2,6-Difluorophenylamine; 2,6-Difluoroaniline -Drug Synthesis Database

【结构式】

【分子编号】17933

【品名】2,6-Difluorophenylamine; 2,6-Difluoroaniline

【CA登记号】5509-65-9

【分子式】C₆H₅F₂N

【分子量】129.1092464

【元素组成】C 55.82% H 3.9% F 29.43% N 10.85%

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：(X)

Conjugated addition of 2-nitroaniline (I) to acrylonitrile (II) in the presence of Triton B in dioxane yielded propionitrile (III), which was hydrogenated to the phenylenediamine (IV). Treatment of ethyl cyanoacetate (V) with a cold saturated solution of HCl in absolute ethanol gave ethyl ethoxycarbonylacetimidate hydrochloride (VI). Reaction of this acetimidate (VI) with phenylenediamine (IV) in refluxing ethanol afforded the benzimidazole (VII), which was converted to the diester (VIII) on treatment with ethanolic HCl. Dieckmann condensation of diester (VIII) in the presence of sodium ethoxide furnished the tricyclic ketoester (IX), which was finally condensed with 2,6-difluoroaniline (X) in refluxing xilene to afford the target carboxamide.

参考文献中间体

合成目标

【1】 Maryanoff, B.E.; et al.; Potential anxiolytic agents. Pyrido[1, 2-a]benzimidazoles: A new structural class of ligands for the benzodiazepine binding site on GABA-A receptors. J Med Chem 1995, 38, 1, 16.
【2】 Maryanoff, B.E.; McComsey, D.F.; Winston, H. (Ortho-McNeil Pharmaceutical, Inc.); 3-Oxo-pyrido(1,2-a)benzimidazole-4-carboxyl and 4-oxo-azepino(1,2-a)benzimidazole-5-carboxyl derivs. useful in treating central nervous system disorders. EP 0656002; WO 9404532 .

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)	11608	o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine	88-74-4	C₆H₆N₂O₂	详情	详情
(II)	10847	Acrylonitrile	107-13-1	C₃H₃N	详情	详情
(III)	17926	3-(2-nitroanilino)propanenitrile		C₉H₉N₃O₂	详情	详情
(IV)	17927	3-(2-aminoanilino)propanenitrile		C₉H₁₁N₃	详情	详情
(V)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(VI)	17929	ethyl 3-ethoxy-3-iminopropanoate	2318-25-4	C₇H₁₃NO₃	详情	详情
(VII)	17930	ethyl 2-[1-(2-cyanoethyl)-1H-benzimidazol-2-yl]acetate		C₁₄H₁₅N₃O₂	详情	详情
(VIII)	17931	ethyl 3-[2-(2-ethoxy-2-oxoethyl)-1H-benzimidazol-1-yl]propanoate		C₁₆H₂₀N₂O₄	详情	详情
(IX)	17932	ethyl 3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxylate		C₁₄H₁₄N₂O₃	详情	详情
(X)	17933	2,6-Difluorophenylamine; 2,6-Difluoroaniline	5509-65-9	C₆H₅F₂N	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Addition of acrylonitrile (II) to 3,4-difluoro-2-nitroaniline (I) gave the anilinopropionitrile (III). Subsequent hydrogenation of the nitro group of (III) over Pd/C led to the phenylenediamine (IV), which was condensed with carbethoxyacetimidate-HCl (V) to produce the benzimidazole (VI). After conversion of the nitrile group of (VI) to ester (VII) with ethanolic HCl, Dieckmann condensation using NaOEt furnished the cyclic ketoester (VIII). Finally, reaction of (VIII) with 2,6-difluoroaniline (IX) in xylene yielded the target carboxamide.

