1-Phenoxyacetone; 1-Phenoxy-2-propanone -Drug Synthesis Database

【结构式】

【分子编号】10875

【品名】1-Phenoxyacetone; 1-Phenoxy-2-propanone

【CA登记号】621-87-4

【分子式】C₉H₁₀O₂

【分子量】150.1772

【元素组成】C 71.98% H 6.71% O 21.31%

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：(II)

A new synthesis of [14C]-labeled CS-045 has been reported: The condensation of 5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone (I) with phenoxyacetone (II) by means of morpholine and p-toluenesulfonic acid in refluxing benzene gives 6-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-benzo[b]pyran-4-one (III), which is reduced with NaBH4 in methanol to the corresponding carbinol (IV). The dehydration of (IV) by means of p-toluenesulfonic acid in refluxing benzene affords 2-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-2H-benzo[b]pyran (V), which is hydrogenated with H2 over Pd/C in methanol to give the corresponding 3,4-dihydro derivative (VI). The hydrolysis of (VI) with NaOH in methanol yields the corresponding phenol (VII), which is chloromethylated with paraformaldehyde and dry HCl in dioxane to afford 2-[4-(chloromethyl)phenoxymethyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-6-ol (VIII). The protection of (VIII) with chloromethyl methyl ether by means of potassium tert-butoxide in THF gives the corresponding 6-(methoxymethoxy) derivative (IX), which is condensed with [5-14C]-thiazolidine-2,4-dione (X) by means of butyllithium in THF-HMPT to yield 5-[4-[6-(methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-2-ylmethoxy]benzyl]-[5-14C]-thiazolidine-2,4-dione (XI). Finally, this compound is deprotected with concentrated HCl in ethylene glycol monomethyl ether at 130 C.

参考文献中间体

合成目标

【1】 Prous, J.; Castaner, J.; CS-045. Drugs Fut 1989, 14, 9, 846.
【2】 Aizawa, Y.; Yoshioka, T.; Fujita, T.; Kawai, K.; Kanai, T.; Studies on hindered phenols. III. Synthesis of (±)-5-[4-(6-hydroxy-2,5,7,8 -tetramethyl-chroman-2-yl-methoxy)benzyl]-5-14C-thiazolidine-2,4-dione (14C-labelled CS-045). J Label Compd Radiopharm 1990, 28, 8, 911.

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)	10874	3-acetyl-2,5,6-trimethylphenyl acetate		C₁₃H₁₆O₃	详情	详情
(II)	10875	1-Phenoxyacetone; 1-Phenoxy-2-propanone	621-87-4	C₉H₁₀O₂	详情	详情
(III)	10876	2,5,7,8-tetramethyl-4-oxo-2-(phenoxymethyl)-3,4-dihydro-2H-chromen-6-yl acetate		C₂₂H₂₄O₅	详情	详情
(IV)	10877	4-hydroxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-chromen-6-yl acetate		C₂₂H₂₆O₅	详情	详情
(V)	10878	2,5,7,8-tetramethyl-2-(phenoxymethyl)-2H-chromen-6-yl acetate		C₂₂H₂₄O₄	详情	详情
(VI)	10879	2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-chromen-6-yl acetate		C₂₂H₂₆O₄	详情	详情
(VII)	10880	2,5,7,8-Tetramethyl-2-(phenoxymethyl)-6-chromanol		C₂₀H₂₄O₃	详情	详情
(VIII)	10881	2-[[4-(Chloromethyl)phenoxy]methyl]-2,5,7,8-tetramethyl-6-chromanol		C₂₁H₂₅ClO₃	详情	详情
(IX)	10882	2-[[4-(Chloromethyl)phenoxy]methyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-6-yl methoxymethyl ether; 2-[[4-(Chloromethyl)phenoxy]methyl]-6-(methoxymethoxy)-2,5,7,8-tetramethylchromane		C₂₃H₂₉ClO₄	详情	详情
(X)	10883	1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione	2295-31-0	C₃H₃NO₂S	详情	详情
(X)	44682	1,3-thiazolidine-2,4-dione		C₃H₃NO₂S	详情	详情
(XI)	10884	5-(4-[[6-(Methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]methoxy]benzyl)-1,3-thiazolane-2,4-dione		C₂₆H₃₁NO₆S	详情	详情
(XI)	44683	5-(4-[[6-(methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]methoxy]benzyl)-1,3-thiazolidine-2,4-dione		C₂₆H₃₁NO₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

