JPS62192354A - Production of aziridine-2-carboxamide - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for pharmaceuticals, agricultural chemicals, etc., in high yield and short time, by using a specific 2,3-dihalopropionic acid derivative, etc., as raw material and reacting the material with NH3 in the presence of an alkali metal or alkaline earth metal hydroxide. CONSTITUTION:The objective compound having physiological activity such as antitumor activity can be produced by reacting (A) a 2,3-dihalopropionic acid derivative of formula I (X is halogen; Y is 1-10C alkoxycarbonyl, carbamoyl or cyano) easily producible by the halogen addition reaction of an acrylic acid ester, acrylamide and acrylonitrile or a haloacrylic acid derivative of formula II produced by the reaction of the above halogen-addition product and an alkali, etc., with (B) NH3 in a solvent in the presence of an alkali metal or alkaline earth metal hydroxide such as Ca(OH)2 at 0-200 deg.C for 5sec-48hr. EFFECT:The process is remarkably improved from the viewpoints of raw material and cost and has industrial advantage. USE:Intermediate for alpha-amino acid, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Summary of the Invention] Enhandan 1 The present invention relates to a method for producing aziridine-2-carboxylic acid amide. More specifically, the present invention provides aziridine-2 by reacting a specific 2,3-dihalopropionic acid derivative or 2-haloacrylic acid derivative with ammonia in the presence of an alkali metal or alkaline earth metal hydroxide. - A method for producing a carboxylic acid amide.

Aziridine-2-carboxylic acid amide itself and its derivatives are compounds that have antitumor and other physiological activities,
It is also a highly reactive and useful compound as a raw material for medicines, agricultural chemicals, intermediates for α-amino acids, and functional resins. However, an industrially advantageous manufacturing method for aziridine-2-carboxylic acid amide has not been established and has not been fully utilized.

Conventional methods for synthesizing aziridine-2-carboxylic acid amide can be broadly classified into the following three methods.

(1) Method by reaction of 2.3-dibromopropionic acid ester or 2-bromoacrylic acid amide with liquid ammonia (-26°C) (Swiss Patent No. 362.0
No. 78 (1957), l1elv.

Chim, Acta, 49.359 (1966
)).

(2) A method by reaction of aziridine-2-carboxylic acid ester with liquid ammonia or alcoholic ammonia (Chew, Ber, 93).

1632 (1960), West German Patent (Publication) No. 2
．． No. 748,015 (1976)).

(3) Method for partially hydrolyzing aziridine-2-nitrile (East German Patent No. 129.551 (1977) 1
．． ”, Prakt, Chem, 321.712 (
1979)).

However, these methods, to the best of the inventors' knowledge,
There are problems as below. In other words, method (1) is
Since the yield is not described and a bromine compound is used as a raw material, it is difficult to say that it is an industrially advantageous method from a cost standpoint.

In this method, when a chlorine compound is used instead of a bromine compound, almost no aziridine-2-carboxylic acid amide is obtained (see Comparative Example 2 below). (2) and (
Method 3) has a yield of about 80% and about 95%, respectively.
However, it is difficult to obtain the aziridine compound as a raw material, and these methods cannot be called industrial methods.

[Summary of the invention]

ff As a result of intensive studies to find an industrially advantageous manufacturing method for aziridine-2-carboxylic acid amide, the present inventors found that 2
, 3-dihalopropionic acid derivatives or 2-heroacrylic l derivatives as raw materials, alkali treatment is carried out under conditions of 0°C to room temperature or heating, which have not been previously carried out due to stability problems of intermediates and products. By reacting with ammonia in the presence of a metal or alkaline earth metal hydroxide, it was surprisingly possible to obtain aziridine-2-carboxylic acid amide in high yield in a short time.

Therefore, the method for producing aziridine-2-carboxylic acid amide according to the present invention is directed to a 2,3-dihalopropionic acid derivative represented by the following formula (I) or a 2,3-dihalopropionic acid derivative represented by the following formula (II).
The method is characterized by reacting an acrylic Wi derivative with ammonia in the presence of an alkali metal or alkaline earth metal hydroxide.

X-CH2-CH-Y (I)0H2=
C-Y (II) (wherein,
and a cyano group, respectively).

Effects According to the present invention, aziridine-2-carboxylic acid amide can be obtained in a short time and in high yield. It can be said that it was unexpected that the group Y remained as a carboxylic acid amide even in the presence of a strong alkali such as an alkali metal or alkaline earth metal hydroxide.

The present invention is also advantageous in terms of raw materials. That is, the raw material 2,3-dihalopropionic acid derivative can be easily obtained by the halogen addition reaction of the corresponding acrylic acid ester, acrylamide, and acryloni l-lyl, and the 2-haloacrylic acid derivative can be obtained by the above-mentioned method. This is because it is obtained by a reaction between a halogen additive and an alkali.

Therefore, the present invention provides an industrially advantageous method for producing aziridine-2-carboxylic acid amide, which is significantly improved in terms of raw material and cost, by finding reaction conditions that have not been available in the past. This is what we provide.

One of the raw materials, 2,3-dihalopropionic acid derivative or 2-haloacrylic acid derivative, is represented by the following formula (■) 2 or I [ is (n).

X-Cl-12-0H-Y
(I)0H2=C-Y
(II) Here, X represents a halogen atom selected from chlorine, bromine and iodine, preferably chlorine. Y is an alkoxy group having 1 to 10 carbon atoms, preferably 1
represents a group selected from an alkoxyl carbonyl group, a carbamoyl group, and a cyan group having a hydrocarbon residue of ~6.0.

Examples of the above hydrocarbon residues include methyl group, ethyl group,
n-propyl group, i-propyl group, n-butyl group, i-
There are butyl groups, t-butyl groups, n-pentyl groups, n-hexyl groups, cyclohexyl groups, n-octyl groups, phenyl groups, benzyl groups, etc., and among these, methyl groups, ethyl groups, and n-propyl groups are preferable. group, 1-propyl group, n
-butyl group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group, cyclohexyl group, n-octyl group, phenyl group, and particularly preferred are methyl group,
They are ethyl group, n-propyl group, and n-butyl group.

Particularly preferred among Y is a cyano group.

Compounds (I) and (n) are 2,
3-dihalopropionic acid ester ((■): Y is an alkoxycarbonyl group), 2.3-dihalopropionic acid amide ((■): Y is a carbamoyl group), 2.3-dihalopropionitrile (( I): Y is cyano group), 2.3-
Heroacrylic acid ester ((I[): Y is an alkoxycarbonyl group), 2-heroacrylamide 1II): Y is a carbamoyl group), and 2-heroacrylonitrile <(II): Y is cyano M) be able to.

These may be used alone in the method of the present invention, or a mixture of two or more may be used.

Raw materials (part 2) The other raw material is ammonia.

Preferred cans of ammonia to be used for each of the above raw materials are:
As shown in the table below.

A more preferable amount is approximately the same for each raw material, and is 5 to 100 mol of ammonia per mole of raw material.

There is no particular upper limit to the amount of ammonia used, and it is okay to use a particularly large amount, but
Considering economic efficiency, the preferable amount to be used is 200 mol or less per 11 mol of raw F.

On the other hand, if the amount of ammonia used is less than 1 mol per mol of the raw material, the yield of aziridine-2-carboxylic acid amide will be significantly reduced, so it is usually used in an amount of 1 mol or more.

Alkali metal or alkaline earth metal hydroxide The present invention is characterized in that the reaction is significantly accelerated when an alkali metal or alkaline earth metal hydroxide is present during the reaction.

Examples of these alkali metal or alkaline earth metal hydroxides include hydroxides of lithium, sodium, potassium, cesium, francium, beryllium, magnesium, calcium, strontium, and barium.

Preferred examples include hydroxides of lithium, sodium, potassium, calcium, and barium, with calcium hydroxide being particularly preferred.

The amount used is usually 0.1 per mole of the raw material (the -).
~20 equivalents, preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, particularly preferably 0.1 to 2 equivalents
．． If the amount used is less than 0.1 equivalent m, the acceleration of the reaction, which is the effect of addition, is hardly expected. If the reaction time exceeds 20, it will not only become complicated to separate these hydroxides from the aziridine-2-carboxylic acid amide formed after the reaction, but also cause decomposition of the formed aziridine-2-carboxylic acid amide or sequential reactions. It may also cause a decrease in reaction yield.

These hydroxides are used in the reaction system in the form of a solution or a suspension.

The reaction is carried out in solvent-free liquid ammonia or in solvated ammonia using a liquid ammonia-soluble solvent. There is no major difference in reactivity between the two, but they differ in terms of optimum reaction temperature, reaction pressure, etc., and the number of uses can be changed depending on the situation.

Examples of solvents used include water, aliphatic alcohol, dimethyl needles, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, hexamedyl phosphate triamide, and preferably water or aliphatic alcohol. The aliphatic alcohol preferably has 1 to 8 carbon atoms, such as methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, 5ec-butanol, t-butanol, Examples include n-pentanol, i-pentanol, n-hexanol, 2-ethylhexanol, n-octatool, and the like.

Among them, water, methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, 5ec-butanol, and t-propanol are preferred as the solvent.
Butanol, etc., and particularly preferred are water, methanol, ethanol, n-propertool, i-propertool, and the like.

In addition, when Y is a cyano group in the raw material (Part 1), it is essential that at least 1 mole or more of water is contained as a solvent per 1 mole of the raw material (Part 1).

Reaction temperature and time The reaction temperature and time are aziridine-2-
is an important factor for the yield of carboxylic acid amide,
It is usually in the range of 0.5 seconds to 48 hours at 0 to 200°C.

Furthermore, the combination of reaction temperature and time is important, and the type of substrate, concentration, type of solvent, Ilr of ammonia! 1
The amount of alkali metal or alkaline earth metal hydroxide used varies, but especially the reactivity of the substrate with ammonia and the decomposition or sequential reaction of the generated aziridine-2-carboxylic acid amide. It is necessary to create a combination that takes into consideration 1. Therefore, it is possible to obtain a high yield of aziridine-2-carboxylic acid amide by grasping the temporal change in reaction yield in advance, such as in preliminary experiments, and suppressing the sequential reactions by means such as cooling immediately after the completion of the reaction. .

That is, at high temperatures, for example, 100° C. or higher, a short time, for example within 2 hours, is preferred, particularly 0.5 seconds to 1 hour. At relatively low temperatures, for example 30° C. or lower, the heating time is preferably 5 seconds or more, particularly preferably 1 minute to 20 seconds.

Additives By adding tertiary amines, quaternary ammonium salts, etc. to the reaction of the present invention, the yield may be improved.

The tertiary amines used include trimethylamine, triethylamine, tri(n-butyl)amine, tri(2-ethylhexyl)amine, tri(n-octyl)amine,
N, N, N', N'-tetramethyl-1,2-diaminoethane, N, N, N'.

N'-tetramethyl-1,3-diaminopropane, N-
Examples include methylpiperidine, N-ethylpiperidine, N-methylpyrrolidine, N-ethylpyrrolidine, N,N-diethylaniline, N,N-diethylaniline, N,N-dimethylbenzylamine, etc. Among them, triethylamine and triethylbenzylamine are preferred. (n-butyl)amine, N-methylpiperidine, N-methylpyrrolidine, and the like.

In addition, examples of quaternary ammonium salts include tetramethylammonium hydroxide, trimedelbenzylammonium hydroxide, 1-benzylbenzylammonium hydroxide, tri(n-butyl)benzylammonium hydroxide, and tetra(n-butyl)benzylammonium hydroxide. -butyl)ammonium hydroxide, 1-(n-octyl)methylammonium hydroxide, N-(n-
lauryl) pyridinium hydroxide, tetramedylammonium hydrogen sulfate, trimedylbenzylammonium hydrogen sulfate,
Triedylbenzylammonium hydrogen sulfate, tri(n-butyl)pendylammonium hydrogen sulfate, tetra(n-butyl) ammonium hydrogen sulfate, tri(n-octyl)methylammonium hydrogen sulfate,
N-(n-lauryl)pyridinium hydrogen nalphate, tetramethylammonium chloride, trimedelbenzylammonium chloride, trimedelbenzylammonium chloride, tri(n-butyl)benzylammonium chloride, tetra(n-butyl)
Among them, preferred are ammonium chloride, tri(n-octyl)methylammonium chloride, N-(n-lauryl)pyridinium chloride, tetra(n-butyl)ammonium bromide, and tetra(n-ethyl)ammonium iodide. Tetramethylammonium hydroxide, trimedelbenzylammonium hydroxide, tetra(n-butyl)ammonium hydroxide, tri(n-octyl)ammonium hydroxide, tri(n-octyl)methylammonium hydroxide etc.

The amount used is a catalytic amount or more.

The one-coat reaction can be carried out batchwise or continuously using a seed reactor, or continuously using a cylindrical reactor.

For example, in a batch system using a seed reactor, there are no particular restrictions on the order in which raw materials are supplied, but the solvent, ammonia, and alkali metal or alkaline earth metal hydroxide are charged into the reactor and reacted. A method is preferably used in which the temperature inside the vessel is maintained at a predetermined temperature and the 2,3-dihalopropionic acid derivative or 2-haloacrylic acid derivative is supplied after being diluted with a solvent if desired.

In a continuous system using a seed reactor or cylindrical reactor, 2
, 3-dihalopropionic acid derivative, or 2-haloacrylic acid derivative, ammonia, a solvent, and an alkali metal or alkaline earth metal hydroxide, each individually or in a mixture in an appropriate combination, if necessary. The reaction mixture is continuously supplied to a reactor maintained at a predetermined temperature, and the reaction mixture is continuously withdrawn from the reactor at a predetermined time.

After the reaction is complete, the reaction mixture is purged of ammonia and then concentrated to obtain a solid containing aziridine-2-carboxylic acid amide. By purifying this using an ion exchange resin or column chromatography, highly pure white crystals of aziridine-2-carboxylic acid amide can be obtained.

In addition, after the reaction, the ammonia and solvent that were distilled off are recovered.
It cannot be used again and again for any purpose.

Experimental Examples In the following analyses, raw materials were analyzed using gas chromatography or high performance liquid chromatography, and products were analyzed using high performance liquid chromatography.

22 q of 12.5% ammonia water (162 mmol as ammonia) and 1.7 oz (22.9 mmol of ammonia) of calcium hydroxide were placed in a glass flask with an internal volume of 100 mm, and the internal temperature was maintained at 50°C. 2,3-dichloropropionitrile. (1 (15.9 mmol)) was quickly added. After stirring at 50°C for 30 minutes, it was immediately cooled to 5°C and filtered. Analysis of the furnace liquid revealed that aziridine-
The yield of 2-carboxylic acid amide was 92.8%.

Examples 2 to 11 2.3-dichloropropionitrile was prepared from various bases n, 15
．． In place of 9 millimoles and in place of the mother of calcium hydroxide,
Example 1 was repeated.

The results are shown in Table 1.

Table 1 Stop JJ Kuyu Example 1 was repeated without calcium hydroxide.

The yield of aziridine-2-carboxylic acid amide is only 18
．． It was 2%. When this reaction was continued for an additional 4 hours, the yield of aziridine-2-carboxylic acid amide was 56.
It was 4%.

12.5% ammonia water 86Q (632 mmol as ammonia) in a glass flask with a 11M unit internal volume of 1001d
and 1.5Q (20.2 mmol) of calcium hydroxide were charged, and while the internal temperature was kept at 60°C, 2.50 (15.9 mmol) of methyl 2,3-dichloropropionate was quickly added.

After stirring at 60°C for 15 minutes, the mixture was immediately cooled to 5°C and filtered. Analysis of the solution revealed that the yield of aziridine-2-carboxylic acid amide was 88.7%.

11L1 Calcium hydroxide I Sodium hydroxide 1.4a (3
5,0 mmol) and the reaction time was changed to 45 minutes,
Example 12 was repeated. The yield of aziridine-2-carboxylic acid azide was 85.5%.

Example 14 In a 1 liter autoclave, add 20C1 (5.88 mol as ammonia) of ammonia terprobanol solution (150% ammonia content) and 12.9 mol of sodium hydroxide.
C1 (0,323 mol) was charged, and while keeping the internal temperature at 60% (at this time, the pressure was 15 Kg/cd),
23.1 g of methyl 2.3-dichloropropionate (0,
147 mol) was rapidly fed. After stirring at 60°C for 1 hour, ammonia was purged, cooled to 5°C, filtered, and the liquid was analyzed, and the yield of aziridine-2-carboxylic acid amide was 86.8%. .

115 units 1 Triethylamine 14.190 (0,147
Example 14 was repeated with the addition of mol). aziridine
The yield of 2-carboxylic acid amide was 90.1%.

Liquid ammonia 1201 is introduced into a glass reactor equipped with a cooling tube for dry ice manufactured by Lej Mekki 2 2001 while being cooled in a dry ice-acetone bath. Here N-phenyl-2
-After addition of 250+ng of naphthylamine, 4.70 (29,9
mmol) dropwise over 30 minutes. Next, the dry ice-acetone bath was removed, and the mixture was reacted for 3 hours under liquid ammonia reflux conditions (-26°C). After the reaction, the cooling tube was removed, liquid ammonia was distilled off, and isopropanol 100111 was added thereto. After the white precipitate of ammonium chloride was separated from the furnace, the solution was analyzed by liquid chromatography, and the yield of aziridine-2-carboxylic acid amide was only 1.7%.

Claims (1)

[Scope of Claims] 1. A 2,3-dihalolopropionic acid derivative represented by the following formula (I) or a 2-haloacrylic acid derivative represented by the following formula (II) is combined with an alkali metal or alkaline earth metal. A method for producing aziridine-2-carboxylic acid amide, which comprises reacting with ammonia in the presence of hydroxide. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) Here, X is a halogen, and Y is an alkoxy group with 1 carbon number.
an alkoxycarbonyl group that is a hydrocarbon residue of ~10,
Each represents a group selected from a carbamoyl group and a cyano group. 2. The method according to claim 1, wherein X is a chlorine atom. 3. The method according to claim 1 or 2, wherein Y is an alkoxycarbonyl group in which the alkoxy group is a hydrocarbon residue having 1 to 6 carbon atoms. 4. The method according to claim 1 or 2, wherein Y is a carbamoyl group. 5. The method according to claim 1 or 2, wherein Y is a cyano group. 6. Claims 1 to 5, wherein the alkali metal or alkaline earth metal hydroxide is calcium hydroxide.
The method described in any one of paragraphs. 7. The method according to any one of claims 1 to 6, wherein the reaction is carried out at a temperature of 0 to 200°C.