Method for producing amino acid t-butyl ester and / or salt therefor

Abstract

To provide a method for producing amino acid t-butyl ester and / or a salt therefor, which is a useful substance.SOLUTION: A method for producing amino acid t-butyl ester and / or a salt therefor is disclosed that includes the step A for t-butylation of amino acids in the presence of fluorinated organic acids.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to a method for producing amino acid t-butyl esters and / or salts thereof. [Background technology]

[0002] The t-butyl group (also called the tert-butyl group or tertiary butyl group) is highly stable against various nucleophiles and reducing agents, and can be easily deprotected under acidic conditions, and is therefore frequently used as a protecting group for the carboxy group of amino acids. A method for producing an amino acid t-butyl ester is known, which is characterized in that an amino acid is reacted with t-butyl acetate in the presence of perchloric acid (HClO4), and then post-treated with an aqueous alkali hydroxide solution to obtain an amino acid t-butyl ester (Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 9-77724 Summary of the Invention [Problem to be solved by the invention]

[0004] The perchloric acid used in Patent Document 1 is a dangerous reagent, and there is still room for improvement in terms of reactivity. The main objective of the present disclosure is to provide a method for producing a useful amino acid t-butyl ester and / or a salt thereof. [Means for solving the problem]

[0005] The present disclosure encompasses the following aspects. [Section 1] A method for producing an amino acid t-butyl ester and / or a salt thereof, comprising step A of t-butylating an amino acid in the presence of a fluorine-containing organic acid. [Section 2] The gas phase acidity ΔG of the fluorine-containing organic acid acidItem 3. The method according to item 1, wherein the calorific value is 301 kcal / mol or less. [Section 3] Item 3. The method according to item 1 or 2, wherein the fluorine-containing organic acid is at least one selected from the group consisting of bis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic acid, tris(trifluoromethanesulfonyl)methane, bis(trifluoromethanesulfonyl)methane, phenylbis(trifluoromethanesulfonyl)methane, pentafluorophenylbis(trifluoromethanesulfonyl)methane, and 1,1,3,3-bis(trifluoromethanesulfonyl)propane. [Section 4] Item 4. The method according to any one of Items 1 to 3, wherein the amino acid is an aliphatic amino acid having a hydroxy group or a mercapto group. [Section 5] The amino acid has the following formula (1): [ka] (In the formula, R 1 and R 2 one of which is -NH2 or -CONH2, and the other is -OH or -SH; R 3 -H or C 1-4 is an alkyl group, L 1 is a single bond or C 1-4 It is an alkylene group. The method according to claim 4, wherein the compound is represented by the formula: [Section 6] The t-butylating agent used in the step A is C 1-4 Item 6. The method according to any one of Items 1 to 5, wherein the alkanoic acid t-butyl ester is used. [Section 7] Item 7. The production method according to any one of Items 1 to 6, further comprising step B of neutralizing the salt of the amino acid t-butyl ester obtained in step A. [Section 8] Item 8. The method according to any one of Items 1 to 7, wherein the neutralizing agent used in step B is at least one selected from the group consisting of alkali metal carbonates, alkali metal hydrogencarbonates, ammonia, alkali metal hydroxides, and alkaline earth metal hydroxides. [Section 9] The following formula (2): [ka] (In the formula, R 4 and R 5 one of which is -NH2 or -CONH2, and the other is -CH3, phenyl, -phenylene-OC(CH3)3, -phenylene-SC(CH3)3, -O-CH3, -S-CH3, -OC(CH3)3, or -SC(CH3)3; R 6 -H or C 1-4 is an alkyl group, L 2 is a single bond or C 1-4 It is an alkylene group. A fluorine-containing organic acid salt of a compound represented by the formula: Effect of the Invention

[0006] The present disclosure provides methods for producing useful amino acid t-butyl esters and / or salts thereof.

[0007] [Method for producing amino acid t-butyl ester and / or its salt] In one embodiment, the method for producing an amino acid t-butyl ester and / or a salt thereof includes a step A of t-butylating an amino acid in the presence of a fluorine-containing organic acid.

[0008] In this specification, an amino acid refers to an organic compound having -COOH (carboxy group) and -NH2 (amino group) or -CONH2 (amide group). -NH2 may be protected with a protecting group. Typical examples of the protecting group include, but are not limited to, a benzyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, and a 9-fluorenylmethyloxycarbonyl group. The amino acid may be a natural amino acid or a non-natural amino acid. The amino acid may be any of an L-amino acid, a D-amino acid, and a DL-amino acid.

[0009] Amino acids include aliphatic amino acids, alicyclic amino acids, aromatic amino acids, and heterocyclic amino acids.

[0010] Examples of aliphatic amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, aspartic acid, glutamic acid, γ-carboxyglutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, 2-hydroxy-4-aminobutyric acid (HABA), γ-aminobutyric acid (GABA), ornithine, aminolevulinic acid, 2-aminoisobutyric acid, methionine, cystine, cystathionine, lanthionine, djenkolic acid, diaminopimelic acid, and 5-amino-2-hydroxy-5-oxopentanoic acid.

[0011] Examples of the alicyclic amino acid include 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclohexanecarboxylic acid, 2-aminocyclohexanecarboxylic acid, and 3-aminocyclohexanecarboxylic acid.

[0012] Examples of aromatic amino acids include phenylalanine, tyrosine, 2-aminobenzoic acid, 4-aminobenzoic acid, 2-amino-3-hydroxybenzoic acid, 4-amino-3-hydroxybenzoic acid, 2-amino-3-methylbenzoic acid, 4-amino-3-methylbenzoic acid, 3-aminosalicylic acid, 4-aminosalicylic acid, 5-aminosalicylic acid, 4-aminophenylacetic acid, 4-aminocinnamic acid, and 6-amino-2-naphthalenecarboxylic acid.

[0013] Examples of heterocyclic amino acids include tryptophan, histidine, proline, 4-hydroxyproline, 3,4-dihydroxy-L-phenylalanine, and pyrrolysine.

[0014] The amino acids may be one type alone or two or more types in combination. The amino acids are preferably aliphatic amino acids and / or have a hydroxyl group or a mercapto group, and are more preferably represented by the following formula (1).

[0015] [ka]

[0016] R 1 and R 2 One of R is -NH2 or -CONH2, and the other is -OH or -SH. 1 and R 2 An example of a combination of 1 -OH, R 2 is -NH2, R 1 -OH, R 2 is -CONH2, R 1 -NH2, R 2 is -OH; R 1 -NH2, R 2 is -SH.

[0017] R 3 -H or C 1-4 is an alkyl group, preferably -H or C 1-3It is preferably an alkyl group, more preferably -H, a methyl group, or an ethyl group, and even more preferably -H or a methyl group.

[0018] L 1 is a single bond or C 1-4 is an alkylene group, preferably a single bond or C 1-4 an alkylene group, more preferably a single bond or C 1-3 It is preferably an alkylene group, more preferably a single bond, a methylene group, or an ethylene group, and even more preferably a single bond or a methylene group.

[0019] The amino acid is preferably at least one selected from the group consisting of HABA, serine, threonine, cysteine, and 5-amino-2-hydroxy-5-oxopentanoic acid.

[0020] In the t-butylation of the amino acid in step A, t-butyl acetate is usually used as the t-butylating agent, but the t-butylating agent is not particularly limited as long as it can t-butylate the carboxyl group without t-butylating -NH2 of the amino acid. When the amino acid has a hydroxyl group or a mercapto group, the t-butylating agent is preferably one that can t-butylate the hydroxyl group or the mercapto group in addition to the carboxyl group. Examples of the t-butylating agent include C 1-4 Examples of the t-butylating agent include t-butyl alkanoate and t-butyl acetoacetate. These t-butylating agents can be used alone or in combination of two or more. Among these t-butylating agents, those that can also be used as solvents are preferred, and C butylating agents such as t-butyl acetate are preferred. 1-4 Alkanoic acid t-butyl esters are preferred.

[0021] The amount of the t-butylating agent used is not particularly limited, but when the above-exemplified components such as t-butyl acetate are used as the t-butylating agent, the amount is, for example, 3 parts by mass or more, preferably 5 parts by mass or more, and more preferably 10 parts by mass or more, per part by mass of the amino acid. The amount of the t-butylating agent used is, for example, 100 parts by mass or less, preferably 90 parts by mass or less, and more preferably 80 parts by mass or less, per part by mass of the amino acid. The amount of the t-butylating agent used is, for example, within the range of 3 to 100 parts by mass, preferably within the range of 5 to 90 parts by mass, and more preferably within the range of 10 to 80 parts by mass, per part by mass of the amino acid.

[0022] The t-butylation of an amino acid in step A is carried out in the presence of a fluorine-containing organic acid. In this specification, the fluorine-containing organic acid refers to an organic compound having -F and an acidic group such as -COOH, -SO3H, -SO2H, -PO3H, or -PO2H. Examples of fluorine-containing organic acids include perfluoroalkanoic acids such as trifluoroacetic acid (TFA), perfluoropropionic acid, and perfluorobutyric acid; perfluoroalkanesulfonic acids such as trifluoromethanesulfonic acid (TfOH), perfluoroethanesulfonic acid, perfluoropropanesulfonic acid, and perfluorobutanesulfonic acid; 2,2,2-trifluoroethyl trifluoromethanesulfonate, 1,1,1,3,3,3-hexafluoroisopropyl trifluoromethanesulfonate, bis(trifluoromethanesulfonyl)methane (Tf2CH2), phenylbis(trifluoromethanesulfonyl)methane, tris(trifluoromethanesulfonyl)methane (Tf3CH), pentafluorophenylbis(trifluoromethanesulfonyl)methane, 1,1,3,3-bis(trifluoromethanesulfonyl)propane, and bis(trifluoromethanesulfonyl)imide (Tf2NH). These fluorine-containing organic acids can be used alone or in combination of two or more. Of these fluorine-containing organic acids, those having a trifluoromethyl group are preferred, those having a trifluoromethanesulfonyl group are more preferred, and at least one selected from the group consisting of TfOH, Tf2CH2, Tf3CH, phenylbis(trifluoromethanesulfonyl)methane, pentafluorophenylbis(trifluoromethanesulfonyl)methane, 1,1,3,3-bis(trifluoromethanesulfonyl)propane, and Tf2NH is even more preferred, and at least one selected from the group consisting of TfOH, Tf3CH, 1,1,3,3-bis(trifluoromethanesulfonyl)propane, and Tf2NH is particularly preferred.

[0023] Gas phase acidity ΔG of fluorine-containing organic acids acidis, for example, 320 kcal / mol or less, preferably 310 kcal / mol or less, more preferably 305 kcal / mol or less, even more preferably 301 kcal / mol or less, and even more preferably 300 kcal / mol or less.

[0024] The amount of the fluorine-containing organic acid used is, for example, 0.1 mol or more, preferably 0.5 mol or more, more preferably 1 mol or more, per mol of the amino acid. The amount of the fluorine-containing organic acid used is, for example, 100 mol or less, preferably 80 mol or less, more preferably 50 mol or less, per mol of the amino acid. The amount of the fluorine-containing organic acid used is, for example, within the range of 0.1 to 100 mol, preferably within the range of 0.5 to 80 mol, more preferably within the range of 1 to 50 mol, per mol of the amino acid.

[0025] Since t-butylating agents such as t-butyl acetate also function as a solvent, an additional solvent is usually not required, but an organic solvent may be used as an additional solvent. Examples of organic solvents include aromatic hydrocarbon solvents such as toluene and xylene, alcohol solvents such as ethanol and propanol, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and ester solvents such as ethyl acetate and propyl acetate. These organic solvents can be used alone or in combination of two or more.

[0026] The amount of the solvent used is, for example, 3 parts by mass or more, preferably 5 parts by mass or more, and more preferably 10 parts by mass or more, per 1 part by mass of the amino acid. The amount of the solvent used is, for example, 100 parts by mass or less, preferably 90 parts by mass or less, and more preferably 80 parts by mass or less, per 1 part by mass of the amino acid. The amount of the solvent used is, for example, within the range of 3 to 100 parts by mass, preferably within the range of 5 to 90 parts by mass, and more preferably within the range of 10 to 80 parts by mass, per 1 part by mass of the amino acid.

[0027] The reaction temperature and reaction time of step A are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, -40°C or higher, preferably -30°C or higher, and more preferably -20°C or higher. The reaction temperature is, for example, 25°C or lower, preferably 20°C or lower, more preferably 10°C or lower, and even more preferably 5°C or lower. The reaction temperature is, for example, within the range of -40 to 25°C, preferably within the range of -30 to 10°C, and even more preferably within the range of -20 to 5°C. The reaction time is, for example, 30 minutes or more, preferably 1 hour or more, and even more preferably 2 hours or more. The reaction time is, for example, 144 hours or less, preferably 120 hours or less, more preferably 96 hours or less, even more preferably 72 hours or less, even more preferably 48 hours or less, and particularly preferably 24 hours or less. Since the reactivity of the reaction of step A is high, it is possible to further shorten the reaction time, for example, 12 hours or less, preferably 6 hours or less, more preferably 4 hours or less, and even more preferably 3 hours or less.

[0028] The method for producing an amino acid t-butyl ester and / or a salt thereof may include, in addition to step A, step B of neutralizing the salt of the amino acid t-butyl ester obtained in step A.

[0029] For the neutralization in step B, a neutralizing agent is usually used. The neutralizing agent may be a strong base or a weak base. Examples of the neutralizing agent include alkali metal carbonates, alkali metal hydrogen carbonates, ammonia, alkali metal hydroxides, and alkaline earth metal hydroxides. Examples of the alkali metal carbonates include lithium carbonate, sodium carbonate, and potassium carbonate. Examples of the alkali metal hydrogen carbonates include sodium hydrogen carbonate and potassium hydrogen carbonate. Examples of the alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Examples of the alkaline earth metal hydroxides include magnesium hydroxide and calcium hydroxide. The neutralizing agents can be used alone or in combination of two or more.

[0030] The amount of the neutralizing agent used is not particularly limited as long as it is an amount capable of neutralizing the salt generated in step A and / or the acid that may be a by-product. The amount of the neutralizing agent used varies depending on the type of the fluorine-containing organic acid and neutralizing agent, and is, for example, within the range of 1 to 200 moles per mole of the product obtained in step A.

[0031] The neutralization temperature is not particularly limited as long as the neutralization reaction proceeds, and can be selected from the same range as the reaction temperature in step A.

[0032] The method for producing an amino acid t-butyl ester and / or a salt thereof may include any additional steps, such as purification steps such as filtration, extraction, distillation, column chromatography, washing, etc., in addition to steps A and B. The above production method can reduce the amount of by-products (e.g., acetic acid when t-butyl acetate is used as the t-butylating agent), and therefore can simplify the purification step.

[0033] The product obtained by the above-mentioned production method includes, for example, a compound represented by the following formula (2) and / or a fluorine-containing organic acid salt thereof. [ka]

[0034] R 4 and R 5 One of R is -NH2 or -CONH2, and the other is -CH3, phenyl, -phenylene-OC(CH3)3, -phenylene-SC(CH3), -O-CH3, -S-CH3, -OC(CH3), or -SC(CH3). 4 and R 5 An example of a combination of 4 -OC(CH3)3, R 5 is -NH2, R 4 -OC(CH3)3, R 5 is -CONH2, R 4 -NH2, R 5 is -OC(CH3)3, R 4 -NH2, R 5is -SC(CH3)3, R 4 -NH2, R 5 is -CH3, phenyl, -phenylene-OC(CH3)3, or -S-CH3.

[0035] R 6 -H or C 1-4 is an alkyl group, preferably -H or C 1-3 It is preferably an alkyl group, more preferably -H, a methyl group, or an ethyl group, and even more preferably -H or a methyl group.

[0036] L 2 is a single bond or C 1-4 is an alkylene group, preferably a single bond or C 1-4 an alkylene group, more preferably a single bond or C 1-3 It is preferably an alkylene group, more preferably a single bond, a methylene group, or an ethylene group, and even more preferably a single bond or a methylene group.

[0037] Specific examples of the compound represented by formula (2) and / or its fluorine-containing organic acid salt include compounds represented by the following formulas (2A) to (2L) and / or their fluorine-containing organic acid salts (e.g., TfNH2 salt, TfOH salt). [ka]

[0038] In an embodiment of the present disclosure, a reaction product obtained in step A, for example, a fluorine-containing organic acid salt of a compound represented by formula (2) (e.g., TfNH2 salt, TfOH salt) and a by-product of step A (e.g., C 1-4 alkanoic acid, acetoacetic acid). EXAMPLES

[0039] Hereinafter, the embodiments of the present disclosure will be described in detail based on examples, but the present disclosure is not limited to these.

[0040] Example 1. Tf of 2-hydroxy-4-aminobutyric acid (HABA) di-t-butyl ester 2 Synthesis of NH salt 2.15g of HABA was dissolved in 180mL of t-butyl acetate (AcOtBu) and cooled to 0℃. 5.58g (1.1 equivalents) of Tf2NH was added and reacted at 0℃ for 2.5 hours. After the reaction was completed, saturated NaHCO3 was added. Extraction was performed with CH2Cl2, and the organic layer was dried with MgSO4, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain the title compound (yield 86%). 1 H NMR (500 MHz, CD3OD): δ 4.15 (dd, J = 7.3, 4.4 Hz, 1H), 3.01 (td, J = 6.4, 1.5 Hz, 2H), 2.03-1.85 (m, 2H), 1.49 (s, 9H), 1.21 (s, 9H)

[0041] Example 2. Synthesis of 2-hydroxy-4-aminobutyric acid (HABA) di-t-butyl ester (Method 1) 195 mg of HABA was dissolved in 16 mL of t-butyl acetate (AcOtBu) and cooled to 0°C. 507 mg (1.1 equivalents) of Tf2NH was added and reacted at 0°C for 2.5 hours. After the reaction was completed, 10% NH3 was added. Extraction was performed with CH2Cl2, and the organic layer was washed with 10% NH3, then dried with MgSO4, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain the title compound (yield 81%). 1 H NMR (500 MHz, CD3OD): δ 4.03 (dd, J = 8.2, 4.6 Hz, 1H), 2.74 (ddd, J = 12.7, 7.8, 6.2 Hz, 1H), 2.71 (dt, J = 12.8, 7.5 Hz, 1H), 1.82-1.69 (m, 2H), 1.48 (s, 9H), 1.19 (s, 9H)

[0042] Example 3. Synthesis of 2-hydroxy-4-aminobutyric acid (HABA) di-t-butyl ester (Method 2) 100 mg of HABA was dissolved in 8.4 mL of AcOtBu and cooled to 0°C. 82 μL (1.1 equivalents) of TfOH was added and reacted at 0°C for 2 hours. After the reaction was completed, saturated NaHCO3 was added. Extraction was performed with CH2Cl2, and the organic layer was dried with MgSO4, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain the title compound in 80% yield. 1 H NMR (500 MHz, CD3OD): δ 4.03 (dd, J = 8.2, 4.6 Hz, 1H), 2.74 (ddd, J = 12.7, 7.8, 6.2 Hz, 1H), 2.71 (dt, J = 12.8, 7.5 Hz, 1H), 1.82-1.69 (m, 2H), 1.48 (s, 9H), 1.19 (s, 9H)

[0043] Example 4. t-Butyl esterification of amino acids other than HABA The same procedure as in Example 2 was repeated except that an amino acid in Table 1 was used instead of HABA, to obtain the t-butyl esters shown in the table below.

[0044] [Table 1] TIFF2025008254000007.tif240170TIFF2025008254000008.tif240170

Claims

1. A method for producing an amino acid t-butyl ester and / or a salt thereof, comprising step A of t-butylating an amino acid in the presence of a fluorine-containing organic acid.

2. The gas phase acidity ΔG of the fluorine-containing organic acid acid The method according to claim 1, wherein the molecular weight is 301 kcal / mol or less.

3. 2. The process according to claim 1, wherein the fluorine-containing organic acid is at least one selected from the group consisting of bis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic acid, tris(trifluoromethanesulfonyl)methane, bis(trifluoromethanesulfonyl)methane, phenylbis(trifluoromethanesulfonyl)methane, pentafluorophenylbis(trifluoromethanesulfonyl)methane, and 1,1,3,3-bis(trifluoromethanesulfonyl)propane.

4. The method according to claim 1, wherein the amino acid is an aliphatic amino acid having a hydroxyl group or a mercapto group.

5. The amino acid has the following formula (1): 【Chemistry 1】 (In the formula, R 1 and R 2 One is -NH 2 or -CONH 2 and the other is -OH or -SH; R 3 -H or C 1-4 is an alkyl group, L 1 is a single bond or C 1-4 It is an alkylene group. The method according to claim 4, wherein the compound is represented by the formula:

6. The t-butylating agent used in the step A is C 1-4 The method according to claim 1, wherein the alkanoic acid t-butyl ester is an alkanoic acid t-butyl ester.

7. The method according to claim 1, further comprising a step B of neutralizing the salt of the amino acid t-butyl ester obtained in the step A.

8. 2. The method according to claim 1, wherein the neutralizing agent used in step B is at least one selected from the group consisting of alkali metal carbonates, alkali metal hydrogen carbonates, ammonia, alkali metal hydroxides, and alkaline earth metal hydroxides.

9. The following formula (2): 【Chemistry 2】 (In the formula, R 4 and R 5 One is -NH 2 or -CONH 2 and the other is -CH 3 , phenyl, -phenylene-OC(CH 3 ) 3 , -phenylene-SC(CH 3 ) 3 , -O-CH 3 , -S-CH 3 , -OC(CH 3 ) 3 , or -SC(CH 3 ) 3 and R 6 -H or C 1-4 is an alkyl group, L 2 is a single bond or C 1-4 It is an alkylene group. A fluorine-containing organic acid salt of a compound represented by the formula:

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