JP2019218333A - Method for producing amidocarboxylic acid compound - Google Patents

Abstract

To provide a method for producing an amidocarboxylic acid compound industrially, economically, and efficiently from an amidoalcohol compound which is by-produced during production of biotin.SOLUTION: Provided is a method for producing an amidocarboxylic acid compound by oxidizing, as shown in the following reaction formula, a specific amidoalcohol compound under an alkaline condition by using water, a nitroxyl radical and/or its precursor, and an oxidant. Further, also provided is a method for producing a trione compound by cyclodehydrating the carboxylic acid compound.SELECTED DRAWING: None

Description

  The present invention relates to a novel method for producing an amide carboxylic acid compound, and also relates to a novel method for producing a trione compound using the amide carboxylic acid compound obtained by the production method.

  Biotin is a water-soluble vitamin used for pharmaceuticals expected to have a diabetic preventive effect, feed additives, and the like.

The biotin has a very long manufacturing process. Therefore, even an intermediate is produced through many steps. For example, a typical intermediate of biotin,
The following equation (5)

(Wherein, R ¹ and R ² are each a hydrogen atom or a protecting group for a ureylene group, and may be the same or different groups). It is manufactured in a very long process as described below (see Patent Document 1). In the following steps, examples in which R ¹ and R ² are benzyl groups (Bn groups) (Examples 1 and 3 of Patent Document 1) are shown.

  In the example of Patent Document 1, first, 1,3-dibenzyl-2-imidazolidone-cis-4,5-dicarboxylic acid is substituted with α-phenethylamine ((R)-(+)-1-methylbenzylamine). An optically active amine is reacted to produce 1,3-dibenzyl-5- (α-phenethyl) -hexahydropyrrolo [3,4-a] imidazole-2,4,6-trione (step 1). Then, reduction (step 2), cyclization (step 3), and sulfidation reaction of 1,3-dibenzyl-5- (α-phenethyl) -hexahydropyrrolo [3,4-a] imidazole-2,4,6-trione (Step 4) shows a method for producing a thiolactone compound having a benzyl group. Patent Literature 1 discloses that the thiolactone compound is further reacted in seven steps to obtain biotin, which is the final target product.

  As described above, biotin is produced through an extremely large number of steps. Therefore, in order to reduce the production cost of biotin, it is also important to improve the production cost of the intermediate in each step, that is, the yield of each intermediate.

  However, among the above-mentioned steps, in the above-mentioned reduction reaction (step 2), in addition to the amide alcohol compound that can eventually become biotin, impurities of its optical isomer are generated, and the yield of the amide alcohol compound is reduced. It has been known. Since the optical isomer cannot be biotin, the yield of the amide alcohol compound is reduced. Specifically, as shown in Example 3 of Patent Document 1, the amide alcohol compound obtained by recrystallizing a product containing impurities obtained in step 2 with a mixed solvent of water and isopropanol is a final product. Only about 50% yield is obtained.

  As described above, if the yield of the amide alcohol compound can be improved, the yield of biotin finally obtained can also be improved. It has been found that the use of the reducing agent of (1) can improve the yield of the amide alcohol compound (see Patent Document 2).

U.S. Pat. No. 3,876,656 JP 2018-024643 A

  However, even by the method described in Patent Document 2, about 25 to 35% of impurities of optical isomers are by-produced. For this reason, impurities of the optical isomer produced as a by-product cause a loss during production, and there is room for further improvement in efficiently producing biotin. Accordingly, an object of the present invention is to provide a production method for minimizing loss of impurities of by-product optical isomers.

  The present inventors have conducted intensive studies to solve the above problems. The by-product optical isomer is similar in structure to the target amide alcohol compound. If the optical isomer can be derived into its precursor, a trione compound, it can be reused as a raw material for producing the amide alcohol compound. Since it can be used, a method for deriving an optical isomer into a trione compound was examined. As a result, by subjecting the amide alcohol compound to a specific oxidation method, an amide carboxylic acid compound can be obtained, and that the obtained amide carboxylic acid compound can be subjected to dehydration cyclization to obtain a trione compound. As a result, the present invention has been completed. That is, the first present invention provides the following formula (1)

中
R ¹ and R ² are respectively a protecting group for a hydrogen atom or a ureylene group, and may be the same or different groups;
R ⁴ is an alkyl group, an aralkyl group, or an aryl group;
R ⁵ , R ⁶ , and R ⁷ are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. ). ｝
By oxidizing the amide alcohol compound represented by the above under alkaline conditions using water, nitroxyl radical and / or a precursor thereof, and an oxidizing agent,
The following equation (2)

(Where
R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ have the same meanings as in the above formula (1). )).

