CZ319599A3 - Process for preparing derivatives of butyric acid esters - Google Patents

Abstract

It is an object of the present invention to provide a process for the preparation of ester derivatives butyric acid of formula (2) which are capable of remove various polluting byproducts whose formation of stems prior art techniques can be avoided, in particular, the compound of general formula (1) is effective. ‘Aj; A process for producing butyric acid ester derivatives of the general formula 2, the slurry comprises treating the mixture containing the compound of Formula (1) was capable of reacting with the addition reagent the ethylenic bond, thereby converting the compound of the formula (1) to the addition product is easy separated from said butyric acid ester derivative of formula 2, and a process for the preparation of a butyric acid ester derivative of formula (2), which comprises reacting a compound of formula (I) of Formula 3, the hydrocyanic acid is a flow method HOCH2 “CH = CH-COOR (1)

Description

Technical field *

The present invention relates to a process for the preparation of butyric acid ester derivatives of the general formula (2):

OH

NCy / COOR ⁽² 'in which:

R represents a straight or branched chain alkyl group having 1 to 4 carbon atoms.

The above butyric acid ester derivatives of formula (2) are important key intermediates for the preparation of sophisticated chemicals such as pharmaceuticals, for example the antihyperlipidemic agent atorvastatin of the following formula (4):

• Japanese Kohyo Publication Japanese Kohyo Publication Japanese Kohyo Publication Japanese Kohyo Publication Japanese Kohyo Publication Japanese Kohyo Publication Japanese Kohyo Publication Hei-7-500105, and other agrochemicals.

BACKGROUND OF THE INVENTION

It is known from the prior art to prepare butyric acid ester derivatives of the above general formula (2) by reacting compounds of the following general formula (3):

OH

X ^ A ^ COOR <3)

in which :

R is as defined above, and

X is selected from the group consisting of chlorine, bromine, iodine, methanesulfonyloxy and substituted or unsubstituted phenylsulfonyloxy, with the hydrocyanic acid salt.

More specifically, a conventional conventional process either involves reacting ethyl 4-bromo-3-hydroxybutyrate or ethyl 4-toluenesulfonyloxy-3-hydroxybutyrate with sodium cyanide (see Japanese Kohyo Publication Hei-7-500105) or comprising reacting 4-chloro-3-hydroxybutyric acid ethyl ester, 4-chloro-3-hydroxybutyric acid n-butyl ester, or. t-butyl 4-chloro-3-hydroxybutyrate with sodium cyanide (see publication *

Kokai Publication Hei-5-331128).

However, literature references describing the above processes are somewhat reticent with respect to impurities occurring as contaminants in the resulting derivatives as products of said processes, methods of inhibiting the formation of such contaminants, or methods of removing these impurities from products, respectively. process.

The present inventors have investigated in detail the published prior art procedures and have found that by carrying out these commonly known methods, an inevitable formation of an ethylene bond-containing compound, such as the following compound of formula (1), is inevitable:

H0CH ₂ -CH = CH-C00R (1) in which R has the same meaning as above, and besides that from this byproduct containing an ethylenic bond as a precursor of other pollutants produced.

In addition, it has been found that conventional routine purification processes, such as extraction, washing, distillation and crystallization, are not effective enough to remove the above-mentioned ethylene-bonded compound and, moreover, carrying out these purification processes to large losses of the butyric acid derivative of the above formula (2), etc. Thus, it has been found that, although generally known and readily practicable, these processes are applied

- 4 - - - - - - - - - - - - - - - - - - - - - - - - - - - - The conventional purification procedures described in the references cited above are very difficult to produce the butyric acid ester of the above formula (2) in a high yield, economically viable and acceptable manner and a sufficiently high degree of quality to obtain the product. which would be suitable for use as an intermediate in the preparation of demanding chemicals such as pharmaceuticals and agrochemicals.

In addition, the reaction between the aforementioned compound of formula (3) and said hydrocyanic acid salt is carried out in a violent exothermic manner so that although the batch process in which the total amount of the two reactants is introduced into the reactor, the compound of formula (3) and the hydrocyanic acid salt are readily feasible and the reaction can be carried out in a controlled manner at once at a controlled reaction temperature in a small laboratory sfc vvz, | scale, since under these conditions it is easy to divert the reaction i

| heat, this procedure cannot be applied to a large industrial scale scale-up process that makes it very difficult

Control of the reaction temperature due to the rapid increase in temperature in the reaction system due to the generation of reaction heat, and in addition, the occasional bursting of the reaction mixture as a result of secret boiling makes this process difficult to manage both in terms of safety and in terms of economic performance of the reaction, since it is to be understood that carrying out the reaction involves the use of a hydrocyanic acid salt, which is highly toxic. Further, in a semi-batch process, which comprises feeding either a compound of the above formula (3) or a hydrocyanic acid salt to the reactor prior to the introduction of the second step.

of these materials, adjusting the reaction temperature to a desired level, and sequentially introducing the second reactant, it is possible to control the rate of heat generation and thereby carry out the reaction in a manner that appropriately monitors the reaction temperature, but surprisingly, the reaction yield in this case is very low, and even lower than that achieved by the laboratory scale batch process.

From the above analysis it is apparent that to date no method of preparing butyric acid ester derivatives of the above general formula (2) is known which suppresses by-products of contaminants or an effective purification process to remove the above impurities from the butyric acid ester derivatives of the above-mentioned general formula (2) produced, and therefore it seems to be extremely important to find a method for producing the butyric acid ester derivatives of the above-mentioned general formula (2), % of said pollutants or containing only a minimal proportion of said pollutants, in high yield and in an economically suitable manner, which could be carried out on an industrial scale.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the preparation of butyric acid ester derivatives of formula (2) above which can remove various contaminants which are by-products of the process and which cannot be formed. to avoid the use of conventional methods known in the art, in particular to the compounds of the above general formula (1), and to a process carried out with high efficiency. Another object of the present invention is to provide a process for the preparation of butyric acid ester derivatives of the above general formula (2), which is preferably carried out in an economical manner which makes it possible to achieve a high product yield while being highly productive.

