JP2002356481A - Method for synthesizing n-carboxylic acid anhydride of amino acid and its derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrial method for synthesizing an N-carboxylic acid anhydride derivative of an amino acid and its derivative useful as an intermediate for producing medicines, agrochemicals, etc. SOLUTION: An amino acid and its derivative represented by general formula (1) are reacted with a phosgene derivative in the presence of an additive reactive with formed hydrogen chloride and promoting a reaction for forming the N- carboxylic acid anhydride when the N-carboxylic acid anhydride derivative represented by general formula (3) is synthesized from the amino acid and its derivative represented by general formula (1). Thereby, the N-carboxylic acid anhydride derivative represented by general formula (3) of the amino acid and its derivative can be provided on an industrial scale.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for synthesizing N-carboxylic anhydrides of amino acids and their derivatives useful as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like.

[0002]

2. Description of the Related Art Generally, N-amino acids and derivatives thereof
Conventional methods for producing carboxylic acid anhydrides include Leuchs
The method, Curtius method, and Fuchs-Farthing method are known. The current production method is mainly based on the Fuchs-Farthing method (method of reacting phosgene in a dehydrated organic solvent) in which the operation is simple and N-carboxylic anhydride is obtained in high yield. The law is known. (1) An amino acid and a derivative thereof are reacted with phosgene in the presence of an organic phosphoric acid triester to form N containing less chlorine.
-Method for producing carboxylic anhydride (JP-B-44-31)
574). (2) A method of reacting an amino acid with phosgene in tetrahydrofuran and then taking out the mixture by regulating the concentration temperature and the concentration (JP-B-45-33178). (3) A method in which an amino acid is reacted with phosgene, and an N-carboxylic anhydride solution dissolved in a solvent is brought into contact with dawsonite to produce an N-carboxylic anhydride solution having a low chlorine content (JP-A-49-24957). No.). (4) A method of producing an N-carboxylic acid anhydride solution by reacting an amino acid or a derivative thereof with trichloromethylchloroformate in an organic solvent (JP-A-49-7096)
No. 2). (5) A method of producing an N-carboxylic anhydride solution by reacting an amino acid or a derivative thereof with bis (trichloromethyl) carbonate in tetrahydrofuran (Tetrahed
oron Letters, Vol. 29, No. 46, 5859-5862 (1988)). (6) An N-protected carboxylic acid anhydride is produced by reacting an amino acid protected with N-trityl or N-phenylfluorenyl with phosgene or bis (trichloromethyl) carbonate in an organic solvent in the presence of 1-ethylpiperidine. (J. Org. Chem., Vol. 64, 2532-2536 (1999)).

However, since the method (1) uses a phosphoric acid triester having a high boiling point as a solvent, it is difficult to isolate the target substance, for example, it is difficult to concentrate under reduced pressure and the decomposition is liable to occur during the concentration. Furthermore, since a large amount of phosphoric triester is used, there is a problem in its treatment, and there is a problem in industrial production. In the method (2), since tetrahydrofuran is actually used as a solvent, there is concern about danger due to the formation of peroxide, which makes safety management difficult. In addition to the fact that tetrahydrofuran is expensive,
It is not an industrially suitable production method because it is difficult to recover and reuse it. The method (3) is a method in which a basic substance is added in order to reduce the chlorine component. The amino acid and its derivative are not isolated as N-carboxylic anhydrides. However, the yield of the amino acid and its derivative cannot be said to be an industrial method for producing N-carboxylic anhydrides of amino acids and derivatives thereof. The method (4) cannot be performed industrially because trichloromethyl chloroformate, which is difficult to obtain, is used as a raw material. The method (5) uses tetrahydrofuran as a solvent similarly to the method (2), and thus cannot be said to be an industrially suitable production method. (6)
In order to complete the reaction, a method for producing an N-protected carboxylic acid anhydride of an amino acid or a derivative thereof includes phosgene or bis (trichloromethyl) carbonate or the like in the presence of an organic base such as triethylamine or 1-ethylpiperidine. It is necessary to react with a phosgene derivative, and there is a problem in avoiding polymerization, and there is a problem in industrial production.

