JPH0742258B2 - Process for producing 3-substituted aminoacrylic acid esters - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing 3-substituted aminoacrylic acid esters.

The 3-substituted aminoacrylic acid esters are extremely effective as a reaction reagent in the production of medicines and the like, and amino groups capable of substituting or reacting with various species adjacent to a carbon-carbon double bond in the molecule. Due to its unique skeleton, which has a group and an alkoxycarbonyl group, it is highly reactive as a raw material for synthesis and is expected to have a wide range of future applications.

[Description of Prior Art]

Conventionally, 3-substituted aminoacrylic acid esters are obtained by esterifying acetylene monocarboxylic acid (also referred to as “propiolic acid” or “propargyl acid”) and then reacting with an amine compound, and a rearrangement reaction of 3-substituted aminoacrolein. Was obtained by.

As the former method, for example, acetylene monocarboxylic acid is heated under reflux for 2 days with anhydrous methanol solution of sulfuric acid adjusted to a concentration of 10% to produce acetylene monocarboxylic acid methyl ester, and then adjusted to 20 ° C. It was found that 3-dimethylaminoacrylic acid methyl ester was produced by adding dimethylamine to a tetrahydrofuran solution of acetylene monocarboxylic acid methyl ester.
a Acta) Vol. 52, p. 2651 (1969).
Furthermore, while stirring the anhydrous ether solution of n-butylamine and cooling with ice, acetylene monocarboxylic acid methyl ester was added dropwise to this solution for 1 hour, and after reacting at room temperature for 48 hours, the conditions were 12 Torr and 125 to 130 ° C. Distillation below yields 3-butylaminoacrylic acid methyl ester as a colorless, easily flowing liquid.
er.) Vol. 99, page 2539 (1966).

Moreover, as the latter method, for example, 3-methoxy-3
When (-dimethylamino) acrolein is heated in trichloromethane at 60 ° C, the isomer trans-3-
Conversion to (dimethylamino) acrylic acid methyl ester is possible by Angew Chemical International
Edition (Angew. Chem. Internat. Edit.), Vol. 7, No. 6, page 460 (1968).

However, in any of the conventional techniques for producing the above-mentioned 3-substituted aminoacrylic acid esters, it is difficult to obtain the starting materials such as acetylene monocarboxylic acid and 3-substituted aminoacrolein, and the produced 3- The yield of the substituted aminoacrylic acid ester is low (for example, it is 57% in the production method described in Angew Chemical International Edition, Vol. 7, No. 6, page 460) or produced. Even though the yield of 3-substituted aminoacrylic acid ester is high, the production reaction requires a long time (for example, in the production method described in Chemi Bar, Vol. 99, page 2539, the yield is 88%. However, the reaction time is 48 as described above.
It takes time. ) Was a drawback.

On the other hand, 3-alkoxyacrylonitrile represented by the general formula R ₁ -O-CH = C (R ₂ ) -CN is converted into the general formula R ₃ -N (R ₄ ).
It is reacted with an amine formula R ₃ -N represented by -H
_{(R 4) -CH = C (} R 2) a method of producing a 3-amino-acrylonitrile represented by -CN (JP 55-130950 JP)
Or an alkoxymethylene cyanoacetaldehyde represented by the general formula R ₁ -O-CH = C (CN) -CHO is represented by the general formula R ₃ -N
(R ₄ ) —H is reacted with an amine represented by the general formula R ₃ —N
Method for producing aminomethylene cyanoacetaldehydes represented by (R ₄ ) -CH = C (CN) -CHO (JP-A-59-
No. 48451) is proposed.

However, in these production methods, the amine is
Not only reacts with alkoxy groups, but also with cyan groups and acetaldehyde groups, and is therefore the desired product.
-There was a problem such as poor reaction selectivity of aminoacrylonitrile and aminomethylene cyanoacetaldehydes. Furthermore, in the former production method, as an amine,
When reacting an amine that does not react easily or completely with 3-alkoxyacrylonitrile, such as an aromatic amine having low basicity, the reaction takes a long time or the reaction time is shortened. There are drawbacks such as catalyzing the reaction and having to add a second reactive amine that is not present in the final product, such as ammonia, morpholine or picoline, and also In the latter production method, a large amount of the reaction solvent is used to smoothly proceed the reaction, or when the reaction solvent is not used, the amine is often used in an excessive amount. However, there are drawbacks such as the high cost of recovering the amine and the complicated recovery operation.