参考文献中间体

合成目标

【1】 Maryanoff, B.E.; et al.; Potential anxiolytic agents. Pyrido[1, 2-a]benzimidazoles: A new structural class of ligands for the benzodiazepine binding site on GABA-A receptors. J Med Chem 1995, 38, 1, 16.
【2】 Nortey, S.O.; Sanfilippo, P.J.; Dubinsky, B.; Maryanoff, B.E.; McComsey, D.F.; Reitz, A.B.; Shank, R.P.; McNally, J.J.; Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles. Bioorg Med Chem Lett 1999, 9, 11, 1547.

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)	31347	3,4-difluoro-2-nitrophenylamine; 3,4-difluoro-2-nitroaniline		C₆H₄F₂N₂O₂	详情	详情
(II)	10847	Acrylonitrile	107-13-1	C₃H₃N	详情	详情
(III)	31348	3-(3,4-difluoro-2-nitroanilino)propanenitrile		C₉H₇F₂N₃O₂	详情	详情
(IV)	31349	3-(2-amino-3,4-difluoroanilino)propanenitrile		C₉H₉F₂N₃	详情	详情
(V)	17929	ethyl 3-ethoxy-3-iminopropanoate	2318-25-4	C₇H₁₃NO₃	详情	详情
(VI)	31350	ethyl 2-[1-(2-cyanoethyl)-4,5-difluoro-1H-benzimidazol-2-yl]acetate		C₁₄H₁₃F₂N₃O₂	详情	详情
(VII)	31351	ethyl 3-[2-(2-ethoxy-2-oxoethyl)-4,5-difluoro-1H-benzimidazol-1-yl]propanoate		C₁₆H₁₈F₂N₂O₄	详情	详情
(VIII)	31352	ethyl 6,7-difluoro-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxylate		C₁₄H₁₂F₂N₂O₃	详情	详情
(IX)	17933	2,6-Difluorophenylamine; 2,6-Difluoroaniline	5509-65-9	C₆H₅F₂N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

In an improved procedure, conjugate addition of divinyl sulfone (II) to 2,6-difluoroaniline (I) in the presence of AlCl3 leads to the N-aryl thiomorpholine sulfone (III). Aromatic nitration of (III) with fuming HNO3 in AcOH affords (IV). The nitroaryl derivative (IV) is then reduced to aniline (V) by catalytic hydrogenation over Raney Ni. Condensation of aniline (V) with isobutyl chloroformate furnishes carbamate (VI). This is finally cyclized with (S)-N-(2-acetoxy-3-chloropropyl)acetamide (VII) to generate the target oxazolidinone compound.

参考文献中间体

合成目标

【1】 Greene, M.L.; et al.; Synthetic studies leading to the identification of PNU-288034, a potent new oxazolidinone antibacterial agent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1333.
【2】 Zurenko, G.E.; Barbachyn, M.R. (Pharmacia Corp.); A thiazine oxazolidinone. EP 1294717; US 2002156072; US 6605609; WO 0198297 .

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)	17933	2,6-Difluorophenylamine; 2,6-Difluoroaniline	5509-65-9	C₆H₅F₂N	详情	详情
(II)	35813	divinyl sulfone; dioxo(divinyl)-lambda(6)-sulfane	77-77-0	C₄H₆O₂S	详情	详情
(III)	62754	4-(2,6-difluorophenyl)-1lambda~6~,4-thiazinane-1,1-dione		C₁₀H₁₁F₂NO₂S	详情	详情
(IV)	62755	4-(2,6-difluoro-4-nitrophenyl)-1lambda~6~,4-thiazinane-1,1-dione		C₁₀H₁₀F₂N₂O₄S	详情	详情
(V)	62756	4-(4-amino-2,6-difluorophenyl)-1lambda~6~,4-thiazinane-1,1-dione		C₁₀H₁₂F₂N₂O₂S	详情	详情
(VI)	62757	isobutyl 4-(1,1-dioxo-1lambda~6~,4-thiazinan-4-yl)-3,5-difluorophenylcarbamate		C₁₅H₂₀F₂N₂O₄S	详情	详情
(VII)	61915	(1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate		C₇H₁₂ClNO₃	详情	详情

Extended Information