The present invention relates to a process for the preparation of butyric acid ester derivatives of general formula (2):

OH

N (kA ^ ^C00R)

in which R has the same meaning as described above, characterized in that a mixture comprising a compound of formula (1) is treated:

H0CH ₂ -CH = CH-C00R (1) in which:

R represents a straight or branched chain alkyl group having 1 to 4 carbon atoms as a contaminant and a butyric acid ester derivative of the above formula (2) as the main component of the reaction mixture by adding a reagent capable of as such to convert the compound of formula (1) to an addition product which can be separated from the butyric acid ester derivative of formula (2).

The process of the invention will be described in more detail below.

The process for producing the butyric acid ester derivatives of the present invention comprises treating a mixture comprising the above compound of formula (1) as a contaminant in the reaction mixture and the above butyric acid ester derivative of the above formula (2) as a major component of the reaction mixture, and recovering the butyric acid ester derivative of the above general formula (2) at a high level of quality from said reaction mixture, which proceeds in an advantageous and economical manner, in high yield and at high productivity.

The above mixture is not particularly limited in composition, provided that it contains a compound of the above formula (1) as a contaminant of the reaction mixture and a butyric acid ester derivative of the above formula (2) as a major component of the reaction mixture, that the solution comprises the presence of the aforementioned butyric acid ester derivative of formula (2) obtained as a purified substance, for example as a distillate or as a crystalline lyophilisate, and the presence of a butyric acid ester derivative of the above formula (2) obtained as a crude product, e.g. as a concentrate, and furthermore, the presence of a butyric acid ester derivative of the above general formula (2) obtained as a solution, such as a reaction mixture resulting from the production of this derivative or as a solvent extract of the latter.

A *

in.

and''

·· ·· ·· 99 9 9 9 9

9 9 9 9 9 9 9 9 9 ·

9 9 · · · · ·

9,999 9,999,999 · 999,999

However, the scope of the present invention is not limited thereto.

The butyric ester derivative of formula (2), which is the major component of the reaction mixture, is not particularly limited as to the type of the individual, including, but not limited to, 4-cyano-3- methyl ester. hydroxybutyric acid ethyl ester

4-Cyano-3-hydroxybutyric acid, n-propyl ester

4-Cyano-3-hydroxybutyric acid, i-propyl ester

4-Cyano-3-hydroxybutyric acid, n-butyl ester

4-Cyano-3-hydroxybutyric acid, i-butyl ester

4-cyano-3-hydroxybutyric acid, s-butyl ester

4-cyano-3-hydroxybutyric acid, and t-butyl ester

4-Cyano-3-hydroxybutyric acid. This butyric acid ester derivative may have its hydroxyl group protected by an alkyl group, an acyl group or other protecting groups.

The aforementioned added reagent is a reagent capable of adding as such an ethylenic bond and converting the above compound of formula (1) to an addition product, such as a water-soluble addition compound that can be readily separated from said butyric acid ester derivative of the above of formula (2).

These reagents are not particularly limited, and include sulfuric acid salts such as lithium sulfite, sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, and the like. Calcium sulphite Magnesium sulphite and ammonium sulphite, and the like. The sulfuric acid salts may be used alone or in combination, i.e. two or more thereof. Of the above compounds, the use of sodium sulfite and potassium sulfite is preferred, since they are cost-effective, commercially available and have the required efficacy in the process of the invention.

In cases where a sulfite is used as said addition reagent, this sulfite forms with the compound of the above general formula (1) an addition product, for example a compound of the following general formula (5):

SOýl

I (5) hoch ₂ -ch-ch ₂ -coor in which:

R represents a hydrogen atom, a cation present in the system or a straight or branched chain alkyl group having 1 to 4 carbon atoms,

M represents a hydrogen atom or a cation present in the system. The above product of formula (5) is so different from the butyric acid ester derivative of the above formula (2) in terms of water solubility, boiling point and other physicochemical properties that it can be separated from said reaction mixture in an easy and highly efficient manner using well known and suitable industrial purification processes such as solvent extraction, washing, distillation and the like other purification processes.

·· ·· ·· 4 4 4 · 44

4 '44 4 4 44 4 · 4 4 4' 4 4 4 4 4 4 4 '4' 4 4 · · 444 4 4 4 4 · 4 · 4 · 4 444

4 4 4 4 4

14 4 4 4 4 4 44

The amount of the above-mentioned addition agent can be chosen arbitrarily according to the amount of the compound of formula (1) and the type of addition reagent used, among other parameters, but it is generally preferred to use equimolar amounts or excess amounts of the addition reagent. of the reagent, preferably 1 to 10 molar equivalents of the reagent relative to the amount of the compound of formula (1).

Treatment of the reaction mixture with the addition reagent can be accomplished by mixing the addition reagent with the mixture. This mixing is preferably carried out in a solvent.

The above solvent may be, for example, water or an organic solvent. The organic solvent is not limited to any type of substance, and these include organic alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, ethylene glycol, methoxyethanol, etc., hydrocarbons such as benzene, toluene , cyclohexane, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, methyl t-butyl ether, dimethoxyethane, etc., esters such as ethyl acetate, butyl acetate, etc., further halogenated hydrocarbons such as methylene chloride, chloroform, etc., ketones such as acetone, methyl ethyl ketone, etc., further nitrogen-containing organic solvents such as dimethylformamide, acetamide, formamide, acetonitrile, etc., and organic solvents containing sulfur such as is, for example, dimethylsulfoxide, and the like other solvents. Water and more ··

4 * 44 44

44 4 · «· 4 • · · 4444 · 4 * 4 · ·· '* 4 ·' 4 • 4 4 '4.4 · 4 4 * 4 4 4 ϊ-

the above organic solvents may be used alone or in combination. However, it is preferred to use either a mixture of solvents containing one or more organic solvents and water or water alone. More preferably, a solvent mixture comprising one or more organic solvents and water is used.