[Problems to be Solved by the Invention]

As described above, the known method for producing a 3-substituted aminoacrylic acid ester is, for example, difficult to obtain the raw material, the yield of the target product is low, and the selectivity of the target product is low. There are various problems such as low temperature, long reaction time, and large amount of reaction solvent used.

Therefore, an object of the present invention is to provide a method capable of producing a 3-substituted aminoacrylic acid ester in a high yield by a novel reaction by using an easily available raw material.

[Means for Solving the Problems]

The present inventors have conducted earnest research to establish a method for producing a 3-substituted aminoacrylic acid ester that can improve various drawbacks of the known method as described above. as a result,
By reacting a 3-alkoxyacrylic acid ester with an amine represented by the general formula (II) described later, the target compound can be produced very easily and with high yield and high selectivity.
They have found that a substituted aminoacrylic acid ester can be produced, and completed the present invention.

That is, the present invention relates to a method for producing a 3-substituted aminoacrylic acid ester, which comprises reacting a 3-alkoxyacrylic acid ester with an amine represented by the general formula (II) described later.

[Detailed description of each requirement of the present invention]

 The method of the present invention will be described in detail below.

In the method of the present invention, the 3-alkoxyacrylic acid ester is reacted with an amine represented by the general formula (II) described below, preferably in the presence of a solvent inert to the reaction, to form a 3-substituted amino group. This reaction is a novel reaction for producing acrylic acid esters.

The 3-alkoxyacrylic acid ester as a raw material in the method of the present invention is usually handled as a liquid and can be represented by the following general formula [I].

R ₁ O—CH═CH—COOR ₂ [I] In the general formula [I], R ₁ is, for example, a lower alkyl group having 1 to 5 carbon atoms. R ₂ is a linear or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group, an alkynyl group, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, or an aromatic group having 6 to 8 carbon atoms. Examples thereof include cyclic hydrocarbon groups such as hydrocarbon groups, and these may all have a substituent that does not inhibit the reaction. These 3-
Specific examples of the alkoxy acrylates include R ₁ in the above general formula [I] is methyl, ethyl, n-
(Or i-) propyl, n- (or i-) butyl,
an alkyl group such as sec-butyl, n- (or i-) pentyl, and R ₂ is methyl, ethyl, n- (or i
-) Propyl, n- (or i-) butyl, sec-butyl, n- (or i-) pentyl, n- (or i-)
Alkyl groups such as hexyl, n- (or i-) heptyl, n- (or i-) octyl, vinyl, allyl, 1
-Alkenyl groups such as propenyl, isopropenyl, 1-butenyl, 2-butenyl, 2-methylallyl, 1-pentenyl, 1-hexenyl, alkynyl groups such as ethynyl and propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, An alicyclic hydrocarbon group such as cyclooctyl, 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, 1-cyclohexenyl, and an aromatic hydrocarbon group such as phenyl, tolyl, xylyl, benzyl, phenethyl and the like 3-
Alkoxy acrylates are mentioned, especially 3
-Methyl methoxyacrylate, ethyl 3-methoxyacrylate, propyl 3-methoxyacrylate, butyl 3-methoxyacrylate, methyl 3-ethoxyacrylate,
Preferable examples include ethyl 3-ethoxyacrylate, propyl 3-ethoxyacrylate, and butyl 3-ethoxyacrylate. These 3-alkoxy acrylates are obtained, for example, by subjecting acrylates as a raw material, and this, an aliphatic alcohol and oxygen to catalytic oxidation reaction in the presence of palladium metal or a salt thereof and a nitrite. Once, 3,3-dialkoxypropionic acid esters, which are acetalization products of acrylic acid esters, were produced (see Japanese Patent Publication No. 61-36733), and the acetalization products were treated by a known method, for example, , Dealcohol by heating in the presence of acid catalyst [J. Chem. Researc
h (S), 1985, p. 80 and J. Chem. Research (M), 1985,
See p.0987 to p.0996. By this, it can be easily produced in a high yield, and acrylic acid esters, which are the raw materials for producing these 3-alkoxyacrylic acid esters, are also easily available on an industrial scale.

The amines which are another raw material in the method of the present invention can be represented by the following general formula [II].

In the general formula, R ₃ and R ₄ are each a hydrogen atom,
Cyclic carbonization such as straight-chain or branched-chain alkyl groups, alkenyl groups, alkynyl groups having 1 to 12 carbon atoms and alicyclic hydrocarbon groups having 3 to 12 carbon atoms, and aromatic hydrocarbon groups having 6 to 12 carbon atoms Hydrogen group (including a heterocycle, and the cyclic compound may have a substituent which does not hinder the reaction in the ring), etc., and R ₃ and R ₄ may be the same or different. It may be a different group. Further, R ₃ and R ₄ may be bonded to each other to form a ring. Specific examples of these amines include the following compounds.

(1) R ₃ and R ₄ both represent a hydrogen atom;
ammonia.

(2) R ₃ is a hydrogen atom and R ₄ is not a hydrogen atom; that is, the following primary amines.

Methylamine, ethylamine, n- (or i-) propylamine, n- (or i-) butylamine, sec-
Butylamine, n- (or i-) pentylamine, n
-(Or i-) hexylamine, n- (or i-)
Heptylamine, n- (or i-) octylamine,
n- (or i-) nonylamine, n- (or i-)
Decylamine, n- (or i-) undecylamine,
Aliphatic saturated amines such as n- (or i-) dodecylamine, allylamine, crotylamine, propargylamine, aliphatic unsaturated amines such as 2-butyn-1-amine, cyclopropylamine, cyclobutylamine,
Cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, cyclononylamine, cyclodecylamine, cycloundecylamine, cyclododecylamine, 1-cyclopropenylamine, 1-cyclobutenylamine, 1-cyclopentenylamine, Alicyclic amines such as 1-cyclohexenylamine, aniline, benzylamine, o-toluidine, 2,
Aromatic amines such as 4-xylidine and α-phenylethylamine.

(3) R ₃ and R ₄ are not both hydrogen atoms;
Secondary amines.

Examples of the secondary amines include R ₃ such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine and diisobutylamine.
And R ₄ have the substituent represented by R _{4 in the} primary amines of the above (2).

(4) A ring in which R ₃ and R ₄ are bonded to each other; that is, the following cyclic amines.

Aziridine, propyleneimine, azetidine, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, octamethyleneimine, morpholine.

These amines can be used in the form of solid, liquid, gas or aqueous solution depending on the type. Therefore, the gaseous amines may be introduced into the reaction system in a gaseous state under normal pressure, or may be used in a liquid state under pressure. As the amines used in the form of an aqueous solution, for example, commercially available products such as a 50% aqueous solution of dimethylamine and a 70% aqueous solution of monoethylamine may be used.

In the method of the present invention, the amines are used in a stoichiometric amount or more, and usually 1 to 20 mol is preferably used with respect to 1 mol of the 3-alkoxyacrylic acid ester. However, as will be described later, it is necessary to recover an excess of amines from the reaction solution, and energy consumption for that purpose can be reduced as much as possible, and from the viewpoint of enabling commercial production,
The amount of these amines to be used must be kept to a minimum, and it is particularly preferable to use 1 to 10 mol per 1 mol of 3-alkoxy acrylates.

In addition, in the method of the present invention, it is preferable that the 3-alkoxyacrylic acid ester and the amine are reacted in the presence of a solvent inert to the reaction. Although this solvent is not essential in the method of the present invention, it is used to further facilitate the reaction between the 3-alkoxyacrylic acid esters and the amines described above and shorten the reaction time. To do.

Examples of the inert solvent used include aprotic solvents, such as benzene, toluene, xylene and n-.
Hydrocarbon solvents such as hexane, n-heptane, cyclohexane, methylene chloride, chloroform, carbon tetrachloride,
Halogenated hydrocarbon solvents such as dichloroethane, diisopropyl ether, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether are preferable, but acetonitrile, nitriles such as propionitrile can also be selected, and further dimethylformamide, It is also possible to use dimethyl sulfoxide or the like. However, considering the economical efficiency and the solubility of the desired product, a 3-substituted aminoacrylic acid ester, in these solvents, aromatic hydrocarbons such as benzene, toluene, xylene, etc., the above ethers, and halogenated carbonization. Hydrogen and the like are particularly suitable.

The amount of these inert solvents used is 3-
The amount is not particularly limited as long as it is an amount at which the substituted aminoacrylic acid ester is dissolved or more, but like the amines used in excess, it is necessary to recover these solvents from the reaction solution as described later. Therefore, the amount of these solvents used must be kept to a minimum in order to reduce energy consumption as much as possible and to enable commercial production. 1 part by weight of 3-alkoxyacrylates On the other hand, it is usually 1 to 50 parts by weight, preferably 2 to
20 parts by weight is desirable.

The reaction temperature is not particularly limited depending on the properties of the amines used, but is -20 ° C to 200 ° C, especially 0 ° C.
It is preferably between 150 ° C and 150 ° C.

The reaction pressure may be normally atmospheric pressure, but a pressure operation is required depending on the type of amines used. That is, among the amines represented by the general formula [II], amines having a small electron donating property of the groups R ₃ and R ₄ , such as the aforementioned aniline, benzylamine, o-toluidine, and 2,4- Aromatic amines having low basicity such as xylidine and α-phenylethylamine require a pressure operation because their reactivity becomes weak. Further, as described above, the pressurizing operation is necessary even when the low boiling point amines, which become gaseous under normal pressure, are used in a liquid state.

In the case of pressurizing operation, it is desirable to perform it under a pressure of usually up to 100 kg / cm ² G, preferably up to 50 kg / cm ² G, though it depends on the kind of amines used.

A special apparatus is not required for the reaction of the 3-alkoxyacrylic acid ester and the amine in the method of the present invention, and a normal stirring tank may be used as the reaction apparatus. Also,
The material of this agitation tank may also be a general material such as stainless steel used in a reaction system device in which the above-mentioned amines are used.

Then, the reaction between the 3-alkoxy acrylates and the amines is carried out while a predetermined amount of the raw material 3-alkoxy acrylates and amines and an inert solvent are supplied to the above-mentioned stirring tank and stirring is performed. Is desirable. The stirring speed is not particularly limited, but it is usually preferably 300 to 400 rpm. In particular, when the starting amines are used in the form of an aqueous solution, when a solvent having no mutual solubility in water is used, strong stirring is preferable.

Further, in the method of the present invention, the reaction between the 3-alkoxyacrylic acid ester and the amine is completed in 1 to 10 hours, depending on the reactivity of the amine used, and for example, When dimethylamine is used as the amine, it is completed in 2 to 5 hours.

After completion of the reaction, remove excess amines and solvent from the reaction solution,
For example, it is separated by distillation (specifically, when water is present in the reaction solution when the amines are used in the form of an aqueous solution and the reaction solution separates into two layers of an aqueous phase and an organic phase, these are separated. Liquid separation is performed, and the aqueous phase and the organic phase are subjected to a distillation operation to distill off the amines from the aqueous phase and the solvent from the organic phase, respectively, and when water is not present in the reaction solution. , The reaction solution is subjected to a distillation operation as it is to distill away the amines and the solvent.), And then an operation such as distillation or crystallization is appropriately adopted to give a compound of the following general formula [III]: The 3-substituted aminoacrylic acid ester of the desired product can be easily isolated and purified.

(However, in the formula, R ₂ represents 3-in the formula [I].
It is the same as the definition of R ₂ in the alkoxy acrylates. Further, in the formula, R ₃ and R ₄ are the general formula [II].
It is the same as the definition of R ₃ and R ₄ in the amines represented by. When the isolation / purification of the above-mentioned 3-substituted aminoacrylic acid ester is carried out by distillation, it is preferable to use an ordinary packed column or plate column, and in this case, generally 3-alkoxyacrylic acid is used. It is considered that a high number of stages is not required because the reaction selectivity between the ester and the amine is good and the solution after recovering the excess amine and the solvent contains few impurities. When the isolation / purification of the 3-substituted aminoacrylic acid ester is performed by crystallization, depending on the type of the target 3-substituted aminoacrylic acid ester, the crystallization device is A crystallizer, a cooling crystallizer, etc. can be preferably used.

〔Example〕

Next, the method of the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

The reaction yields and acquisition yields of 3-substituted aminoacrylic acid esters in each example are 3-
It is a standard for alkoxy acrylates and was calculated by the following formula.

C = (B / A) × 100 In the above formula, A: the number of moles of charged 3-alkoxyacrylates (value converted to 100% purity) B: the number of generated or obtained 3-substituted aminoacrylates Number (value converted to 100% purity) This is the reaction or acquisition yield (%) of C: 3-substituted aminoacrylic acid esters.

Example 1 Internal volume 1 equipped with a thermometer, stirrer and reflux condenser
145 g of methyl 3-methoxyacrylate,
When 250 g of 50% aqueous solution of dimethylamine and 500 ml of methylene chloride as a solvent were added, the mixture was allowed to react at room temperature for 4 hours with stirring and left to stand. The product was separated into two layers, an organic phase containing methyl 3-dimethylaminoacrylate and the like. Then, as a result of quantitative analysis of this organic phase by gas chromatography by the absolute calibration curve method, it was confirmed that the target product, methyl 3-dimethylaminoacrylate, was 91.1%.
It was found that the reaction yield was%.

Next, the aqueous phase was separated and removed from the reaction solution separated into two layers, the organic phase was washed twice with 250 ml of water, and anhydrous sodium sulfate was added to dry the organic phase. The organic phase thus dried, i.e. the methylene chloride solution, is concentrated,
White crystals were precipitated from this concentrated liquid, and the crystals were filtered and dried to obtain 131.4 g of a dried crystal product. As a result of quantitative analysis of the dried crystal product by gas chromatography by an absolute calibration curve method, the purity of methyl 3-dimethylaminoacrylate was 99.5% by weight. Therefore, it was found that methyl 3-dimethylaminoacrylate was obtained with an acquisition yield of 81%.

Example 2 A flask having an internal volume of 50 ml equipped with a thermometer and a reflux condenser was charged with 5.80 g of methyl 3-methoxyacrylate, 7.70 g of a 70% aqueous solution of monoethylamine and 20 ml of toluene as a solvent and stirred with a magnetic stirrer. While about 72
The mixture was heated to reflux at 0 ° C for 2 hours. As a result of quantitative analysis of the obtained reaction liquid by gas chromatography by the absolute calibration curve method, it was found that the desired product, methyl 3-ethylaminoacrylate, was obtained in a reaction yield of 88.2%.

Then, the reaction solution was concentrated to obtain 5.60 g of crystals of methyl 3-ethylaminoacrylate. As a result of quantitative analysis of the crystals by a gas chromatography by an absolute calibration curve method, the purity was 92% by weight. Therefore, it was found that methyl 3-ethylaminoacrylate was obtained with an acquisition yield of 80%.

Example 3 In a flask having an internal volume of 50 ml similar to that shown in Example 2, 3
-Methyl methoxyacrylate (5.80 g), cyclopropylamine (6.6 g) and solvent (20 ml) were added, and the mixture was heated under reflux at about 78 ° C for 10 hours while stirring with a magnetic stirrer, and the obtained reaction solution was subjected to gas chromatography. As a result of quantitative analysis by the absolute calibration curve method, it was found that the desired product, methyl 3-cyclopropylaminoacrylate, was obtained in a reaction yield of 88.7%.

Then, this reaction liquid was concentrated to obtain 6.15 g of a pale yellow liquid of methyl 3-cyclopropylaminoacrylate. As a result of quantitative analysis of this liquid by an absolute calibration curve method by gas chromatography, the purity was 93% by weight. Therefore, 3
It was found that methyl cyclopropylaminoacrylate was obtained with an acquisition yield of 81%.

Example 4 34.78 g of methyl 3-methoxyacrylate and 100 ml of toluene were placed in an electromagnetic induction type autoclave having an internal volume of 300 ml, and the autoclave was sealed. After purging with nitrogen, liquid ammonia was further added.
6.9 g was added, and the mixture was heated with stirring at 100 ° C. for 4 hours.
The pressure inside the autoclave reached a maximum of 26 kg / cm ² G. After the reaction, the mixture was cooled to 25 ° C., the reaction solution was taken out from the autoclave, and concentrated under reduced pressure with an evaporator to obtain 27.2 g of a solid product of methyl 3-aminoacrylate as a product. As a result of quantitative analysis of this solid by a gas chromatography by an absolute calibration curve method, the purity was 87% by weight. Therefore, it was found that methyl 3-aminoacrylate was obtained with an acquisition yield of 78%.

[Explanation of Action and Effect] As described above, the method of the present invention has problems that it is difficult to obtain the raw materials, the yield of the target product is low, and the reaction takes a long time. In contrast to the conventionally known method for producing 3-substituted aminoacrylic acid esters, using easily available 3-alkoxyacrylic acid esters and amines represented by the general formula (II) as raw materials, A novel production of the above-mentioned 3-substituted amino acrylates which can be produced extremely easily and in a high yield by reacting these with a wide range of uses as a pharmaceutical raw material. It has the effect of providing the law.

Claims (1)

[Claims] 1. A process for producing a 3-substituted aminoacrylic acid ester, which comprises reacting a 3-alkoxyacrylic acid ester with an amine represented by the following general formula. (In the formula, R ₃ and R ₄ are a hydrogen atom and a carbon number of 1 to 12, respectively.
A linear or branched alkyl group, alkenyl group, alkynyl group, and alicyclic hydrocarbon group having 3 to 12 carbon atoms, cyclic hydrocarbon group such as aromatic hydrocarbon group having 6 to 12 carbon atoms (heterocycle Further, the cyclic compound may have a substituent which does not inhibit the reaction in the ring), and R ₃ and R ₄ may be the same or different groups, Further, they may form a ring bonded to each other. )