2,3-dimethylphenol -Drug Synthesis Database

【结构式】

【分子编号】40074

【品名】2,3-dimethylphenol

【CA登记号】526-75-0

【分子式】C₈H₁₀O

【分子量】122.1668

【元素组成】C 78.65% H 8.25% O 13.1%

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：

Reaction of the N-carbobenzyloxy-protected tetrahydropyridine derivative (I) with m-chloroperbenzoic acid (MCPBA) in ethylene chloride gives the stable oily epoxide (II), which, upon treatment with 2,3-dimethyphenol in acetonitrile in the presence of aqueous NaOH, affords the crystalline trans-3 hydroxy-4-phenoxy derivative (III). Oxidation of this aicohol to the corresponding ketone (IV) is best achieved by means of DMSO reagents, in particular DMSO and pyridine-SO3 adduct. Treatment of the ketone (IV) with potassium tri-sec-butylborohydride (K-Selectride(R)) in THF yields the cis-3-hydroxy-4-phenoxy derivative (V) in a highly stereoselective reaction. Hydrogenation of (V) with H2 over Pd/C in ethanol and subsequent salt formation with aqueous H2SO4 leads to racemic, diastereomerically pure CGP-l5210 G.

参考文献中间体

合成目标

【1】 Paioni, R.; et al.; CGP 15 210 G, an unusual inhibitor of serotonin (5-HT) uptake. VIIIth Intl Symp Med Chem (Aug 27-31, Uppsala) 1985, 2, 130.
【2】 Paioni, R. (Novartis AG); Derivs. of perhydro-aza-heterocycles. DE 2738477; US 4160837 .
【3】 Waldmeier, P.C.; Paioni, R.; Delini-Stula, A.; Ifoxetine sulfate. Drugs Fut 1987, 12, 2, 126.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40074	2,3-dimethylphenol	526-75-0	C₈H₁₀O	详情	详情
(I)	22854	benzyl 3,6-dihydro-1(2H)-pyridinecarboxylate		C₁₃H₁₅NO₂	详情	详情
(II)	22855	benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate		C₁₃H₁₅NO₃	详情	详情
(III)	22856	benzyl (3R,4R)-4-(2,3-dimethylphenoxy)-3-hydroxy-1-piperidinecarboxylate		C₂₁H₂₅NO₄	详情	详情
(IV)	22857	benzyl (4R)-4-(2,3-dimethylphenoxy)-3-oxo-1-piperidinecarboxylate		C₂₁H₂₃NO₄	详情	详情
(V)	22858	benzyl (3S,4R)-4-(2,3-dimethylphenoxy)-3-hydroxy-1-piperidinecarboxylate		C₂₁H₂₅NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

It can be prepared in two different ways: 1) The reaction of 1-chloro-2,3-propylene oxide (I) with tert-butylamine (II) in ether yields 1-chloro-3-tert-butylamino-2-propanol (III), which is condensed with 2,3-xylenol (IV) by means of KOH in ether-water. 2) By heating a mixture of 1-tert-butyl-3-azetidinol (V) and 2,3-xylenol (IV) at 155 C with KOH.

参考文献中间体

合成目标

【1】 Suzuki, Y.; et al.; JP 45029294 .
【2】 Tsukamoto, K.; et al.; JP 46028534 .
【3】 Castaner, J.; Weetman, D.F.; D-32. Drugs Fut 1977, 2, 2, 91.

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)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(II)	17895	2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine	75-64-9	C₄H₁₁N	详情	详情
(III)	31720	1-(tert-butylamino)-3-chloro-2-propanol		C₇H₁₆ClNO	详情	详情
(IV)	40074	2,3-dimethylphenol	526-75-0	C₈H₁₀O	详情	详情
(V)	40075	1-(tert-butyl)-3-azetidinol	13156-04-2	C₇H₁₅NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The condensation of 2,3-dimethylphenol (I) with 3-bromoanisole (II) by means of K2CO3 and CuO in pyridine gives the diaryl ether (III), which is demethylated by means of HBr in refluxing acetic acid to yield the phenol (IV). The condensation of (IV) with 4,4,4-trifluorobutylsulfonyl chloride (V) by means of t-BuOK in THF affords the sulfonate (VI), which is brominated by means of NBS in refluxing CCl4 to provide the bis(bromomethyl)compound (VII). The cyclization of (VII) with dimethyl malonate (VIII) by means of K2CO3 in refluxing butanone furnishes the indane-dicarboxylate (IX), which is hydrolyzed and monodecarboxylated by means of HBr in refluxing acetic acid/water to give the indane-carboxylic acid (X). The reduction of the CO2H group of (X) by means of BH3/Me2S in THF yields the racemic hydroxymethyl derivative (XI), which is finally submitted to optical resolution by means of chiral preparative HPLC over Chiracel OD to provide the target (R)-enantiomer.

参考文献中间体

合成目标

【1】 Dressel, J.; Matzke, M.; Mittendorf, J.; De Vry, J.-M.V.; Mauler, F.; Friedl, A.; Horvath, E.; Keldenich, J.; Franz, J.; Spreyer, P.; Vöhringer, V.; Rock, M.-H.; Schumacher, J. (Bayer AG); Novel aryl sulphonamide amino acid esters and analogues. CA 2341028; DE 19837627; EP 1105371; US 6545050; WO 0010968 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	60555	4,4,4-trifluorobutyl methanesulfonate		C₅H₉F₃O₃S	详情	详情
(A)	60556	4,4,4-trifluoro-1-butanol		C₄H₇F₃O	详情	详情
(I)	40074	2,3-dimethylphenol	526-75-0	C₈H₁₀O	详情	详情
(II)	35983	m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether	2398-37-0	C₇H₇BrO	详情	详情
(III)	60552	3-(2,3-dimethylphenoxy)phenyl methyl ether; 1-(3-methoxyphenoxy)-2,3-dimethylbenzene		C₁₅H₁₆O₂	详情	详情
(IV)	60553	3-(2,3-dimethylphenoxy)phenol		C₁₄H₁₄O₂	详情	详情
(V)	26779	1-butanesulfonyl chloride	2386-60-9	C₄H₉ClO₂S	详情	详情
(VI)	60557	3-(2,3-dimethylphenoxy)phenyl 4,4,4-trifluoro-1-butanesulfonate		C₁₈H₁₉F₃O₄S	详情	详情
(VII)	60558	3-[2,3-bis(bromomethyl)phenoxy]phenyl 4,4,4-trifluoro-1-butanesulfonate		C₁₈H₁₇Br₂F₃O₄S	详情	详情
(VIII)	19373	dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester	108-59-8	C₅H₈O₄	详情	详情
(IX)	60559	dimethyl 4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-1,3-dihydro-2H-indene-2,2-dicarboxylate		C₂₃H₂₃F₃O₈S	详情	详情
(X)	60560	4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-2-indanecarboxylic acid		C₂₀H₁₉F₃O₆S	详情	详情
(XI)	60551	3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenyl 4,4,4-trifluoro-1-butanesulfonate		C₂₀H₂₁F₃O₅S	详情	详情
(C)	60554	4,4,4-trifluoro-1-butanesulfenyl cyanide		C₅H₆F₃NS	详情	详情

Extended Information