JPH10139751A - Production of 2-n-alkoxycarbonyl-2,3-diaminopropionic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject product useful as a raw material or an intermediate for synthesizing medicines, agrochemicals, etc., at a low cost on industrial scale by reacting an alkoxycarbonylasparagine with diacetoxyiodobenzene in a solvent. SOLUTION: The objective compound of formula II (R is a 1-4C alkyl) is produced by reacting 2-N-alkoxycarbonylasparagine (e.g. 2-N-n-butoxycarbonyl-L- asparagine) of formula I with diacetoxyiodobenzene, preferably in an amount of 1-2mol times, in a solvent such as water at 0-50 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing methyl 2-N-alkoxycarbonyl-2,3-diaminopropionate. This compound is useful as a raw material for synthesis of pharmaceuticals, agricultural chemicals, and the like.
organic & MedicalChemis
try Letters. Vol. 6, No. 3,33
9 (1996) ", and is useful as an intermediate of a raw material for producing a drug represented by the following formula (III). In addition,
In the formula (III), R represents an alkyl group having 1 to 4 carbon atoms.

[0002]

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[0003]

2. Description of the Related Art Conventionally, the Hoffman rearrangement reaction for converting an amide group to an amino group is generally carried out using sodium hypochlorite or sodium hypobromite. However, "A
nn. Chem. , 529, 1 (1937) "or" B
ull. Chem. Soc. Japan. , 41, 27
48 (1968) ", for example, when benzyloxycarbonyl-substituted asparagine is subjected to a rearrangement reaction with the above reagent, rearrangement and ring closure occur simultaneously, and the desired 2-N-benzyloxycarbonyl-
2,3-diaminopropionic acid cannot be obtained.

[0004] J. Org. Chem., 44, 174
No. 6 (1979) ", a specific amide compound represented by the following formula is reacted with bistrifluoroacetoxyiodobenzene in a solvent in which acetonitrile and water are mixed at a ratio of 1: 1 to obtain a corresponding amino compound. It is reported to be produced in yield.

[0005]

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In the above-mentioned known literature, when diacetoxyiodobenzene is used in the Hoffman rearrangement reaction of the amide compound, a urea form is formed from the formed amine form and the isocyanate form as a precursor to form an amine. It has also been reported that a mixture of the urea and urea forms is not suitable for Hoffmann rearrangement. Furthermore, it is also reported that when bistrifluoroacetoxyiodobenzene is used, the resulting trifluoroacetic acid suppresses the formation of the above-mentioned urea compound, so that a high yield can be obtained.

[0007] In fact, "Synthesis, 266 (1
981)], by reacting benzyloxycarbonyl-substituted or tert-butoxycarbonyl-substituted asparagine with bistrifluoroacetoxyiodobenzene in a solvent in which dimethylformamide and water are mixed at a ratio of 1: 1. 2-N substitution-2,3
-Diaminopropionic acid is reported to be obtained in high yield. It is also reported that the reaction rate can be dramatically increased without lowering the yield by increasing the pH of the reaction solution with pyridine.

[0008] In fact, regarding the reaction in the case where pyridine is not added, for example, "Aust. J. Biol. Sci.,
34,395 (1981) ", a reaction of asparagine substituted with benzyloxycarbonyl with a large excess (8-fold mol) of bistrifluoroacetoxyiodobenzene in a solvent in which acetonitrile and water are mixed at a ratio of 1: 1. It is reported that diacetoxyiodobenzene having a weak acidity may be superior in the reaction rate in the early stage of the reaction because the reaction rate is extremely slow in the case of the reaction.

In recent literature, for example, "Tetra
hedoron. Letters. , 33 (30), 4
275 (1992) ", by reacting tert-butoxycarbonyl-substituted asparagine with bistrifluoroacetoxyiodobenzene in a solvent in which dioxane and water are mixed at a ratio of 1: 1 in the presence of pyridine. 2-N-tert-butoxycarbonyl-2,3-diaminopropionic acid is reported to be obtained.

As described above, as a method for producing 2-N-substituted-2,3-diaminopropionic acid, a solvent in which a water-soluble organic solvent and water are mixed at a ratio of 1: 1 is used in the presence of pyridine.
A general method is to react 2-N-substituted-asparagine with bistrifluoroacetoxyiodobenzene.

[0011]

However, in the above method, expensive and unstable bistrifluoroacetoxyiodobenzene is required, and pyridine is added to a mixed solvent of a water-soluble organic solvent and water. The number of components to be recovered is large and the operation is complicated, which is not industrially advantageous.

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a method for producing 2-N-alkoxycarbonyl-2,3-diaminopropionic acid at lower cost and more efficiently.

[0013]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that they are also a raw material of bistrifluoroacetoxyiodobenzene, are easily available industrially, and Diacetoxyiodobenzene, which was believed to be unsuitable for rearrangement, surprisingly
Findings show that Hoffman rearrangement occurs very well for certain derivatives of asparagine (2-aminosuccinamic acid), giving the corresponding amino compounds in higher yields than the conventional method using bistrifluoroacetoxyiodobenzene. I got

The present invention has been completed based on the above findings, and the gist of the present invention is to provide a compound represented by the following formula (I):
A method for producing 2-N-alkoxycarbonyl-2,3-diaminopropionic acid represented by the following formula (II), characterized by reacting N-alkoxycarbonylasparagine with diacetoxyiodobenzene in a solvent. .

[0015]

Embedded image (In the formulas (I) and (II), R represents an alkyl group having 1 to 4 carbon atoms.)

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In 2-N-alkoxycarbonylasparagine used as a raw material in the present invention, the alkoxycarbonyl group is an alkoxy group having 1 to 4 carbon atoms, and specific examples thereof include a methoxy group, an ethoxyoxy group, an n-propoxy group, and i -Propoxy group, n-butoxy group, i-butoxy group. Therefore, specific examples of 2-N-alkoxycarbonyl asparagine include 2-N-n-methoxycarbonyl asparagine, 2-N-n-ethoxycarbonyl asparagine, 2-N-n-propoxycarbonyl asparagine, 2-N-n -Butoxycarbonyl asparagine and the like.

[0017] 2-N-Alkoxycarbonyl asparagine can be easily produced, for example, by reacting L-asparagine with an alkyl chloroformate in the presence of a dehydrochlorinating agent. When producing 2-Nn-butoxycarbonyl asparagine, n-butyl chloroformate is used as the alkyl chloroformate. Also, diacetoxyiodobenzene is described in, for example, "J. Prakt.
Chem. , 131, 285 (1931) "by adding iodobenzene to a mixture of acetic anhydride and 30% by weight of hydrogen peroxide.

The reaction between 2-N-alkoxycarbonylasparagine and diacetoxyiodobenzene is usually carried out by suspending or dissolving 2-N-alkoxycarbonylasparagine in a solvent and adding diacetoxyiodobenzene. .

As the solvent, in addition to water, a mixed solution of a water-soluble organic solvent and water is used. Examples of the water-soluble organic solvent include dimethylformamide, acetonitrile, dioxane, dimethylsulfoxide, tetrahydrofuran, methanol, ethanol and the like. From the viewpoint of operation, water alone is preferable. The amount of the solvent is usually at least 5 times the volume, preferably 8 to 20 times the weight of 2-N-alkoxycarbonyl asparagine in terms of productivity.

The amount of diacetoxyiodobenzene used is:
It is usually at least equimolar to 1 mol of 2-N-alkoxycarbonyl asparagine, but from an economic viewpoint, it is 1 mol.
About 2 mol is preferable. The reaction temperature is usually from 0 to 80
° C, preferably from 0 to 50 ° C.

The 2-N-alkoxycarbonyl-2,3-diaminopropionic acid produced by the reaction, when precipitated in the reaction solution, can be easily isolated by filtration. When no precipitation occurs, the reaction solution can be easily isolated by concentrating the reaction solution or adding salt such as sodium chloride to the reaction solution and salting out. Further, a method of extracting the reaction solution with an organic solvent and then distilling and separating the organic solvent from the extract can also be adopted.

In the production method of the present invention, iodobenzene is produced as the reaction proceeds. This iodobenzene can be easily recovered and reused as a raw material for diacetoxyiodobenzene. As a method for recovering iodobenzene, a simple liquid separation method or the like can be adopted in addition to a method of extracting the reaction solution with an organic solvent and then distilling and separating the organic solvent from the extract. The recovered iodobenzene may be purified by distillation if necessary.

[0023]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist.

Example 1 1.16 g (0.005 mol) of 2-Nn-butoxycarbonyl-L-asparagine was suspended in 16 ml of water. When 1.77 g (0.0055 mol) of diacetoxyiodobenzene was added to this suspension at room temperature, the raw material dissolved while foaming. After stirring for 5 hours, the reaction was completed, and the reaction solution was analyzed by liquid chromatography. As a result, 0.853 g (yield 84%) of 2-Nn-butoxycarbonyl-2,3-diaminopropionic acid was produced. I knew it was there. In addition, the isolated 2-N-n-
As a result of analyzing the optical purity of butoxycarbonyl-2,3-diaminopropionic acid, it was found to be 100% ee.

Example 2 A reaction was carried out in the same manner as in Example 1 except that a mixed solvent of 6 ml of acetonitrile and 6 ml of water was used as a solvent. 2-N-n-butoxycarbonyl-
0.858 g of 2,3-diaminopropionic acid was obtained. The yield was 84%.

Example 3 In Example 1, dimethylformamide 6 was used as a solvent.
Example 1 except that a mixed solvent of 6 ml of water and 6 ml of water was used.
The reaction was carried out in the same manner as White crystals precipitated during the reaction. At the end of the reaction, the white crystals were collected by filtration, washed with ethanol, and the attached solvent was removed to give 2-Nn-butoxycarbonyl-2,3-diaminopropionic acid 0.40.
4 g (40% yield) were obtained. Further, as a result of analyzing the filtrate by liquid chromatography, 0.378 g of 2-N-n-butoxycarbonyl-2,3-diaminopropionic acid was obtained.
(Yield 37%) was found to remain.

Comparative Example 1 A mixed solvent of 6 ml of dimethylformamide and 6 ml of water was mixed with 2
-Nn-butoxycarbonyl-L-asparagine
16 g (0.005 mol) was dissolved. At room temperature, 2.37 g (0.0055 mol) of bistrifluoroacetoxyiodobenzene and 0.79 of pyridine were added to this solution.
After adding g (0.01 mol), stirring was continued for 5 hours to complete the reaction. After the completion of the reaction, the reaction solution was analyzed by liquid chromatography. As a result, 0.65 g of 2-Nn-butoxycarbonyl-2,3-diaminopropionic acid was obtained.
(Yield 64%) was found to be formed.

[0028]

According to the present invention described above, 2-N-alkoxycarbonyl-2,3-diaminopropionic acid, which is useful as a raw material for medicines and agricultural chemicals, can be produced industrially advantageously.

Claims (4)

[Claims] 1. A reaction between 2-N-alkoxycarbonylasparagine represented by the following formula (I) and diacetoxyiodobenzene in a solvent, wherein 2-N- represented by the following formula (II) is obtained. Alkoxycarbonyl-2,
A method for producing 3-diaminopropionic acid. Embedded image (In the formulas (I) and (II), R represents an alkyl group having 1 to 4 carbon atoms.) 2. The method according to claim 1, wherein the 2-N-alkoxycarbonyl asparagine is 2-Nn-butoxycarbonyl asparagine. 3. The method according to claim 1, wherein the solvent is water. 4. The production method according to claim 1, wherein diacetoxyiodobenzene is present in an amount of 1 to 2 times the molar amount of 2-N-alkoxycarbonyl asparagine, and the reaction is carried out at 0 to 50 ° C.