The amount of the solvent can be selected according to the type and amount of the above-mentioned addition reagent, taking into account the type of solvent used.

The conditions for carrying out the treatment of the reaction mixture with said addition reagent depend on the type and amount of said addition reagent used and on the treatment temperature, as well as the treatment time selected, and processing under strong acidic or strongly basic conditions is not recommended. of the above formula (2) is susceptible to side reactions such as solvolysis or hydrolysis and transesterification under these conditions. In this regard, when a solvent mixture consisting of an organic solvent and water is used as the solvent, or water alone is used as the solvent, the pH of the system, which is treated with said addition reagent, is usually in the range of pH 1 to pH 12 Preferably, the pH is in the range of 2 to 11, and more preferably the pH is in the range of 3 to 10, with the pH in the range of 4 to 9 being particularly preferred.

· F · f · I I I • • * I * * *

The treatment temperature of the reaction mixture by the above addition reagent can be arbitrarily selected according to the desired treatment time and other factors such that the temperature ranges from the freezing point to the boiling point of the treatment system, but is usually in the range from 0 to 100 ° C, and preferably from about room temperature to 90 ° C.

The progress of treatment of the reaction mixture with the addition reagent can be monitored by gas chromatography or high performance liquid chromatography, and the treatment time can usually be from 5 minutes to 4 hours when, for example, processing is carried out within the preferred temperature range from room temperature to 90 ° C. Deň: 32 ° C.

In order to suppress as much side reactions as possible such as oxidation, this treatment of the reaction mixture with said addition reagent is preferably carried out under an inert gas atmosphere, such as under a nitrogen atmosphere.

Upon completion of the above treatment of the reaction mixture with the addition reagent, the mixture thus obtained is purified using one method or a combination of suitable routine purification procedures, such as solvent extraction, washing, concentration, crystallization and distillation, to form a compound. of formula (1) is removed in the form of an addition product with said addition reagent so as to obtain a butyric acid ester derivative of the above formula (2) in a high degree of quality. When 44 44 44 44 i 4 4 4 4> 4 4

4 4 4 4 4 4 4 4

4 444 · · 4

.4

It is preferred to avoid using conditions under which this adduct could be readily decomposed to carry out this process.

In carrying out the process of the present invention, where the butyric acid ester derivative of formula (2) as the major component of the reaction mixture is in the form of an optically active compound, the butyric acid ester derivative of formula (2) is obtainable after processing. said addition reagent also in the form of an optically active compound.

The present invention further relates to a process for preparing a butyric acid ester derivative of formula (2), which comprises reacting a compound of formula (3):

OH

X ^ / Á / COOR ⁽³⁾ · in which:

R is a straight or branched chain alkyl group having 1 to 4 carbon atoms, and

X represents a group selected from chlorine, bromine, iodine, methanesulfonyloxy and substituted or unsubstituted phenylsulfonyloxy, with a hydrocyanic acid salt in the presence of an addition reagent capable of adding to the ethylene bond to convert the above compound of formula (1) to an addition product which can then be separated from the butyric acid ester derivative of the above r:

'· I *' ··· · ^τ · ► t ¹ · ···. - · ^of the general formula (2).

In a process for producing a butyric acid ester derivative of formula (2) by reaction between said compound of formula (3) and said hydrocyanic acid salt, when this reaction is carried out in the presence of said addition reagent, an acid ester derivative is thereby obtained. buttery of the formula (2) at a high level of quality.

L

In the process according to the invention, there is no restriction on the compound of the above general formula (3), for example 4-chloro-3-hydroxybutyric acid methyl ester, ethyl ester of the acid can be used.

4-chloro-3-hydroxybutyric acid, n-propyl ester

4-chloro-3-hydroxybutyric acid, i-propyl ester

4-chloro-3-hydroxybutyric acid, n-butyl ester

4-chloro-3-hydroxybutyric acid, i-butyl ester

4-chloro-3-hydroxybutyric acid, s-butyl ester

4-chloro-3-hydroxybutyric acid t-butyl ester

4-chloro-3-hydroxybutyric acid methyl ester

4-bromo-3-hydroxybutyric acid ethyl ester

4-bromo-3-hydroxybutyric acid, n-propyl ester

4-bromo-3-hydroxybutyric acid, i-propyl ester

4-bromo-3-hydroxybutyric acid, n-butyl ester

4-bromo-3-hydroxybutyric acid, i-butyl ester

4-bromo-3-hydroxybutyric acid, s-butyl ester

4-bromo-3-hydroxybutyric acid t-butyl ester

4-bromo-3-hydroxybutyric acid methyl ester

4-Iodo-3-hydroxybutyric acid ethyl ester

4-iodo-3-hydroxybutyric acid, n-propyl ester

4-iodo-3-hydroxybutyric acid i-propyl ester

4-iodo-3-hydroxybutyric acid n-butyl ester · ♦ · 9 99 99 ··

9- i · '9-: 9 9 9 9' 9 9 ι «« <9. · «- '·· ·' · '9 9 9' 9 <<9 ί * * '···' · 9 9 999 9 99 ^: 9 99 9 9 9 9 9 9 9 9 9 9

4-iodo-3-hydroxybutyric acid, i-butyl ester

4-iodo-3-hydroxybutyric acid, s-butyl ester

4-iodo-3-hydroxybutyric acid t-butyl ester

4-iodo-3-hydroxybutyric acid methyl ester

4-methanesulfonyloxy-3-hydroxybutyric acid, 4-methanesulfonyloxy-3-hydroxybutyric acid ethyl ester and 4-methanesulfonyloxy-3-hydroxybutyric acid n-propyl ester.

s-butyl ester t-butyl ester jf

and'

Among others, mention may be made in particular of 4-methanesulfonyloxy-3-hydroxybutyric acid i-propyl ester, n-butyl ester