2-Aminoacetophenone.HCl (IV) is prepared from acetophenone (I) via 2-bromoacetophenone (II) and the quaternary urotropine salt (III). Acetylation of (IV) with acetic anhydride in water in the presence of sodium hydrogen carbonate yields 2-acetamidoacetophenone (V), which is converted to 2-acetamido-3-hydroxypropiophenone.HCl (VI) with formaldehyde in water. After removing the acetyl group with hydrochloric acid in ethanol, 2-amino-3-hydroxypropiophenone.HCl (VII) is formed, which is reduced with hydrogen over Pd/C in methanol to rac-erythro-2-amino-1-phenyl-1,3-propanediol.HCl (VIII). Reductive condensation of the corresponding base (IX) with phenoxyacetone (X) and hydrogen over PtO2 affords a mixture of aminodiols epimeric at C-1' (XI). (XI) is finally converted to the corresponding hydrochloride salts, from which the salt of the less soluble [1R*,2S*(S*)]-stereoisomer, i.e., solpecainol is isolated by crystallization. Structure and purity of solpecainol have been confirmed by x-ray crystallography and HPLC-MS.

参考文献中间体

合成目标

【1】 Central Res. Inst. Chem. Hung. Acad. Sci. Report (27.10.1983) 1983.
【2】 Levai, L.; Fazekas, G.; Petocz, L.; Grasser, K. (Egis Pharmaceuticals Ltd.); Novel N-alkyl derivs. of 1-phenyl-2-amino-1,3-propandiol and process for preparing same. DE 2810482; GB 1560470; JP 1978112827; US 4259257 .
【3】 Vida, L.; Szepesy, L.; Lakszner, K.; Comparison and evaluation of derivatization methods for gas chromatographic determination of various propanediols. Chromatographia 1984, 19, 304.
【4】 Berényi, E.; Petócz, L.; Blaskó, G.; Nógrádi, M.; Solpecainol Hydrochloride. Drugs Fut 1991, 16, 6, 514.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	34873	1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane	100-97-0	C₆H₁₂N₄	详情	详情
(I)	10317	Acetophenone	98-86-2	C₈H₈O	详情	详情
(II)	10315	2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone	70-11-1	C₈H₇BrO	详情	详情
(III)	14599	2-(1-bromo-1lambda(5),3,5,7-tetraazatricyclo[3.3.1.1(3,7)]dec-1-yl)-1-phenyl-1-ethanone		C₁₄H₁₉BrN₄O	详情	详情
(IV)	14600	2-(chloroamino)-1-phenylethanone		C₈H₈ClNO	详情	详情
(V)	14601	N-(2-oxo-2-phenylethyl)acetamide		C₁₀H₁₁NO₂	详情	详情
(VI)	14602	N-[1-(hydroxymethyl)-2-oxo-2-phenylethyl]acetamide		C₁₁H₁₃NO₃	详情	详情
(VII)	14603	2-(Cloroamino)-3-hydroxy-1-phenyl-1-propanone		C₉H₁₀ClNO₂	详情	详情
(VIII)	14604	(1R,2S)-2-(Chloroamino)-1-phenylpropane-1,3-diol		C₉H₁₂ClNO₂	详情	详情
(IX)	14605	(1R,2S)-2-amino-1-phenyl-1,3-propanediol		C₉H₁₃NO₂	详情	详情
(X)	10875	1-Phenoxyacetone; 1-Phenoxy-2-propanone	621-87-4	C₉H₁₀O₂	详情	详情
(XI)	14607	(1R,2S)-2-[(1-methyl-2-phenoxyethyl)amino]-1-phenyl-1,3-propanediol		C₁₈H₂₃NO₃	详情	详情

Extended Information