JPH07258196A - Method for producing N-vinylcarbamic acid ester derivative - Google Patents

Abstract

(57) [Summary] [Objective] A high-purity N-vinylcarbamic acid ester derivative is produced in a single-step reaction and in a high yield. [Structure] A mixture of N-ethylidene-1-phenylethylamine and triethylamine is added dropwise to benzyl chloroformate to carry out a reaction to produce benzyl N- (1-phenylethyl) -N-vinylcarbamate.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a high-purity N-vinylcarbamic acid ester derivative useful as a pharmaceutical intermediate in a high yield.

[0002]

2. Description of the Related Art Heretofore, the following production method has been known for N-vinylcarbamic acid ester derivatives prepared from imine derivatives. That is, by reacting an imine derivative with phosgene or a dimer of phosgene, trichloromethyl chloroformate in the presence of a base to convert it into N-vinylcarbamic acid chloride, and then reacting with an alkali metal alkoxide to give N-vinyl. A carbamic acid ester derivative was obtained (JP-A-5-163212).

However, since this production method uses or generates highly toxic phosgene, industrially, in addition to a dedicated synthetic reaction facility, a facility for treating phosgene is required, and the reaction process is 2 steps. This is a two-step reaction, and the reaction conditions and operations become complicated, which is a significant disadvantage in terms of equipment, operation, and economy.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing a high-purity N-vinylcarbamic acid ester derivative in a one-step reaction and in a high yield.

[0005]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies in order to solve the above problems. As a result, when the imine derivative represented by the general formula (1) is reacted with the chloroformate represented by the general formula (2) in the presence of the basic organic compound, the compound represented by the general formula (3) is obtained. It was found that the N-vinylcarbamic acid ester derivative according to the present invention can be produced in high purity and high yield by a one-step reaction, and the present invention was completed.

That is, the present invention comprises reacting an imine derivative represented by the following general formula (1) with a chloroformate represented by the following general formula (2) in the presence of a basic organic compound. Characteristically, N− represented by the general formula (3)
A method for producing a vinylcarbamic acid ester derivative.

[0007]

[Chemical 4]

[0008]

[Chemical 5]

[0009]

[Chemical 6]

(Wherein R ¹ represents a 1-arylalkyl group, and R ² , R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an aryl group, or R ² and R ³ combine to form an alkylene chain having 1 to 4 carbon atoms, R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ⁵ represents an unsubstituted or substituted group. The alkyl group, allyl group, aryl group or menthyl group having 1 to 6 carbon atoms is shown.) The present invention will be described in detail below.

The imine derivative represented by the general formula (1) used as the raw material in the present invention (also called Schiff base)
Is an aldimine derived from an aldehyde or a ketimine derived from a ketone. These aldimines or ketimines are usually easily obtained by dehydration condensation of an aldehyde or ketone with a primary amine. In the present invention, the imine derivative must have an alkyl group having at least one hydrogen bonded to the imine carbon.

Such aldimine is represented by R ³ CH (R ⁴ )
Unsubstituted or substituted C2 carbon atoms represented by CHO
~ 6 aliphatic aldehydes, such as acetaldehyde, n
An imine derivative derived from capronaldehyde or 2-phenylpropionaldehyde and a primary amine represented by R ¹ NH ₂ , for example, benzylamine, 1-phenylethylamine, 1-phenylpropylamine, 1-phenylbutylamine Is mentioned.

Specific examples of the aldimine include N-ethylidenebenzylamine, N-ethylidene-1-phenylethylamine, N-ethylidene-1-phenylpropylamine, N-ethylidene-1-phenylbutylamine and N-
Hexylidenebenzylamine, N-hexylidene-1-
Phenylethylamine, N-hexylidene-1-phenylpropylamine, N-hexylidene-1-phenylbutylamine, N- (2-phenylpropylidene) benzylamine, N- (2-phenylpropylidene) -1-phenylethylamine, N- (2 -Phenylpropylidene) -1-phenylpropylamine, N- (2-phenylpropylidene) -1-phenylbutylamine and the like are shown.

On the other hand, as ketimine, R ² COCH
(R ³ ) R ⁴ is a cyclic or acyclic aliphatic ketone or aromatic ketone such as acetophenone, methyl isobutyl ketone, cyclohexanone, or isopropyl phenyl ketone, and an imine derivative derived from the primary amine. Can be mentioned.

Specific examples of ketimines include N- (1-phenylethylidene) benzylamine, N- (1-phenylethylidene) -1-phenylethylamine and N- (1-
Phenylethylidene) -1-phenylpropylamine,
N- (1-phenylethylidene) -1-phenylbutylamine, N- (1,3-dimethylbutylidene) benzylamine, N- (1,3-dimethylbutylidene) -1-phenylethylamine, N- (1, 3-dimethylbutylidene) -1-phenylpropylamine and the like.

Further, N- (1,3-dimethylbutylidene) -1-phenylbutylamine, N-cyclohexylidenebenzylamine, N-cyclohexylidene-1-phenylethylamine, N-cyclohexylidene-1-phenylpropyiene. Luamine, N-cyclohexylidene-1-
Phenylbutylamine, N- (2-methyl-1-phenylpropylidene) benzylamine, N- (2-methyl-1-phenylpropylidene) -1-phenylethylamine, N- (2-methyl-1-phenylpropylidene)-
1-phenylpropylamine, N- (2-methyl-1-phenylpropylidene) -1-phenylbutylamine and the like are shown.

Of these imine derivatives, N-ethylideneamine derivatives derived from acetaldehyde and primary amines are preferable, and N-ethylidene-1-phenylethylamine is particularly preferable.

In the production method of the present invention, chloroformic acid esters represented by the general formula (2) are used as a reactant. Examples of the chloroformates include methyl chloroformate, ethyl chloroformate, n-propyl chloroformate,
Isopropyl chloroformate, isobutyl chloroformate, 2-ethoxyethyl chloroformate, sec-butyl chloroformate, benzyl chloroformate, 2-ethylhexyl chloroformate, allyl chloroformate, phenyl chloroformate, 2,2,2-trichloroethyl chloroformate , 2-butoxyethyl chloroformate, menthyl chloroformate, etc. are exemplified, and methyl chloroformate and benzyl chloroformate are particularly preferable.

In the production method of the present invention, the reaction is carried out in the presence of a basic organic compound. These basic organic compounds act as a deoxidizing agent that removes hydrogen chloride generated in the reaction from the reaction system. Examples of the basic organic compound include tertiary amines and nitrogen-containing heterocyclic compounds having aromaticity, and examples thereof include triethylamine, N, N-diethylaniline, pyridine, dimethylpyridine, dimethylaminopyridine,
Triphenylamine, tetramethylethylenediamine,
Tetramethylpropanediamine, tetramethylhexamethylenediamine, pentamethyldiethylenetriamine,
Triethylenediamine, N, N'-dimethylpiperazine, trimethylaminoethylpiperazine and the like are used. Of these, triethylamine, diethylaniline and pyridine are preferable, and triethylamine is particularly preferable.

The present invention reacts these raw materials and reactants to produce an N-vinylcarbamic acid ester derivative represented by the general formula (3). Then, the reaction is carried out by mixing an imine derivative with a basic organic compound and, if necessary, an organic solvent, and keeping this at a predetermined reaction temperature under stirring in a predetermined atmosphere, and if necessary, chloroformic acid ester containing an organic solvent. It is a particularly preferable method to carry out the addition by dropping.

At this time, the amount of chloroformic acid ester used is not particularly limited as long as it is 1 equivalent or more with respect to the raw material imine derivative, but it is preferably 1 to 3 equivalents. If the amount is larger than this, the reactants are merely wasted, and if the amount is smaller, the conversion of the imine derivative may be insufficient and the yield may be low. The amount of the basic organic compound used is not particularly limited as long as it is 1 equivalent or more with respect to the imine derivative, but is preferably 1 to 2 equivalents. Since the reaction proceeds sufficiently in this range, the amount used beyond this is unnecessary,
On the other hand, if it is less than this, the removal of hydrogen chloride becomes insufficient,
It may reduce the purity and yield.

In the reaction of the present invention, an organic solvent can be used if necessary. The organic solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, aliphatic hydrocarbons such as n-hexane and cyclohexane, diethyl ether, dimethoxyethane, tetrahydrofuran, Ethers such as dioxane are used. Of these, aromatic hydrocarbons are preferable, and toluene is more preferable. These organic solvents can be used alone or as a mixed solvent. With the progress of the reaction in the present invention, a hydrochloride of the basic organic compound is produced, and the reaction liquid becomes a slurry liquid. Therefore, the amount of the organic solvent used is not particularly limited, but it is preferable to use the same amount or more as the raw material imine derivative because the slurry liquid can be easily stirred.

In the production method of the present invention, the predetermined reaction temperature is -50 to 50 ° C, preferably -30 to 30 ° C.
It is carried out in. If the reaction temperature is higher than 50 ° C, some of the chloroformates may decompose, while -50
If the temperature is lower than ℃, the reaction rate becomes slow. The reaction in the production method of the present invention is preferably carried out in an atmosphere of a predetermined inert gas such as nitrogen or argon.

In the production method of the present invention, the reaction time varies depending on the kinds of the raw material imine derivative, the reactant chloroformate and the basic organic compound, but is usually 0.5 to 15 hours, preferably 1 hour to 10
It's time. Since the reaction in the present invention proceeds relatively quickly, longer reaction time is not necessary.

Since the reaction between the imine derivative and the chloroformate is an exothermic reaction, it is important to control the mixing rate to keep the temperature at the predetermined reaction temperature. The reaction of the present invention includes, for example, a method in which a mixture of an imine derivative and a basic organic compound is added dropwise to a chloroformate, and a method in which a chloroformate is added to a mixture of an imine derivative and a basic organic compound. A method in which a basic organic compound and chloroformates are separately added simultaneously to the derivative, a chloroformate is added dropwise to the imine derivative, and the basic organic compound is added in the middle of the reaction to add chloroformates. It may be carried out by a method of terminating the dropping at the same time as the termination, but in these methods as well, it is important to control the heat of reaction to keep it at a predetermined reaction temperature. Among them, the method of dropping the mixture of the above-mentioned imine derivative and the basic organic compound into chloroformates to carry out the reaction provides a much higher purity and high yield of the N-vinylcarbamic acid ester derivative. More preferable.

According to the production method of the present invention, the reaction liquid containing the N-vinylcarbamic acid ester derivative obtained by the above reaction is then subjected to the operation of removing the hydrochloride of the basic organic compound. This may be separated or removed by a known method such as washing with water or filtration. When separating by washing with water, the amount of water may be the amount of water required for two-phase separation of the organic phase and the aqueous phase, and it is not particularly necessary to wash with a large amount of water. After this, N
-The organic phase containing the vinylcarbamate derivative is
If necessary, the organic solvent, unreacted raw materials and the like can be distilled off, preferably under reduced pressure, and the mixture can be concentrated. The obtained concentrated liquid may be distilled under reduced pressure to purify the N-vinylcarbamic acid ester derivative, if necessary.

If coloring is observed in the concentrated solution, a decoloring operation may be carried out using a decolorizing agent such as activated carbon, if necessary. The bleaching operation can be carried out by a known method, and examples thereof include a method in which activated carbon is added to the concentrated liquid, stirred and then filtered, or a column filled with activated carbon is passed. At this time, an organic solvent may be used if necessary.

[0028]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 To a 200 ml four-necked flask equipped with a dropping funnel, a stirrer and a thermometer, 60 ml of toluene and 2 benzyl chloroformates were placed.
8.1 g (0.165 mol) was added, and the mixture was stirred and cooled under a nitrogen atmosphere. On the other hand, 12.1 g (0.0825 mol) of N-ethylidene-1-phenylethylamine, 8.35 g (0.0825 mol) of triethylamine and 20 ml of toluene were mixed and placed in a dropping funnel under a nitrogen atmosphere. Toluene solution of benzyl chloroformate is -1
When the temperature reached 0 ° C, the dropping of the solution was started from the dropping funnel. The reaction mixture was added dropwise over 1 hour while maintaining the reaction temperature at -10 ° C, and the mixture was cooled and stirred for 2 hours.

Then, the reaction solution was warmed to room temperature, 20 ml of water was added, and the mixture was stirred, transferred to a separating funnel and allowed to stand, and then the lower phase was removed. The upper phase is 20 to 3 mmHg, 40
Toluene and unreacted raw materials were removed at -80 ° C and concentrated. After adding 20 ml of toluene and 5 g of activated carbon to the obtained light brown concentrated liquid and stirring the mixture at room temperature for 30 minutes, the activated carbon was separated by filtration, and the toluene in the mother liquor was distilled off again under reduced pressure. The obtained pale yellow liquid was analyzed by gas chromatography, and as a result, benzyl N- (1-phenylethyl) -N-
Vinyl carbamate was obtained in a yield of 81.4 mol%. The purity was 99.0% (gas chromatogram area percentage). The purity is calculated by the following formula.

Purity (%) = (N-VCBn area) / (N
-VCBn area + CBn area) x 100 N-VCBn: benzyl N- (1-phenylethyl)
-N-vinyl carbamate CBn: benzyl N- (1-phenylethyl) carbamate The results are shown in Table 1.

Example 2 N-ethylidene-1-phenylethylamine and triethylamine were charged into a dropping funnel without using toluene, and toluene 4 was added to a 200 ml four-necked flask.
The reaction was performed in the same manner as in Example 1 except that 0 ml and benzyl chloroformate were charged.

After the reaction, the temperature of the reaction solution was raised to room temperature, 20 ml of water was added and the mixture was stirred, transferred to a separating funnel and allowed to stand, and then the lower phase was removed. 20 toluene contained in the upper phase
mmHg, concentrated solution distilled at 40 ℃, about 1.5m
The pale yellow liquid obtained by distilling at mHg and collecting fractions at 165 to 170 ° C. was analyzed in the same manner as in Example 1. The results are shown in Table 1.

Example 3 The reaction was performed in the same manner as in Example 1 except that 20 ml of toluene and benzyl chloroformate were charged in a 200 ml four-necked flask. The results are shown in Table 1.

Example 4 Diethylaniline 12.3 in place of triethylamine
The reaction was performed in the same manner as in Example 1 except that g (0.0825 mol) was used. The results are shown in Table 1.

Example 5 Diethylaniline 12.3 in place of triethylamine
The reaction was performed in the same manner as in Example 1 except that g (0.0825 mol) was used and benzyl chloroformate was 15.5 g (0.091 mol). The results are shown in Table 1.

EXAMPLE 6 6.53 g of pyridine (0.
(0825 mol) was used, and the reaction was carried out in the same manner as in Example 1. The results are shown in Table 1.

Example 7 6.53 g of pyridine (0.
The reaction was performed in the same manner as in Example 1 except that 0825 mol) was used and 15.5 g (0.091 mol) of benzyl chloroformate was used. The results are shown in Table 1.

Example 8 In a 200 ml four-necked flask equipped with a dropping funnel, a stirrer and a thermometer, 60 ml of toluene and 1 part of methyl chloroformate were added.
5.6 g (0.165 mol) was added, and the mixture was stirred and cooled under a nitrogen atmosphere. On the other hand, 12.1 g (0.0825 mol) of N-ethylidene-1-phenylethylamine, 8.35 g (0.0825 mol) of triethylamine and 20 ml of toluene were mixed and placed in a dropping funnel under a nitrogen atmosphere. When the toluene solution of methyl chloroformate reached 0 ° C, the dropping of the solution was started from the dropping funnel. While maintaining the reaction temperature at 0 ° C., the mixture was added dropwise over 1 hour, and the mixture was cooled and stirred for 2 hours.

Thereafter, the reaction solution was warmed to room temperature, 20 ml of water was added and stirred, and the mixture was transferred to a separating funnel and allowed to stand, and then the lower phase was removed. 20 toluene contained in the upper phase
mmHg, the concentrated liquid distilled at 40 ° C is further heated to 4 mmHg.
The pale yellow liquid obtained by distilling at 105 ° C. to 110 ° C. was collected and analyzed by gas chromatography. As a result, methyl N- (1-phenylethyl) -N-vinyl carbamate was found to be 82.7 mol%. Obtained in yield. The purity was 96.6% (gas chromatogram area percentage). The purity is calculated by the following formula.

Purity (%) = (N-VCMe area) / (N
-VCMe area + CMe area) x 100 N-VCMe: methyl N- (1-phenylethyl)-
N-Vinylcarbamate CMe: Methyl N- (1-phenylethyl) carbamate Example 9 N-Cyclohexylidene-1-phenylethylamine 1 in place of N-ethylidene-1-phenylethylamine
6.6 g (0.0825 mol) was used, and 12.3 g of diethylaniline instead of triethylamine
Example 8 except that (0.0825 mol) was used.
The reaction was carried out in the same manner as in. The results are shown in Table 1.

[0042]

[Table 1]

[0043]

INDUSTRIAL APPLICABILITY In the present invention, in the presence of a basic organic compound,
The imine derivative represented by the general formula (1) is reacted with the chloroformic acid ester represented by the general formula (2), whereby the N-vinylcarbamic acid ester represented by the general formula (3). The derivative can be produced in high purity and high yield by a one-step reaction.

Claims (2)

[Claims] 1. An imine derivative represented by the following general formula (1) and a chloroformic acid ester represented by the following general formula (2) are reacted in the presence of a basic organic compound. A method for producing an N-vinylcarbamic acid ester derivative represented by the general formula (3). [Chemical 1] [Chemical 2] [Chemical 3] (In the formula, R ¹ represents a 1-arylalkyl group, and R ² , R
³ and R ⁴ are each independently hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an aryl group, or R ² and R ³ are combined to form a alkylene chain having 1 to 4 carbon atoms, R ⁴ Represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. In the formula, R ⁵ is unsubstituted or has a substituent and has 1 to 6 carbon atoms.
Represents an alkyl group, an allyl group, an aryl group or a menthyl group. ) 2. The production method according to claim 1, wherein the reaction is carried out while dropwise adding a mixture of the imine derivative and the basic organic compound to chloroformates.