4-methanesulfonyloxy-3-hydroxybutyrate, 4-methanesulfonyloxy-3-hydroxybutyrate 4-methanesulfonyloxy-3-hydroxybutyrate

4-Methanesulfonyloxy-3-hydroxybutyric acid, 4-phenylsulfonyloxy-3-hydroxybutyric acid methyl ester, 4-phenylsulfonyloxy-3-hydroxybutyric acid ethyl ester

4-phenylsulfonyloxy-3-hydroxybutyric 4-phenylsulfonyloxy-3-hydroxybutyric 4-phenylsulfonyloxy-3-hydroxybutyric 4-phenylsulfonyloxy-3-hydroxybutyric 4-phenylsulfonyloxy-3-hydroxybutyric

4-phenylsulfonyloxy-3-hydroxybutyric acid, 4-toluenesulfonyloxy-3-hydroxybutyric acid methyl ester, 4-toluenesulfonyloxy-3-hydroxybutyric acid ethyl ester

4-toluenesulfonyloxy-3-hydroxybutyric acid

4-toluenesulfonyloxy-3-hydroxybutyrate, n-butyl 4-toluenesulfonyloxy-3-hydroxybutyrate, 4-toluenesulfonyloxy-3-hydroxybutyric acid i-butyl ester, 4-toluenesulfonyloxy-3-hydroxybutyric acid s-butyl ester, and 4-toluenesulfonyloxy-3-hydroxybutyrate -toluenesulfonyloxy-3-hydroxybutyric acid.

n-propyl ester i-propyl ester n-butyl ester i-butyl ester s-butyl ester t-butyl ester n-propyl ester i-propyl ester

From the group of these compounds, the following compounds are preferred in terms of economic cost and industrial availability:

4-chloro-3-hydroxybutyric acid methyl ester, 4-chloro-3-hydroxybutyric acid ethyl ester, n-propyl ester. ''^{<<<<<<<........................} : · ⁽ · '* * * «« «« «• • •» »» »» »» »»

i-propyl ester n-butyl ester i-butyl ester s-butyl ester t-butyl ester

5 '

I f

4-chloro-3-hydroxybutyric,

4-chloro-3-hydroxybutyric,

4-chloro-3-hydroxybutyric,

4-chloro-3-hydroxybutyrate.

4-chloro-3-hydroxybutyrate.

4-chloro-3-hydroxybutyric acid, 4-bromo-3-hydroxybutyric acid methyl ester, 4-bromo-3-hydroxybutyric acid ethyl ester, 4-bromo-3-hydroxybutyric acid n-propyl ester, 4-bromo-3- acid i-propyl ester hydroxybutyric acid, 4-bromo-3-hydroxybutyric acid n-butyl ester, 4-bromo-3-hydroxybutyric acid i-butyl ester, 4-bromo-3-hydroxybutyric acid s-butyl ester and 4-bromo-3-hydroxybutyric acid t-butyl ester. Even more preferred are 4-chloro-3-hydroxybutyric acid methyl ester, 4-chloro-3-hydroxybutyric acid ethyl ester, 4-chloro-3-hydroxybutyric acid t-butyl ester, 4-bromo-3-hydroxybutyric acid methyl ester, 4-bromoethyl ethyl ester 3-hydroxybutyric acid and 4-bromo-3-hydroxybutyric acid t-butyl ester. Especially preferred are ethyl 4-chloro-3-hydroxybutyrate and ethyl 4-bromo-3-hydroxybutyrate.

The above compounds of formula (3) may be prepared by conventional methods known in the art, for example by carboalkoxylation of the corresponding epihalohydrin as described in Journal of Organic Chemistry 32, 3888 (1967), further by chemical or enzymatic methods. reduction • '♦. ·. · · • i ^f · *>

• (· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The corresponding β-ketoester is described in Tetrahedron Letters 35, No. 44, 8119 (1994) and Japanese Kokai Publication Sho-64-60391, or by sulfonating the corresponding β, γ-dihydroxyester as described in Japanese Kohyo Publication Hei-7-500105.

HIVE

Á £

1 '

AND'

There is no particular restriction on the above-mentioned hydrocyanic acid salt, which includes salts with inorganic bases such as sodium cyanide, potassium cyanide, etc., and also salts of hydrocyanic acid with organic bases such as The salts of hydrocyanic acid may be used alone or in combination with two or more of this type.

From the point of view of cost and industrial availability, hydrocyanic acid salts with inorganic bases are preferred, sodium cyanide or potassium cyanide being particularly preferred.

The amount of the hydrocyanic acid salt used is not particularly limited, but is preferably used in an amount of 1 to 2 equivalents based on the amount of the compound of formula (3) above. More preferably, the amount is in the range of 1 to 1.5 equivalents, and more preferably, the amount is in the range of 1.1 to 1.4 equivalents.

The amount of the above-mentioned addition reagent can be chosen as desired, taking into account the type of addition reagent used and the like, but in general, an amount in the range of 0.01

9'9 9 · 9 99 '··> 9 99 •' 9 · · '· 9' · · / 9 * '· «.: 9 · 9> 9 9 9' 9 9 ·>9'9 j <9 • ·> 91.9 9 19 9 9 '9 4 9 9 99 9 99 9''> 9 ·. 9 9 19 ^ν 9 .9 9 9 9 99 '<9 9 9 9

1 '£;

Mole to 1 mole, based on each mole of the aforementioned compound of formula (3). More preferably, the amount is in the range of from 0.1 mol to 0.1 mol

0.5 mol.

The reaction between the aforementioned compound of formula (3) and said hydrocyanic acid salt, which takes place in the presence of said addition reagent, is carried out by mixing said compound of formula (3) with the hydrocyanic acid salt and said addition reagent. This mixing is preferably carried out in a solvent.

The solvent may be water or an organic solvent. The choice of this organic solvent is not particularly limited so that alcohols such as methanol, ethanol, n-propyl alcohol, isopropanol, ethylene glycol, methoxyethanol, etc., hydrocarbons such as benzene, toluene, cyclohexane, etc., further ethers such as diethyl ether, tetrahydrofuran, dioxane, methyl t-butyl ether, dimethoxyethane, etc., esters such as ethyl acetate, butyl acetate, etc., halogenated hydrocarbons such as e.g. methylene chloride, chloroform, etc., ketones such as acetone, methyl ethyl ketone, etc., further nitrogen-containing organic solvents such as dimethylformamide, acetamide, formamide, acetonitrile, etc., and organic sulfur-containing solvents such as dimethylsulfoxide, and the like other solvents. Water and other organic solvents mentioned above may be used alone or in combination. However, it is preferred to use either a mixture of solvents ^; · 4 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

99 9 9 99

9 99 «· <

• 9 9 ·

999 ·· <

containing one or more water-miscible organic solvents and water or water alone. According to an even more preferred embodiment of the invention, a solvent mixture comprising one or more water-miscible organic solvents and water is used.

ť:

The amount of the solvent can be chosen according to the type and amount of the compound of formula (3) used, the type and amount of the hydrocyanic acid salt used, the type and amount of the addition reagent used and the kind of solvent used. to provide the required concentration of said compound of the above formula (3), which preferably ranges from 1 to 100 percent w / v, more preferably from 10 to 50 percent w / v.

In carrying out the above reaction, the temperature may be chosen arbitrarily, taking into account the desired processing time and other factors, and generally ranges from freezing point to boiling point of the process system, but usually the temperature is in the range of 0 to 100 ° C and preferably is in the range of about room temperature to 90 ° C.

The progress of the reaction can be monitored by gas chromatography or high performance liquid chromatography, and if the reaction is carried out in the range of about room temperature to 90 ° C, it is preferable to select a reaction interval of 5 minutes to 4 hours. which is an interval sufficient ·· 00 • · · 0

0 0 0

0 · »0 ·

0 0

0 0 0 ·· • 0 00 00 * · 0 0 ··

0 0 0 0

0 ·· 9 00 0 00 0 0 0

00 00 to the complete conversion to the above main reaction addition product.

$ sSri »

ί after completion

In order to minimize side reactions such as oxidation, the above reactions may preferably be carried out under an inert gas atmosphere, such as under a nitrogen atmosphere.

After completion of the above reaction, the reaction mixture thus obtained is subjected to treatment by any of the following methods or a combination of these commonly used and well known methods, such as solvent extraction, washing, concentration, crystallization and distillation, where of formula (1) is removed as an addition product with said addition reagent so that the butyric acid derivative of the above formula (2) can be separated in a high degree of quality. In carrying out this process, it is preferable to avoid the use of conditions under which this adduct could be; easily laid out.

In carrying out the process of the present invention, when the compound of the above formula (3) is in the form of an optically active compound, it is possible to obtain the product of this process, i.e. the butyric acid ester derivative of the formula (2) with the same steric configuration. corresponding to the steric configuration of the compound of formula (3).

In a further aspect, the present invention relates to a process for producing a butyric acid ester derivative of the above general formula (2), which comprises the reaction of: ·,, «« «« «« «« «« «« «« «« «« «« «« «« «« ««

a compound of the above formula (3) with a hydrocyanic acid salt by the flow method.

In a process for producing a butyric acid ester derivative of formula (2) by reaction between said compound of general formula (3) and said hydrocyanic acid salt, if this is carried out by the flow method, a butyric acid ester derivative of general formula (2) high quality, high quality. ,

This reaction between the compound of the above formula (3) and said hydrocyanic acid salt involves the generation of a considerable amount of heat, so that the temperature of the reaction system is usually difficult to control, but this reaction temperature can be easily controlled when this reaction is carried out by the flow method.

The flow-through reaction is preferably carried out using a tubular reactor, a thin-film reactor, or a series of continuously stirred tank reactors. These reactors are advantageous because they have a relatively high heat exchange capacity compared to a tank reactor equipped with a stirrer, which is commonly used to carry out batch or semi-batch processes.

The above reaction, which is carried out by the flow method, is carried out by introducing the aforementioned compound of formula (3) and the hydrocyanic acid salt into the reactor as parallel streams which are then introduced into the reactor. ··

or the compound of the above formula (3) is premixed with or outside the hydrocyanic acid salt and then introduced into the reactor. In this process, the mixing and reaction is preferably carried out in a solvent.

With respect to the aforementioned reaction by the flow method, the flow rate of the reaction mixture can be freely selected, taking into account, inter alia, the type and amount of said compound of the general formula (3), the type and amount of said hydrocyanic acid salt, the type and amount of solvent used and the reaction temperature, usually the flow rate can be adjusted in such a way that the residence time during which the reaction mixture is passed through said reactor is equal to or longer than the time necessary to complete the reaction. It is also possible to select an arrangement where the reaction mixture is passed through the reactor several times, the total residence time being again at least corresponding to the time required to complete the reaction.

Regarding the above reaction and the flow method applied, the type and amount _f of the solvent used, the reaction temperature and the type and amount of the above salt, hydrocyanic acid and the process selected f.

separating the obtained addition product after the reaction may be similar to the reaction conditions between the compound of formula (3) and the hydrocyanic acid salt in the presence of said addition reagent, as described in more detail above. Similarly, in cases where the compound of formula (3) above is in the form of i

The optically active compound can then be obtained from the process, i.e. the butyric acid ester derivative of the general formula (2) with the same steric configuration corresponding to the steric one. the configuration of the compound of formula (3).

By carrying out the above reaction by a flow method in the presence of the above addition reagent, a butyric acid ester derivative of the above general formula (2) containing a minimal proportion of the impurity compound of the above general formula (1) in high yield can be obtained.

The amount of the above addition reagent can be selected according to the amount of the above compound of formula (1) and the type of addition reagent used, but generally 0.01 to 1 molar equivalent is preferred. of an addition reagent, based on the amount of the compound of the above formula (3), more preferably 0.1 to 0.5 molar equivalent of the addition reagent, based on the amount of the compound of the above formula (3).

The reaction, which is carried out by a flow method in the presence of said addition reagent, is carried out by injecting the compound of formula (3), said hydrocyanic acid salt and said addition reagent into the reactor in parallel flow, for mixing, or said compound of formula (3), said hydrocyanic acid salt and said addition reagent

• · ► · · ·

The mixture is premixed or external to the system, and then the mixture is introduced into the reactor, in which the stirring and reaction are preferably carried out in a solvent.

As regards the two production processes referred to above, namely:

(i) a process comprising treating a mixture comprising the aforementioned compound of formula (1) as a contaminant and a butyric acid ester derivative of the above formula (2) as a major component of a reaction mixture with an addition reagent capable of adding to the ethylenic binding said compound of formula (1) to convert said compound of formula (1) to an addition product which is separable from said butyric acid ester derivative of formula (2) (including a process comprising reacting said compound of formula (3) with said hydrocyanic acid salt in the presence of said addition reagent, and (ii) a process comprising reacting said compound of formula (3) with said hydrocyanic acid salt using a flow method, said first use of said first being procedure (i) from the perspective and to obtain a butyric acid ester derivative of the aforementioned general formula (2) with a high degree of quality and with minimal contamination of the product contaminating the compound of the aforementioned general formula (1). On the other hand, if this process is carried out in a second process (ii), a butyric acid ester derivative of the above general formula (2) can be obtained in high yield. Further, if this process is carried out in a combined process of (i) and (ii), it is possible to obtain a butyric acid ester derivative of the foregoing.

99 of the formula (2) at a high level of quality and with minimal contamination by the polluting compound of formula (1) and at the same time a high yield.

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention will be explained in more detail below with reference to specific examples which serve only to illustrate the process and to provide further details of the process, without however limiting the scope of the invention.

In the following examples, (R) -4-cyano-3-hydroxybutyric acid ethyl ester (compound of formula (2) wherein R is ethyl)) was used as the butyric acid ester derivative of the above general formula (2). treated with an addition reagent capable of adhering to the ethylene bond, and the compound of formula (3) above was ethyl (S) -4-chloro-3-hydroxybutyrate (compound of formula (3) wherein X is chlorine) and R is ethyl), which compound is reacted with a hydrocyanic acid salt.

Yields and contents of 4-hydroxycrotonic acid ethyl ester (compound of formula (1) in which R is ethyl), ethyl 4-cyano-3-hydroxybutyrate and ethyl 4-chloro-3-hydroxybutyrate mentioned in The following examples were determined using the following analytical system:

High Performance Liquid Chromatography (HPLC):

equipment: HPLC system equipped with UV detector,

Column packing: octylsilylated silica gel (0 5 µm), Column size: 4.6 mm x 250 mm,

mobile phase: 18 parts of acetonitrile for HPLC + 82 parts of distilled water for HPLC, column temperature: 25 ± 1 ° C flow rate: 1.0 ml / min, detector: UV 205 nm, <s. .

Detention period:

- 4-hydroxycrotonic acid ethyl ester for about 9 to 10 minutes,

- ethyl 4-cyano-3-hydroxybutyrate, for about 8 minutes,

- ethyl 4-chloro-3-hydroxybutyrate for about 15 minutes.

Example 1

4-Cyano-3-hydroxybutyric acid ethyl ester (10.6 grams) containing 5.2% w / w (based on 4-cyano-3-hydroxybutyric acid ethyl ester), which will similarly be used in followed by 4-hydroxycrotonic acid ethyl ester, which was mixed with 25.2 g of ethyl acetate. 10.1 grams of this mixture were removed, and 10.2 grams of water and 1.0 grams of sodium sulfite were added, followed by stirring at room temperature for 4 hours. 3.2 grams of sodium chloride was added to make the aqueous layer saturated with sodium chloride.

The yield of ethyl 4-cyano-3-hydroxybutyrate in the ethyl acetate layer was 93% and the ethyl 4-hydroxycrotonic acid content of this layer was 0.01%.

and?

'1:

«2.

·· ··

w / w (weight based on 4-cyano-3-hydroxybutyric acid ethyl ester, the same expression will be used hereinafter) with a removal rate of 99.9%.

4-Hydroxycrotonic acid ethyl ester:

¹ H-NMR (CDCl ₃ ,

1.29 (3 H, t),

4.33 (2H, br), ¹³ C-NMR (gdci ₃ ,

14.22, 60.53,

Example

The procedure was carried out in the same manner as in Example 1 except that 1.1 grams of potassium sulfite was used instead of 1.0 grams of sodium sulfite.

The yield of ethyl 4-cyano-3-hydroxybutyrate in the ethyl acetate layer was 94% and the ethyl 4-hydroxycrotonic acid content was 0.01% w / w. (degree of removal: 99.9%).

Comparative Example 1

The procedure was carried out in the same manner as in Example 1, but 1.0 grams of sodium sulfite was not added.

The yield of ethyl 4-cyano-3-hydroxybutyrate in the ethyl acetate layer was 94% and the ethyl 4-hydroxycrotonic acid content was 5.5% w / w. (degree of removal: 0.6%).

400 MHz) σ:

2.75 (1 H, br), 4.20 (2 H, q),

6.09 (1H, m); 7.03 (1H, m).

100 MHz) σ:

61.81, 120.13, 147.04, 166.62.

fc l'S;

e ⁵ '

Example 3

10.0 grams of 4-chloro-3-hydroxybutyric acid ethyl ester (92% purity), 3.0 grams of sodium cyanide, 1.4 grams of sodium sulfite were used,

17.6 grams of water and 15.0 grams of formamide were mixed and stirred at 60 ° C for 2 hours, then allowed to cool to room temperature.

The yield of ethyl 4-cyano-3-hydroxybutyrate was 67% and the content of ethyl 4-hydroxycrotonic acid was 0.08% w / w. (weight based on 4-cyano-3-hydroxybutyric acid ethyl ester, the same principle being applied in the next).

Example 4

The procedure was carried out in the same manner as in Example 3 except that 1.8 g of potassium sulfite was used instead of 1.4 g of sodium sulfite.

The yield of ethyl 4-cyano-3-hydroxybutyrate was 66% and the content of ethyl 4-hydroxycrotonic acid was 0.03% w / w.

Comparative Example 2

The procedure was carried out in the same manner as in Example 3, except that 1.4 grams of sodium sulfite was not added.

·· '

4 '«* 4

The yield of ethyl 4-cyano-3-hydroxybutyrate was 69% and the ethyl 4-hydroxycrotonic acid content was

3.3% w / w

Example 5

From the reaction mixture containing 3.3% w / w. 15.0 grams of the 4-hydroxycrotonic acid ethyl ester pollutant obtained in Comparative Example 2 was collected, and then 0.6 grams of sodium sulfite was added and the mixture was stirred at room temperature for 4 hours.

The yield of ethyl 4-cyano-3-hydroxybutyrate was 93% and the content of ethyl 4-hydroxycrotonic acid was 0.46% w / w. (degree of removal: 85%).

Example 6

The procedure was as in Example 5, except that 0.6 grams of potassium sulfite was used instead of 0.6 grams of sodium sulfite. .

The yield of ethyl 4-cyano-3-hydroxybutyrate was 98% and the ethyl 4-hydroxycrotonic acid content was 0/06% w / w. (degree of removal: 98%).

Example 7

36.0 grams of ethyl ester were mixed with ice-cooling

44 t '«· 4» / 4 4 · • 44 ··· · · · · · 4

4-chloro-3-hydroxybutyrate (92% purity), 13.0 grams of sodium cyanide, 32.0 grams of water and 74.5 grams of formamide. The reaction mixture was immediately passed through a tubular reactor having an internal diameter (i.d.) of 5 millimeters and a length of 1 meter at which the temperature was controlled at 80 ° C with a flow rate of approximately 5 milliliters / minute. The reaction mixture exiting the reactor was immediately cooled with ice. The resulting reaction mixture was monitored for ethyl 4-cyano-3-hydroxybutyrate using a high performance liquid chromatography method and was repeatedly fed through a tubular reactor. The yield of the process was maximal after 8 passes.

The yield of ethyl 4-cyano-3-hydroxybutyrate was 85.0%. The 4-hydroxycrotonic acid ethyl ester content was 1.3% w / w. ’

Comparative Example 3

36.0 grams of 4-chloro-3-hydroxybutyric acid ethyl ester (92% purity) was mixed with 74.5 grams of formamide and the temperature of the reaction mixture was adjusted to 80 ° C. An aqueous solution of sodium cyanide (13.0 grams in 32.0 grams of water) was added while stirring, dropwise over a period of about 50 minutes. Upon completion of the dropwise addition, the resulting mixture was further allowed to react at 80 ° C for about 1 hour.

The yield of ethyl 4-cyano-3-hydroxybutyrate was 77.5%.

Comparative Example 4

13.0 grams of sodium cyanide, 74.5 grams of formamide and 32.0 grams of water were mixed together to adjust the temperature of the reaction mixture to 80 ° C. While stirring, 36.0 grams of 4-chloro-3-hydroxybutyric acid ethyl ester (92% purity) was added dropwise over about 50 minutes. Upon completion of the dropwise addition, the resulting mixture was further allowed to react at 80 ° C for about 1 hour.

The yield of 4-cyano-3-hydroxybutyric acid ethyl ester was 55.4%.

Example 8

36.0 grams of ethyl ester were mixed with ice-cooling

4-chloro-3-hydroxybutyrate (92% purity), 11.0 grams of sodium cyanide, 25.0 grams of sodium sulfite, 21.5 grams of water and 74.5 grams of formamide. The reaction mixture was immediately passed through a tubular reactor having an internal diameter (i.d.) of 5 millimeters and a length of 1 meter at which the temperature was controlled at 80 ° C with a flow rate of approximately 5 milliliters / minute. The reaction mixture exiting the reactor was immediately cooled with ice. The resulting reaction mixture was monitored for ethyl 4-cyano-3-hydroxybutyrate using a high performance liquid chromatography method and was repeatedly fed through a tubular reactor. The yield of 4-cyano-3-hydroxybutyric acid ethyl ester showed a maximum value of 85.4% after 8 passes.

·· «· · · ·

9 9

· ♦ · · ««

The ethyl 4-hydroxycrotonic acid content at this point was 0.07% w / w.

Industrial applicability

By the process of producing the butyric acid ester derivatives of the present invention described above, it is now possible to prepare butyric acid esters of formula (2) of high quality with minimal contamination. the compounds of formula (1) in a convenient, economical and efficient manner.

Claims (33)