As described above, the conventional methods have problems in use of a problematic solvent, use of a raw material that is difficult to obtain, difficulty in controlling the reaction, difficulty in isolating the target product after the reaction, and the like. A method for producing an N-carboxylic anhydride derivative overcoming these disadvantages has not been known.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrially feasible method for producing an N-carboxylic anhydride derivative which has solved the conventional disadvantages.

[0006]

Means for Solving the Problems The present inventors have conducted research to develop an efficient method for producing a compound represented by the general formula (2), which is extremely important as a synthetic intermediate for pharmaceuticals and agricultural chemicals. As a result, it was found that when an additive that reacts with the generated hydrogen chloride to promote the N-carboxylic anhydride reaction is added, the reaction proceeds promptly. In particular, in this case, it has been found that the reaction proceeds very easily even in a solvent such as an aromatic hydrocarbon or an aliphatic ester which has been rarely used. It has also been found that in the case of N-protected amino acids, N-carboxylic anhydrides can be obtained without using the usually required organic bases. That is, in the present invention, N-carboxylic anhydride of the target amino acid and its derivative can be taken out with industrially usable phosgene in good yield.

The present invention is as described in the following [1] to [6]. [1] General formula (1)

[0008]

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(Wherein R1 and R2 are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted R 1 and R 2 may combine to form a cycloalkyl group, and the cycloalkyl group may have an aromatic ring or a hetero ring as a condensed ring, and R 3 is hydrogen. It represents an atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, a heterocyclic ring which may be substituted, or a commonly used amino acid protecting group. )
General formula (2)

[0010]

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(Wherein R4, R5, R6 and R7 are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted An aryl group or an optionally substituted heterocyclic ring, and R4, R5 and R6
And R7 may combine to form a cycloalkyl group,
Further, the cycloalkyl group may have an aromatic ring or a hetero ring as a condensed ring. A1 and A2 each independently represent an oxygen atom, a sulfur atom and a direct bond. n and m
And each independently represents an integer of 0 to 2. ) Wherein the compound is reacted with a phosgene derivative in the presence of an additive which reacts with the generated hydrogen chloride to promote the N-carboxylic acid anhydride reaction represented by the general formula (3): ]

[0012]

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(Wherein R1, R2 and R3 have the same meanings as defined above), and a method for synthesizing N-carboxylic anhydrides of the amino acids and derivatives thereof represented by the formula [2]: An additive that promotes the carboxylic acid anhydride reaction,
General formula (4)

[0014]

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Wherein R4, R5, R6, R7 and A1
Is as defined above. [3] The method according to [1], which is a compound represented by the formula [5], wherein the additive which reacts with the produced hydrogen chloride to promote the N-carboxylic anhydride conversion reaction is represented by the general formula (5):

[0016]

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(Wherein R4, R5, R6 and R7 are as defined above), which is a method according to [2], wherein [4] reacts with the produced hydrogen chloride to form an N-carboxylic acid. The additive for accelerating the acid anhydride reaction is represented by the general formula (6):

[0018]

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(Wherein R8, R9, R10, and R11 are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted Shows a good hetero ring.
R8 and R9 or R10 and R11 may combine to form a cycloalkyl group, and the cycloalkyl group may have an aromatic ring or a hetero ring as a condensed ring. The method according to [1], which is a compound represented by the formula [7], wherein the additive which reacts with the produced hydrogen chloride to promote the N-carboxylic anhydride conversion reaction is represented by the general formula (7):
4]

[0020]