In the first aspect of the present invention, the following aspects can be suitably adopted.
(1) The nitroxyl radical is 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetoxy-2, 2,6,6-tetramethylpiperidine-1-oxyl, 4-acetamino-2,2,6,6-tetramethylpiperidine 1-oxyl, 2-azaadamantane-N-oxyl, and the nitroxyl radical precursor 1-hydroxy-4-acetoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-acetamino-2,2,6,6-tetramethylpiperidine, 2-hydroxy-2-azaadamantane At least one selected from the following.
(2) The oxidizing agent is at least one selected from sodium hypochlorite and calcium hypochlorite.
(3) The oxidation reaction is performed in a pH range of 7.0 to 10.

  Further, the second invention provides a carboxylic acid compound represented by the above formula (2) by the above-mentioned method and then dehydration-cyclization of the carboxylic acid compound, whereby the following formula (3)

(Where
R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ have the same meanings as in the above formula (1). ) Is a method for producing a trione compound.

  According to the method of the present invention, an optical isomer that is a by-product when producing an amide alcohol compound that is a biotin intermediate can be derived into a trione compound that is a precursor of the amide alcohol compound. Since the obtained trione compound can be reused as a raw material for producing an amide alcohol compound, loss of the raw material in producing biotin can be suppressed to a minimum, and biotin can be produced industrially efficiently.

  The present invention provides the following formula (1)

中
R ¹ and R ² are respectively a protecting group for a hydrogen atom or a ureylene group, and may be the same or different groups;
R ⁴ is an alkyl group, an aralkyl group, or an aryl group;
R ⁵ , R ⁶ , and R ⁷ are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. ). ｝
By oxidizing the amide alcohol compound represented by the above under alkaline conditions using water, nitroxyl radical and / or a precursor thereof, and an oxidizing agent,
The following equation (2)

(Where
R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ have the same meanings as in the above formula (1). )).

(Amide alcohol compound)
In the present invention, the amide alcohol compound represented by the formula (1) is oxidized.

In the formula, each of R ¹ and R ² is a protecting group for a hydrogen atom or a ureylene group, and may be the same or different.

  Examples of the protecting group for the ureylene group include an alkyl group, an aryl group, an aralkyl group, and an acyl group. Among them, an alkyl group having 1 to 10 carbon atoms, an aryl group having 5 to 10 carbon atoms, an aralkyl group having 6 to 11 carbon atoms, and an acyl group having 1 to 11 carbon atoms are preferable. In particular, each is preferably a benzyl group.

  Here, the ureylene group is a group represented by -NHCONH-. The ureylene group-protecting group is a group that is substituted with a ureylene group and inactivated during a predetermined reaction. After a predetermined reaction, a ureylene group is formed by deprotection.

R ⁴ is an alkyl group, an aralkyl group, or an aryl group. Among them, an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 6 to 11 carbon atoms, and an aryl group having 5 to 10 carbon atoms are preferable. Particularly, a methyl group is preferable.

R ⁵ , R ⁶ , and R ⁷ are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. Among them, a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom is preferable. In particular, each is preferably a hydrogen atom.

  Among them, particularly preferred examples of the amide alcohol compound include (4R, 5S) -1,3-dibenzyl [N- (R) -1-phenethylcarbamoyl] -5-hydroxymethyltetrahydroimidazol-2-one. Is mentioned.

  The amide alcohol compound represented by the above formula (1) is obtained by converting the above formula (3)

(Where
R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ have the same meanings as in the above formula (1). )) Can be produced by reducing the trione compound. As a method for reducing the trione compound, the method described in Patent Document 1 or 2 can be suitably adopted. As described above, by reducing the trione compound, the amide alcohol compound represented by the above formula (1) and the biotin intermediate represented by the following formula (4)

(Where
R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ have the same meanings as in the above formula (1). ) Is obtained. Here, the amide alcohol compound represented by the formula (1) and the amide alcohol compound represented by the formula (4) have significantly different solubility in an organic solvent, and the amide alcohol compound represented by the formula (4) is an organic solvent. Thus, the amide alcohol compound represented by the above formula (1), which is a raw material of the present invention, can be obtained by reducing the trione compound and then filtering off the precipitated solid. Preferable examples of the organic solvent include water-containing or anhydrous methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, tert-butanol and the like.

(Nitroxyl radical and its precursor)
The nitroxyl radical and its precursor in the production method of the present invention are a nitroxyl radical and a precursor that produces a nitroxyl radical under the production conditions of the present invention. Specific examples of the nitroxyl radical include 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (4 -HO-TEMPO), 4-acetoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetamino-2,2,6,6-tetramethylpiperidine 1-oxyl, 2-azaadamantane- N-oxyl and the like.

  Examples of the nitroxyl radical precursor include 1-hydroxy-4-acetoxy-2,2,6,6-tetramethylpiperidine and 1-hydroxy-4-acetamino-2,2,6,6-tetramethylpiperidine. , 2-hydroxy-2-azaadamantane and the like. These nitroxyl radicals and precursors thereof may be used alone or a plurality of nitroxyl radicals and precursors thereof may be used. Among these nitroxyl radicals and the precursors thereof, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl and 2-azaadamantane-N-oxyl are industrially inexpensive and available. Etc. are particularly preferred.

  The amount of the nitroxyl radical and the precursor thereof may be used in an amount sufficient for the reaction to proceed, and is preferably 0.001 to 1 equivalent, more preferably 1 equivalent to 1 equivalent of the amide alcohol compound. It is preferable to use in the range of 0.1 to 0.5 equivalent.

(Oxidant)
In the production method of the present invention, an oxidizing agent is used. The oxidizing agent has an action of oxidizing a nitroxyl radical. Accordingly, in the present invention, the oxidizing agent is not particularly limited as long as it is an oxidizing agent that oxidizes a nitroxyl radical, and a known oxidizing agent can be used. Specific examples of such an oxidizing agent include hypochlorite, iodobenzene diacetate, oxygen and the like. Specific examples of the hypochlorite include sodium hypochlorite, potassium hypochlorite, calcium hypochlorite (silver powder), and the like. The hypochlorite may be in the form of a solid or an aqueous solution, and may be suitably used as a hydrate. Further, these hypochlorites may be used alone or in combination of a plurality of hypochlorites. Among these hypochlorites. It is particularly preferable to select from at least one selected from sodium hypochlorite and calcium hypochlorite from the viewpoint of industrial availability at low cost and the reaction yield.

  The amount of the oxidizing agent to be used may be an amount sufficient for the reaction to proceed, and is preferably used in the range of 2 to 10 equivalents, more preferably 2 to 5 equivalents, per equivalent of the amide alcohol compound. Is preferred.

(water)
In the production method of the present invention, it is necessary to use water. The oxidation reaction in the production method of the present invention is a so-called TEMPO oxidation. Usually, in the TEMPO oxidation, as shown in the following reaction formula, in the oxidation of a primary alcohol compound, the oxidation reaction proceeds only up to the corresponding aldehyde compound. Carboxylic acid cannot be obtained. In the production method of the present invention, it is presumed that the aldehyde compound is acetalized and further oxidized by the use of water and under alkaline conditions to produce a carboxylic acid compound.

  The amount of the water used may be an amount sufficient for the reaction to proceed, and is preferably used in the range of 0.1 to 10 parts by volume with respect to 1 part by mass of the amide alcohol compound. Moreover, it is preferable to use it in the range of 1 to 10 parts by volume with respect to 100 parts by volume of the organic solvent described later.

(Alkaline conditions)
In the production method of the present invention, the amide alcohol compound represented by the formula (1) is oxidized under alkaline conditions using a nitroxyl radical and / or a precursor thereof and an oxidizing agent. From the viewpoint of the reaction yield, it is preferable to carry out the reaction under alkaline conditions, preferably at pH 7.0 to 10, more preferably at pH 7.5 to 9.5, and particularly preferably at pH 8.0 to 9.0. Examples of the type of alkali include alkali metal carbonates such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, cesium hydrogen carbonate, cesium carbonate, lithium hydrogen carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, and hydroxide. Examples thereof include alkali metal hydroxides such as potassium, sodium acetate, potassium acetate, potassium phosphate, potassium hydrogen phosphate, triethylammonium hydroxide, benzyltrimethylammonium hydroxide, N-methylimidazole, pyridine and quinoline. Among these, alkali metal carbonates are preferable from the viewpoint of reactivity, and sodium hydrogen carbonate or sodium carbonate is particularly preferable. After dissolving or dispersing the above alkali in water, it is preferable to use it for production.

(Organic solvent)
In the production method of the present invention, a solvent used for TEMPO oxidation can be suitably used as a solvent. Specific examples of such a solvent include acetonitrile, propionitrile, THF, 2-methyl-THF, 1,4-dioxane, t-butyl-methyl ether, dimethoxyethane, diglyme, methylene chloride, chloroform, carbon tetrachloride, , 2-dichloroethane, chlorobenzene, toluene, xylene, hexane, heptane, ethyl acetate and the like. These solvents may be used alone or as a mixed solvent of the above solvents. Among these solvents, ethyl acetate, toluene, methylene chloride and a mixed solvent thereof are preferable from the viewpoint of reactivity.

