WO2004007420A1 - PROCESS FOR PRODUCING α-METHYL-ß-KETO ESTER - Google Patents

Abstract

A process for efficiently producing an α-methyl-ß-keto ester from a ß-keto ester as a starting material without using any toxic reagent or highly severe conditions. The process comprises dissolving pellet-form paraformaldehyde in a liquid mixture of a ß-keto ester and acetic anhydride, adding a hydrous lower alcohol, and conducting hydrolysis in a hydrogen atmosphere with the aid of a palladium-carbon catalyst.

Description

 Description Method for producing α-methyl-β-ketoester [Background of the invention]

Field of the invention

 The present invention relates to a method for producing α-methyl- | 3_ketoester, which is useful as a raw material for producing pharmaceuticals, agricultural chemicals, and the like.

Background technology

 3-ketoesters, typified by ethyl acetate, are useful compounds as raw materials for producing pyrin-type antipyretics and sulfonamide-type agricultural chemicals, and are widely used.

 Among these, many methods are known for producing an α-methyl-j3-ketoester having a methyl group introduced at the cysteine position. For example, it is known to produce acetyl acetate by reacting it with methyl bromide or methyl iodide in the presence of a base, or by reacting ethyl bromoacetate with acetic anhydride in the presence of zinc. You. However, the former method has limited use in terms of the toxicity and cost of bromide or iodide, and the latter method uses stoichiometric metal zinc, so that it can be treated as industrial waste. Care must be taken.

 In addition, Japanese Patent Publication No. 49-34661 discloses that a / 3-ketoester such as ethyl acetate is condensed with formaldehyde and the resulting alkylidene compound is hydrogenated in the presence of a palladium catalyst. A method for producing a 1-methyl-3-ketoester has been disclosed. However, in this production method, the yield of the target compound is usually

It is about 40%, and since zinc chloride is used as a catalyst, there is a problem of industrial waste, and there is room for improvement as an industrial production method. Also, the Swiss patent C H 560

In 176, ethyl 2-acetoxymethyl-acetoacetate is formed by condensing ethyl acetate with formaldehyde in the presence of acetic anhydride. A production method is disclosed in which hydrogenolysis is carried out in the presence of a radium catalyst to obtain the desired ethyl 2-methylacetoacetate. In this method, a pressure of 50 atm is applied, and solid paraformaldehyde is One method is to heat the mixture to 80 ° C or more and thermally decompose it to form gaseous formaldehyde, which is then introduced into the reaction solution in gaseous form. Thus, treating a compound that is highly carcinogenic and irritating in a gaseous state should be avoided as an industrial-scale production method.

 Therefore, there is still a need for a production method capable of safely and safely obtaining the -methyl / 3-ketoester.

[Overview of the invention]

 The present inventors have now used inexpensive) 3-ketoester as a starting material, dissolve solid paraformaldehyde in] 3-ketoester and acetic anhydride without thermally decomposing paraformaldehyde, and present the presence of a lower alcohol. It has been found that by performing the following reaction and then subjecting to hydrogenolysis, it is possible to obtain hexamethyl-1-β-ketoester in a good yield.

 Accordingly, an object of the present invention is to provide a production method capable of obtaining a monomethyl_-ketoester in good yield and safely.

 And, the production method according to the present invention is a production method of the following general formula (I) monomethyl ketoester:

の

of

 [Where,

R ¹ represents an optionally substituted straight-chain or branched-chain — 6 alkyl group or a cycloalkyl group, and —R ² represents a straight-chain or branched-chain C ₄ alkyl group . ], The following general formula (II):

(II)

(II)

[Wherein, R ¹ and R ² are as defined above. ]

After dissolving paraformaldehyde in a mixture of β-ketoester and acetic anhydride represented by the following formula, and reacting in the presence of a hydrous lower alcohol, the following general formula (ΙΠ):

(III)

[Wherein, R ¹ and R ₂ are as defined above. ]

At least comprising generating an a-acetoxymethyl-β-ketoester represented by the formula: and hydrolyzing it.

[Specific description of the invention]

Compounds of formula (I)

An object of the production method according to the present invention is a monomethyl- | 3-ketoester represented by the above formula (I). In the formula (I), R ¹ represents a Ct- ₆ alkyl group or a cycloalkyl group, and the alkyl group may be linear or branched. The alkyl group may be substituted with one or more substituents. Examples of the substituent include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a hydroxyl group, and a Examples include branched alkyl groups c The cycloalkyl group represented by R ¹ is preferably a C-cycloalkyl group. In the formula (I), R ² represents a linear or branched -4 alkyl group.

 The compound represented by the formula (I) is useful as an intermediate for synthesizing various useful compounds. For example, a 6-t-butyl-8-fluoroquinoline derivative disclosed in WO 01/9223 31 is a compound having excellent control activity against agricultural and horticultural diseases. The compounds of the formula (I) are used. That is, 41-t-butyl-2-fluoroaerin or a salt thereof was prepared by the method described in WOO 1/922331, J. Chem. Soc., (C). 2426 (1970) or Tetrahedron Lett., 4945 (1968). Dehydrocondensation reaction with 1-methyl-ketoester according to the method described in 1), and then heating to 250 ° C in a fehlether to obtain 6-t-butyl-3,4-dimethyl-8-fluoroquinolone. Then, this can be converted to an acetyl form to obtain 4-acetoxy-6-t-butyl-3,4-monodimethyl-8-fluoroquinoline. Process for producing compounds of formula (I)

 In the method according to the present invention, first, equation (Π):

(Π)

[Wherein R ¹ and R ² are as defined above]

A mixture of 3-ketoester and acetic anhydride is prepared. The ratio of the compound of the formula (II) to acetic anhydride is not limited as long as the paraformaldehyde added next can be dissolved, but is preferably about 1:10 to 10: 1 (weight ratio), more preferably It is about 1: 5 to 5: 1 (weight ratio).

Next, paraformaldehyde is added to and dissolved in the mixture of the compound of the formula (II) and acetic anhydride. As mentioned above, the use of formaldehyde as a gas in the reaction is disadvantageous or desired to be avoided in industrial production processes. In the present invention Is advantageous in that paraformaldehyde is dissolved in a mixture of the compound of the formula (II) and acetic anhydride, so that handling thereof is extremely easy. According to a preferred embodiment of the present invention, paraformaldehyde is preferably used in an amount of 1 to 10 equivalents, more preferably about 1 to 3 equivalents, based on the formula (II). In addition, it is preferable to use paraformaldehyde in a pellet form because of its easy handling.

 In the process according to the invention, the reaction of the compound of formula (II) with acetic anhydride and paraformaldehyde is carried out in the presence of a hydrous lower alcohol.

In the present invention, the lower alcohol is preferably a ₆ -valent alcohol, more preferably ethyl alcohol. In the present invention, the lower alcohol contains water. The amount is 0.1-1.5% by weight alcohol /. And preferably from 0.3 to 0.8% by weight, most preferably 0.5% by weight. By the presence of such a lower alcohol containing a trace amount of water, by-products are extremely suppressed, and the yield can be significantly improved. The present inventors have experimentally confirmed that such advantages cannot be obtained with dehydrated lower alcohol. These advantages obtained by proceeding the reaction in the presence of the hydrated lower alcohol can be said to be extremely advantageous as compared with conventionally known methods for producing α-methyl / 3-ketoester. The amount of the water-containing lower alcohol present in the reaction system may be appropriately determined, but is preferably about 2 to 50% by weight, more preferably about 2 to 50% by weight based on the total amount of the compound of the formula (II), acetic anhydride, and paraformaldehyde. Is about 3 to 30% by weight.

The reaction of the compound of formula (II), acetic anhydride and paraformaldehyde in the presence of a hydrous lower alcohol is carried out under heating. The temperature and the reaction time may be determined as appropriate while taking into account the formation of by-products, the yield, etc., but are generally from room temperature to about 100 ° C., preferably from 35 to 50 ° C. ° C, most preferably about 40 ° C, and the reaction time is generally about 5 to 100 hours, preferably 7 to 80 hours. By the above reaction, the formula (in)

(III)

[Wherein, R ¹ and R ² are as defined above. ]

Α-Acetoxymethyl-β-ketoester represented by In the present invention, the compound of the formula (III) is subjected to hydrogenolysis to obtain a thiomethylketoester represented by the formula (I). This hydrogenolysis may be appropriately determined as long as the compound of the formula (I) is obtained. According to a preferred embodiment of the present invention, the hydrogenolysis is carried out by contact with hydrogen under a palladium-carbon catalyst (for example, the reaction of hydrogen with hydrogen). It is preferable to pass the mixture directly or place the reaction mixture in a hydrogen atmosphere). The reaction conditions may be determined as appropriate, but the hydrogen pressure is preferably about 1 to 50 atm, more preferably about 1 to 20 atm. preferably room temperature to about 100 ° C (212 ° F), more preferably about. 35 to 50 ° C, the reaction time is 5 to preferably about 100 hours, _c palladium and more preferably about 7-80 hours - abundance of carbon May be appropriately determined, but is preferably about 0.01 to 0.2% by weight, more preferably about 0.02 to 0.1% by weight, based on the compound of the formula (III).

According to a preferred embodiment of the present invention, a step of producing a compound of the formula (III) by reacting the compound of the formula (II) with acetic anhydride and paraformaldehyde, and hydrogenating the compound of the formula (II I) the reaction conditions for the decomposition reaction, one can be carried out continuously in a reaction system _c at this time, about the hydrogen pressure to 50 atm, more preferably from about 1 to 20 atmospheres, a temperature from room temperature to The reaction temperature is preferably about 100 ° C., more preferably about 35 to 50 ° C., and the reaction time is preferably about 5 to 100 hours, more preferably about 7 to 80 hours. The resulting compound of formula (I) is then isolated from the reaction system, for example

It is preferable to purify by the following steps.

[ Example ]

 Hereinafter, the present invention will be described specifically with reference to examples.

 Example 1 Synthesis of ethyl 2-methylacetoacetate (hydrogen pressure 1 atm)

Dissolve pelleted paraformaldehyde (46.0 g, 1.54 mol) in a mixture of ethyl acetate acetate (100 g, 0.768 mol) and acetic anhydride (86.0 g, 0.845 mol) I let it. To this solution was added 45 OmL of 99.5% ethanol (water content: 0.5% by weight), and 5.00 g of 10% palladium-carbon catalyst, 5% of the substrate weight (AD100 manufactured by Kawaken Fine Chemicals Co., Ltd.) % Pd / C) was added to the reactor to perform degassing. After then, hydrogen was introduced while Chi coercive the reactor to a hydrogen atmosphere of 1 atm, warmed to 40 ° C, and the _c-reactive liquid reaction mixture was subjected to vigorous stirring for 22 hours the reaction was cooled, The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. This was distilled using a Helipack column to obtain 11 g of 2-methylacetoethyl acetate as a colorless oil. Yield 74.8%. Example 2 Synthesis of ethyl 2-methylacetate (hydrogen pressure: 10 atm)

A mixture of acetate ethyl acetate (100 g, 0.768 mol) and acetic anhydride (86.0 g, 0.845 raol) was added to a pelleted parahonolemuanolaldehyde (46.0 g, 1. 54raol) was dissolved. To this solution was added 99.5% ethanol (water content: 0.5% by weight), 45 OmL, and 500 mg of 10% palladium-carbon catalyst (0.5% by weight of the substrate) (AD, manufactured by Kawaken Fine Chemicals) 10% Pd / C) was added to the autoclave. After the atmosphere in the autoclave was replaced with a hydrogen atmosphere, the hydrogen pressure was increased to 10 atm, and the mixture was heated to 40 ° C and stirred. The reaction was carried out for 48 hours while maintaining the pressure at 10 atm with occasional replenishment of hydrogen. After cooling the reaction solution, solids were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. This is distilled using a Helipack column. Thus, 84.6 g of 2-methylacetoethyl acetate was obtained as a colorless oil. Yield 57.0%. Example 3 Synthesis of ethyl 2-methylacetoacetate (hydrogen pressure 10 atm)

 A paraformaldehyde pellet (4.60 g, 1 mol) was added to a mixture of ethyl acetate (1.0 g, 0.768 mol) and acetic anhydride (8.60 g, 0.845 mol). .5 4 mol) was dissolved. To this solution was added 99.5% ethanol (water content: 0.5% by weight), 45 OmL, and 50 Omg of 5% palladium-carbon catalyst (0.5% by weight based on the substrate weight) (Kawaken Fine Chemicals AD) 5% Pd / C) was added to the auto tare. After the atmosphere in the autoclave was replaced with a hydrogen atmosphere, the hydrogen pressure was increased to 10 atm, and the mixture was heated to 40 ° C and stirred. The reaction was carried out for 72 hours while maintaining the pressure at 10 atm by replenishing hydrogen. After cooling the reaction solution, solids were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. This was distilled using a Helipack column to obtain 92.0 g of ethyl 2-methylacetoacetate as a colorless oil. Yield 65.0%. Comparative Example 1 Synthesis of 2-ethyl methyl acetate (hydrogen pressure 1 atm)

 In a mixture of ethyl acetate acetate (100 g, 0.768 mol) and acetic anhydride (8.60 g, 0.845 mol), pelleted paraformaldehyde (4.6 O) was added. g, 1.54 mol) were dissolved. This solution, sodium acetate (63.0 g, 0.768 mol) as a basic catalyst, and 5.0 g of a palladium-carbon catalyst (AD10% Pd / C manufactured by Kawaken Fine Chemicals) Was added to the reactor and degassed. Thereafter, hydrogen was introduced, the reactor was heated to 40 ° C. while keeping the inside of the reactor at a hydrogen atmosphere of 1 atm, and the reaction was carried out for 6 hours while stirring the reaction solution vigorously. After cooling the reaction solution, solids were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. This was distilled using a 2 O cm Helipack column to obtain 23.7 g of 2-methylacetoethyl acetate as a colorless oil. Yield 16.0%

EI one MS; m / Z 1 4 5 (M + H) +; 1 HNMR (CD C 1 3) δ 1. 2 8 (3 Η, t, J = 7. 1 H z), 1. 3 5 ( 3H, d, J = 7.3Hz), 2.25 (3H, s), 3.51 (1H, q, J = 7.3Hz), 4.20 (1H ,

(z HO · T 'ε ■ 1 = [' P ¾

L 8800 / £ 00ZdT / 13d 0h00 contract OAV

Claims

The scope of the claims 1. A method for producing a monomethyl- | 3-ketoester represented by the following general formula (I):

(I)  [Where, R ¹ represents a linear or branched alkyl group which may have a substituent, or a cycloalkyl group; R ² represents a straight or branched chain 〇 ₄ alkyl group. ], The following general formula (Π):

(II) [Wherein, R ¹ and R ² are as defined above. ] After dissolving paraformaldehyde in a mixture of iS-ketoester and acetic anhydride represented by the following formula, and reacting in the presence of a hydrous lower alcohol, the following general formula (III):

 (III) [Wherein, R ¹ and R ₂ are as defined above. ] A method for producing, comprising, at least, producing a perethoxymethyl-1-β-ketoester represented by the formula: and hydrolyzing it. 2. The method according to claim 1, wherein the monoketoester represented by the formula (II) is methyl acetoacetate or ethyl acetoacetate. 3. The method according to claim 1, wherein the lower alcohol is a C-hydric alcohol. ' 4. The method according to any one of claims 1 to 3, wherein the Cn monohydric alcohol is ethyl alcohol. 5. The method according to any one of claims 1 to 4, wherein the hydrogenolysis is carried out by contacting the compound of the formula (II) with hydrogen in the presence of a palladium-carbon catalyst.