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[4] The method according to [4], which is α-methylstyrene.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. R1 and R2 in the general formula (1) of the present invention
Is the side chain of an amino acid. The amino acid used as a raw material for the amino acid may be a natural product or a synthetic product, and may be any of a racemic form, an L-form, and a D-form. R1,
The optionally substituted alkyl group represented by R2 and R3 means an alkyl group in which any part of the alkyl group may be substituted, and includes a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. , N-butyl group, isobutyl group, sec-butyl group, tert-butyl group, trichloroethyl group, adamantyl group, methylmercaptoethyl group, hydroxymethyl group, hydroxyethyl group, mercaptomethyl group, mercaptoethyl group, methylmercaptoethyl Group, carboxymethyl group, carboxyethyl group,
Aminopropyl group, aminobutyl group, aminocarbonyl methyl group, aminocarbonyl ethyl group, pentyl group, heptyl group, octyl _{group, - (CH 2) 3 -NH} -C (= N
_{H) -NH 2, - (CH} 2) 3 NH-CO-NH 2 and the like.

The optionally substituted cycloalkyl group represented by R1, R2 and R3 means a cycloalkyl group in which a part of the cycloalkyl group may be optionally substituted, such as a cyclopropyl group or a cyclopropylmethyl group. Groups, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, cyclooctyl and the like.

The optionally substituted aryl group represented by R1, R2 and R3 means an aryl group in which any part of the aryl group may be substituted, such as a phenyl group, a tolyl group or a methoxyphenyl group. , Fluorenylmethyl group,
Benzyloxyphenyl, ethylphenyl, nitrobenzyl, aminobenzyl, bromobenzyl, chlorophenyl, fluorophenyl, hydroxyphenyl, nitrophenyl, benzyl, methoxybenzyl, nitrobenzyl, methoxyphenacyl Group, hydroxybenzyl group, dihydroxybenzyl, cinnamoyl group and the like.

The optionally substituted heterocyclic ring represented by R1, R2 and R3 means a heterocyclic ring in which any part of the heterocyclic ring may be substituted, and includes a tetrahydropyranyl group, a tetrahydrofuranyl group , Tetrahydrothienyl group, piperidyl group, morpholinyl group, piperazinyl group, pyrrolyl group, furyl group, thienyl group, pyridyl group,
Examples include a furfuryl group, a thenyl group, a pyridylmethyl group, a pyrimidyl group, a pyrazyl group, an imidazoyl group, an imidazoylmethyl group, an indolyl group, an indolylmethyl group, an isoquinolyl group, a quinolyl group, and a thiazolyl group.

The commonly used protecting groups for amino acids represented by R3 include, for example, benzyloxycarbonyl group,
A benzyloxycarbonyl group substituted by a methoxy group, a chloro group, a nitro group, etc., a t-butoxycarbonyl group, a p-
Urethane-type protecting groups such as biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, and ethoxycarbonyl group, and acyl-type protection groups such as formyl group, trifluoroacetyl group, phthalyl group, tosyl group, benzoyl group, chloroacetyl group, and acetyl group. And alkyl-type protecting groups such as a group, trityl group and phenylfluorenyl group. A halogen atom is a fluorine atom, a chlorine atom,
Shows bromine and iodine atoms.

When the amino acid has a carboxyl group in the side chain, the amino acid is protected with an ester-type protecting group, and when the amino acid has a side chain, it is protected with an amino-protecting group. In the case of having a hydroxyl group, those protected with an ether-type protecting group and the like, and in the case of having a mercapto group, those protected with a sulfide-type protecting group and the like are also included.

Examples of the phosgene derivative include phosgene, trichloromethylchloroformate and bis (trichloromethyl) carbonate.

The additive which reacts with the produced hydrogen chloride to promote the N-carboxylic anhydride reaction is not particularly limited as long as it does not react with the produced N-carboxylic anhydride, but it has an unsaturated bond. And compounds having the property of undergoing an addition reaction with hydrogen chloride. Examples thereof include acrylates, cyclohexene, styrene, and methylstyrene. Further, a cyclic compound containing a hetero atom may be mentioned,
For example, there may be mentioned an ethylene oxide derivative which may have a halogen atom, an aromatic ring having an epoxy group, and the like.
These compounds having the property of reacting with and removing hydrogen chloride can be used alone or in combination of two or more. In addition, a substance in which these are supported on a polymer can also be used.

