JP2000053622A - Production of 3-amino-2,2,3-trimethylbutanoic ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing 3-amino-2,2,3-trimethyl butanoic ester with good operability in high yield. SOLUTION: This method is conducted by reacting 3,3,4,4- tetramethylazetidine-2-one with alcohol in the presence of acid catalyst. The alcohol used in the invention is selected based on the objective ester, e.g. a primary or secondary alcohol of e.g. methanol, ethanol, propanol, butanol, isopropyl alcohol, isobutyl alcohol or secondary butyl alcohol. The use of methanol results in raising the reactivity and facilitating the aftertreatment of the reaction liquid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 3-amino-2,
The present invention relates to a method for producing 2,3-trimethylbutanoic acid ester. Specifically, the present invention relates to a method for producing 3-amino-2,2,3-trimethylbutanoic acid ester from 3,3,4,4-tetramethylazetidin-2-one. 3-Amino-2,2,3-trimethylbutanoate is a pharmaceutical,
Used as various organic products such as pesticides or their intermediates.

[0002]

2. Description of the Related Art Several methods are known for producing 3-amino-2,2,3-trimethylbutanoic acid ester. For example, Justus Liebigs Annalen der Chemie (Justus Liebig)
s Ann. Chem. ) Vol. 661, 111-15
Page 7 (1963) describes a method of reacting 3- (alkoxysulfonylamino) -trialkylbutanoic acid ester with an alcohol and hydrogen chloride. Also, Journal of Chemical Society C
(J. Chem. Soc. (C)) Nos. 1665-166
Page 6 (1971) describes a method of reacting hydrochloric acid with an isocyanate compound of 3-amino-2,2,3-trimethylbutanoic acid ester, and a method of reacting 3- (benzyloxycarbonylamino) -2,2,3-trimethyl A method is described in which butyrate is reacted with hydrogen bromide in acetic acid.

[0003]

However, these conventional methods are not satisfactory in terms of difficulty in preparing raw materials, operability of post-treatment of the reaction and the reaction solution, yield, and the like. Is not preferred. In view of such circumstances, the present inventors have good operability and high yields of 3-
As a result of intensive studies on the method for producing amino-2,2,3-trimethylbutanoate, 3,3,3
By selecting 4,4-tetramethylazetidin-2-one and reacting this compound with an alcohol in the presence of an acidic compound, the inventors have found that the above object can be achieved, and have completed the present invention.

[0004]

That is, the present invention relates to
Reacting 3,4,4-tetramethylazetidin-2-one with an alcohol in the presence of an acidic compound, and comprising reacting 3-amino-2,2,3-trimethylbutanoic acid ester Amino-2,2,3-trimethylbutanoate includes salts with acidic compounds).

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. The method for producing 3,3,4,4-tetramethylazetidin-2-one used in the present invention is not particularly limited. For example, 1-chlorosulfonyl-3,3,3
It can be produced by dechlorosulfonylation of 4,4-tetramethylazetidin-2-one. This method is described in Journal of Organic Chemistry (J. Org. Chem.) Vol. 33, No. 9, No. 34.
48-3452 (1968). The purity of 3,3,4,4-tetramethylazetidin-2-one, the type and content of impurities, etc. are not particularly limited, but are usually about 80% by weight or more, preferably about 90% by weight.
% Or more, more preferably about 95% or more by weight.

[0006] The alcohol used in the present invention is selected depending on the desired ester.
Primary and secondary alcohols such as ethanol, propanol, butanol, isopropyl alcohol, isobutyl alcohol and secondary butyl alcohol are exemplified. When methanol is used, the reactivity is high and the post-treatment of the reaction solution is easy. The method for producing the alcohol, the purity, the type and content of impurities, and the like are not particularly limited, but those having a purity of about 90% by weight or more, preferably about 95% by weight or more are usually used. The amount used is 3,3,4,4-tetramethylazetidine-
Usually, about 1 molar equivalent to about 50 molar equivalents, preferably about 5 molar equivalents to about 20 molar equivalents, based on 2-one.

The type of the acidic compound used in the present invention is not particularly limited. For example, hydrogen chloride, hydrogen bromide,
Protic acids such as hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, lithium hydrogen sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like can be mentioned. Further, an ion exchange resin having a sulfonic acid group, perfluorocarbon, or the like can also be used. Hydrogen chloride is preferred from the viewpoint of reactivity and operability of post-treatment of the reaction. The production method, purity, type and content of the impurity used for the acidic compound are not particularly limited, but are usually about 90% by weight or more, preferably about 9% by weight.
Those having a purity of 5% by weight or more are used. The water content in the acidic compound used in the present invention is preferably as small as possible, but may contain some water. If water is contained, impurities such as carboxylic acid are generated, which is not preferable, and the water content is not more than about 10% by weight, preferably about 5% by weight.
Below, more preferably about 2% by weight or less is used. Although the amount of the acidic compound used is not particularly limited, it is usually about 1 molar equivalent to about 30 molar equivalents as a proton with respect to 3,3,4,4-tetramethylazetidin-2-one.
It is a molar equivalent, preferably about 1 to 15 molar equivalents.

The method of supplying 3,3,4,4-tetramethylazetidin-2-one, alcohol and acidic compound in the present invention is not particularly limited, and various methods are employed. For example, an acidic compound may be supplied to a mixture of 3,3,4,4-tetramethylazetidin-2-one and an alcohol, and 3,3,4,4 may be supplied to a mixture of an alcohol and an acidic compound. -Tetramethylazetidine-2
-On may be supplied, and 3,3 in alcohol
4,4-Tetramethylazetidin-2-one and the acidic compound may be supplied simultaneously.

At the time of supply, at least one of 3,3,4,4-tetramethylazetidin-2-one, an alcohol and an acidic compound is dissolved or suspended by diluting with an appropriate diluent. The solution or suspension may be supplied. 3,3,4,4-tetramethylazetidine-2-
As for ON, a reaction mixture for producing 3,3,4,4-tetramethylazetidin-2-one or a post-treatment liquid or the like after removing acidic compounds and / or diluents may be used. Examples of the diluent include aliphatic hydrocarbons such as hexane, cyclohexane and heptane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene and mesitylene, diethyl ether, diisopropyl ether, dibutyl ether and tertiary butyl methyl. Ethers, ethers such as tetrahydrofuran, acetone,
Ketones such as ethyl methyl ketone, isobutyl methyl ketone, and cyclohexanone; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; esters such as methyl acetate, ethyl acetate, isopropyl acetate, and butyl acetate Although aromatic hydrocarbons are preferred from the viewpoint of operability and suppression of side reactions. The amount of the diluent used is usually about 1 to about 20 parts by weight, preferably about 1 to about 20 parts by weight, based on 1 part by weight of 3,3,4,4-tetramethylazetidin-2-one, alcohol and acidic compound. Parts by weight to about 5 parts by weight.

The reaction conditions in the present invention are preferably such that the reaction system maintains a liquid phase, and the reaction temperature is usually about 0 ° C.
It is about 150C, preferably about 20C to about 80C. The reaction pressure is generally about 101 kPa to about 507 kPa (about 1 kPa).
atm to about 5 atm), preferably about 101 kPa to about 203 kPa (about 1 atm to about 2 atm). The reaction time is generally about 1 hour to about 20 hours, preferably about 2 hours to about 10 hours. The atmosphere of the reaction system is not particularly limited, but it is preferable to carry out the reaction under an atmosphere of an inert gas such as nitrogen.

In the present invention, since 3-amino-2,2,3-trimethylbutanoic acid ester is a compound having an amino group in the reaction solution after the completion of the reaction, it is present in the form of a salt with an acidic compound. I do. The post-treatment operation of the reaction is not particularly limited, and may be a post-treatment operation used in a commonly known organic synthesis reaction, specifically, in the production of a known amino acid ester or a salt thereof with an acidic compound. The post-processing operation used may be employed.

When 3-amino-2,2,3-trimethylbutanoic acid ester is obtained as it is (in the form of a free amino group), for example, a basic compound or a solution thereof is added to a reaction solution or a concentrated solution thereof. Is made alkaline by adding an amount sufficient to neutralize the acidic compound, and then added with an organic solvent.
-Amino-2,2,3-trimethylbutanoic acid ester may be extracted and the extract may be concentrated. Examples of the organic solvent to be used include, for example, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene and mesitylene, diethyl ether, diisopropyl ether, dibutyl ether and tertiary butyl. Methyl ether, ethers such as tetrahydrofuran, acetone, ethyl methyl ketone, isobutyl methyl ketone, ketones such as cyclohexanone, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, halogenated hydrocarbons such as dichlorobenzene, ethyl acetate, Ethyl acetate, isopropyl acetate, esters such as butyl acetate and the like, but from the viewpoint of operability and suppression of side reactions,
Aromatic hydrocarbons are preferred. The amount of organic solvent used is 3-
It is generally about 1 to about 20 parts by weight, preferably about 2 to about 10 parts by weight, per part by weight of the amino-2,2,3-trimethylbutanoate. Also, once the 3-amino-2,2,3-trimethylbutanoic acid ester is obtained in the form of a salt with an acidic compound by the method described below, the 3-amino-2,2,3-trimethylbutanoate is obtained by the method described above. Trimethylbutanoate may be obtained. If necessary, a purification operation such as distillation may be performed.

When extracting the above-mentioned 3-amino-2,2,3-trimethylbutanoic acid ester, a more preferable operation from the viewpoint of yield, quality, operability and the like is as follows. The solution is added, preferably to a pH of about 3 to about 7, and partially concentrated. Then, a required amount of a basic compound or a solution thereof is added to make the mixture alkaline, and 3-amino-2,2,3-solvent is added with an organic solvent. A method of extracting trimethylbutanoate is exemplified. By performing this operation, prior to extraction with an organic solvent, excess alcohol or low boiling compounds present in the reaction solution (for example, when methanol is used as the alcohol and hydrogen chloride is used as the acidic compound), they are reacted. All or most of the resulting methyl chloride) can be removed, thereby improving extraction efficiency and suppressing quality deterioration.

When the 3-amino-2,2,3-trimethylbutanoic acid ester is obtained in the form of a salt with an acidic compound,
For example, (1) the reaction liquid is crystallized as it is from the concentrated liquid, and the reaction liquid or the concentrated liquid is cooled and crystallized,
-Amino-2,2,3-trimethylbutanoic acid ester and a salt of the acidic compound may be separated by filtration, or (2) 3-amino-2,2,3-trimethylbutanoic acid ester may be added to the reaction solution or a concentrated solution thereof. The solubility of the salt between the acidic compound and the 3-amino-2,2,3-trimethylbutanoic acid ester such as an excess alcohol is added after or while adding an organic solvent having low solubility of the salt of the acidic compound with the acid compound. After distilling off high components, the salt of the precipitated 3-amino-2,2,3-trimethylbutanoic acid ester and the acidic compound may be separated by filtration.
The type of organic solvent used is not particularly limited, but benzene, toluene, ethylbenzene, xylene,
Aromatic hydrocarbons such as mesitylene, chlorobenzene and dichlorobenzene are preferred. If necessary, purification operations such as crystallization and washing may be performed.

[0015]

EXAMPLES Examples of the present invention will be described below, but the present invention is not limited to these examples. The products were analyzed by gas chromatography and / or liquid chromatography. Example 1 10 g (0.0786 mol) of 3,3,4,4-tetramethylazetidin-2-one using a round bottom flask equipped with a stirrer, cooling tube, thermometer, dropping funnel and gas inlet tube.
And 40 g of methanol were supplied, stirred and mixed. 31 g (0.850 mol) of hydrogen chloride gas was supplied therein at room temperature, and the mixture was heated under reflux for 7 hours. After allowing the reaction mixture to cool, it was concentrated and dried to give 3-amino-2,2,3-trimethylbutanoic acid methyl ester hydrogen chloride 15 g (purity: 95%).
%, 0.0728 mol, yield; 93%).

Example 2 Using the same apparatus as in Example 1, 10 g (0.0786 mol) of 3,3,4,4-tetramethylazetidin-2-one and 40 g of methanol were supplied, stirred and mixed. 37 g (1.01 mol) of hydrogen chloride gas was supplied at room temperature, and the mixture was heated under reflux for 7 hours. While heating the reaction mixture,
While dropping 43 g of toluene, volatile components were distilled off so as to keep the internal volume constant. After cooling the internal solution to 5 ° C,
After filtration, the residue is washed with 10 g of toluene and dried,
3-amino-2,2,3-trimethylbutanoic acid methyl ester hydrogen chloride 11 g (purity; 99%, 0.0556
Mol, yield; 71%).

Example 3 Using the same apparatus as in Example 1, 55 g (0.432 mol) of 3,3,4,4-tetramethylazetidin-2-one
And 220 g of methanol were supplied, stirred and mixed, 181 g (4.96 mol) of hydrogen chloride gas was supplied at room temperature, and the mixture was heated under reflux for 7 hours. While heating the reaction mixture,
While dropping 302 g of toluene, volatile components were distilled off so as to keep the internal volume constant. The inner solution was cooled to 5 ° C., filtered, and the residue was washed with 100 g of toluene and dried, and dried to give 3-amino-2,2,3-trimethylbutanoic acid methyl ester hydrogen chloride 62 g (purity: 99%, 0%). .3
14 mol, yield; 73%). Further, the filtrate and the washing solution were mixed, concentrated and dried to obtain 3-amino-2,
2,3-trimethylbutanoic acid methyl ester hydrogen chloride 21 g (purity; 95%, 0.102 mol, yield; 24)
%)was gotten.

Example 4 Using the same apparatus as in Example 1, 23 g (0.181 mol) of 3,3,4,4-tetramethylazetidin-2-one
And 46 g of methanol were supplied, stirred and mixed, and 11.5 g (0.315 mol) of hydrogen chloride gas was supplied therein at 50 ° C. for 0.5 hour, and then the temperature was maintained at 50 ° C. for 1 hour. While heating, 120 g of toluene was dropped into the reaction mixture while heating, and volatile components were distilled off so as to keep the internal volume constant. After the internal solution was cooled to 5 ° C., it was filtered, and the residue was filtered with toluene 2
After washing with 5 g and drying, 3-amino-2,2,3-
34 g of trimethylbutanoic acid methyl ester hydrogen chloride
(Purity; 98%, 0.170 mol, yield; 94%) was obtained.

Example 5 Using the same apparatus as in Example 1, 46 g (0.362 mol) of 3,3,4,4-tetramethylazetidin-2-one
And 92 g of methanol were supplied, stirred and mixed, and 46 g (1.262 mol) of hydrogen chloride gas was added thereto while heating under reflux.
After feeding for 1 hour, the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to 5 ° C., filtered, and the residue was washed with 31 g of toluene and dried to obtain 52 g of methyl 3-amino-2,2,3-trimethylbutanoate hydrogen chloride (purity: 99%).
%, 0.263 mol, yield; 73%). In the filtrate, 19% yield of 3-amino-2,2,3
-Trimethylbutanoic acid methyl ester hydrogen chloride was included.

Example 6 Using the same apparatus as in Example 1, 40 g (0.314 mol) of 3,3,4,4-tetramethylazetidin-2-one
And 80 g of methanol were supplied, stirred and mixed, and 23 g (0.631 mol) of hydrogen chloride gas was added thereto while heating under reflux.
After feeding for 1 hour, the mixture was heated under reflux for 1 hour. While heating, 398 g of toluene was added dropwise to the reaction mixture, volatile components were distilled off so as to keep the internal volume constant. After cooling, 60 g of water and 50 g of a 25% NaOH aqueous solution were added and mixed well, and then separated into an oil layer and an aqueous layer. Further, 60 g of toluene was added to the aqueous layer and mixed well, and then separated into an oil layer and an aqueous layer. In 163 g of a liquid obtained by mixing the obtained two oil layers and washing with 20 g of water, 45 g of methyl 3-amino-2,2,3-trimethylbutanoate (0.283 mol, yield;
90%).

Example 7 Using the same apparatus as in Example 1, 40 g (0.314 mol) of 3,3,4,4-tetramethylazetidin-2-one
And 80 g of methanol were supplied, stirred and mixed, and 23 g (0.631 mol) of hydrogen chloride gas was added thereto while heating under reflux.
After feeding for 1 hour, the mixture was heated under reflux for 1 hour. After cooling, 100 g of toluene and 200 g of a 25% NaOH aqueous solution were added and mixed well, and then separated into an oil layer and an aqueous layer. Further, 100 g of toluene was added to the aqueous layer and mixed well, and then separated into an oil layer and an aqueous layer. Liquid 260 obtained by mixing the obtained two oil layers
In g, 48 g of 3-amino-2,2,3-trimethylbutanoic acid methyl ester (0.301 mol, yield: 96
%) Was included.

Example 8 Using the same apparatus as in Example 1, 40 g (0.314 mol) of 3,3,4,4-tetramethylazetidin-2-one
And 80 g of methanol were supplied, stirred and mixed, and 23 g (0.631 mol) of hydrogen chloride gas was added thereto while heating under reflux.
After feeding for 1 hour, the mixture was heated under reflux for 1 hour. After standing to cool, water 8
0 g and 32 g of a 25% aqueous NaOH solution,
After that, the mixture was concentrated to 50 ° C. at 100 mmHg. 100 g of toluene and 25% NaOH aqueous solution 8
After adding 8 g and mixing well, the mixture was separated into an oil layer and an aqueous layer. Further, 100 g of toluene was added to the aqueous layer and mixed well, and then separated into an oil layer and an aqueous layer. 48 g (0.301 mol, yield; 3-amino-2,2,3-trimethylbutanoic acid methyl ester) in 243 g of a liquid obtained by mixing the obtained two oil layers.
96%). This liquid was added at 13.3 kPa (1
After concentrating to an internal temperature of 80 ° C.
Distillation to an internal temperature of 80 ° C. at 3 kPa (10 mmHg) yielded 41 g of 3-amino-2,2,3-trimethylbutanoic acid methyl ester having a purity of 99% or more.

Example 9 Using the same apparatus as in Example 1, 40 g (0.314 mol) of 3,3,4,4-tetramethylazetidin-2-one
And 80 g of methanol were supplied, stirred and mixed, and 57 g (0.570 mol) of concentrated sulfuric acid (98% by weight) was supplied thereto under heating and reflux for 1 hour, and then heated and refluxed for 1 hour. After cooling, 80 g of water and 64 g of a 25% aqueous NaOH solution were added to adjust the pH to 7, and then 13.3 kPa (100 mmH
g) to 50 ° C. Toluene 100 in the concentrate
g and 46 g of a 25% aqueous NaOH solution were added and mixed well, and then separated into an oil layer and an aqueous layer. Further, 100 g of toluene was added to the aqueous layer and mixed well, and then separated into an oil layer and an aqueous layer. In 231 g of a liquid obtained by mixing the obtained two oil layers, 3
-Amino-2,2,3-trimethylbutanoic acid methyl ester 36 g (0.226 mol, yield; 72%) was contained.

Example 10 Using the same apparatus as in Example 1, 10 g (0.0786 mol) of 3,3,4,4-tetramethylazetidin-2-one and 40 g of methanol were supplied, stirred and mixed. 84 g (0.852 mol) of concentrated hydrochloric acid (37% by weight) was placed therein.
After supplying at room temperature, the mixture was heated under reflux for 7 hours. After allowing the reaction mixture to cool, it was concentrated and dried to give 3-amino-2,2,3-
16 g of a mixture of trimethylbutanoic acid methyl ester hydrochloride and 3-amino-2,2,3-trimethylbutanoic acid were obtained. The content of 3-amino-2,2,3-trimethylbutanoic acid methyl ester hydrochloride is 61% (yield; 61%).
%) And the content of 3-amino-2,2,3-trimethylbutane hydrochloride was 29% (yield; 31%).

COMPARATIVE EXAMPLE 1 Using the same apparatus as in Example 1, 10 g (0.0395 mol) of methyl 3- (methoxysulfonylamino) -2,2,3-trimethylbutanoate and 40 g of methanol were used.
Is supplied, stirred and mixed, into which 27 g of hydrogen chloride gas is added.
(0.741 mol) was supplied at room temperature, followed by heating under reflux for 7 hours. After allowing the reaction mixture to cool, it was concentrated and dried.
-Amino-2,2,3-trimethylbutanoic acid methyl ester hydrogen chloride 10 g (purity; 15%, 0.0077 mol, yield; 19%) was obtained.

[0026]

According to the method of the present invention described in detail above, 3-amino-2,2,3-trimethylbutanoic acid ester can be produced with good operability and high yield, and its industrial application is possible. The value is extremely large.

Claims (8)

[Claims] 1. A method of reacting 3,3,4,4-tetramethylazetidin-2-one with an alcohol in the presence of an acidic compound, characterized in that 3-amino-2,2,3-trimethylbutanoic acid is obtained. Method for producing ester. 2. The method according to claim 1, wherein the 3-amino-2,2,3-trimethylbutanoate is a salt of 3-amino-2,2,3-trimethylbutanoate and an acidic compound. 3. The method according to claim 1, wherein the water content of the acidic compound is 10% by weight or less. 4. The method of claim 1, wherein the acidic compound is hydrogen chloride.
4. The production method according to 2 or 3. 5. The method according to claim 1, wherein the alcohol is methanol.
The manufacturing method as described. 6. The method according to claim 1, wherein the reaction is carried out in the presence of a solvent. 7. The method according to claim 1, wherein an aromatic hydrocarbon is added to the reaction mixture after the reaction or a solution obtained by concentrating the reaction mixture. 8. The method according to claim 1, wherein water, a basic compound or a solution thereof is added to the reaction mixture after the reaction, and the mixture is concentrated.