JP4204921B2 - Method for producing acetate derivative - Google Patents

Description

  The present invention relates to a production method for obtaining an acetate derivative useful as a perfume material or a physiologically active substance in a high yield.

  Conventionally, as a method for producing an acetate derivative by supplying water to a 2-alkyl-3-oxo-cycloalkylmalonic acid diester and demonocarboxylating it, for example, Patent Document 1 discloses a 2-alkyl under atmospheric pressure. A method is disclosed in which -3-oxo-cycloalkylmalonic acid diester is reacted with 1 to 1.5 moles of water with respect to the diester at a temperature of 200 to 260 ° C. Patent Document 2 discloses a method in which a 2-alkyl-3-oxo-cycloalkylmalonic acid diester is reacted with water at 1 to 3 mol times with respect to the diester at a temperature of 150 to 250 ° C. Patent Document 3 discloses a method in which 2-alkyl-3-oxo-cycloalkylmalonic acid diester is reacted with water at 1 to 10 atm and at a temperature of 180 to 210 ° C.

However, in these reactions, carbon dioxide and alcohol are generated as by-products during demonocarboxylation, and unreacted water is vaporized to supply water at a high temperature. There is a problem that the yield is inevitably lowered because the part is entrained and distilled out of the system.
Japanese Patent Laid-Open No. 53-12842 JP-A-9-183754 JP 56-147740 A

  An object of the present invention is to provide a method for producing an acetate derivative in a high yield from 2-alkyl-3-oxo-cycloalkylmalonic acid diester.

  When the present inventors decarboxylate 2-alkyl-3-oxo-cycloalkylmalonic acid diester, a separation means is provided outside the reaction system, and among the distillate components, the generated alcohol and carbon dioxide are systemized. It was found that by carrying out the reaction while removing it outside, the loss of the reaction solution was suppressed and the acetate derivative was obtained in high yield.

  That is, the present invention provides an acetic acid ester derivative represented by the formula (II) by supplying water to the malonic acid diester represented by the formula (I) (hereinafter referred to as malonic acid diester (I)) to demonocarboxylate it. Acetic acid (hereinafter referred to as acetate ester derivative (II)) is prepared by providing a separation means outside the reaction system and carrying out the reaction while removing generated alcohol and carbon dioxide out of the system out of the distillate components. A method for producing an ester derivative is provided.

(Wherein n represents an integer of 1 or 2, R ¹ and R ² each represent a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, or R ¹ and R ² together And may form a cyclopentane ring or a cyclohexane ring with adjacent carbon atoms, and R ³ represents a linear or branched alkyl group having 1 to ³ carbon atoms, and two R ³ may be the same or different. May be.)

  By the method of the present invention, the acetate derivative (II) can be produced from the malonic acid diester (I) in a high yield.

In the malonic acid diester (I) used as the raw material of the present invention, R ¹ and R ² each have the above-mentioned meaning, but a hydrogen atom or an alkyl group having 1 to 8 carbon atoms is preferable, and from the viewpoint of use as a fragrance material. , in which R ¹ is a hydrogen atom, more preferably R ² is an alkyl group having 3 to 5 carbon atoms, with R ¹ is a hydrogen atom, R ² is a linear alkyl group having 4 carbon atoms is particularly preferred . n represents an integer of 1 or 2, but 1 is preferable. R ³ represents a linear or branched alkyl group having 1 to ³ carbon atoms, preferably a methyl group.

  Malonic acid diester (I) can be generally produced by a known method. For example, a cycloalkanone having 5 or 6 carbon atoms is reacted with an aldehyde or ketone represented by the formula (IV) to obtain a compound represented by the formula (V), and the resulting compound (V) is subjected to a dehydration reaction and It can be obtained by carrying out an isomerization reaction to obtain a compound represented by the formula (III) and then reacting with a compound represented by the formula (VI).

(In the formula, n, R ¹ , R ² and R ³ have the above-mentioned meanings.)
In the production method of the present invention, when demonocarboxylation is performed by supplying water to the malonic acid diester (I), a separation means is provided outside the reaction system, and among the distillate components, the generated alcohol and The reaction is performed while removing carbon dioxide outside the system.

  In the present invention, “providing separation means outside the reaction system” means providing separation means such as a separation apparatus outside the reaction system separately from the reaction apparatus that performs the demonocarboxylation reaction.

  The separation means in the present invention has a mechanism capable of separating generated alcohol and / or carbon dioxide from unreacted substances, water and reaction products distilled from the reaction system.

  In the present invention, the generated alcohol and carbon dioxide are removed from the system out of the distillate components, but other components, that is, malonic acid diester (I), acetate ester derivative (II), and malon during the reaction. Formula (III) produced by decomposition of acid diester (I)

(In the formula, n, R ¹ and R ² have the above-mentioned meanings.)
It is preferable to collect | recover the component containing the compound (henceforth a compound (III)) represented by in a reaction tank. Further, from the viewpoint of effectively using the supplied water, it is preferable to collect the water in the reaction tank.

  As a means for separating the distillate component, there are a means for directly separating, a means for installing a cooler to condense the vapor and separating it. Means for directly separating the vapor include means such as membrane separation, adsorption, and absorption. Examples of means for condensing and separating steam include rectification and partial condensation. In consideration of separation efficiency and recovery efficiency, means for condensing and separating the vapor is preferable.

  When separating the distillate component while rectifying, a rectifying column is installed at the top of the reaction tank and refluxed, so that malonic acid diester (I), acetate ester derivative (II), compound (III ) And water containing one or more components are returned to the reaction vessel, and the generated alcohol or carbon dioxide is condensed by a condenser installed outside the system and selectively removed outside the system. preferable.

  Also, when distillate components are separated by partial condensation, two or more cooling pipes (condensers) are installed in series to give a difference in the temperature of the refrigerant or to control the flow rate of the refrigerant. A component containing any one or more of the acid diester (I), acetate derivative (II), compound (III) and water can be selectively separated from alcohol and carbon dioxide. The separated component containing at least one of malonic acid diester (I), acetic acid ester derivative (II), compound (III) and water can be returned to the reaction vessel after completion of the reaction or used for the next reaction. However, in order to perform an efficient reaction, it is preferable to continuously return the reaction vessel.

  When industrially producing, selective separation of malonic acid diester (I), acetic acid ester derivative (II), compound (III) and water-containing components from alcohol and carbon dioxide In the case of rectification, it is preferable to manage the vapor temperature at the upper part of the rectification column, and in the case of partial reduction, it is preferable to manage the outlet temperature of the cooling pipe vapor side. The generated carbon dioxide can also be recovered by an absorption operation.

  The temperature of the demonocarboxylation reaction in the present invention can be applied in a wide range from a low temperature to a high temperature, but is preferably 150 ° C. or higher, more preferably 170 ° C. or higher in consideration of productivity. Moreover, from a viewpoint of preventing decomposition | disassembly of malonic acid diester and suppressing the fall of a yield, 250 degrees C or less is preferable and 230 degrees C or less is still more preferable. The reaction pressure is not particularly limited, but it is preferably carried out at normal pressure because no special apparatus is required.

  The supply of water is not particularly limited and may be supplied at a constant flow rate. However, it is preferable to control the water concentration in the reaction solution by changing the supply flow rate of water from the beginning of the reaction. Moreover, considering the reaction efficiency, the water supply method is preferably supplied from the bottom of the reactor through piping, a sparger, or the like.

  The analysis of the raw material and the reaction finished product in this example was performed by gas chromatography internal standard method (column: DB-1 (manufactured by Agilent), temperature increase: from 80 ° C. to 200 ° C., 4 ° C./min).

Production Example 1
A 6m ³ reaction vessel equipped with a dripping vessel was charged with 2241 kg (26.6 kmol) of cyclopentanone, 1007 kg of water, and 11 kg of 48% NaOH, cooled to 15 ° C. with stirring, and then 985 kg (11. 4 kmol) was added dropwise over 5 hours. After completion of dropping, the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was neutralized and excess cyclopentanone was recovered by distillation, and the organic layer was analyzed. As a result, 1868 kg of 2- (1-hydroxypentyl) -cyclopentanone was contained in the reaction finished product 1868 kg. I found out.