The reaction solvent is not particularly restricted but includes aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane and heptane, esters such as ethyl acetate and butyl acetate, acetonitrile and the like. Nitriles, tetrahydrofuran, dioxane, methyl t
Preferred are ethers such as -butyl ether and halogenated solvents such as 1,2-dichloroethane, particularly hydrocarbons,
Esters and ethers are preferred. Further, an additive for removing hydrogen chloride can be used as a solvent. The reaction temperature is not particularly limited, but the boiling point of the solvent used is good from 0 ° C, and preferably from room temperature to 60 ° C.

The reaction mixture can be isolated from the reaction mixture by using ordinary separation and purification means, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography and the like. The amount of the compound having the property of reacting with and removing hydrogen chloride is 0.1% with respect to the amino acid or its derivative.
The molar amount is from 001 to 30 times, preferably from 0.01 to 5 times, more preferably from 0.05 to 2.5 times.

[0032]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Synthesis of L-alanine N-carboxylic anhydride (phosgene method) Under a nitrogen atmosphere, 6.0 g of L-alanine was dehydrated and dried.
14.0 ml of ethyl acetate was added and suspended, and 1.7 parts of the suspension was added thereto.
g of α-methylstyrene (0.2% based on L-alanine).
Eq.) Was added. After heating to 40 to 50 ° C., 30 g of phosgene gas was blown in (1 to L-alanine).
5 equivalents). Then, it was aged at 55 ° C. for 3 hours. Then, the mixture was concentrated under reduced pressure to obtain a slurry-like concentrate. Insoluble L-alanine hydrochloride was removed by filtration, and n-heptane was added while stirring the filtrate at room temperature to precipitate white crystals. After cooling to 0 ° C and crystallization for 60 minutes, the crystals were collected by filtration and washed with n-heptane. The wet crystals were dried under reduced pressure at 25 ° C. to obtain 3.2 g of the title compound. L-alanine N
The purity of the carboxylic anhydride is 99.9%; (HPLC analysis) The Cl content was 0.05 wt%. ¹ H-NMR (CDCl ₃ , 90 MHz) δppm: 1.58 (3H, d, 7 Hz), 4.42 (1H,
q, 7Hz), 6.5 (1H, broad) IR (KBr) ν _max 3342,1857,1771,1285,1143,926,756cm ^-1

Example 2 Synthesis of L-alanine N-carboxylic anhydride (bis (trichloromethyl) carbonate method) Under nitrogen atmosphere, pulverized 0.75 g of L-alanine was added to 4
The suspension was added and suspended in 0 ml of ethyl acetate, and 1.0 g of propylene oxide was added thereto. A solution obtained by dissolving 1.0 g of bis (trichloromethyl) carbonate in 10 ml of ethyl acetate was heated to 40 to 50 ° C., and added dropwise over about 2 hours. After completion of the dropwise addition, the mixture was further aged at 50 to 55 ° C for 2 hours. A clear and colorless solution was obtained. After cooling to room temperature
Concentration under reduced pressure gave an oil. N- while stirring at room temperature
When hexane was added, white crystals precipitated. After stirring for 30 minutes, the crystals were collected by filtration, washed with n-hexane, and dried.
87 g of the title compound were obtained. ¹ H-NMR (CDCl ₃ , 90 MHz) δppm: 1.58 (3H, d, 7 Hz), 4.42 (1H,
q, 7Hz), 6.5 (1H, broad) IR (KBr) ν _max 3342,1857,1771,1285,1143,926,756cm ^-1

