JP2012077052A - Method for producing amino acid-n-carboxy anhydride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an amino acid-N-carboxy anhydride by which the amino acid-N-carboxy anhydride can be synthesized via a series of steps without requiring isolation and purification of an amino acid carbamate being a precursor, midway through production.SOLUTION: The production method includes the steps of: (1) mixing an amino acid (for example, L-valine, L-phenylalanine etc.), an onium salt (for example, tetrabutyl ammonium hydrogensulfate etc.), a carbonate (for example, diphenyl carbonate etc.), water, and an organic solvent (for example, methyl isobutyl ketone etc.), making them react with one another, and preparing a reaction solution; (2) adding an acid for removing a reaction residue originating from the onium salt to the obtained reaction solution; (3) removing water included in the reaction solution to which the acid has been added; (4) heating the reaction solution from which water has been removed; and (5) obtaining the amino acid-N-carboxy anhydride by crystallizing it from the heated reaction solution.

Description

  The present invention relates to a method for producing an amino acid-N-carboxyanhydride. More specifically, the present invention eliminates the need for isolating and purifying the amino acid carbamate, which is a precursor, on the way, and a method for producing an amino acid-N-carboxy anhydride capable of synthesizing an amino acid-N-carboxy anhydride by a series of steps. About.

  Conventionally, amino acid-N-carboxyanhydrides are useful as intermediate raw materials when synthesizing polypeptides from amino acids. As a method for synthesizing this amino acid-N-carboxyanhydride, a method in which phosgene is reacted with an amino acid is known.

  However, since phosgene is a very toxic gas, handling thereof requires strict attention from the viewpoint of environmental problems and safety. Therefore, the use of phosgene is severely limited, limiting the industrial use of amino acid-N-carboxyanhydrides. From this point of view, various methods that do not use phosgene have been studied (Patent Documents 1 to 4 and Non-Patent Documents 1 to 3), but none of them are industrially applicable or the problem of using phosgene as a raw material There was a point.

  Therefore, the applicant of the present invention reacts an amino acid with bis (substituted phenyl) carbonate, or reacts an amino acid ester with bis (substituted phenyl) carbonate to obtain a product (amino acid) obtained through an amino acid ester carbamate. It was found that an amino acid-N-carboxyanhydride can be obtained efficiently by collecting a carbamate body and then heating (Patent Document 5).

US Pat. No. 5,359,086 JP-A-11-29560 JP 2000-327666 A JP 2002-322160 A JP 2007-22932 A

Tetrahedron Letters, 1996, 37, 9043. Chemistry Letters, 2003, 32, 830. Macromolecules 2004, 37, 251.

The method described in Patent Document 5 is an industrially applicable method without using phosgene.
However, from the viewpoint of further improving productivity, there is currently a demand for a method capable of producing the target amino acid-N-carboxyanhydride in a simpler and higher yield.

  The present invention has been made in view of the above circumstances, and without using phosgene and without isolating and purifying the precursor amino acid carbamate from the reaction solution in the course of production, the amino acid-N-carboxyl is obtained by a series of steps. It aims at providing the manufacturing method of the amino acid-N-carboxy anhydride which can synthesize | combine an anhydride.

The present invention is as follows.
[1] (1) A reaction solution preparation step in which an amino acid, an onium salt, a carbonate, water, and an organic solvent are mixed and reacted to prepare a reaction solution;
(2) an acid addition step of adding an acid for removing the reaction residue derived from the onium salt to the obtained reaction solution;
(3) a water removal step of removing water contained in the reaction solution to which the acid is added;
(4) a heating step of heating the reaction solution from which the water has been removed;
(5) A crystallization step obtained by crystallizing amino acid-N-carboxyanhydride from the heated reaction solution.
[2] The process for producing an amino acid-N-carboxy anhydride according to [1], wherein the onium salt is a quaternary ammonium salt.
[3] The method for producing an amino acid-N-carboxyanhydride according to the above [1] or [2], wherein the anion of the onium salt is HSO ₄ ⁻ or SO ₄ ²⁻ .
[4] The method for producing an amino acid-N-carboxy anhydride according to any one of [1] to [3], wherein the organic solvent is a solvent having a boiling point higher than that of the water.
[5] The method for producing an amino acid-N-carboxy anhydride according to any one of [1] to [4], wherein the organic solvent is a ketone.
[6] The method for producing an amino acid-N-carboxy anhydride according to any one of [1] to [5], wherein the water content in the reaction solution after the water removal step is 500 ppm or less.
[7] The method for producing an amino acid-N-carboxy anhydride according to any one of [1] to [6], wherein an acid is added to the reaction solution when heating in the heating step.
[8] The method for producing an amino acid-N-carboxy anhydride according to [7], wherein the acid added in the heating step is a carboxylic acid.
[9] The method for producing an amino acid-N-carboxy anhydride according to [8], wherein the carboxylic acid is liquid at 20 ° C.
[10] The method for producing an amino acid-N-carboxy anhydride according to any one of [1] to [9], wherein a hydrocarbon is used as a poor solvent for the amino acid-N-carboxy anhydride in the crystallization step.
[11] The method for producing an amino acid-N-carboxy anhydride according to [10], wherein in the crystallization step, in addition to the poor solvent, at least one of toluene and ethers is used.

According to the present invention, it is not necessary to isolate and purify the precursor amino acid carbamate from the reaction solution during the production, and the amino acid-N-carboxy anhydride can be produced in a high yield by a series of steps. Furthermore, the amino acid-N-carboxyanhydride can be produced in a high yield all at once using the same solvent.
Moreover, when a quaternary ammonium salt is used as the onium salt, the yield of the target product can be further improved.
Furthermore, when the anion of the onium salt is HSO ₄ ⁻ or SO ₄ ²⁻ , generation of impurities in the reaction solution can be sufficiently suppressed, and the yield of the target product can be improved.
Further, when the organic solvent has a boiling point higher than that of water, it is easier to remove water, and productivity can be improved.
Further, when the organic solvent is a ketone, the amino acid-N-carboxyanhydride can be stably produced in a high yield with the same solvent.
Moreover, when the water content in the reaction solution after the water removal step is 500 ppm or less, the amino acid-N-carboxyanhydride can be stably produced in a high yield.
Furthermore, when an acid is added to the reaction solution in the heating step, the stability of the produced target product in the solution can be improved and the yield can also be improved.
Moreover, when the acid added in a heating process is carboxylic acid, while being able to improve the stability in the solution of the target object to produce | generate, a yield can also be improved.
Furthermore, when the carboxylic acids are liquid at 20 ° C., the target product can be easily isolated without precipitation during crystallization.
In the crystallization step, when hydrocarbon is used as the poor solvent for the target product, amino acid-N-carboxyanhydride can be produced in high yield.
Furthermore, in the crystallization step, when at least one of toluene and ethers is used in addition to the poor solvent, the purification efficiency of the amino acid-N-carboxy anhydride can be further improved.

Hereinafter, the present invention will be described in detail.
The method for producing an amino acid-N-carboxyanhydride of the present invention includes (1) a reaction solution preparation step, (2) an acid addition step, (3) a water removal step, (4) a heating step, and (5). And a crystallization step.

[1] Reaction solution preparation step The reaction solution preparation step is a step of preparing a reaction solution by mixing and reacting an amino acid, an onium salt, a carbonate, water, and an organic solvent.

〔一般式（１）において、Ｘは置換基を有していてもよい２価の炭化水素基を示す。〕 As said amino acid, what is represented by following General formula (1) is preferable.

[In General formula (1), X shows the bivalent hydrocarbon group which may have a substituent. ]

  X in the general formula (1) is preferably a divalent hydrocarbon group represented by the following general formula (a).

〔一般式（ａ）において、Ｒ^１及びＲ^２は、互いに独立に、水素原子又は置換基を有していてもよい１価の炭化水素基を示す。ｍは１〜１５の整数を示す。〕

[In General Formula (a), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group which may have a substituent. m shows the integer of 1-15. ]

The monovalent hydrocarbon group for R ¹ and R ² in the general formula (a) includes an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, and a substituent. An aryl group which may be substituted, an arylalkyl group which may have a substituent, a heterocyclic group which may have a substituent, a heterocyclic alkyl group which may have a substituent, and the like It is done.
Examples of groups that can be substituted for these hydrocarbon groups include halogen atoms such as chlorine and fluorine, phenyl groups, hydroxy groups, mercapto groups, amino groups, carboxy groups, ester groups, alkoxycarbonyl groups, aralkyloxycarbonyl groups, and the like. Is mentioned.

The alkyl group which may have a substituent for R ¹ and R ² means an alkyl group which is unsubstituted or partially substituted, and specifically includes a methyl group, an ethyl group, n -Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, trichloroethyl group, adamantyl group, methyl mercaptoethyl group, hydroxymethyl group, hydroxyethyl group, mercaptomethyl group, mercapto Ethyl group, methyl mercaptoethyl group, carboxymethyl group, carboxyethyl group, aminopropyl group, aminobutyl group, aminocarbonylmethyl group, aminocarbonylethyl group, pentyl group, heptyl group, octyl group, — (CH ₂ ) ₃ — _{NH-C (= NH) -NH} 2, - (CH 2) 3 NH-CO-NH 2 and the like can be mentioned It is done.

The cycloalkyl group optionally having a substituent for R ¹ and R ² means a cycloalkyl group which is unsubstituted or partially substituted, and specifically includes a cyclopropyl group, a cyclopropyl group, Examples thereof include a propylmethyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexylmethyl group, a cycloheptyl group, and a cyclooctyl group.

The aryl group optionally having a substituent for R ¹ and R ² means an aryl group which is unsubstituted or partially substituted, and specifically includes a phenyl group, a tolyl group, a methoxy group. Examples include a phenyl group, a benzyloxyphenyl group, an ethylphenyl group, a chlorophenyl group, a fluorophenyl group, a hydroxyphenyl group, and a nitrophenyl group.

The arylalkyl group optionally having a substituent for R ¹ and R ² means an arylalkyl group which is unsubstituted or partially substituted, and specifically, a fluorenylmethyl group. Benzyl group, nitrobenzyl group, aminobenzyl group, bromobenzyl group, methoxybenzyl group, hydroxybenzyl group, dihydroxybenzyl group, phenacyl group, methoxyphenacyl group, cinnamyl group, phenethyl group and the like.

The heterocyclic group optionally having a substituent of R ¹ and R ² means an unsubstituted or optionally substituted heterocyclic group, specifically, a tetrahydropyranyl group, Tetrahydrofuranyl group, tetrahydrothienyl group, piperidyl group, morpholinyl group, piperazinyl group, pyrrolyl group, pyrrolidinyl group, furyl group, thienyl group, pyridyl group, furfuryl group, tenenyl group, pyrimidyl group, pyrazyl group, imidazolyl group, indolyl group, An isoquinolyl group, a quinolyl group, a thiazolyl group, etc. are mentioned.