  0.0206 mol of oxalic acid was added to the above reaction-finished product containing 1.01 mol of 2- (1-hydroxypentyl) -cyclopentanone and reacted at 120 ° C. The amount of 2-pentylidenecyclopentanone contained in this was 141 g (0.93 mol). The filtered product was dissolved in 153 g of n-butanol, heated to 130 ° C., and then mixed with 14.5 g (0.15 mol) of 3-picoline and 10.5 g (0.1 mol) of 35% hydrochloric acid at the same temperature. It was dripped in 30 minutes. After completion of dropping, the mixture was heated and stirred at the same temperature for 3.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with an aqueous sodium hydroxide solution, and the organic layer was analyzed. As a result, it was confirmed that 118 g of 2-pentyl-2-cyclopentenone was contained in the finished product. all right.

  From this finished product, 95 g (0.6 mol) of 2-pentyl-2-cyclopentenone was purified. Furthermore, 118 g (0.9 mol) of dimethyl malonate was dissolved in 38 g of anhydrous methanol under a nitrogen atmosphere, cooled to 0 ° C., and 6.5 g (0.036 mol) of sodium methoxide (30% methanol solution) was added. To the obtained product, 95 g (0.6 mol) of 2-pentyl-2-cyclopentenone obtained above was added dropwise at 0 ° C. over 2 hours. After completion of dropping, unreacted dimethyl malonate was distilled off under reduced pressure to obtain 160 g of dimethyl 2-pentyl-3-oxo-cyclopentylmalonate.

Example 1
It consists of a reaction tank 1 consisting of a 1 L four-necked flask equipped with a stirrer 2, a supply device 3, a thermometer 4 and a packed tube 5, a cooling tube (condenser) 6 and a receiver 7 installed at the end of the packed tube 5. Reaction was performed using the reaction apparatus shown in FIG.

  A reaction vessel 1 was charged with 600 g of a raw material containing 556 g (1.96 mol) of dimethyl 2-pentyl-3-oxo-cyclopentylmalonate produced in the same manner as in Production Example 1, and heated to 215 ° C. with stirring at normal pressure. After that, water was supplied from the supply device 3 at 12 g / h. Among the vapors generated during the reaction, the components containing methyl 2-pentyl-3-oxo-cyclopentyl acetate, dimethyl 2-pentyl-3-oxo-cyclopentylmalonate, 2-pentyl-2-cyclopentenone are packed. Condensed in the tube 5 and continuously returned to the reaction vessel 1, methanol and carbon dioxide were distilled out of the system, condensed in the condenser 6, and recovered in the receiver 7. And reaction was complete | finished in 3.75 hours from the supply start. The finished product contains 413 g (1.83 mol, yield 93.5%) of methyl 2-pentyl-3-oxo-cyclopentylacetate, and 69.8 g (2.18 mol) of methanol from the fraction condensed outside the system. ) Could be recovered.

Comparative Example 1
A raw material containing 545 g (1.92 mol) of dimethyl 2-pentyl-3-oxo-cyclopentylmalonate produced in the same manner as in Production Example 1 in a 1 L four-necked flask equipped with a stirrer, a feeding device, a thermometer, and a glass tube After charging 600 g and heating to 215 ° C. with stirring under normal pressure, the glass tube was kept warm and water was supplied at 12 g / h. And reaction was complete | finished in 3.75 hours from the supply start. It was found that the finished product contained 372 g (1.65 mol, yield 85.7%) of methyl 2-pentyl-3-oxo-cyclopentyl acetate.

Example 2
A reaction tank 10 comprising a 1 L four-necked flask equipped with a stirrer 2, a supply device 3 and a thermometer 4 and two cooling pipes (condensers) 8 and 9 are provided in series, and the temperature between the two cooling pipes The reaction was performed using the reaction apparatus shown in FIG.

  The reaction vessel 10 was charged with 1111 g of a raw material containing 1068 g (3.76 mol) of dimethyl 2-pentyl-3-oxo-cyclopentylmalonate produced in the same manner as in Production Example 1, and heated to 180 ° C. with stirring under normal pressure. After that, the supply of water from the supply device 3 was started. During supply, the flow rate is set to 11.6 g / h from the start of supply to the second hour, to 5.6 g / h from the second to the eighth hour, and to 2.3 g / h after the eighth hour. Adjusted. Among the steam generated during the reaction, methyl 2-pentyl-3-oxo-cyclopentyl acetate and 2-pentyl- were controlled while controlling the amount of cooling water supplied so that the steam temperature at the outlet of the cooling pipe 8 was 65 ° C. A component containing dimethyl 3-oxo-cyclopentylmalonate and 2-pentyl-2-cyclopentenone is condensed in the first cooling pipe 8 and continuously returned to the reaction vessel 10 while supplying a 0 ° C. refrigerant. Methanol and carbon dioxide were condensed in the second cooling pipe 9 and recovered in the receiver 7. And reaction was complete | finished in 15 hours from the supply start. The finished product contains 811 g (3.59 mol, yield 95.5%) of methyl 2-pentyl-3-oxo-cyclopentyl acetate, and 132.6 g (4.14 mol) of methanol from the fraction condensed outside the system. ) Could be recovered.

Example 3
A reaction vessel 13 comprising a 1 L four-necked flask equipped with a stirrer 2, a supply device 3, a thermometer 4 and a 15-stage rectifying column 11, and a cooling pipe (condensation) installed at the end of the rectifying column 11 equipped with a thermometer 15 The reaction was carried out using the reaction apparatus shown in FIG.

  A reaction vessel 13 was charged with 1933 g of a raw material containing 1840 g (6.48 mol) of dimethyl 2-pentyl-3-oxo-cyclopentylmalonate produced in the same manner as in Production Example 1, and heated to 180 ° C. with stirring under normal pressure. After that, the supply of water from the supply device 3 was started. During the supply, the flow rate was adjusted to 19 g / h from the start of supply to the second hour, to 9.5 g / h from the second to the eighth hour, and to 3.8 g / h after the eighth hour. . Among the vapors generated during the reaction, by refluxing at a reflux ratio of 5 while maintaining the upper temperature at 65 ° C. in a rectifying column, methyl 2-pentyl-3-oxo-cyclopentyl acetate, 2-pentyl- A component containing dimethyl 3-oxo-cyclopentylmalonate and 2-pentyl-2-cyclopentenone is continuously returned to the reaction vessel 13, and methanol and carbon dioxide are condensed in the condenser 12 outside the system. It was collected at. And reaction was complete | finished in 14 hours from the supply start. The finished product contains 1414 g (6.26 mol, yield 96.6%) of methyl 2-pentyl-3-oxo-cyclopentylacetate and 177.2 g (5.54 mol) of methanol from the fraction condensed outside the system. ) Could be recovered.

  The reaction conditions and results of Examples 1 to 3 and Comparative Example 1 are summarized in Table 1.

1 is a schematic diagram of a reactor used in Example 1. FIG. 2 is a schematic diagram of a reaction apparatus used in Example 2. FIG. 2 is a schematic diagram of a reactor used in Example 3. FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Reaction tank 2 Stirrer 3 Supply apparatus 4 Thermometer 5 Filling pipe 6 Cooling pipe (condenser)
7 Receiver 8 Cooling pipe (condenser)
9 Cooling pipe (condenser)
10 reaction tank 11 rectification column 12 cooling pipe (condenser)
13 Reaction tank 14 Thermometer 15 Thermometer

Claims (3)

Water is supplied to the malonic acid diester represented by the formula (I) (hereinafter referred to as malonic acid diester (I)) while controlling the water concentration in the reaction solution by changing the supply flow rate to demonocarboxylate. In the production of an acetic ester derivative represented by the formula (II) (hereinafter referred to as acetic ester derivative (II)), a separation means is provided outside the reaction system, and among the distillate components, malonic acid diester (I) , Acetate ester derivative (II), compound represented by formula (III) produced by decomposition of malonic acid diester (I) during the reaction (hereinafter referred to as compound (III)) and water A method for producing an acetic ester derivative, in which components to be condensed are separated and continuously returned to the reaction vessel, and the reaction is carried out while removing the generated alcohol and carbon dioxide from the system.

(Wherein n represents an integer of 1 or 2, R ¹ and R ² each represent a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, or R ¹ and R ² together And may form a cyclopentane ring or a cyclohexane ring with adjacent carbon atoms, and R ³ represents a linear or branched alkyl group having 1 to ³ carbon atoms, and two R ³ may be the same or different. May be.) A component containing any one or more of malonic acid diester (I), acetate derivative (II), compound (III) and water among the distillate components while rectifying, and alcohol and carbon dioxide produced the separated, method according to claim 1 Symbol placement. A component containing any one or more of malonic acid diester (I), acetic acid ester derivative (II), compound (III) and water, and alcohol and carbon dioxide produced by partial condensation. separating, method according to claim 1 Symbol placement.