  In the production method of the present invention, the amount of the solvent to be used may be appropriately determined in consideration of the capacity of the reaction vessel and the like, but it is usually 1 to 100 parts by mass with respect to 1 part by mass of the amide alcohol compound. good.

(Other additives)
In the production method of the present invention, additives other than water, nitroxyl radical and / or a precursor thereof, and an oxidizing agent may be used for accelerating the reaction. Examples of such additives include surfactants such as tetraalkylammonium halide and Triton B. The surfactant may be used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent, per 1 equivalent of the amide alcohol compound.

(Method for producing amide carboxylic acid compound)
The order of adding the amide alcohol compound represented by the formula (1), water, nitroxyl radical and / or a precursor thereof, and the oxidizing agent is not particularly limited, and may be appropriately determined in consideration of a production apparatus and the like. Specifically, it is preferable to add water and an organic solvent to the amide alcohol compound, adjust the pH by adding hypochlorite and an alkali, and then add the nitroxyl radical.

  The reaction temperature and the reaction time in the production method of the present invention may be appropriately set in a temperature range of usually -20 to 50 ° C, preferably -10 to 20 ° C, and in a range of 0.5 to 48 hours.

  After the reaction, the remaining oxidizing agent is decomposed by adding a reducing agent such as sodium sulfite to the reaction solution, and water is added to separate the solution.The aqueous layer is washed with an organic solvent such as toluene, and then acidified by adding hydrochloric acid. By doing so, the amide carboxylic acid compound can be isolated as a solid. Alternatively, the amide carboxylic acid compound can be obtained as crystals by acidifying with hydrochloric acid, extracting with ethyl acetate, washing, and concentrating.

(Method for producing trione compound)
The amide carboxylic acid compound obtained by the production method of the present invention is subjected to dehydration cyclization to give the following formula (3)

(Where
R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ have the same meanings as in the above formula (1). ) Can be obtained.

  When the amide carboxylic acid compound is heated, a dehydration cyclization reaction proceeds, and a trione compound can be obtained. As the dehydration cyclization reaction, a known method can be employed.However, since the dehydration reaction can be carried out under relatively mild conditions, a method of draining water from the solution in which the amide carboxylic acid compound is dissolved is used. It is preferable to employ it.

  Specific examples of the solvent in the dehydration cyclization reaction include toluene, xylene, mesitylene, butyl acetate, dibutyl ether and the like. The amount of the solvent used may be appropriately determined in consideration of the capacity of the reaction vessel and the like, but may be appropriately determined in the range of 2 to 50 parts by volume with respect to 1 part by mass of the amide carboxylic acid.

  The dehydration cyclization reaction is preferably performed in such a state that the inside of the reaction system is sufficiently mixed, and it is preferable to perform stirring and mixing. The reaction temperature is preferably the reflux temperature of the reaction solution, specifically, preferably in the range of 110 ° C to 210 ° C, and more preferably in the range of 120 to 170 ° C. This dehydration cyclization reaction may be carried out under any of reduced pressure, normal pressure and increased pressure conditions. However, in order to sufficiently perform dehydration, it is preferable to carry out the reaction in a range from reduced pressure to normal pressure. Above all, when an aromatic hydrocarbon solvent such as toluene or xylene is used, it can be at normal pressure because it easily azeotropes with water and the dehydration reaction proceeds easily.

  The reaction time is also not particularly limited, and may be determined as appropriate by checking the state of formation of the trione compound. That is, the progress of the reaction is confirmed by confirming the amount of azeotropic water, and the process may be carried out until no azeotropic water is generated. Usually, 0.5 to 20 hours is sufficient. The reaction atmosphere is not particularly limited, and the reaction can be carried out under an air atmosphere or an inert gas atmosphere such as nitrogen gas.

  Further, a catalyst may be used to promote the dehydration cyclization reaction. Specific examples of such a catalyst include p-toluenesulfonic acid and methanesulfonic acid. The catalyst may be used in an amount of 0.01 to 1 equivalent based on 1 equivalent of the amide carboxylic acid compound.

  After the completion of the dehydration cyclization reaction, the trione compound can be obtained as crystals by distilling off the solvent.

  Hereinafter, examples of the present invention will be described, but the present invention is not limited to these examples.

Example 1 (Synthesis of amide carboxylic acid compound)
An amide carboxylic acid compound represented by the following reaction formula was synthesized.