A process for producing butyric acid ester derivatives of the general formula (2): OH NC ^ / A / COOR ⁽² > in which : R represents a straight or branched chain alkyl group having 1 to 4 carbon atoms, characterized in that a mixture comprising a compound of formula (1) is treated: HOCH ₂ -CH = CH-COOR (1) wherein R has the same meaning as above as a contaminant and a butyric acid ester derivative of the above formula (2) as a major component of the reaction mixture with an addition reagent which is capable of adding as such to the ethylene bond and thereby converting the compound of formula (1) to an addition product which is separable from the butyric acid ester derivative of formula (2). A process for the preparation of butyric acid ester derivatives according to claim 1, characterized in that R represents an ethyl group or a t-butyl group. 34 19 9 9 9 • 9 '99 9 9 »· · · I ♦ '9 »í>' 9 • 99 '« The method of claim 2, the group. The process according to claim 1, wherein the product is in the manufacture of butyric acid ester derivatives characterized in that R represents ethyl production of butyric acid ester derivatives 2 or 3, characterized in that the water-soluble compound is added. A process for the preparation of butyric acid ester derivatives according to claim 1, 2 or 3, characterized in that the addition reagent is sulfuric acid. 6. A process for the production of butyric acid ester derivatives according to claim 5, wherein the addition reagent is sodium sulfite or potassium sulfite. A process for the production of butyric acid ester derivatives according to claim 1, 2, 3, 4, 5 or 6, characterized in that the butyric acid ester derivative of the general formula (2) is an optically active compound. A process for producing butyric acid ester derivatives of the general formula (2): OH ^NC \ As / ^{C00R (2)} in which: R represents an alkyl group straight or branched having 1-4 carbon atoms, characterized in that it comprises reacting a compound of ·· ·· ·· * ♦ '··, ΐ ·' · ^(· '· ^J' · ··· '··· ♦ ·. ·· ·· formulas (3) OH X ^ / k ^ COOR < ³ > in which : R is as defined above, and X is selected from the group consisting of chlorine, bromine, iodine, methanesulfonyloxy and substituted or unsubstituted phenylsulfonyloxy, with a hydrocyanic acid salt in the presence of an addition reagent capable of addition to an ethylene bond to convert a compound of formula (1):. boy ₂ -ch = ch-cgor. (1) in which R has the same meaning as above, to an addition product which can then be separated from the butyric acid ester derivative of the above general formula (2). 9. A process for the preparation of butyric acid ester derivatives according to claim 8, wherein R is ethyl or t-butyl; A process for the preparation of butyric acid ester derivatives according to claim 9, wherein R is ethyl. ř l ·. ίϊ 9 9 '9 9 9 9 9 9 · »Tf> 9 <9 9 9 9'9 9 59 9 · '' 9 9 <·· '9 9 9 ^ι: · <9 <9 · 99 «··· 9 ·, j9 9> 9 9 A process for the preparation of butyric acid ester derivatives according to claim 8, 9 or 10, characterized in that the addition product is a water-soluble compound. A process for the preparation of butyric acid ester derivatives according to claim 8, 9 or 10, characterized in that the addition reagent is sulfuric acid. The process for producing butyric acid ester derivatives according to claim 12, wherein the addition reagent is sodium sulfite or potassium sulfite. A process for the preparation of butyric acid ester derivatives according to claim 8, 9, 10, 11, 12 or 13, characterized in that X represents a chlorine atom or a bromine atom. A process for the preparation of butyric acid ester derivatives according to claim 14, wherein X is a chlorine atom. ζ ^ν · .v A process for the preparation of butyric acid ester derivatives according to claim 8, 9, 10, 11, 12, 13, 14 or 15, characterized in that the hydrocyanic acid salt is sodium cyanide or potassium cyanide. 17. A process for the preparation of butyric acid ester derivatives according to claim 16, wherein the hydrocyanic acid salt is sodium cyanide. A process for the preparation of butyric acid ester derivatives according to claim 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, characterized in that both the compound of said general formula (3) and the butyric acid ester derivative of general formula (3). 2) are optically active compounds. ·· ·· I '4 A process for producing butyric acid ester derivatives of the general formula (2): OH NC ^ / k ^ COOE 3 2) * in which : R represents a straight or branched chain alkyl group having 1 to 4 carbon atoms, characterized in that it comprises reacting a compound of formula (3) OH X. A .COOR <3> in which : R is as defined above, and X represents a group selected from chlorine, bromine, iodine, methanesulfonyloxy and substituted or unsubstituted phenylsulfonyloxy, with the hydrocyanic acid salt, the reaction being carried out by the flow method. 20. The process for producing a butyric acid ester derivative according to claim 19, wherein the flow reaction is carried out using a reactor selected from the group consisting of a tubular reactor, a thin reactor. ·· *. • • • • • • • • • • • • • • • • • • • • • • • • • • • • 4. 21. A process for producing butyric acid ester derivatives according to claim 20, wherein the reactor used is a tubular reactor. * 4 ' 22. The process for producing butyric acid ester derivatives according to claim 20, wherein the reactor used is a thin film reactor. A process for the preparation of butyric acid ester derivatives according to claim 19, 20, 21 or 22, characterized in that R represents an ethyl group or a t-butyl group. 24. A process for the preparation of butyric acid ester derivatives according to claim 23, wherein R is ethyl. 25. A process for the preparation of butyric acid ester derivatives according to claim 19, 20, 21, 22, 23 or 24 wherein X is chlorine or bromine. ý 26. The process for producing a butyric acid ester derivative according to claim 25 wherein X is chlorine. ’ A process for producing butyric acid ester derivatives according to claim 19, 20, 21, 22, 23, 24, 25 or 26, wherein the hydrocyanic acid salt is sodium cyanide or potassium cyanide. 28. The process for producing a butyric acid ester derivative according to claim 27 wherein the acid salt • 9 9 0 »8 ·· 9 9 9 • 9 0 0 · 0 10 0.0 ζ9 .9 9 Hydrogen cyanide is sodium cyanide. A method for producing a butyric acid ester derivative according to claim 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, characterized in that both the compound of said general formula (3) and the butyric acid ester derivative of general formula ( 2) are optically active compounds. A process for the preparation of butyric acid ester derivatives according to claim 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29, characterized in that the reaction is carried out in the presence of an addition reagent capable of adding to the ethylenic ester. a bond to convert a compound of formula (1): H0CH ₂ -CH = CH-C00R (1) in which R has the same meaning as above, to an addition product separable from the butyric acid ester derivative of the above formula (2): OH in which R is as defined above. 31. The process for producing a butyric acid ester derivative according to claim 30, wherein the addition product is a water-soluble compound. ···························· 32. The process for producing a butyric acid ester derivative according to claim 30, wherein the addition reagent is sulfuric acid. t r * <ř 33. The process for producing a butyric acid ester derivative according to claim 32, wherein the addition reagent is sodium sulfite or potassium sulfite.