4-bromo-2,6-dimethylphenol -Drug Synthesis Database

【结构式】

【分子编号】31142

【品名】4-bromo-2,6-dimethylphenol

【CA登记号】2374-05-2

【分子式】C₈H₉BrO

【分子量】201.06286

【元素组成】C 47.79% H 4.51% Br 39.74% O 7.96%

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：(VI)

The condensation of 3,5-dimethylisoxazole (I) with ethylene oxide (II) by means of butyllithium in THF gives 3-(3-methylisoxazol-5-yl)-1-propanol (III), which by reaction with refluxing SOCl2 yields the corresponding propyl chloride (IV). The condensation of (IV) with 4-hydroxy-3,5-dimethylbenzonitrile (V) [obtained by reaction of 4-bromo-2,6-dimethylphenol (VI) with Cu2CN2 in refluxing DMF] by means of K2CO3 and KI in hot N-methylpyrrolidone affords 3,5-dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]benzonitrile (VII). The reaction of (VII) with hydroxylamine (VIII) and K2CO3 in refluxing ethanol gives the corresponding benzohydroxamic acid (IX), which is finally cyclized with refluxing trifluoroacetic anhydride and pyridine.

参考文献中间体

合成目标

【1】 Diana, G.D.; Rudewicz, P.; Pevear, D.C.; et al.; Picornavirus inhibitors: Trifluoromethyl substitution provides a global protective effect against hepatic metabolism. J Med Chem 1995, 38, 1355-71.
【2】 Fromtling, R.A.; Castañer, J.; VP-63843. Drugs Fut 1997, 22, 1, 40.
【3】 Diana, G.D.; Nitz, T.J. (Sanofi-Synthelabo); 1,2,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents. EP 0566199; JP 1994049066; US 5349068 .
【4】 Diana, G.D.; Nitz, T.J. (Sanofi-Synthelabo); 1,2,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents. US 5464848 .

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)	31138	3,5-dimethylisoxazole	300-87-8	C₅H₇NO	详情	详情
(II)	10393	Oxirane; Ethylene oxide	75-21-8	C₂H₄O	详情	详情
(III)	31139	3-(3-methyl-5-isoxazolyl)-1-propanol		C₇H₁₁NO₂	详情	详情
(IV)	31140	5-(3-chloropropyl)-3-methylisoxazole	130800-76-9	C₇H₁₀ClNO	详情	详情
(V)	31141	4-Hydroxy-3,5-dimethylbenzonitrile; 2,6-Dimethyl-4-hydroxybenzonitrile	4198-90-7	C₉H₉NO	详情	详情
(VI)	31142	4-bromo-2,6-dimethylphenol	2374-05-2	C₈H₉BrO	详情	详情
(VII)	31143	3,5-dimethyl-4-[3-(3-methyl-5-isoxazolyl)propoxy]benzonitrile		C₁₆H₁₈N₂O₂	详情	详情
(IX)	31144	N-hydroxy-3,5-dimethyl-4-[3-(3-methyl-5-isoxazolyl)propoxy]benzenecarboximidamide		C₁₆H₂₁N₃O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Racemic ethyl 3-piperidinecarboxylate (Ia, Ib) was resolved with D-(-)-tartaric acid in EtOH to afford the (S)-piperidine tartrate salt (II). After protection of (II) as the N-Boc derivative (III) by treatment with di-tert-butyl dicarbonate and NaOH, reduction of the carboxylate group of (III) by means of LiBH4 provided alcohol (IV). Subsequent coupling of (IV) with 4-bromo-2,6-dimethylphenol (V) under Mitsunobu conditions provided ether (VI). The N-Boc protecting group of (VI) was then cleaved employing trifluoroacetic acid to give piperidine (VII). Finally, Eschweiler-Clarke methylation using formaldehyde and formic acid furnished the corresponding N-methyl piperidine, which was isolated after conversion to the hydrochloride salt.

参考文献中间体

合成目标

【1】 Kojima, N.; Nishino, C. (Shiseido Co. Ltd.); Benzamide deriv., anti-ulcer drug, and antibacterial drug. EP 0869124; JP 1998279570; US 5891890 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Ib)	12453	ethyl (3R)hexahydro-3-pyridinecarboxylate		C₈H₁₅NO₂	详情	详情
(Ia),(II)	35224	ethyl (3S)-3-piperidinecarboxylate		C₈H₁₅NO₂	详情	详情
(III)	35220	1-(tert-butyl) 3-ethyl (3S)-1,3-piperidinedicarboxylate		C₁₃H₂₃NO₄	详情	详情
(IV)	35221	tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate		C₁₁H₂₁NO₃	详情	详情
(V)	31142	4-bromo-2,6-dimethylphenol	2374-05-2	C₈H₉BrO	详情	详情
(VI)	35222	tert-butyl (3S)-3-[(4-bromo-2,6-dimethylphenoxy)methyl]-1-piperidinecarboxylate		C₁₉H₂₈BrNO₃	详情	详情
(VII)	35223	(3S)-3-[(4-bromo-2,6-dimethylphenoxy)methyl]piperidine; 4-bromo-2,6-dimethylphenyl (3S)piperidinylmethyl ether		C₁₄H₂₀BrNO	详情	详情

Extended Information