  Ethyl acetate (25 mL) and water (2.5 mL) were added to the amide alcohol (500 mg, 1.13 mmol), and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1- was added to the resulting slurry. Oxyl (4-HO-TEMPO) (19.41 mg, 0.113 mmol), sodium bicarbonate (14.2 mg, 0.169 mmol), and sodium hypochlorite pentahydrate (408.02 mg, 2.48 mmol) ) Was added at 5 ° C, and the mixture was stirred at 5 ° C for 2 hours and at 20 ° C for 17 hours. The pH at this time was 8.0 to 8.5.

  After completion of the reaction, sodium sulfite (313 mg, 2.48 mmol) was added to stop the reaction. Water was added to the reaction solution, which was washed with toluene. The aqueous layer was separated, and concentrated hydrochloric acid was added until pH3. The product was extracted with ethyl acetate, washed and concentrated to obtain an amide carboxylic acid compound as crystals (370 mg, 71.7%).

[Evaluation of the physical properties]
The analysis results of the obtained amide carboxylic acid compound are shown below.

  1H-NMR (DMSO-d6) [delta] 1.22-1.30 (m, 3H), 3.33 (s, 1H), 3.92-4.10 (m, 3H), 4.73-4. 91 (m, 2H), 7.17-7.35 (m, 15H), 8.51 (d, J = 7.6 Hz, 1H).

Example 2 (Synthesis of trione compound)
A trione compound represented by the following reaction formula was synthesized.

  Mesitylene (1 mL) was added to the amide carboxylic acid compound (200 mg, 0.437 mmol), a Dean-Stark tube was attached, and the mixture was heated under reflux until water distillation was stopped (about 3 hours).

  After completion of the reaction, mesitylene was distilled off to obtain a trione compound as crystals (167 mg, 87%).

[Evaluation of the physical properties]
Various analysis results of the obtained trione compound are shown below.
mp: 157 ° C.
IR (KBr): 1780, 1705, 1680 cm- ¹ .

Example 3 (Synthesis of amide carboxylic acid compound)
An amide carboxylic acid compound represented by the following reaction formula was synthesized.

  Ethyl acetate (25 mL) and water (2.5 mL) were added to the amide alcohol (500 mg, 1.13 mmol), and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1- was added to the resulting slurry. Oxyl (4-HO-TEMPO) (19.41 mg, 0.113 mmol), sodium bicarbonate (14.2 mg, 0.169 mmol), and 12% aqueous sodium hypochlorite solution (1.53 g, 2.48 mmol) The mixture was added at 5 ° C and stirred at 5 ° C for 2 hours and at 20 ° C for 19 hours. The pH at this time was 8.0 to 8.5.

  After completion of the reaction, sodium sulfite (313 mg, 2.48 mmol) was added to stop the reaction. Water was added to the reaction solution, which was washed with toluene. Separate the aqueous layer and add concentrated hydrochloric acid to pH3. The precipitated solid was filtered, washed with water, and dried to obtain an amide carboxylic acid compound as crystals (300 mg, 58%).

[Evaluation of the physical properties]
When 1H-NMR of the obtained amide carboxylic acid compound was measured, the same result as in Example 1 was obtained.

Claims (5)

The following equation (1)

中
R ¹ and R ² are respectively a protecting group for a hydrogen atom or a ureylene group, and may be the same or different groups;
R ⁴ is an alkyl group, an aralkyl group, or an aryl group;
R ⁵ , R ⁶ , and R ⁷ are each a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. ). ｝
By oxidizing the amide alcohol compound represented by the above under alkaline conditions using water, nitroxyl radical and / or a precursor thereof, and an oxidizing agent,
The following equation (2)

(Where
R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ have the same meanings as in the above formula (1). )).   The nitroxyl radical is 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetoxy-2,2,6 , 6-tetramethylpiperidine-1-oxyl, 4-acetamino-2,2,6,6-tetramethylpiperidine 1-oxyl, 2-azaadamantane-N-oxyl, and the nitroxyl radical precursor is 1 -Hydroxy-4-acetoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-acetamino-2,2,6,6-tetramethylpiperidine, 2-hydroxy-2-azaadamantane 2. The method according to claim 1, which is at least one kind.   The method according to claim 1 or 2, wherein the oxidizing agent is at least one selected from sodium hypochlorite and calcium hypochlorite.   The method according to any one of claims 1 to 3, wherein the oxidation reaction is performed in a pH range of 7.0 to 10. The method according to any one of claims 1 to 4, wherein the carboxylic acid compound represented by the formula (2) is produced, and then the carboxylic acid compound is subjected to dehydration cyclization.
The following equation (3)

(Where
R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ have the same meanings as in the above formula (1). A) producing a trione compound represented by the formula: