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Preparation method of naphthonone and analogues thereof

A technology of analogue and naptolone, which is applied in the field of compound preparation, can solve the problems of complex reaction conditions, troublesome post-processing, high production cost, etc., and achieve the effects of simple post-processing, less reaction by-products and low production cost

Inactive Publication Date: 2014-03-05
CHONGQING MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In order to solve the problems of complex reaction conditions, low yield, many by-products, difficult separation, troublesome post-processing and high production cost in the preparation of naptolone and its analogues, the invention provides a simple reaction condition, high yield, The preparation method of naptolone and its analogs with simple aftertreatment and low production cost

Method used

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  • Preparation method of naphthonone and analogues thereof
  • Preparation method of naphthonone and analogues thereof
  • Preparation method of naphthonone and analogues thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: 2-naphthol reacts with 2-chlorocyclohexanone to generate naptolone

[0032]

[0033] Sodium carbonate (0.15mol), 2-naphthol (0.1mol) and 150mL trifluoroethanol solvent were added respectively in a 500mL round bottom flask, then 2-chlorocyclohexanone (0.11mol) was dissolved in 50mL trifluoroethanol solvent, Slowly drop into a round bottom flask through a constant pressure dropping funnel. The reaction mixture was stirred at room temperature for 12 h. After the TCL monitors the reaction, the inorganic salts are removed by filtration. The filtrate was distilled under reduced pressure to recover the trifluoroethanol solvent to obtain the crude product as off-white solid. Further purification and recrystallization with ethanol gave colorless crystalline compound (Va), namely naptolone (0.091 mol), with a yield of 91%. Naptolone: ​​Mp: 136-137°C; 1 H NMR (400MHz, CDCl 3 )δ7.81(d, J=8.3Hz, 1H), 7.69(t, J=9.2Hz, 2H), 7.45(ddd, J=8.2, 6.9, 1.2Hz, 1H), 7.31(...

Embodiment 2

[0034] Embodiment 2: 2-naphthol reacts with 2-bromocyclohexanone to generate naptolone

[0035]

[0036]In a 500mL round bottom flask, add triethylamine (0.2mol), 2-naphthol (0.1mol) and 150mL hexafluoroisopropanol solvent, then dissolve 2-bromocyclohexanone (0.15mol) in 50mL hexafluoro The isopropanol solvent was slowly dropped into the round bottom flask through the constant pressure dropping funnel. The reaction mixture was stirred at room temperature for 8 h. After the reaction was monitored by TCL, the solid mixture was obtained by distillation under reduced pressure, then dissolved in water, and extracted with dichloromethane. The extract was distilled under reduced pressure to obtain the primary product, which was further purified and recrystallized from ethanol to obtain colorless crystalline compound (Va), namely naptolone (0.090 mol), with a yield of 90%.

Embodiment 3

[0037] Embodiment 3: 2-naphthol reacts with 2-chloro-6-methylcyclohexanone to generate compound (Vb)

[0038]

[0039] Potassium carbonate (0.15mol), 2-naphthol (0.1mol) and 150mL of hexafluoroisopropanol were added to a 500mL round bottom flask, and then 2-chloro-6-methylcyclohexanone (0.15mol) was dissolved Slowly drop 50 mL of hexafluoroisopropanol into a round bottom flask through a constant pressure dropping funnel. The reaction mixture was stirred at room temperature for 8 h. After the TCL monitors the reaction, the inorganic salts are removed by filtration. The filtrate was distilled under reduced pressure to recover the hexafluoroisopropanol solvent to obtain a brown solid crude product, which was then purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate (1:1 by volume) as the eluent to obtain the compound (Vb) (0.089 mol), 73% yield. 1 H NMR (400MHz, CDCl 3 )δ7.80(d, J=8.2Hz, 1H), 7.69(d, J=8.8Hz, 2H), 7.48-7.4...

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Abstract

The invention provides a preparation method of naphthonone and analogues thereof, which is simple in reaction condition, simple in after-treatment, high in yield and low in production cost. According to the preparation method, in the presence of alkali, a compound shown by a general formula (I) reacts with a compound shown by a general formula (II) or (III) at room temperature by taking multi-fluorine alcohol as a solvent to prepare a compound shown by a general formula (IV) or (V), and the chemical equations are shown in the specification, wherein R is H, C1-C4 alkyl, chlorine or bromine, R' is H or C1-C4 alkyl, X is chlorine or bromine, the multi-fluorine alcohol is trifluoro-ethanol or hexafluoro-isopropanol, and the alkali is sodium carbonate, potassium carbonate, trifluoro-ethanol sodium or triethylamine.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of naptolone and its analogues. Background technique [0002] Naphthonone is a cough suppressant. The document Helvetica Chimica Acta1929, 12 (1), 3-16 reports that naptolone was successfully synthesized by reacting 2-chlorocyclohexanone with 2-naphthol. U.S. Patent 2882201A discloses that naptolone has a good antitussive effect. In terms of its chemical structure, in fact, there is no peak of carbonyl carbon in the carbon NMR spectrum of naptolone, and the carbonyl and hydroxyl in the molecule react with each other. It exists in the form of hemiketal isomers and belongs to the four-ring structure of Brazan (Brazan) substances (as shown in the structure Va in the following formula). The English chemical name is 7a, 8, 9, 10, 11, 1la-hexahydronaphtho[ 2,1-b]benzofuran-7a-ol. The Journal of Organic Chemistry 1966, 31 (8), 2646-2648 reported that the stru...

Claims

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Application Information

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IPC IPC(8): C07D307/77
CPCC07D307/77C07D307/93
Inventor 唐强罗娟蒋启华蒋文高
Owner CHONGQING MEDICAL UNIVERSITY
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