N₂O₂	详情	详情
(IX)	22146	1-isothiocyanatobenzene; phenyl isothiocyanate	103-72-0	C₇H₅NS	详情	详情
(X)	22147	ethyl 4-[(anilinocarbothioyl)(methyl)amino]-1-piperidinecarboxylate		C₁₆H₂₃N₃O₂S	详情	详情
(XI)	22148	ethyl 4-[1,3-benzothiazol-2-yl(methyl)amino]-1-piperidinecarboxylate		C₁₆H₂₁N₃O₂S	详情	详情
(XII)	16742	N-(1,3-benzothiazol-2-yl)-N-methyl-N-(4-piperidinyl)amine; N-methyl-N-(4-piperidinyl)-1,3-benzothiazol-2-amine		C₁₃H₁₇N₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

Alkylation of 2-(S)-tert-butyl-5-(S)-methyl-1,3-dioxolan-4-one (I) with 1,1,1-trifluoro-2-iodoethane (II) in the presence of LDA in THF at -72 C provided trifluoroethyl compound (III). Condensation of (III) with 4-(methylthio)phenyllithium (IV), prepared from 4-bromothioanisole and BuLi, gave (V), which was hydrolyzed with p-toluenesulfonic acid in boiling water to afford ketone (VI). Subsequent oxidation of sulfide group with KHSO5 (Oxone(R)) in the presence of Oct3NMeCl (Aliquat 336(R)) produced sulfone (VII). Esterification of (VII) with chloroacetic acid using 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (CMC) as the condensing agent provided chloroacetate (VIII). Finally, condensation with 3,4-difluorophenol (IX) in the presence of DBU in acetonitrile gave the intermediate ether (X), which cyclized to produce the target furanone.

参考文献中间体

合成目标

【1】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 .

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)	18805	(2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolan-4-one		C₈H₁₄O₃	详情	详情
(II)	18806	1,1,1-trifluoro-2-iodoethane	353-83-3	C₂H₂F₃I	详情	详情
(III)	18807	(2S,5R)-2-(tert-butyl)-5-methyl-5-(2,2,2-trifluoroethyl)-1,3-dioxolan-4-one		C₁₀H₁₅F₃O₃	详情	详情
(IV)	18808	[4-(methylsulfanyl)phenyl]lithium		C₇H₇LiS	详情	详情
(V)	18809	(2S,5R)-2-(tert-butyl)-5-methyl-4-[4-(methylsulfanyl)phenyl]-5-(2,2,2-trifluoroethyl)-1,3-dioxolan-4-ol		C₁₇H₂₃F₃O₃S	详情	详情
(VI)	18810	(2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-butanone		C₁₂H₁₃F₃O₂S	详情	详情
(VII)	18811	(2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-butanone		C₁₂H₁₃F₃O₄S	详情	详情
(VIII)	18812	(1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-chloroacetate		C₁₄H₁₄ClF₃O₅S	详情	详情
(IX)	16739	3,4-difluorophenol	2713-33-9	C₆H₄F₂O	详情	详情
(X)	18814	(1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-(3,4-difluorophenoxy)acetate		C₂₀H₁₇F₅O₆S	详情	详情

Extended Information