The above-mentioned heterocyclic alkyl group optionally having a substituent for R ¹ and R ² means an unsubstituted or optionally substituted heterocyclic alkyl group, specifically, a pyridylmethyl group. , An imidazolylmethyl group, an indolylmethyl group, and the like.

R ¹ and R ² bonded to the same carbon atom may be bonded to each other to form a cycloalkyl skeleton (particularly having 3 to 6 carbon atoms). In addition, the cycloalkyl skeleton may have an aromatic ring or a hetero ring (eg, indole, pyrrolidine, imidazole, pyrrole, piperidine, dihydroquinoline, etc.) as a condensed ring.

In addition, R ¹ and R ² are either (1) a hydrogen atom, or (2) R ¹ or R ² is a hydrogen atom, and the remaining R ¹ or R ² has a substituent. It is preferably an alkyl group that may be substituted, an arylalkyl group that may have a substituent, or a heterocyclic alkyl group that may have a substituent.

  Moreover, it is preferable that m in the said general formula (a) is an integer of 1-10, More preferably, it is an integer of 1-8, More preferably, it is 1.

  Here, as specific amino acids, for example, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, proline, histidine, methionine, cysteine, cystine, arginine, lysine, serine, threonine, glutamic acid, glutamine, Examples include α-amino acids that are the main constituents of proteins such as aspartic acid and asparagine, as well as ortinin, norleucine, selenocysteine, and cysteine sulfonic acid. Furthermore, β-amino acids, γ-amino acids and the like can be mentioned.

  As said onium salt, what is represented by following General formula (2) is preferable.

〔一般式（２）において、［ＡＹ^＋］はカチオンを示し、Ｚ⁻はアニオンを示す。〕

In [Formula (2), [AY ^+] represents a cation, Z ^- represents an anion. ]

Y in the general formula (2) is preferably an atom of a Group 14 element, Group 15 element, Group 16 element or Group 17 element.
As the group 14 element atom, a tin atom is preferable. Examples of the group 15 element atom include a nitrogen atom, a phosphorus atom, an arsenic atom, an antimony atom, and a bismuth atom. Among these, a nitrogen atom and a phosphorus atom are preferable. Examples of the group 16 element atom include an oxygen atom, a sulfur atom, a selenium atom, a tellurium atom, and a polonium atom. Among these, an oxygen atom and a sulfur atom are preferable. Examples of the atom of the Group 17 element include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an astatine atom, and the like, and an iodine atom is preferable.

When Y is a tin atom, [AY ⁺ ] is a stannonium ion, and a tertiary stannonium ion is preferable. When Y is a nitrogen atom, [AY ⁺ ] is an ammonium ion, preferably a quaternary ammonium ion. When Y is a phosphorus atom, [AY ⁺ ] is a phosphonium ion, preferably a quaternary phosphonium ion. When Y is an arsenic atom, [AY ⁺ ] is an arsonium ion, preferably a quaternary arsonium ion. When Y is an antimony atom, [AY ⁺ ] is a stignium ion, preferably a quaternary stibonium ion. When Y is an oxygen atom, [AY ⁺ ] is an oxonium ion, preferably a tertiary oxonium ion. When Y is a sulfur atom, [AY ⁺ ] is a sulfonium ion, preferably a tertiary sulfonium ion. When Y is a selenium atom, [AY ⁺ ] is a selenonium ion, preferably a tertiary selenonium ion. When Y is an iodine atom, [AY ⁺ ] is an iodonium ion, and a secondary iodonium ion is preferred.
Among these, Y is preferably a nitrogen atom from the viewpoint of obtaining the target product in high yield. In particular, [AY ⁺ ] is preferably a quaternary ammonium ion.

In the general formula (2), [AY ⁺ ]
(A): [(R ³ ) _n Y ⁺ ] (wherein R ³ is the same or different and represents a monovalent hydrocarbon group which may have a substituent. N is 2 to 4) A cation represented by an integer),
(B): a carbon atom which may have a substituent, may have a hydrogen atom or a substituent on the Y atom of the heterocyclic ring containing one or more Y atoms (Y atom-containing heterocyclic ring) A cation having one hydrogen group bonded thereto, or
(C): The cation of (a) or (b) bonded to a polymer is preferable.

If the [AY ^+] is the _{^{(a), [(R 3}} ) n Y +] As examples of the monovalent hydrocarbon group ^{R 3} in, which may have a substituent alkyl group, a substituent A cycloalkyl group that may have, an alkenyl group that may have a substituent, a cycloalkenyl group that may have a substituent, an aryl group that may have a substituent, and a substituent. The arylalkyl group which may have is mentioned. Among these, an alkyl group which may have a substituent is preferable from the viewpoint that the target product can be obtained in high yield.

  Examples of the substituent in these hydrocarbon groups include alkoxy groups such as methoxy group, ethoxy group, isopropoxy group, and tert-butoxy group; silyl group; trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, Trisubstituted silyl groups such as phenylsilyl group; halogen atoms such as chlorine and fluorine; alkenyl groups such as vinyl group, allyl group, 1-propenyl group and isopropenyl group; alkoxycarbonyl groups such as methoxycarbonyl group and ethoxycarbonyl group; Amino group; N, N-disubstituted amino group such as N, N-dimethylamino group and N, N-diethylamino group; hydroxyl group; siloxy group; substituted siloxy group such as methylsiloxy group and ethylsiloxy group; cyano group and the like Can be mentioned.

Examples of the alkyl group include linear or branched alkyl groups having 1 to 20 (preferably 1 to 15, particularly 1 to 12) carbon atoms. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n -Heptyl group, n-octyl group, n-nonyl group, n-decanyl group, etc. are mentioned. Among these, an n-butyl group is more preferable.
As said cycloalkyl group, a C3-C20 (especially 3-10) cycloalkyl group is mentioned. Specific examples include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

As said alkenyl group, a C2-C18 (especially 2-10) alkenyl group is mentioned. Specifically, a vinyl group, a propenyl group, 3-butenyl, etc. are mentioned, for example.
As said cycloalkenyl group, a C5-C18 (especially 5-10) cycloalkenyl group is mentioned. Specific examples include cyclohexenyl, cyclooctenyl, cyclododecenyl and the like.

As said aryl group, a C6-C14 (especially 6-10) aryl group is mentioned. Specific examples include phenyl, tolyl, naphthyl and the like.
As said arylalkyl group, a C7-C13 (especially 7-9) arylalkyl group is mentioned. Specific examples include benzyl, phenethyl, naphthylmethyl, naphthylethyl and the like.

^Also, in ^{_{[(R 3) n Y +}} ], n represents an integer of 2 to 4. When Y is a group 14 element atom, n = 3, when Y is a group 15 element atom, n = 4, and when Y is a group 16 element atom, n = 4. 3. When Y is an atom of a Group 17 element, n = 2.

Specific examples of the cation represented by [(R ³ ) _n Y ⁺ ] include, for example, tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, tetrapentylammonium, tetrahexylammonium, tetraoctylammonium, and trimethyl. Quaternary ammonium ions such as phenylammonium, trimethylbenzylammonium, triethylbenzylammonium and tributylbenzylammonium; quaternary phosphonium ions such as tetrabutylphosphonium and butyltriphenylphosphonium; tertiary such as triethyloxonium and trimethyloxonium Oxonium ion; (2-carboxyethyl) dimethylsulfonium, (3-chloropropyl) diphenylsulfonium, Tertiary sulfonium ions such as chloropropyldiphenylsulfonium, diphenyl (methyl) sulfonium, tri-n-butylsulfonium, tri-p-tolylsulfonium, triethylsulfonium, trimethylsulfonium, toiphenylsulfonium; secondary iodonium such as diphenyliodonium And ions.
Of these, tetrabutylammonium, tributylbenzylammonium, tetrapropylammonium, and tetraethylammonium are preferable.

Examples of the one or more Y atom-containing heterocycles in the case where [AY ⁺ ] is the above (b) include aromatic heterocycles and unsaturated heterocycles.
When Y is a nitrogen atom, an aromatic heterocyclic ring is preferable, and a 5-membered ring, a 6-membered ring having 1 to 3 nitrogen atoms, or a condensed ring containing them is more preferable.
When Y is a sulfur atom, a 5-membered ring, 6-membered ring having 1 or 2 sulfur atoms, or a condensed ring containing them is preferable.

Examples of the hydrocarbon group that may have a substituent and bonded to the Y atom of the Y atom-containing heterocyclic ring include the same hydrocarbon groups as those described above for R ³ .
In particular, the hydrocarbon group is preferably a linear or branched alkyl group (having 1 to 6 carbon atoms) which may have a substituent. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and an n-hexyl group. In particular, a methyl group and an ethyl group are preferable.

  In addition, a substituent such as an alkyl group, a halogen atom, an alkoxy group, a nitro group, or a cyano group may be present on the Y atom and carbon atom other than the Y atom forming the cation in the Y atom-containing heterocyclic ring. Good. The alkyl group is preferably a linear or branched group having 1 to 12 carbon atoms. Moreover, as an alkoxy group, a C1-C6 thing is preferable.

Here, when Y is a nitrogen atom, specific heterocyclic cations include, for example, pyrrolium, imidazolium, 2H-pyrrolium, pyrazolium, pyridinium, pyrazinium, pyrimidinium, pyridazinium, indolizinium, indolium, 3H-indo. Lithium, 1H-indazolium, isoindolium, purinium, 4H-quinolizinium, isoquinolinium, quinolinium, phthalazinium, naphthyridinium, quinoxalinium, quinazolinium, cinolinium, pteridinium, 4aH-carbazolium, carbazolium, β-carbolinium, phenanthridinium, acridinium, acridinium, acridinium , Phenanthrolinium, phenazinium and the like. Among these, imidazolium, pyridinium, and pyrrolidinium are preferable, and imidazolium is more preferable.
When Y is an oxygen atom, specific heterocyclic cations include, for example, 2,4,6-trimethylpyrylium, 2,6-di-tert-butyl-4-methylpyrylium, and the like.
Further, when Y is a sulfur atom, specific heterocyclic cations include 1,3-benzodithiolylium, 1-benzyltetrahydrothiophen-1-ium and the like.

As in (c) above, when [AY ⁺ ] is a cation of (a) or (b) bonded to a polymer, the cation of (a) or (b) is as described above. Is mentioned. Further, the polymer is not particularly limited, but for example, aromatics such as polystyrene, poly α-methyl styrene, poly m-methyl styrene, poly p-methyl styrene, polyvinyl toluene, poly p-methoxy styrene, and polyallylbenzene. Aliphatic vinyl polymers; Aliphatic vinyl polymers such as polypropylene, polybutene and polypentene; Aliphatic vinyl ether polymers such as polymethyl vinyl ether, polyethyl vinyl ether, polypropyl vinyl ether and polybutyl vinyl ether; Polycyclopentyl vinyl ether, polycyclohexyl vinyl ether, etc. Alicyclic vinyl ether polymers; aromatic vinyl ether polymers such as polyphenyl vinyl ether and polybenzyl vinyl ether; poly (meth) acrylic acid, poly (meta Methyl acrylate, poly (meth) acryl-based polymers such as ethyl acrylate.

Examples of Z ⁻ (anion) of the onium salt include HSO ₄ ⁻ , SO ₄ ²⁻ , Br ⁻ , Cl ^{− and the} like. Among these, HSO ₄ ⁻ and SO ₄ ²⁻ are preferable from the viewpoint that generation of impurities in the reaction solution can be sufficiently suppressed and the yield of the target product can be improved.

In particular, the onium salt in the present invention is preferably a quaternary ammonium salt.
Specific quaternary ammonium salts include, for example, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium hydrogensulfate, tetrapropylammonium sulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate Salt, tetrabutylammonium sulfate and the like. Of these, tetrabutylammonium hydrogen sulfate is preferable.

  The compounding amount of the onium salt is preferably 0.5 to 10.0 mol, more preferably 0.8 to 3.0 mol, per 1 mol of amino acid.

  As said carbonate, what is represented by following General formula (3) is preferable.

〔一般式（３）において、Ｒ^５は、互いに独立に、置換基を有していてもよい１価の炭化水素基を示す。〕

[In General formula (3), R < ⁵ > shows the monovalent | monohydric hydrocarbon group which may have a substituent mutually independently. ]

Examples of the monovalent hydrocarbon group which may have a substituent of R ⁵ in the general formula (3) include an alkyl group which may have a substituent and a substituent. A cycloalkyl group, an alkenyl group which may have a substituent, a cycloalkenyl group which may have a substituent, an aryl group which may have a substituent, and a substituent. An arylalkyl group etc. are mentioned. Among these, an aryl group which may have a substituent is preferable.

  Examples of the substituents in these hydrocarbon groups include, for example, nitro groups; halogen atoms such as chlorine atoms and fluorine atoms; perfluoroalkyl groups (wherein the alkyl groups are straight-chain, A branched or cyclic saturated and unsaturated alkyl group, etc.); a perchloroalkyl group (wherein the alkyl group is the same as the perfluoroalkyl group); an ester group; an acetyl group; A cyano group; a benzoyl group, and the like. Among these, a nitro group, a halogen atom, and a halogen-substituted alkyl group (here, the same alkyl group as the perfluoroalkyl group can be mentioned) are preferable.

Examples of the alkyl group include linear or branched alkyl groups having 1 to 20 carbon atoms (particularly 1 to 10). Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n -Heptyl group, n-octyl group, n-nonyl group, n-decanyl group, etc. are mentioned.
As said cycloalkyl group, a C3-C20 (especially 3-10) cycloalkyl group is mentioned. Specific examples include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

As said alkenyl group, a C2-C18 (especially 2-10) alkenyl group is mentioned. Specifically, a vinyl group, a propenyl group, 3-butenyl, etc. are mentioned, for example.
As said cycloalkenyl group, a C5-C18 (especially 5-10) cycloalkenyl group is mentioned. Specific examples include cyclohexenyl, cyclooctenyl, cyclododecenyl and the like.

As said aryl group, a C6-C14 (especially 6-10) aryl group is mentioned. Specific examples include phenyl, tolyl, naphthyl and the like.
As said arylalkyl group, a C7-C13 (especially 7-9) arylalkyl group is mentioned. Specific examples include benzyl, phenethyl, naphthylmethyl, naphthylethyl and the like.

Specific carbonates include, for example, diphenyl carbonate, bis (4-nitrophenyl) carbonate, bis (2-nitrophenyl) carbonate, bis (2,4-dinitrophenyl) carbonate, bis (2, 4, 6 -Trinitrophenyl) carbonate, bis (pentafluorophenyl) carbonate, bis (4-chlorophenyl) carbonate, bis (2,4-dichlorophenyl) carbonate, bis (2,4,6-trichlorophenyl) carbonate and the like. Of these, diphenyl carbonate is preferred.
In addition, carbonate can be manufactured by a well-known method and can use a commercially available thing.

  It is preferable that the compounding quantity of the said carbonate is 0.5-10.0 mol with respect to 1 mol of amino acids, More preferably, it is 0.8-3.0 mol.

The said water is not specifically limited, For example, ion-exchange water, distilled water, etc. can be used.
The blending amount of water is not particularly limited as long as the amino acid and the onium salt can be sufficiently reacted, and can be appropriately adjusted.

  The organic solvent is preferably one that can dissolve the carbonate, and more preferably one that can dissolve the target product (amino acid-N-carboxyanhydride) and its precursor (amino acid carbamate).

  The organic solvent is preferably one having low compatibility with water. Specifically, the solubility (20 ° C.) of the organic solvent in water is preferably 50% by mass or less, more preferably 0 to 20% by mass, and still more preferably 0 to 10% by mass.

  Furthermore, it is preferable that the boiling point (standard boiling point) of this organic solvent is higher than water, More preferably, it is 100-400 degreeC, More preferably, it is 100-200 degreeC. When the boiling point of the organic solvent is higher than that of water, water can be removed more easily, and productivity can be improved.

Specific examples of the organic solvent include ketones and ethers.
Examples of the ketones include methyl isobutyl ketone, methyl isoamyl ketone, methyl-n-propyl ketone, benzyl methyl ketone, diethyl ketone, methyl pentyl ketone, methyl hexyl ketone, and acetophenone.
Examples of the ethers include dioxane, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, cyclopentane monomethyl ether, and methyl-t-butyl ether.
Among these, ketones are preferable from the viewpoint that the target amino acid-N-carboxyanhydride can be stably produced in high yield with the same organic solvent. Among the ketones, those having a total carbon number of 5 to 10 are preferable. In particular, methyl isobutyl ketone (boiling point: 116.2 ° C., solubility in water (20 ° C.); 1.91% by mass), methyl hexyl ketone (boiling point: 173 ° C., solubility in water (20 ° C.); 0.9 Mass%) is preferred.
In addition, these organic solvents may be used individually by 1 type, and may be used in combination of 2 or more type.

Further, in the reaction solution preparation step in the present invention, the above-mentioned raw materials are mixed and reacted to produce an amino acid carbamate [the following formula (4)] which is a precursor of the target product, as shown below. Is done. In formula (4), R ⁵ and X have the same meanings as X in general formula (1) and R ⁵ in general formula (3), respectively.

  Moreover, when preparing the said reaction solution, in order to accelerate | stimulate reaction with the amino acid and onium salt (especially quaternary ammonium salt) in water, sodium hydroxide, potassium hydroxide calcium hydroxide, magnesium hydroxide, water An alkali such as strontium oxide, barium hydroxide, ammonium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like can be blended.

  In the reaction solution preparation step, the order of mixing the respective raw materials is not particularly limited. Specifically, for example, (i) an amino acid, an onium salt, a carbonate, water, and an organic solvent may be mixed together in the same system and reacted to prepare a reaction solution. (Ii) A mixture or reaction product of an amino acid, an onium salt and water and a mixture of a carbonate and an organic solvent may be mixed and reacted to prepare a reaction solution. In particular, from the viewpoint of improving the yield of the target product, the preparation method (ii) is preferred. In addition, a commercial item can also be used for the mixture and reaction material in said (ii).

The reaction conditions for preparing the reaction solution are not particularly limited. Usually, it can be carried out in the atmosphere, but it may be carried out in an atmosphere of an inert gas such as argon or nitrogen. Further, it can be carried out in any state of normal pressure, reduced pressure, and increased pressure.
Moreover, reaction temperature is -70-120 degreeC normally, Preferably it is -10-70 degreeC.
Furthermore, reaction time is 0.1 to 100 hours normally, Preferably it is 0.5 to 20 hours.

[2] Acid addition step The acid addition step is a step of adding an acid for removing the reaction residue derived from the onium salt to the obtained reaction solution.
Specifically, the compounding of the acid stops the formation reaction of the amino acid carbamate (precursor), and the reaction residue derived from the onium salt in the unreacted product with the carbonate is removed, thereby suppressing the generation of impurities. it can.
And in the manufacturing method of this invention, since generation | occurrence | production of an impurity is suppressed in this way, it can progress to a post process in the state of a solution, without isolating and purifying a precursor on the way.

  The acid is not particularly limited as long as the above action can be obtained, and examples thereof include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, and boric acid. Among these, sulfuric acid, hydrochloric acid, and nitric acid are preferable from the viewpoint of being industrially produced in large quantities, easily available, and inexpensive.

  It is preferable that the addition amount of the acid in the said acid addition process is 0.1-30 mol with respect to 1 mol of amino acids, More preferably, it is 0.5-5.0 mol.

[3] Water removal step The water removal step is a step of removing water contained in the reaction solution after the acid addition step.
The method for removing water from the reaction solution is not particularly limited, and a known method such as heating or decompression can be used.
The water content contained in the reaction solution after the water removal step is preferably 500 ppm or less, and more preferably 50 ppm or less. When this content is 500 ppm or less, amino acid-N-carboxyanhydride can be stably produced in high yield.

[4] Heating step The heating step is a step of heating the reaction solution after the water removal step.
By this heating step, the precursor (amino acid carbamate) of the following formula (4) can be cyclized in the reaction solution as shown below, and the target product of the amino acid-N-carboxy of the following formula (5) Anhydrides can be produced.
In formulas (4) and (5), R ⁵ and X have the same meanings as X in general formula (1) and R ⁵ in general formula (3), respectively.

  The heating conditions in this heating step are not particularly limited. Specifically, for example, the heating temperature is preferably 50 to 200 ° C, more preferably 70 to 150 ° C. The heating time is preferably 0.1 to 300 hours, more preferably 1 to 150 hours.

Further, in this heating step, it is preferable to add an acid as a catalyst to the reaction solution when heating from the viewpoint of improving the stability of the target product to be produced in the solution and improving the yield.
Examples of the acid include carboxylic acids, phenols, phosphoric acids, sulfonic acids, and the like. In addition, these acids may be used individually by 1 type, and may be used in combination of 2 or more type.

  Examples of the carboxylic acids include substituents such as acetic acid, hexanoic acid, octanoic acid, octylic acid, lauric acid, palmitic acid, stearic acid, acetic anhydride, phenylacetic acid, diphenylacetic acid, oxalic acid, malonic acid, and succinic acid. Saturated fatty acid which may have; unsaturated carboxylic acid, benzoic acid, p-nitrobenzoic acid, pentafluoro which may have a substituent such as oleic acid, linoleic acid, linolenic acid, fumaric acid, maleic acid Examples thereof include aromatic carboxylic acids which may have a substituent such as benzoic acid, 2,4-dinitrobenzoic acid, salicylic acid and phthalic acid. Specific examples of these substituents include a halogen atom, a nitro group, a hydroxy group, a mercapto group, a cyano group, and an alkoxy group.

Examples of the phenols include 2,4-dinitrophenol, pentafluorophenol, cyanophenol, (2-butanone) phenol, and the like.
Examples of the phosphoric acids include phosphoric acid, phosphorous acid, hypophosphorous acid and the like.
Examples of the sulfonic acids include aliphatic sulfonic acids such as methanesulfonic acid and ethanesulfonic acid; aromatic sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid, and the like.

  Of these acids, carboxylic acids are preferred. In particular, it is preferable to use carboxylic acids that are liquid at 20 ° C. The use of carboxylic acids that are liquid at 20 ° C. is preferable because the target product can be easily isolated without precipitation in the subsequent crystallization step, and the target product can be obtained in high yield.

  It is preferable that the usage-amount of the acid in the said heating process is 0.1-30 mol with respect to 1 mol of amino acid carbamates (precursor), More preferably, it is 0.1-10 mol.

[5] Crystallization Step The crystallization step is a step obtained by crystallizing the target amino acid-N-carboxy anhydride from the heated reaction solution. That is, in this step, by utilizing the temperature dependence of the solubility, the target product is crystallized from the reaction solution, and the target product is selectively separated.
Moreover, when crystallizing, from the viewpoint of improving the yield of the target product, it is preferable to use a reaction solution concentrated in advance using a known means such as an evaporator.

  The poor solvent used in this crystallization step (a solvent having low solubility with respect to the target product, amino acid-N-carboxyanhydride) is not particularly limited, and examples thereof include hydrocarbons, ketones, esters, alcohols, and the like. Is mentioned. Among these, from the viewpoint of improving the yield of the target product, hydrocarbons are preferable, and hydrocarbons having 5 to 11 carbon atoms such as pentane, n-hexane, heptane, and octane are more preferable.

Moreover, when using the said poor solvent, it is preferable to use together at least one of toluene and ethers from a viewpoint of improving the purification efficiency of a target object. Examples of ethers include diethyl ether, dibutyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, and the like.
The blending ratio when toluene or ether is used in combination is preferably 0.1 to 1000% by volume, more preferably 0.1 to 100% by volume, when the poor solvent is 100% by volume.

  Hereinafter, the embodiment of the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

[1] Production of amino acid-N-carboxy anhydride An amino acid-N-carboxy anhydride was produced as in Examples 1 to 8 below.

<Example 1>
Step (1) [Reaction Solution Preparation Step]
Glass flask, L- valine 0.52g (4.4mmol), was added tetrabutylammonium hydrogen sulfate _{(TBA-HSO 4) 1.36g (} 4mmol). Thereafter, 1.54 g (containing 4 mmol of sodium hydroxide) of a 20.78 wt% sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 30 minutes. Next, 2.36 g (containing 4 mmol of diphenyl carbonate) of 30 wt% diphenyl carbonate (DPC) -methyl isobutyl ketone (MIBK) solution was added, and the mixture was reacted at room temperature for 3 hours to prepare a reaction solution.

Step (2) [acid addition step]
After adding 24 g of methyl isobutyl ketone to the reaction solution obtained in the above step (1), 18 g of 1 mol / L sulfuric acid was added and stirred to stop the reaction.

Step (3) [water removal step]
The reaction solution to which the acid was added in the above step (2) was transferred to a separatory funnel and stirred, and then the aqueous phase was removed. Further, 18 g of 1 mol / L sulfuric acid was added again and stirred, and then the aqueous phase was removed (that is, sulfuric acid was washed twice in total).
Subsequently, 20 g of water was added and stirred, and then the aqueous phase was removed. Further, the organic phase was washed twice with 20 g of water (that is, the water was washed three times in total).
Thereafter, 130 g of methyl isobutyl ketone was added to the obtained organic phase, and then the water contained in the reaction solution was removed by concentration under reduced pressure using an evaporator until the liquid weight reached 52.3 g.

Process (4) [heating process]
To the sufficiently dried glass flask, 52.3 g of the reaction solution obtained in the above step (3) and 0.89 ml of oleic acid were added. Next, the flask was heated in an oil bath and stirred at an internal temperature of 102 ° C. for 12 hours.
Thereafter, the obtained reaction solution was cooled and then subjected to NMR measurement. As a result, valine-N-carboxyanhydride was produced in a yield of 63%.

Process (5) [crystallization process]
The reaction solution obtained in the above step (4) was concentrated under reduced pressure using an evaporator until the liquid weight became 3.34 g. Next, 9 ml of dibutyl ether was added, then 90 ml of n-hexane was added, and the mixture was stirred in an ice bath for 2 hours. The precipitated white solid was collected by suction filtration, and 0.16 g of valine-N-carboxyanhydride was obtained (purification yield: 44%).

<Example 2>
In the step (5) in Example 1, except that 9 ml of diethyl ether was used instead of dibutyl ether, the precipitated solid was recovered and 0.26 g of valine-N-carboxyanhydride was recovered. Things were obtained.

<Example 3>
In step (4) in Example 1, 0.16 ml of acetic acid was used instead of oleic acid, and the same procedure as in Example 1 was performed. The precipitated solid was recovered, and 0.11 g of valine-N-carboxyl was recovered. Anhydrous was obtained.

<Example 4>
In step (5) in Example 1, except that 9 ml of toluene was used instead of dibutyl ether, the precipitated solid was recovered and 0.15 g of valine-N-carboxyanhydride was recovered. was gotten.