Example 3 Synthesis of N-benzyl-L-alanine N-carboxylic anhydride 1.5 g of ground N-benzyl-L-alanine was kneaded in 40 ml of ethyl acetate under a nitrogen atmosphere. Then 1.0 g of propylene oxide was added. Heat to 45-55 ° C and add 1.0 g of bis (trichloromethyl)
A solution of carbonate in 10 ml of ethyl acetate was added dropwise over about 1.5 hours. A solution containing trace amounts of insolubles was obtained. After the completion of the dropwise addition, the mixture was further reacted at the same temperature for 1 hour. After cooling to room temperature, a trace amount of insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure to give an oil. When 5 ml of diisopropyl ether was added with stirring, white crystals precipitated. After further adding 15 ml of n-hexane and stirring under ice cooling for 30 minutes, the crystals were collected by filtration and washed with n-hexane to obtain 1.36 g of the title compound. ¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 1.462 (3H, d, 7 Hz), 4.043 (1
H, q, 7Hz), 4.174 (1H, d, 15Hz), 4.942 (1H, d, 15Hz), 7.26-7.41 (5H, m) IR (KBr) ν max 1847,1766,1415,1287,984,712cm - ¹

[0036]

Industrial Applicability According to the present invention, an N-carboxylic anhydride derivative of an amino acid and its derivative represented by the general formula (3), which is extremely useful as an intermediate for synthesizing medicines and agricultural chemicals, is derived from amino acids and their derivatives. It can be easily obtained on a production scale. The method of the present invention overcomes various disadvantages of the conventionally known methods for producing N-carboxylic anhydrides of amino acids and derivatives thereof, and is useful for industrially producing these compounds.

 ────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Masahiko Kusumoto 30 Asamuta-cho, Omuta-shi, Fukuoka Mitsui Chemicals Co., Ltd. F-term (reference) 4C056 AA01 AB01 AC02 AD01 AE03 AF01 BA03 BB08 BC02

Claims (5)

[Claims] 1. A compound of the general formula (1) (Wherein R 1 and R 2 are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted hetero group. Represents a ring, and R1 and R
2 may combine to form a cycloalkyl group, and the cycloalkyl group may have an aromatic ring or a hetero ring as a condensed ring. R3 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocycle, or a commonly used amino acid protecting group Is shown. ) Is converted to a compound represented by the general formula (2): (Wherein R4, R5, R6 and R7 are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or R4 and R5 and R6 and R7 may combine to form a cycloalkyl group, and the cycloalkyl group has an aromatic ring or a heterocyclic ring as a condensed ring. A1 and A2 each independently represent an oxygen atom, a sulfur atom or a direct bond; n and m each independently represent an integer of 0 to 2); Wherein the compound is reacted with a phosgene derivative in the presence of an additive which reacts with a phosgene derivative to promote the N-carboxylic anhydride conversion reaction. (Wherein, R1, R2 and R3 have the same meanings as described above). 2. An additive which reacts with the produced hydrogen chloride to promote the N-carboxylic anhydride conversion reaction is represented by the general formula (4): ## STR4 ## The method according to claim 1, wherein R4, R5, R6, R7 and A1 are as defined above. 3. An additive which reacts with the produced hydrogen chloride to accelerate the N-carboxylic anhydride conversion reaction is represented by the general formula (5): ## STR5 ## The method according to claim 2, wherein the compound is a compound represented by the formula: wherein R4, R5, R6 and R7 are as defined above. 4. An additive which reacts with generated hydrogen chloride to promote an N-carboxylic anhydride conversion reaction is represented by the following general formula (6): (In the formula, R8, R9, R10, and R11 are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted Represents a hetero ring which may be substituted.
R8 and R9 or R10 and R11 may combine to form a cycloalkyl group, and the cycloalkyl group may have an aromatic ring or a hetero ring as a condensed ring. The method according to claim 1, which is a compound represented by the formula: 5. An additive which reacts with generated hydrogen chloride to promote an N-carboxylic anhydride conversion reaction is represented by the following formula (7): ## STR7 ## The method according to claim 4, which is α-methylstyrene represented by the following formula: