JP2001002626A - Production of nitric ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a nitric ester safely on an industrial level by using only inexpensive reagents under mild reaction conditions without using a strong acid and a reaction or a reagent having high danger. SOLUTION: In a nitration reaction of a compound containing one or more hydroxyl group, nitric acid is added to a solution containing the compound, an acid anhydride, a carboxylic acid and an organic solvent. Preferably nitric acid is gradually dripped or dropped dividedly twice or more times. Preferably nitric acid is dripped on the solution containing the carboxylic acid, the organic solvent, the acid anhydride and the compound containing one or more hydroxyl groups and then the addition or drop of the compound containing one or more hydroxyl groups which may be dissolved in the organic solvent and the drop of nitric acid are successively carried out and, if required, repeatedly carried out.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a nitrate ester by a nitration reaction of a compound having one or more hydroxyl groups. More specifically, nitrate is added to a solution containing one or more hydroxyl groups, an acid anhydride, a carboxylic acid, and an organic solvent by nitric acid dropwise to form a nitrate ester that is safe and can be industrially produced. Related to manufacturing method.

[0002]

2. Description of the Related Art As a method for producing a nitrate ester compound from a compound having a hydroxyl group, (1) a method using a mixed acid using sulfuric acid and nitric acid [Synthesis, 22, 65 (1);
942)], (2) A method of preparing acetyl nitrate from acetic anhydride and nitric acid and nitrating with it [Chemist
ry and Industry (Septmber
26, 1953) 1035], (3) a method in which a hydroxyl group is iodinated with iodine, triphenylphosphine and imidazole and then nitrated with silver nitrate [Synth
ess Commun. , 22 (5), 677 (19
92)], (4) a method using boron trifluoride and potassium nitrate [Synthesis, 207 (1993)],
(5) Method using tetrabutylammonium nitrate, trifluoroacetic anhydride and pyridine [J. Heterocyc
lic Chem. , 31 (6), 1589 (199
4)], (6) A method of preparing thionyl nitrate or thionyl chloride nitrate with silver nitrate and thionyl chloride and nitrating [Helv. Chem. Ac
ta, 67 (3), 906 (1984)], (7) N-
Method using nitro-2,4,6-coridinium fluoroborate [Synthesis, 452 (1978)]
And so on.

[0003]

However, when the nitrate ester is produced industrially by these methods, the method (1) using a mixed acid involves a reaction under extremely strong acidic conditions. The compound having a hydroxyl group is limited to an acid-stable compound and has a strong nitration condition, so that not only a hydroxyl group portion but also a carbon atom which is easily nitrated may be nitrated. In the method using (2) acetyl nitrate, the prepared acetyl nitrate itself is very unstable, and exothermic decomposition starts even at room temperature or lower, and further decomposes explosively as the temperature rises. And it is very dangerous to prepare it in large quantities. (3)
In the method using silver nitrate, considering that silver nitrate itself is very expensive, sublimable, uses highly toxic iodine, and further treats triphenylphosphine after the reaction, etc. Improper.
In the method (4) using boron trifluoride and potassium nitrate, the reaction is carried out under a strong acid condition. Therefore, similarly to the method (1), the compound having a hydroxyl group as a raw material is limited to an acid-stable compound. Would be done. The method (5) is unsuitable as an industrial production method because the reagent itself is very expensive and requires a low temperature condition of −50 ° C. In the method (6), as in the method (3), one or more equivalents of expensive silver nitrate are used, which is unsuitable as an industrial production method. In the method (7), nitronium tetrafluoroborate required for preparing the reagent is very expensive.
It is still unsuitable for production at an industrial level.

[0004]

Means for Solving the Problems As a result of diligent studies on these problems, the present inventor has found that the use of inexpensive reagents under mild conditions without the use of strong acids or highly dangerous reagents makes it possible to achieve an industrial level. A method for nitric acid esterification of a compound having one or more hydroxyl groups, which is advantageous in the production of the compound and is also advantageous in cost, has been found. That is, a method for producing a safe and industrially-producible nitrate ester, which is nitrated by dropping nitric acid into a solution containing a compound having one or more hydroxyl groups, an acid anhydride, a carboxylic acid, and an organic solvent, is added dropwise. The present invention has been completed. That is, the present invention relates to the following production methods [1] to [21].

[1] In a nitration reaction of a compound having one or more hydroxyl groups, nitric acid is added to a solution containing the compound, an acid anhydride, a carboxylic acid and an organic solvent, wherein the nitric acid is added to the compound. Method for producing ester form. [2] The production method of the above-mentioned [1], wherein the addition of nitric acid is carried out gradually or dropwise in two or more portions. [3] Nitric acid is dropped into a solution containing a carboxylic acid, an organic solvent, an acid anhydride and a compound having one or more hydroxyl groups,
Next, a method for producing a nitrate ester of a compound having one or more hydroxyl groups, in which the addition or dropping of a compound having one or more hydroxyl groups which may be dissolved in an organic solvent and the dropping of nitric acid are sequentially repeated as necessary. [4] The method of the above-mentioned [3], wherein the addition or dropwise addition of the compound having one or more hydroxyl groups and the dropwise addition of nitric acid are repeated once or 2 to 5 times. [5] The reaction according to any one of the above [1] to [4], wherein the reaction is performed using 1 to 5 equivalents of an acid anhydride and 1 to 3 equivalents of nitric acid with respect to 1 equivalent of the hydroxyl group of the compound having one or more hydroxyl groups. Manufacturing method.

[6] 1 to 3 equivalents of an acid anhydride and 1 equivalent of nitric acid per 1 equivalent of a hydroxyl group of a compound having at least one hydroxyl group
The method according to any one of the above [1] to [4], wherein the reaction is carried out using 2 to 2 equivalents. [7] The above-mentioned [1] to [6], wherein the compound having one or more hydroxyl groups is a compound having a hydrocarbon residue having 1 to 18 carbon atoms which may contain a nitrogen, oxygen or sulfur atom.
Manufacturing method. [8] The method of any of the above-mentioned [1] to [7], wherein the compound having one or more hydroxyl groups is an alcohol compound. [9] The method of the above-mentioned [8], wherein the alcohol compound is an amino alcohol compound protected with an acyl group or a urethane-forming protecting group. [10] The method of any of the above-mentioned [1] to [9], wherein the acid anhydride is an acid anhydride having 4 to 14 carbon atoms.

[11] The method of the above-mentioned [10], wherein the acid anhydride is acetic anhydride. [12] The method according to any one of [1] to [11], wherein the carboxylic acid is a carboxylic acid having 1 to 10 carbon atoms. [13] The method of the above-mentioned [12], wherein the carboxylic acid is acetic acid. [14] For compounds having one or more hydroxyl groups,
The method according to any one of the above [1] to [13], wherein the reaction is carried out using a carboxylic acid in an amount of 1 to 5 times by weight. [15] The method of any of the above-mentioned [1] to [14], wherein the organic solvent is an aliphatic saturated hydrocarbon, an ester-based hydrocarbon solvent, a halogen-based hydrocarbon solvent, or a mixed solvent thereof. [16] The aliphatic saturated hydrocarbon is n-pentane, n-hexane, n-heptane or n-octane, the ester hydrocarbon solvent is butyl acetate, propyl acetate, ethyl acetate or methyl acetate, and the halogenated hydrocarbon is The method according to the above [15], wherein the hydrogen solvent is methylene chloride or chloroform. [17] The method of the above-mentioned [15], wherein the organic solvent is ethyl acetate.

[18] The production method according to any one of [1] to [17], wherein the reaction is carried out on a compound having one or more hydroxyl groups using an organic solvent in a weight ratio of 1 to 20 times. [19] The production method according to any one of the above [1] to [18], wherein the reaction is performed at a reaction temperature of −20 to 60 ° C. [20] The above-mentioned [1], wherein the reaction is carried out at a reaction temperature of 5 to 30 ° C.
To any one of [18] to [18]. [21] The compound having one or more hydroxyl groups is (1S)
-N- (t-butoxycarbonyl) -1-methyl-2-
The production method according to any one of the above [1] to [20], which is hydroxyethylamine.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a compound having one or more hydroxyl groups refers to a compound having one or more alcoholic hydroxyl groups or phenolic hydroxyl groups. The number of hydroxyl groups is not limited to one because the production method of the present invention can be applied to compounds having many hydroxyl groups that require nitration, but is usually about 1 to 6. Specific examples include a monool, a diol, a triol, a tetraol, a pentaol, and a hexaol.

Specific examples of the compound having one or more hydroxyl groups include compounds having a hydrocarbon residue having 1 to 18 carbon atoms which may contain a nitrogen, oxygen or sulfur atom. As the hydrocarbon residue having 1 to 18 carbon atoms,
Any of saturated, unsaturated, linear, branched, cyclic, and combinations thereof may be used, and specific examples include an alkyl group, a cycloalkyl group, and a heterocyclic group. Examples of such an alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.
-Butyl, tert-butyl, pentyl, hexyl, decyl, octadecyl and the like, and an alkyl group having 1 to 18 carbon atoms. Examples of the cycloalkyl group include, for example, a cycloalkyl group having 3 to 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. And heterocyclic groups such as pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, and pyrrolidinemethyl, which are nitrogen-, oxygen- and / or sulfur-containing 5- or 6-membered heterocyclic groups. Group. These hydrocarbon groups may have a substituent that does not participate in the reaction. Examples of such a substituent include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, pentyl and hexyl; halogen atoms such as fluorine, chlorine and bromine; methoxy, ethoxy, propoxy, Carbon number 1 such as pentoxy
C-6 alkoxy group; acetyl, propionyl, butyryl, etc .; C2-6 acyl group; acetyloxy, propynyloxy, butyryloxy, etc., C2-6 acyloxy group; methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc. An alkoxycarbonyl group having 2 to 6 carbon atoms; an amino group substituted with an alkyl group having 1 to 6 carbon atoms such as methylamino, dimethylamino and ethylamino; an acyl group having 2 to 6 carbon atoms such as acetylamino and propionylamino And carboxyl groups; carbamoyl groups; nitro groups and the like. In the present invention, among the above compounds having one or more hydroxyl groups, compounds having one or more alcoholic hydroxyl groups, that is, alcohol compounds are preferable, and alcohol compounds having an amino group as a substituent, that is, amino alcohol compounds are particularly preferable. preferable. The amino group may be modified with a protecting group or the like. Examples of the amino alcohol compound include 2-hydroxyethylamine, 1-methyl-
Preferred are hydroxyalkylamines having 2 to 8 carbon atoms such as 2-hydroxyethylamine, 1-hydroxyisopropylethylamine and 3-hydroxypropylamine.

The protecting group for the amino group in the amino alcohol compound includes an acyl group or a urethane-forming protecting group. These protective groups are not particularly limited as long as they are not involved in the reaction. Specific examples include, for example, acyl groups such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl. Examples include acetyl, propionyl, butyryl, isobutyryl, pivaloyl, groups such as benzoyl substituted with the above-mentioned substituents, unsubstituted benzoyl, and phthaloyl. Urethane-forming protecting groups include groups such as methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, cyclobutoxycarbonyl, and the like. Further, the amino alcohol compound may be acylated with a heterocyclic carbonyl group. Examples of such a heterocyclic carbonyl group include nicotinoyl, thiazolylcarbonyl, and pyrazinecarbonyl groups.

The compounds having one or more hydroxyl groups in the present invention include, for example, the following. [1] 2-hydroxyethylamine [2] 1-methyl-2-hydroxyethylamine [3] 1-hydroxyisopropylethylamine [4] 3-hydroxypropylamine [5] (1S) -N- (t-butoxycarbonyl)- 1
-Methyl-2-hydroxyethylamine [6] (1S) -N- (t-butoxycarbonyl) -1
-Isopropyl-2-hydroxyethylamine [7] N- (t-butoxycarbonyl) -2-hydroxyethylamine [8] ethanolamine

[9] 1,6-hexanediol [10] glycerol [11] mannitol [12] isosorbide [13] N-nicotinoyl-2-hydroxyethylamine [14] (4R) -N-[(1S) -1-methyl- 2-
Hydroxyethyl] -2-oxothiazolidine-4-carboxamide

Next, the production method of the present invention will be described in detail together with the solvent, reagents and conditions used for the reaction. In the present invention, the nitrate is produced by nitrating nitric acid to a solution containing one or more hydroxyl groups, an acid anhydride, a carboxylic acid and an organic solvent.

Examples of the acid anhydride include sulfonic anhydrides such as carboxylic anhydride, methanesulfonic anhydride and p-toluenesulfonic anhydride; and phosphoric anhydrides such as propanephosphonic anhydride. . Preferred are aliphatic or aromatic carboxylic anhydrides having 4 to 14 carbon atoms. Specific preferred anhydrides include acetic anhydride, chloroacetic anhydride, and propionic anhydride having 4 carbon atoms.
And aliphatic carboxylic anhydrides of No. 6 to 6, and acetic anhydride, which is easily available and easily handled, is particularly preferable. The amount of the hydroxyl group used in the compound having one or more hydroxyl groups
The reaction is usually performed in an amount of about 1 to 5 equivalents, preferably 1 to 3 equivalents, based on the equivalents. In the nitration reaction of the present invention, the use of a small amount of an acid anhydride such as acetic anhydride has an advantage that post-reaction of the reaction can be easily performed, and minimizes the production of a nitrate ester having a danger of explosion. This is particularly preferred for production on an industrial scale.

The type of nitric acid is not particularly limited as long as the reaction proceeds, and examples thereof include concentrated nitric acid and fuming nitric acid. Preferably, the reaction speed is high, such as hydrolysis with water in nitric acid. The reaction is carried out using fuming nitric acid which does not cause side reactions. The amount of use is usually about 1 to 3 equivalents to 1 equivalent of the hydroxyl group of the compound having one or more hydroxyl groups, and preferably 1 to 2 equivalents in consideration of treatment after the reaction. In addition, in the production method of the present invention, the method of adding or dropping nitric acid is preferably a method using nitric acid alone.However, a solvent capable of dissolving nitric acid such as a carboxylic acid described below, and further mixed with an organic solvent or the like are used. No problem. The use of nitric acid mixed with acetic anhydride is not preferred because the generated acetyl nitrate has a risk of explosion.

The addition of a carboxylic acid has the advantage that it can be used to improve the safety that explosion can be avoided. The carboxylic acid is, for example, an aliphatic or aromatic carboxylic acid having 1 to 10 carbon atoms, and specific preferred carboxylic acids are those having 1 to 5 carbon atoms such as formic acid, acetic acid, propionic acid, butyric acid, and pivalic acid. Aliphatic carboxylic acids are mentioned, and acetic acid, which is easily available, is particularly preferred. The amount of the carboxylic acid to be used is desirably the necessary amount in consideration of the post-reaction treatment on an industrial scale, and is usually about 1 to 5 times the weight ratio to the compound having one or more hydroxyl groups, preferably about 1 to 5 times. It is about 1 to 3 times.

The organic solvent is not particularly limited as long as it dissolves a compound having one or more hydroxyl groups and does not participate in the reaction. Examples of the organic solvent include aliphatic saturated hydrocarbons,
Ester hydrocarbon solvents or halogenated hydrocarbon solvents are exemplified. Specific preferred aliphatic saturated hydrocarbon solvents include n-pentane, n-hexane, n-heptane, n-octane and the like. Examples of the ester-based hydrocarbon solvent include methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, and ethyl butyrate. Examples thereof include lower alkyl esters having 1 to 4 carbon atoms, and particularly preferred is ethyl acetate which is inexpensive and easily available. As the halogenated hydrocarbon solvent,
Methylene chloride and chloroform are preferred. These aliphatic saturated hydrocarbon solvents, ester hydrocarbon solvents, and halogen hydrocarbon solvents may be used in combination. The amount of the organic solvent used may be in a small amount to an excess amount as long as it does not affect the reaction and the post-treatment, but it is usually 1 to 1 in a weight ratio to the compound having one or more hydroxyl groups.
It is about 20 times, preferably about 2 to 6 times.

As a preferred operation method of the method for producing a nitrate ester of the present invention, a compound having one or more hydroxyl groups is added to a mixed solution of an acid anhydride which may contain an organic solvent and a carboxylic acid. When the mixed solution contains an organic solvent, it is added or added as it is or as a solution dissolved in the organic solvent, nitric acid is added dropwise thereto, and then, if necessary, the addition or addition of the compound dissolved in the organic solvent is performed. Nitration is performed by repeating the addition of nitric acid and nitric acid as necessary. Alternatively, a method in which a total amount of a compound having one or more hydroxyl groups is added to a mixed solution of a carboxylic acid, an acid anhydride and an organic solvent, and then nitric acid is slowly and continuously added dropwise, or only nitric acid is divided into several parts And divided dropping.

As a specific example, an ethyl acetate solution of a compound having at least one hydroxyl group is added or dropped to a mixed solution of acetic acid and acetic anhydride, and then fuming nitric acid is continuously dropped slowly and dropwise. A method or a mixed solution of acetic acid and acetic anhydride is added or added dropwise with an ethyl acetate solution of a compound having one or more hydroxyl groups, and only fuming nitric acid is added to the solution.
And a method of dropping dividedly into 5 parts. Preferably, a part of a compound solution having one or more hydroxyl groups, which is dissolved in ethyl acetate and divided into two to five parts, is mixed in a mixed solution of acetic acid and acetic anhydride so that the reaction heat is dispersed and the reaction rate is constant. Is added or dropped, a part of 2-5 divided fuming nitric acid is dropped, and then the addition or dropping of the compound solution and the dropping of fuming nitric acid are repeated once or plural times.

The reaction temperature is not particularly limited as long as it is a temperature at which the reaction proceeds.
About 0 ° C., preferably, the reaction rate is relatively high,
It is preferable to carry out the reaction at 5 to 30 ° C., where there are few side reactions and temperature control is easy.

The post-treatment after the reaction is carried out according to a conventional method.
For example, a nitric acid ester can be obtained by appropriately combining means such as concentration, extraction, and crystallization. As a specific example, water and an organic solvent are added to the reaction solution, extraction and liquid separation are performed, and the obtained organic layer is sequentially washed with a basic aqueous solution, preferably a weakly basic sodium hydrogen carbonate aqueous solution, and water. Then, by concentrating, a product of a nitrate ester can be obtained.

Examples of the nitrate obtained by the production method of the present invention include the following. In addition,
The compounds described in [5] and [6] are used as intermediates for prophylactic or therapeutic drugs for angina pectoris (Japanese Patent Laid-Open No.
0-120566). [1] 2-nitroxyethylamine [2] 1-methyl-2-nitroxyethylamine [3] 1-nitroxyisopropylethylamine [4] 3-nitroxypropylamine [5] (1S) -N- (t- Butoxycarbonyl) -1
-Methyl-2-nitroxyethylamine [6] (1S) -N- (t-butoxycarbonyl) -1
-Isopropyl-2-nitroxyethylamine [7] N- (t-butoxycarbonyl) -2-nitroxyethylamine [8] 2-nitroxyethylamine

[9] 1,6-dinitroxyhexane [10] nitroglycerin [11] mannitol hexanitrate [12] isosorbide dinitrate [13] N-nicotinoyl-2-nitroxyethylamine [14] (4R) -N- [ (1S) -1-methyl-2-
Nitroxyethyl] -2-oxothiazolidine-4-carboxamide

When the production method of the present invention is applied to N- (t-butoxycarbonyl) -1-methyl-2-hydroxyethylamine which is a preferred example of a compound having one or more hydroxyl groups, -(T-Butoxycarbonyl) -1-methyl-2-nitroxyethylamine is obtained, and N- [1-methyl-2-nitro], which is useful as a preventive or therapeutic agent for angina pectoris using this compound as a starting material [Xyethyl] -2-oxothiazolidine-4-carboxamide. That is, by reacting N- (t-butoxycarbonyl) -1-methyl-2-nitroxyethylamine with a deprotecting agent in a solvent, 1-
Methyl-2-nitroxyethylamine or a salt thereof (preferably hydrochloride) is prepared, and then the product and 2-oxothiazolidine-4-carboxylic acid are acylated by adding a condensing agent in a solvent in the presence of a base. The desired compound can be obtained by a chemical reaction.

The solvent used in the deprotection reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not participate in the reaction. For example, n-pentane, n-hexane, n-heptane, n-octane Aliphatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; esters such as ethyl formate, methyl acetate and ethyl acetate; nitriles such as acetonitrile Halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, chlorobenzene, and dichlorobenzene; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-
Amides such as 2-pyrrolidone can be mentioned.
Also, a mixed solvent in which these are appropriately combined can be used. Preferred among these are esters (especially ethyl acetate).

The deprotecting agent used is preferably an acid, and is not particularly limited as long as it is used as an acid catalyst in a usual reaction. Examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid and perchloric acid. , Inorganic acids such as phosphoric acid or Bronsted acids such as formic acid, organic acids such as acetic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid; zinc chloride, tin tetrachloride, boron trichloride, Lewis acids such as boron trifluoride, boron tribromide and aluminum trichloride; and acidic ion exchange resins. Preferred among these are inorganic acids (particularly hydrochloric acid). When hydrochloric acid is used as a deprotecting agent, hydrogen chloride gas can be used by directly introducing it into the reaction system, or can be used after being dissolved in a solvent. The solvent is not particularly limited as long as it can be used as a reaction solvent, but the same solvent as the reaction solvent is preferable.

The reaction temperature is usually -10 to 50 ° C,
Preferably it is 10 to 30C. The reaction time varies depending on the deprotecting agent used, the reaction temperature and the like, but is usually from 10 minutes to
10 hours, preferably 1 to 5 hours. After the completion of the reaction, the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, and crystallization. When an inorganic acid (particularly hydrochloric acid) is used as a deprotecting agent, it can be obtained as precipitates or crystals by adding a solvent that does not dissolve the target salt. The excess acid may be removed by washing and then filtered, or the suspension may be used in the next step.

Next, the solvent used in the acylation reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not participate in the reaction. The same solvent as that used in the deprotection reaction can be used. Preferably they are esters (especially ethyl acetate) or nitriles (especially acetonitrile), most preferably acetonitrile. The base to be used is not particularly limited as long as it is used as a base in a usual reaction, and for example, N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine , 4-
Pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, quinoline, 2,6-di (t-butyl) -4-methylpyridine, N, N-dimethylaniline, N, N-diethylaniline and the like Organic bases. Most preferred among these is triethylamine. In addition, 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine can be used in a catalytic amount in combination with another base.

Examples of the condensing agent used include halogenated formate esters such as methyl chloroformate, ethyl chloroformate and isopropyl chloroformate; cyanophosphate diesters such as diethyl cyanophosphate; N-hydroxysuccinimide, 1-hydroxy Benzotriazole, N
N-hydroxy derivatives such as -hydroxy-5-norbonene-2,3-dicarboximide; disulfide compounds such as 2,2'-dipyridyl disulfide;
Succinic compounds such as N'-disuccinimidyl carbonate; phosphinic chloride compounds such as N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride; N, N'-disuccinyl Imidyl oxalate (DSO), N, N'-diphthalimide oxalate (DPO), N, N'-bis (norbornenylsuccinimidyl) oxalate (BNO), 1,
1'-bis (benzotriazolyl) oxalate (BB
Oxalate derivatives such as TO); N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3
-(3-dimethylaminopropyl) carbodiimide (E
Carbodiimide derivatives such as DAPC); imidazole derivatives such as 1,1'-oxalyldiimidazole and N, N'-carbonyldiimidazole; and alkanephosphonic anhydrides such as propanephosphonic anhydride (T3P). Can be mentioned. Preferred are cyanophosphoric diesters (particularly diethyl cyanophosphate) or alkanephosphonic anhydrides (particularly propanephosphonic anhydride (T3P)), most preferably propanephosphonic anhydride (T3P). is there.

The carboxylic acid component can be used in an amount of usually 0.5 to 2 molar equivalents, preferably 1.0 to 1.1 molar equivalents, based on the amine component to be acylated. The condensing agent is usually 1
10 to 10 molar equivalents can be used, preferably 1.0 to 1.1 equivalents. The base can be used usually in an amount of 1 to 10 equivalents, and preferably 1.0 to 1.2 equivalents. When the amine component is a salt, the base is further added in an amount of 1.0 to 1.1 molar equivalents. The reaction temperature is usually -10 to 50C, preferably 0 to 30C. The reaction time varies depending on the condensing agent, base, reaction temperature and the like to be used, but is usually 10 minutes to 10 hours, preferably 0.5 to 3 hours. After completion of the reaction, according to a conventional method, for example, concentration, extraction, activated carbon treatment,
The target product can be obtained by appropriately combining techniques such as crystallization. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off. The target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.

The preferred production method in the above-mentioned production method includes:
N- (t-Butoxycarbonyl) -1-methyl-2-nitroxyethylamine is dissolved in a solvent and 1-methyl-2-nitroxyethylamine hydrochloride is prepared by adding hydrochloric acid. -Oxothiazolidine-4-carboxylic acid in a solvent in the presence of a base is added with cyanophosphate diesters or alkanephosphonic anhydrides to give N- [1-methyl-2-nitroxyethyl] -2-oxo. This is a method for producing thiazolidine-4-carboxamide.

[0031]

Next, the present invention will be described in detail with reference to examples. However, the present invention is not limited to these examples. Example 1 A mixed solution of acetic acid and acetic anhydride was dissolved in ethyl acetate.
Drop a part of the amino alcohol compound solution
After that, a part of the fuming nitric acid divided into two parts is dropped, and then
The compound solution and fuming nitric acid once.
(1S) -N- (t-butoxycarbonyl) -1-me
In a mixture of manufacturing acetic 50.0g and acetic anhydride 89.96g chill 2-nitroxy-ethylamine, Boc-L-alaninol [(1S) -N- (t- butoxycarbonyl dissolved in ethyl acetate 71.3ml ) -1-Methyl-2-hydroxyethylamine] 2
5.0 g is added dropwise and cooled to 15 ° C. or lower. After cooling, 8.87 ml of fuming nitric acid is added dropwise and stirred for 1 hour. Next, 25.0 g of Boc-L-alaninol dissolved in 71.3 ml of ethyl acetate is added, and 8.87 ml of fuming nitric acid is added dropwise at 20 ° C. or lower, and the mixture is stirred for 1.5 hours. After the completion of the reaction, 200 ml of cold water and 285 ml of ethyl acetate are added, and the mixture is stirred. Separate the ethyl acetate layer with 5
After washing with 250 ml of a 200% aqueous solution of sodium hydrogen carbonate and 200 ml of water, the mixture was concentrated to obtain 118.84 g of a crude product of (1S) -N- (t-butoxycarbonyl) -1-methyl-2-nitroxyethylamine (content: 55.81 g). , Yield 88.8
%).

Example 2 A total amount of ethyl acetate was added to a mixed solution of acetic acid and acetic anhydride.
After dripping the solution in which the amino alcohol compound was dissolved, 4
Drop a part of the divided fuming nitric acid, and then drop the fuming nitric acid
(1S) -N- (t-butoki)
(Cicarbonyl) -1-methyl-2-nitroxyethyla
Production of Min In a mixture of 10 ml of acetic acid and 10.5 ml of acetic anhydride, 10.0 g of Boc-L-alaninol dissolved in 28 ml of ethyl acetate was added dropwise, and after cooling to 10 ° C. or lower,
2.13 ml of fuming nitric acid are added dropwise. After the addition, 0.71 ml of fuming nitric acid is added again while checking the progress of the reaction. This is repeated twice to complete the reaction. After the completion of the reaction, 28 ml of ethyl acetate and 50 ml of water are added, and the mixture is stirred, allowed to stand, and separated. 5% of the separated ethyl acetate layer
After washing with 50 ml of aqueous sodium bicarbonate and 50 ml of water, the mixture is concentrated.
To the concentrate, 50 ml of n-heptane was added while stirring,
Further cooling precipitates needle-like crystals. After cooling on ice, this was collected by filtration to give (1S) -N- (t-
7.93 g (butoxycarbonyl) -1-methyl-2-nitroxyethylamine (content: 98.3%) in a yield of 62.
Obtained at 0%.

1H-NMR (CDCl 3) δ (ppm) 1.23 (3H, d, J = 6.9 Hz) 1.45 (9H, s) 3.92 to 4.15 (1H, m) 4.29 ４4.70 (3H, m) Specific rotation [α] 20D = −2.657 (c 1.016, MeOH) Melting point 35-36 ° C.

Reference Example 1 Preparation of (2S) -2-aminopropyl nitrate hydrochloride
Concrete (1S) -N- (t- butoxycarbonyl) -1-ethyl acetate 1.5L added to methyl 2-nitroxy-ethylamine 1.71 kg, stirring cooled to 0 ° C.. After cooling, 4 mol / L hydrogen chloride / ethyl acetate solution 10.2 L
And the mixture is stirred at 15 to 20 ° C. for 3 hours. After completion of the reaction, 7.5 L of ethyl acetate is added, and the mixture is stirred and allowed to stand, and then the supernatant is decanted. This decant was repeated four times to obtain a suspension of (2S) -2-aminopropyl nitrate hydrochloride / ethyl acetate. This suspension was used for the next step as it was. Withdraw a portion of the suspension, filter, dry,
A powder of (2S) -2-aminopropyl nitrate hydrochloride was obtained.

1H-NMR (CDCl3 + DMSO-d
6) 134-135 ° C

Reference Example 2 (4R) -N-[(1S) -1-methyl-2-nitrox
Siethyl] -2-oxothiazolidine-4-carboxy
Preparation of amide To a suspension of (2S) -2-aminopropyl nitrate hydrochloride / ethyl acetate obtained in Reference Example 1 was added 15 L of acetonitrile and 1.26 kg of (R) -2-oxo-4-thiazolidinecarboxylic acid. Stir and cool to 0-5 ° C. After cooling, 2.64 kg of triethylamine was added dropwise at 0 to 10 ° C., and further, at 0 to 20 ° C., 5.69 k of propane phosphoric anhydride.
g is added dropwise. Stir at 15-20 <0> C for 2 hours. After completion of the reaction, 13 L of ethyl acetate is added, and the mixture is washed three times with 6 L of water. The ethyl acetate layer was treated with activated carbon, and the ethyl acetate layer was treated with 2.
Concentrate under reduced pressure to 17 kg. After concentration, methyl acetate 13.
After pouring 9 L, stirring and dissolving the crystals, 4.52 k
The solution is concentrated under reduced pressure at an external temperature of 40 ° C. or less to g. 8.27 L of water was added dropwise to the concentrated solution at 22 to 28 ° C. over 1 hour with stirring, then cooled to 0 to 5 ° C., and filtered (4R)
This gave 1.13 kg (96.7% content) of -N-[(1S) -1-methyl-2-nitroxyethyl] -2-oxothiazolidine-4-carboxamide.

1H-NMR (acetone-d6) δ (ppm) 1.26 (3H, d, J = 6.9 Hz) 3.53 (1H, dd, J = 11.3, 5.5 Hz) 3.76 (1H, dd, J = 11.3, 8.4 Hz) 4.3 to 4.5 (2H, m) 4.51 (1H, dd, J = 11.2, 7.0 Hz) 4.64 (1H) , Dd, J = 11.2, 4.6 Hz) 7.27 (1H, br, s) 7.60 (1H, br, s) IR spectrum (KBr tablet) ν (cm−1) 3285, 3101, 2982 −2898, 1682, 1665, 1624, 1564, 1452, 1301, 1288, 1253, 1230, 992, 902, 890

[0038]

According to the present invention, the reaction can be carried out under mild conditions using only inexpensive reagents without using strong acids or highly dangerous reactions or reagents, and the nitrate ester can be safely produced. It can be manufactured on an industrial level.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Hitoshi Sato 401, 6-404 F-term (reference) 4H006 AA02 AC59 BB11 BB12 BB17 BC10 BE02 RA42 RB34

Claims (21)

[Claims] 1. A nitrate of a compound having one or more hydroxyl groups, wherein nitric acid is added to a solution containing the compound, an acid anhydride, a carboxylic acid and an organic solvent. How to make the body. 2. The method according to claim 1, wherein the nitric acid is added slowly or dropwise.
2. The production method according to claim 1, wherein the method is carried out by dividing and dropping at least twice. 3. A solution containing a carboxylic acid, an organic solvent, an acid anhydride and a compound having one or more hydroxyl groups, wherein nitric acid is dropped, and then a compound having one or more hydroxyl groups which may be dissolved in the organic solvent. A method for producing a nitrate ester of a compound having one or more hydroxyl groups, wherein the addition or the dropwise addition of nitric acid and the dropwise addition of nitric acid are sequentially repeated as necessary. 4. The method according to claim 3, wherein the addition or dropwise addition of the compound having one or more hydroxyl groups and the dropwise addition of nitric acid are repeated once or 2 to 5 times. 5. The reaction according to claim 1, wherein the reaction is carried out using 1 to 5 equivalents of an acid anhydride and 1 to 3 equivalents of nitric acid per 1 equivalent of the hydroxyl group of the compound having one or more hydroxyl groups. Manufacturing method. 6. The reaction according to claim 1, wherein the reaction is carried out using 1 to 3 equivalents of an acid anhydride and 1 to 2 equivalents of nitric acid per 1 equivalent of the hydroxyl group of the compound having at least one hydroxyl group. Manufacturing method. 7. A compound having at least one hydroxyl group having 1 carbon atom which may contain a nitrogen, oxygen or sulfur atom.
A compound having from 18 to 18 hydrocarbon residues.
6. The production method according to any one of 6. 8. The method according to claim 1, wherein the compound having one or more hydroxyl groups is an alcohol compound. 9. The method according to claim 8, wherein the alcohol compound is an amino alcohol compound protected with an acyl group or a urethane-forming protecting group. 10. The method according to claim 1, wherein the acid anhydride is an acid anhydride having 4 to 14 carbon atoms. 11. The method according to claim 10, wherein the acid anhydride is acetic anhydride.
Production method as described. 12. The production method according to claim 1, wherein the carboxylic acid is a carboxylic acid having 1 to 10 carbon atoms. 13. The method according to claim 12, wherein the carboxylic acid is acetic acid. 14. The production method according to claim 1, wherein the reaction is carried out using a carboxylic acid in an amount of 1 to 5 times by weight the compound having one or more hydroxyl groups. 15. The method according to claim 1, wherein the organic solvent is an aliphatic saturated hydrocarbon, an ester hydrocarbon solvent, a halogen hydrocarbon solvent, or a mixed solvent thereof. 16. The aliphatic saturated hydrocarbon is n-pentane,
n-hexane, n-heptane or n-octane;
Ester hydrocarbon solvent is butyl acetate, propyl acetate,
An ethyl acetate or methyl acetate, and the halogenated hydrocarbon solvent is methylene chloride or chloroform.
Production method as described. 17. The method according to claim 1, wherein the organic solvent is ethyl acetate.
5. The production method according to 5. 18. The production method according to claim 1, wherein the reaction is carried out with respect to a compound having one or more hydroxyl groups by using an organic solvent in an amount of 1 to 20 times by weight. 19. The production method according to claim 1, wherein the reaction is carried out at a reaction temperature of -20 to 60 ° C. 20. The method according to claim 1, wherein the reaction is carried out at a reaction temperature of 5 to 30 ° C. 21. The compound having one or more hydroxyl groups is (1S) -N- (t-butoxycarbonyl) -1-methyl-2-hydroxyethylamine.
The production method according to any one of the above.