<Example 5>
In Step (1) in Example 1, 0.80 g (4.4 mmol) of L-phenylalanine was used instead of L-valine, and in Step (3) of Example 1, stirring was performed at an internal temperature of 90 ° C. for 8 hours. Except for this, the procedure was the same as in Example 1, and the precipitated solid was collected. As a result, 0.29 g of phenylalanine-N-carboxyanhydride was obtained.

<Example 6>
In the step (4) in Example 1, except that 0.16 ml of acetic acid was used instead of oleic acid, the same was performed as in Example 5. The precipitated solid was recovered, and 0.27 g of phenylalanine-N-carboxyl was recovered. Anhydrous was obtained.

<Example 7>
In the step (4) in Example 1, except that 0.31 ml of hexanoic acid was used instead of oleic acid, the precipitated solid was recovered and 0.30 g of phenylalanine-N— was recovered. Carboxy anhydride was obtained.

<Example 8>
In step (1) in Example 1, 0.80 g (4.4 mmol) of L-phenylalanine, 1.36 g (4 mmol) of tetrabutylammonium hydrogen sulfate, and 20.78 wt% aqueous sodium hydroxide solution were placed in a glass flask. The precipitated solid was recovered in the same manner as in Example 5 except that 54 g (containing 4 mmol of sodium hydroxide), 0.71 g (4 mmol) of diphenyl carbonate, and 1.65 g of methyl isobutyl ketone were simultaneously added to prepare a reaction solution. As a result, 0.22 g of phenylalanine-N-carboxyanhydride was obtained.

[2] Evaluation of Examples Yields (Carbamate Yield, Cyclization Yield, Yield to Cyclization, Purification Yield, Total Yield) in Production of Amino Acid-N-Carboxy Anhydrides of Examples 1-8 Rate) and relative evaluation are shown in Table 1. Furthermore, the raw materials used for manufacture of each Example are collectively shown in Table 1.
In addition, the calculation method of each yield and the evaluation criteria of relative evaluation are as follows.

(1) Carbamate yield Amino acid carbamate (precursor) yield in raw material comparison (vs. carbonate) (2) Cyclization yield Amino acid-N-carboxy anhydride when the amino acid carbamate of (1) is 100% (3) Yield until cyclization [Carbamate yield of (1) above] × [Cyclization yield of (2) above]
(4) Purification yield Yield of amino acid-N-carboxyanhydride obtained by crystallization when the amino acid-N-carboxyanhydride of (2) is 100% (5) Total yield [above Yield until cyclization of (3)] × [Purification yield of (4) above]
(6) Relative evaluation When the total yield of (5) is 40% or more, “「 ”is given, and when the total yield is 15% or more and less than 40%,“ ◯ ”is given.

[3] Effect of Examples According to the production method of the present invention, an amino acid-N-carboxyanhydride can be produced without using phosgene, and the precursor amino acid carbamate is isolated from the reaction solution during the production. There was no need for purification, and the amino acid-N-carboxyanhydride could be produced in high yield by a series of steps. Furthermore, it was found that the solvent (methyl isobutyl ketone) can be used at once, and the amount of the solvent used can be reduced as compared with the conventional production method.

  The amino acid-N-carboxyanhydride obtained by the production method of the present invention is useful as a raw material for synthetic polyamino acids, and the production method of the amino acid-N-carboxyanhydride of the present invention can be used for cosmetics, medical / pharmaceutical products, various functions. It can be suitably used in industrial fields such as chemicals.

Claims (11)

(1) A reaction solution preparation step in which an amino acid, an onium salt, a carbonate, water, and an organic solvent are mixed and reacted to prepare a reaction solution;
(2) an acid addition step of adding an acid for removing the reaction residue derived from the onium salt to the obtained reaction solution;
(3) a water removal step of removing water contained in the reaction solution to which the acid is added;
(4) a heating step of heating the reaction solution from which the water has been removed;
(5) A crystallization step obtained by crystallizing amino acid-N-carboxyanhydride from the heated reaction solution.   The method for producing an amino acid-N-carboxy anhydride according to claim 1, wherein the onium salt is a quaternary ammonium salt. Method for producing or _SO ^{4 2-amino} acid -N- carboxyanhydride of claim 1 or 2, ^- wherein the anion of the onium salt, HSO _4.   The method for producing an amino acid-N-carboxy anhydride according to any one of claims 1 to 3, wherein the organic solvent is a solvent having a boiling point higher than that of the water.   The method for producing an amino acid-N-carboxy anhydride according to any one of claims 1 to 4, wherein the organic solvent is a ketone.   The method for producing an amino acid-N-carboxy anhydride according to any one of claims 1 to 5, wherein a water content in the reaction solution after the water removal step is 500 ppm or less.   The method for producing an amino acid-N-carboxy anhydride according to any one of claims 1 to 6, wherein an acid is added to the reaction solution when heating in the heating step.   The method for producing an amino acid-N-carboxy anhydride according to claim 7, wherein the acid added in the heating step is a carboxylic acid.   The method for producing an amino acid-N-carboxy anhydride according to claim 8, wherein the carboxylic acids are liquid at 20 ° C.   The method for producing an amino acid-N-carboxy anhydride according to any one of claims 1 to 9, wherein a hydrocarbon is used as a poor solvent for the amino acid-N-carboxy anhydride in the crystallization step.   The method for producing an amino acid-N-carboxy anhydride according to claim 10, wherein at least one of toluene and ethers is used in addition to the poor solvent in the crystallization step.