Process for producing amide compounds

Abstract

An object of the present invention is to provide a method for producing an amide compound. The present invention provides a method for producing a purified amide compound of formula (1) and an effective industrial production method from D-serine to the compound of formula (1). The method for producing the purified amide compound of formula (1) is characterized in that the compound of formula (1) is crystallized from a crystallization mother liquor containing the amide compound of formula (1) and 2.0 moles or less of water relative to 1 mole of the amide compound of formula (1).

Description

Technical Field

[0001] The present invention relates to a method for producing an amide compound. Background Art

[0002] Lacosamide is an amino acid derivative having an analgesic effect and an antispasmodic effect (Patent Document 1: US5773475).

[0003] As a method for synthesizing lacosamide, a method is known in Patent Document 2 in which N-Boc-D-serine is reacted using a methylating agent and an organolithium compound or in the presence of a methylating agent and a phase transfer catalyst to perform O-methylation, and then N-benzylamidation, deprotection, and acetylation are carried out.

[0004] Patent Document 1: US5773475

[0005] Patent Document 2: Japanese Patent No. 5128281 Gazette Summary of the Invention

[0006] The yield of the N-benzylamidated compound produced by the method of Patent Document 2 is not necessarily satisfactory, and the crystallization yield of lacosamide is also not necessarily satisfactory. The present invention provides an improved method for producing lacosamide.

[0007] The inventors of the present invention conducted in-depth research to solve the above problems, and as a result, found that by adjusting the moisture content of the crystallization mother liquor during the crystallization of lacosamide, a purified target product can be obtained efficiently. In addition, improvement points were also found in the process of obtaining the target product from D-serine, and thus the following method for producing lacosamide was completed.

[0008] The present invention provides a method for producing lacosamide (hereinafter, referred to as the amide compound of formula (1)). The present invention includes the embodiments described in the following items, but is not limited thereto.

[0009] 1. A method for producing a purified amide compound of formula (1), characterized in that the compound of formula (1) is crystallized from a crystallization mother liquor containing the amide compound of formula (1) and 2.0 moles or less of water relative to 1 mole of the amide compound of formula (1). (Hereinafter, referred to as "the method for producing the purified amide compound of the present invention").

[0010]

[0011] 2. A method for manufacturing a purified amide compound of formula (1), comprising: a step of acetylating an amino compound of formula (2) to manufacture the amide compound of formula (1) described in item 1 above; a step of preparing a solution containing the resulting amide compound of formula (1) and water in an amount of 2.0 moles or less per mole of the amide compound of formula (1); and the step described in item 1 above.

[0012]

[0013] 3. A method for manufacturing a purified amide compound of formula (1), comprising: a step of reacting hydrochloric acid with a compound of formula (3) to manufacture the amino compound of formula (2); and the step described in item 2 above.

[0014]

[0015] (In the formula, Boc represents tert-butoxycarbonyl)

[0016] 4. A method for manufacturing a compound of formula (3) above, comprising: dropping a mixed solution of a carboxylic acid compound of formula (4) and N-methylmorpholine into a solution of isobutyl chloroformate, and further adding benzylamine. (Hereinafter, it is referred to as "the method for manufacturing a Boc-protected amide compound of the present invention").

[0017]

[0018] (In the formula, Boc represents tert-butoxycarbonyl)

[0019] 5. A method for manufacturing a compound of formula (3) above, comprising: using tetrahydrofuran and water as solvents, reacting a compound of formula (5) with dimethyl sulfate in the presence of an alkali metal hydroxide to manufacture the compound of formula (4); and the step described in item 4 above. (It is referred to as "the method for manufacturing a Boc-protected carboxylic acid compound of the present invention").

[0020]

[0021] (In the formula, Boc represents tert-butoxycarbonyl)

[0022]

[0023] (In the formula, Boc represents tert-butoxycarbonyl)

[0024]

[0025] (In the formula, Boc is as described above)

[0026] 6. A method for producing a compound of formula (3), comprising: a step of producing the compound of formula (5) described in the preceding item 5 by tert-butoxycarbonylating the amino group of D-serine, and the step of the preceding item 5.

[0027] 7. A method for producing a purified amide compound of formula (1), comprising: a step of producing the compound of formula (3) described in the preceding item 4, 5 or 6, and the step of the preceding item 3.

[0028] 8. A crystallization mother liquor described in the preceding item 1, comprising a compound of formula (1) and water in an amount of 2.0 moles or less relative to 1 mole of the compound of formula (1).

[0029] According to the production method of the present invention, the target amide compound can be purified efficiently, and the target product of high quality can be produced. In addition, an industrially advantageous production method for increasing the yield of the production process of lacosamide and effectively connecting a plurality of processes has been found. Detailed Description

[0030] Hereinafter, the present invention will be described in detail. It should be noted that in this specification, "comprise" also includes the meanings of "essentially consist of" and "consist of".

[0031] A method for producing a purified amide compound of formula (1) (the "method for producing a purified amide compound of the present invention") characterized by crystallizing the compound of formula (1) from a crystallization mother liquor containing the amide compound of formula (1) and water in an amount of 2.0 moles or less relative to 1 mole of the amide compound of formula (1) will be described. The solution containing the amide compound of formula (1) used in the crystallization is typically obtained by the method described below.

[0032] The compound of formula (1) can be produced, for example, by acetylating the compound of formula (2). Acetylation can typically use acetic anhydride. From the viewpoint of efficient operation, in the reaction of the compound of formula (2) and acetic anhydride, an aqueous solution containing the hydrochloride of the compound of formula (2) obtained in the production process of the compound (2) is preferably used.

[0033] As the solvent used in the reaction, for example, water, an ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate, a ketone solvent such as methyl ethyl ketone, methyl isobutyl ketone, or a mixture thereof can be used as the solvent. A mixed solution of water and ethyl acetate is a preferred solvent.

[0034] The reaction of the compound of formula (2) and acetic anhydride (Ac 2 O) can be carried out in an aqueous sodium hydroxide solution, sodium bicarbonate (NaHCO 3) in the presence of potassium bicarbonate (KHCO 3 ), or a mixture thereof.

[0035] The reaction temperature is generally in the range of 0 °C to the boiling point of the solvent, and a range of 20 to 50 °C is the preferred temperature.

[0036] Per 1 mole of the compound of formula (2), preferably 0.9 to 2.0 moles of acetic anhydride (Ac 2 O) is used. From an economic point of view, 1.0 to 1.1 moles is more preferred. By performing, for example, a liquid separation operation on the reaction mixture and a liquid separation and washing operation using aqueous sodium bicarbonate, water, etc., by-products such as inorganic salts and organic acid salts are removed to obtain an organic solvent solution containing the compound of formula (1).

[0037] The adjustment of the water content of the organic solvent solution can be carried out, for example, by concentrating and removing water together with the solvent of the solution containing the compound of formula (1) obtained by the liquid separation operation. Dehydrating agents such as sodium sulfate, magnesium sulfate, and molecular sieves can be used for the adjustment of the water content. The confirmation of the water content can be measured, for example, by the Karl Fischer titration method. The water content only needs to be 2.0 moles or less per 1 mole of the compound of formula (1). Crystallization is carried out using an organic solvent solution containing the compound of formula (1) in which the water content is adjusted to the above-specified amount.

[0038] As the organic solvent, for example, ester solvents such as methyl acetate, ethyl acetate, and isopropyl acetate, ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, or a mixture thereof can be used as the solvent. From the viewpoint of efficiency, it is preferred to use the same organic solvent as that used in the reaction when acetylating the compound of formula (2), and ethyl acetate is the preferred solvent.

[0039] The amount of the organic solvent used is generally 30 to 100 parts by weight, preferably 30 to 50 parts by weight, based on 10 parts by weight of the compound of formula (1) in total.

[0040] The amount of the above-mentioned organic solvent can be adjusted by concentration, or the above-mentioned organic solvent can be further distilled to below its lower limit value and then an organic solvent can be added to adjust it to the above range. The starting temperature of crystallization is usually in the range of 40 to 70 °C, and a seed crystal can also be used. A poor solvent for the amide compound of formula (1) can also be added to the above-mentioned organic solvent solution or the crystallization slurry mixture in which a part of the amide compound of formula (1) has precipitated from the organic solvent solution. As the poor solvent, for example, cyclohexane, n-hexane can be used, and cyclohexane is preferred. The amount of the poor solvent used is usually 3 to 20 parts by weight, preferably 3 to 10 parts by weight, relative to 10 parts by weight of the solvent used in crystallization. Next, the obtained slurry mixture is cooled. The cooling temperature is usually -10 °C to 20 °C, and from the viewpoints of yield and operability, it is preferably -5 °C to 5 °C. The cooling rate can be in the range of 1 °C to 20 °C per hour, preferably in the range of 5 °C to 20 °C per hour.

[0041] For the cooled mixture, the amide compound of formula (1) precipitates in the liquid, and the solid (crystal) is obtained and dried, whereby the amide compound of formula (1) is obtained. The precipitated amide compound of formula (1) can be obtained according to a known solid-liquid separation method. Specifically, solid-liquid separation operations such as filtration and decantation can be cited. The crystals of the amide compound of formula (1) obtained can be washed with a solvent as needed. The solvent used in the washing is not particularly limited, and the same solvent as the crystallization solvent (preferably a mixture of ethyl acetate and cyclohexane) can be used. The separated amide compound of formula (1) can be dried under normal pressure or reduced pressure.

[0042] The compound of formula (2) can generally be produced by de-Boc (tert-butoxycarbonyl)ating the compound of formula (3) using hydrochloric acid. In the de-Boc reaction using the compound of formula (3) and hydrochloric acid, from the viewpoint of efficient operation, it is preferable to use the solution containing the compound of formula (3) obtained when producing the compound of formula (3).

[0043] As the solvent used in the reaction, aromatic solvents such as toluene, ester solvents such as methyl acetate, ethyl acetate, and isopropyl acetate, and ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone can be used as the solvent, and toluene is preferred.

[0044] Relative to 1 mole of the compound of formula (3), 1 to 10 moles of hydrochloric acid are preferably used, and from the viewpoints of reactivity and economy, 3 to 5 moles of hydrochloric acid are more preferred. The reaction temperature is usually within the range of 0 °C to the boiling point of the solvent, preferably in the range of 10 to 30 °C. After the reaction, the compound of formula (2) is contained in the aqueous layer in the form of a hydrochloride, so it can be separated from the organic solvent by liquid separation and obtained in the form of an aqueous solution.

[0045] The compound of formula (3) can be prepared by dropwise adding a mixed solution of the carboxylic acid compound of formula (4) and N-methylmorpholine to a solution of isobutyl chloroformate, and further dropwise adding benzylamine. The compound of formula (3) can be prepared by a known method, but according to the method for preparing the Boc-protected amide compound of the present invention, the compound of formula (3) can be prepared in a better yield.

[0046] In the reaction of the compound of formula (4) with isobutyl chloroformate and benzylamine, from the viewpoint of efficient operation, it is preferable to use the solution containing the compound of formula (4) obtained in the manufacturing process of the compound of formula (4). As the solvent used in the reaction, aromatic solvents such as toluene, ester solvents such as methyl acetate, ethyl acetate, and isopropyl acetate, and ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone can be used as the solvent, and toluene is preferred. The reaction temperature is preferably carried out at a temperature of 10 °C or lower, more preferably in the range of -15 to 0 °C.

[0047] The usage amounts of isobutyl chloroformate (IBCF), N-methylmorpholine (MMP), and benzylamine are preferably 0.9 to 2.0 moles, more preferably 1.0 to 1.1 moles, relative to 1 mole of the compound of formula (4).

[0048] By using a liquid separation and washing operation with water, hydrochloric acid water, sodium bicarbonate water, etc., by-products such as inorganic salts and organic acid salts can be removed from the reaction mixture generated by the reaction of the compound of formula (4) with isobutyl chloroformate and benzylamine, and a solution containing the compound of formula (3) can be obtained in the form of an organic layer. By adopting the reaction method described above, the reactivity of the carboxyl group is improved, and the compound of formula (3) can be obtained in a good yield.

[0049] The compound of formula (4) is typically prepared by reacting the Boc-protected D-serine of formula (5) with dimethyl sulfate in the presence of an alkali metal hydroxide using tetrahydrofuran (THF) and water as solvents.

[0050] In the reaction of the compound of formula (5) with dimethyl sulfate, from the viewpoint of efficient operation, it is preferable to use the aqueous solution containing the sodium salt of the compound of formula (5) obtained when preparing the compound of formula (5). From the viewpoint of reactivity, the additional solvent is preferably a solvent that dissolves dimethyl sulfate and is easily miscible with water, such as tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethylacetamide, N-methylmorpholine, dimethyl sulfoxide, methanol, ethanol, 2-propanol, tert-butanol, etc. Among these solvents, tetrahydrofuran is preferred. From the viewpoint of reactivity, the usage amount of the solvent relative to water is preferably 1 to 10 parts by weight relative to 10 parts by weight of water. From the viewpoint of economy, it is more preferably 2 to 5 parts by weight.

[0051] As the alkali metal hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. can be used, and among them, sodium hydroxide is preferred. From the viewpoint of reactivity, the amount of the alkali metal hydroxide used is preferably 0.05 to 1 mole in excess compared with the amount of dimethyl sulfate used, more preferably 0.1 to 0.5 mole in excess. The amount of dimethyl sulfate used is preferably 3 to 10 moles, more preferably 5 to 8 moles, per 1 mole of the compound of formula (5). The reaction temperature is not particularly limited, but from the viewpoint of preventing racemization, a lower temperature is preferred, preferably -10 to 10 °C. By adding an organic solvent to the reaction mixture after the reaction and further adding an acid to the resulting mixture for neutralization, the carboxylic acid compound of formula (4) can be extracted into the organic solvent. As the added acid, for example, inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; organic acids such as acetic acid, formic acid, propionic acid, oxalic acid, and citric acid can be cited. Since the pH is preferably adjusted to 2 or less, hydrochloric acid is preferably used. As the organic solvent used in the extraction, aromatic solvents such as toluene, ester solvents such as methyl acetate, ethyl acetate, and isopropyl acetate, and ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone can be used, and toluene is preferred. The solution containing the compound of formula (4) obtained by the extraction operation can be concentrated to remove the organic solvent.

[0052] The compound of formula (5) is typically produced by reacting D-serine with di-tert-butyl dicarbonate in the presence of a base using tetrahydrofuran (THF) and water as solvents.

[0053] In this reaction, water is usually used as the solvent, and an organic solvent can also be mixed. From the viewpoint of reactivity, the organic solvent is preferably a solvent that dissolves di-tert-butyl dicarbonate and is easily miscible with water. For example, tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethylacetamide, N-methylmorpholine, dimethyl sulfoxide, methanol, ethanol, 2-propanol, tert-butanol, etc. can be used, and tetrahydrofuran is preferred.

[0054] The amount of water used only needs to be able to dissolve D-serine and the sodium salt of the compound of formula (5) formed by the reaction, and is usually 3 to 10 parts by weight relative to 10 parts by weight of D-serine. The amount of di-tert-butyl dicarbonate used is preferably 1.0 to 2.0 moles, more preferably 1.0 to 1.5 moles, per 1 mole of D-serine.

[0055] As the above base, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. can be used, and among them, sodium hydroxide is preferred, and sodium hydroxide can also be used in combination with sodium carbonate or sodium bicarbonate. The amount of the base used is preferably 1.0 to 3.0 moles, more preferably 1.1 to 1.3 moles, per 1 mole of D-serine.

[0056] The reaction temperature of D-serine and di-tert-butyl dicarbonate is not particularly limited, and from the viewpoint of reactivity, 30 to 50 °C is preferred. The mixture formed by the reaction can be subjected to liquid separation washing operation using an organic solvent such as toluene to remove residual di-tert-butyl dicarbonate reagent, etc., and a solution containing the alkali metal salt (preferably sodium salt) of the compound of formula (5) can be obtained from the aqueous layer.

[0057] In the method of the present invention, from D-serine to the compound of formula (1), it can be directly produced in solution state without separating the intermediates (formulas (5) to (2)) in a connected manner, and the connection between processes is easy, and it is excellent as an effective industrial production method. According to this method, a purified amide compound of formula (1) with a reduced content of the compound of the following formula (6) can be produced.

[0058] The compound of formula (6) (hereinafter, sometimes also referred to as the OH form) is an impurity from the compound of formula (5) which is a raw material remaining in the production of the compound of formula (4), and has a structure in which the amide compound of formula (1) is demethylated.

[0059]

[0060] In the method of the present invention, the amide compound of formula (1) can be produced from D-serine in a good yield, and the purity of the obtained amide compound of formula (1) can usually be 99.9% or more, and further can be 99.95% or more. In addition, the content of the OH form in the obtained amide compound of formula (1) can usually be reduced to less than 0.05%, and further reduced to less than 0.03%.

[0061] The following scheme shows a typical example of the production process of the amide compound of the present invention.

[0062]

[0063] Examples

[0064] Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples and the like.

[0065] Production Example 1

[0066] 1) Production of the compound of formula (5)

[0067] A mixture of water (350 mL), 25% aqueous sodium hydroxide solution (152 g, 0.95 mol), sodium bicarbonate (16 g, 0.19 mol), and D-serine (100 g, 0.95 mol) was heated to 40 °C, and tetrahydrofuran (50 mL) was added. A mixture of di-tert-butyl dicarbonate (249 g, 1.14 mol) and tetrahydrofuran (50 mL) was added dropwise to this solution at 40 °C over 3 h or more. After maintaining the temperature at 40 °C and confirming the disappearance of the starting materials, toluene (200 mL) was added, and liquid separation and washing were carried out at 40 °C to obtain a sodium salt solution of the compound of formula (5) from the aqueous layer. The yield of the compound of formula (5) was 100%, and the HPLC purity was 97.6%.

[0068] 2) Preparation of the compound of formula (4)

[0069] After adding tetrahydrofuran (160 mL) to the sodium salt solution of the compound of formula (5) (0.48 mol), the mixture was cooled to 0 °C, and while maintaining the temperature, dimethyl sulfate (420 g, 3.33 mol) and 50% aqueous sodium hydroxide solution (285 g, 3.57 mol) were simultaneously injected at 0 °C. After the simultaneous injection, the temperature was raised to 20 °C over about 2 h and maintained. After confirming the disappearance of the starting materials, toluene (500 mL) was added, and 35% hydrochloric acid was added at 20 °C to adjust the pH to 1 - 2. After liquid separation, the obtained organic layer was washed with 20% brine (100 mL) at 20 °C. About 350 g of the solvent was distilled off under reduced pressure from the obtained organic layer to obtain a solution of the compound of formula (4). The yield of the compound of formula (4) obtained from the compound of formula (5) was 99%, the HPLC purity was 96.3%, and the optical purity was 97.6%.

[0070] 3) Preparation of the compound of formula (3)

[0071] Isobutyl chloroformate (67 g, 0.49 mol) was mixed with toluene (220 mL) and cooled to -10 °C. A mixture obtained by adding N-methylmorpholine (50 g, 0.49 mol) to the solution of the compound of formula (4) (0.47 mol) was added dropwise to this solution at -10 °C. The mixture was maintained at -10 °C, and after confirming the disappearance of the starting materials, a mixture of isopropyl alcohol (44 mL) and benzylamine (52 g, 0.49 mol) was added dropwise at -10 °C. After the addition was completed, the temperature was raised to 10 °C over about 2 h and maintained. After confirming the disappearance of the intermediate, the mixture was washed successively with water (196 mL), 3.5% hydrochloric acid (98 mL), and 8% aqueous sodium bicarbonate solution (98 mL) to obtain a toluene solution of the compound of formula (3). The yield of the compound of formula (3) obtained from the compound of formula (4) was 96.9%.

[0072] 4) Preparation of the amino compound of formula (2)

[0073] The toluene solution (0.44 mol) of the compound of formula (3) was adjusted to 15°C, and 35% hydrochloric acid (167 g, 1.60 mol) was added dropwise while maintaining the temperature. The mixture was kept at 15°C to confirm the disappearance of the starting material. After cooling to 5°C, water (96 mL) was added dropwise to the mixture, followed by liquid separation to obtain an aqueous solution of the hydrochloride of the amino compound of formula (2) from the aqueous layer.

[0074] 5) Preparation of the purified amide compound of formula (1)

[0075] A 50% aqueous sodium hydroxide solution (110 g, 1.37 mol) was added dropwise to the aqueous hydrochloride solution of the compound of formula (2) at 30°C or lower, and sodium bicarbonate (27 g, 0.32 mol) was added. Ethyl acetate (720 mL) was further added thereto, and the temperature was raised to 35°C. While maintaining the temperature, acetic anhydride (47 g, 0.46 mol) was added dropwise. The mixture was kept at 35°C to confirm the disappearance of the starting material, and then the mixture was separated by liquid separation. Subsequently, it was washed with an 8% aqueous sodium bicarbonate solution (96 mL) and water (48 mL). The content of the OH form in the obtained organic layer was 0.3%. (The content of the OH form is a value calculated based on the peak area value in the high-performance liquid chromatography chart according to the following formula ((area value of the OH form of formula (6)) / ((area value of the OH form of formula (6)) + (area value of the compound of formula (1)))) × 100). After adding ethyl acetate (141 mL) to the obtained organic layer, about 700 g of the solvent was distilled off under reduced pressure. After adding 188 mL of ethyl acetate to the distillation residue, filtration was carried out at 50°C or higher, and it was washed with 50 mL of ethyl acetate. After adding ethyl acetate (500 mL) to the filtrate, about 420 g of the solvent was distilled off under reduced pressure. After confirming that the water content in the distillation residue was 2.0 moles or less per 1 mole of the compound of formula (1), the temperature was adjusted to 60°C, seeds were inoculated, and it was kept warm for 2 hours. Cyclohexane (235 mL) was added dropwise to the resulting slurry mass over 1 hour or more, and then it was kept warm for 1 hour and cooled to 0°C over about 6 hours. After filtration, it was washed with a mixed solution of cyclohexane (141 mL) and ethyl acetate (141 mL) cooled to 0°C, and the obtained crystals were dried under reduced pressure to obtain the purified compound of formula (1). The yield was 92.3 g, and the yield was 84.2% (the overall yield from D-serine was 80.7%). The HPLC purity was 99.98% (OH form 0.02%), and the optical purity was 99.9% ee.

[0076] Production Example 2

[0077] 1) Preparation of the compound of formula (5)

[0078] A mixed solution of water (330 mL), 25% aqueous sodium hydroxide solution (183 g, 1.14 moles), and D-serine (100 g, 0.95 moles) was heated to 40 °C, and tetrahydrofuran (50 mL) was added. A mixed solution of di-tert-butyl dicarbonate (249 g, 1.14 moles) and tetrahydrofuran (50 mL) was added dropwise to this solution at 40 °C over 3 h or more. After holding at 40 °C and confirming the disappearance of the raw materials, toluene (200 mL) was added, and liquid separation and washing were carried out at 40 °C to obtain a sodium salt solution of the compound of formula (5) from the aqueous layer. The yield of the compound of formula (5) was 100%, and the HPLC purity was 98.6%.

[0079] 2) Preparation of the compound of formula (4)

[0080] After adding tetrahydrofuran (160 mL) to the sodium salt solution of the compound of formula (5) (0.48 moles), it was cooled to 0 °C, and dimethyl sulfate (420 g, 3.33 moles) was added dropwise while maintaining the temperature. Then, 50% aqueous sodium hydroxide solution (285 g, 3.57 moles) was added dropwise at 0 °C. After holding at 0 °C and confirming the disappearance of the raw materials, toluene (1000 mL) was added, and 35% hydrochloric acid was added at 0 °C to adjust the pH to 1 - 2. After liquid separation, the obtained organic layer was washed with 20% brine (100 mL) at 0 °C. Approximately 700 g of the solvent was distilled off under reduced pressure from the obtained organic layer to obtain a solution of the compound of formula (4). The yield of the compound of formula (4) obtained from the compound of formula (5) was 99%, the HPLC purity was 96.4%, and the optical purity was 98.9%.

[0081] Comparative Example 1

[0082] 1) Preparation of the compound of formula (5)

[0083] A mixed solution of water (125 mL), aqueous sodium bicarbonate solution (24 g, 1.14 moles), and D-serine (25 g, 0.24 moles) was heated to 30 °C. Di-tert-butyl dicarbonate (60 g, 0.27 moles) was added dropwise to this solution. After holding at 30 °C and confirming the disappearance of the raw materials, toluene (50 mL) was added, and liquid separation and washing were carried out at 30 °C to obtain a sodium salt solution of the compound of formula (5) from the aqueous layer. The yield of the compound of formula (5) was 100%, and the HPLC purity was 99.4%.

[0084] 2) Preparation of the compound of formula (4)

[0085] After adding tetrahydrofuran (45 mL) to a sodium salt solution (0.14 mol) of the compound of formula (5), the mixture was cooled to 0 °C, and 50% aqueous sodium hydroxide solution (5.7 g, 0.07 mol) was added. Then, while maintaining the temperature, dimethyl sulfate (108 g, 0.86 mol) and 50% aqueous sodium hydroxide solution (69 g, 0.86 mol) were simultaneously injected at 0 °C. After the simultaneous injection, the mixture was kept at 0 °C. After confirming the disappearance of the starting materials, toluene (150 mL) was added, and 35% hydrochloric acid was added at 0 °C to adjust the pH to 1 - 2. After liquid separation, the obtained organic layer was washed with 20% brine (30 mL) at 0 °C. A solution of the compound of formula (4) was obtained from the obtained organic layer. The yield of the compound of formula (4) obtained from the compound of formula (5) was 99%, the HPLC purity was 96.6%, and the optical purity was 97.6%.

[0086] 3) Preparation of the compound of formula (3)

[0087] The solution of the compound of formula (4) (0.14 mol) was cooled to -10 °C, and isobutyl chloroformate (21.5 g, 0.16 mol) and N-methylmorpholine (21.6 g, 0.21 mol) were successively added dropwise while maintaining the temperature. The mixture was kept at -10 °C. After confirming the disappearance of the starting materials, a mixture of isopropyl alcohol (15 mL) and benzylamine (16.0 g, 0.15 mol) was added dropwise at -10 °C. After the addition was completed, the temperature was raised to 10 °C over about 2 h and kept at this temperature. After confirming the disappearance of the intermediate, the mixture was washed with water (60 mL), 3.5% hydrochloric acid (30 mL), and 8% aqueous sodium bicarbonate solution (30 mL) to obtain a toluene solution of the compound of formula (3) in the form of an organic layer. The yield of the compound of formula (3) obtained from the compound of formula (4) was 87.8%.

[0088] Reference Examples 1, 2 and Production Examples 6, 7, 8

[0089] In the crystallization mother liquor (mass) of the compound of formula (1) with the OH form content of the compound of formula (6) as shown in Table 1 respectively, the water content of each was set as recorded in Table 1. Except for this, crystallization, filtration, and washing were carried out with the same solvent and solvent ratio as in Production Example 5, and the obtained crystals were dried under reduced pressure to obtain the compound of formula (1). The OH form content of the compound of formula (6) in the obtained crystals and the yield of the compound of formula (1) obtained from the compound of formula (3) are shown in Table 1.

[0090] [Table 1]

[0091]

[0092] The content of the *OH form is a value calculated based on the area value of the peak in the high-performance liquid chromatogram and the following formula ((area value of the OH form in formula (6)) / (area value of the OH form in formula (6) + area value of the compound in formula (1))) × 100)

[0093] **Molar ratio of water to 1 mole of the amide compound of formula (1)

[0094] The method described in Comparative Example 2, Patent Document 2

[0095] 1) Preparation of the compound of formula (4)

[0096] Cool a suspension of toluene (75 mL), the compound of formula (5) (15 g, 0.07 mole), and tetrabutylammonium bromide (0.9 g, 0.003 mole) to 10°C or lower. Add 20% aqueous sodium hydroxide solution (14.6 g, 0.07 mole) thereto, and age the resulting mixture for 30 minutes. While maintaining the temperature at 10°C or lower, add dimethyl sulfate (36.9 g, 0.29 mole) and 50% aqueous sodium hydroxide solution (26.5 g, 0.33 mole), and age the reaction mixture for 1 hour or more. Add water (45 mL) to the mixture for liquid separation. Adjust the aqueous layer to pH 3.5 or lower with 50% aqueous citric acid solution, extract with dichloromethane (2 × 62 mL, 1 × 45 mL), mix the extracts, and perform dehydration and concentration to obtain the compound of formula (4). (23.8 g after concentration, apparent yield 100%, HPLC purity 95.6%, optical purity 96.5%)

[0097] 2) Preparation of the compound of formula (3)

[0098] Cool the solution of the compound of formula (4) to -10°C or lower, add isobutyl chloroformate (9.0 mL, 0.07 mole) at -5°C or lower, then add N-methylmorpholine (7.6 mL, 0.07 mole) at -5°C or lower, and age the mixture at -5°C or lower for 30 minutes or more. Add benzylamine (7.8 mL, 0.07 mole) dissolved in dichloromethane at -5°C or lower, and warm the mixture to room temperature. After aging for 1 hour or more, wash the mixture with water (29 mL), 1N hydrochloric acid aqueous solution (29 mL), 8% sodium bicarbonate aqueous solution (29 mL), and water (29 mL) to obtain the solution of the compound of formula (3). The yield of the compound of formula (3) obtained from the compound of formula (4) is 90.7%.

[0099] Industrial applicability

[0100] According to the method of the present invention, a high-quality amide compound can be efficiently produced.

Claims

1. A method for producing a purified amide compound of formula (1), characterized in that, a compound of formula (1) is crystallized from a crystallization mother liquor containing the amide compound of formula (1) and water in an amount of 2.0 moles or less per mole of the amide compound of formula (1), 2. The production method according to claim 1, characterized in that, further comprising: a step of acetylating an amino compound of formula (2) to produce an amide compound of formula (1); 3. The production method according to claim 2, characterized in that, further comprising: a step of reacting hydrochloric acid with a compound of formula (3) to produce an amino compound of formula (2); wherein Boc represents tert-butoxycarbonyl, 4. The production method according to claim 3, characterized in that, further comprising: a step of dropping a mixed solution of a carboxylic acid compound of formula (4) and N-methylmorpholine into a solution of isobutyl chloroformate, and further adding benzylamine to produce a compound of formula (3); wherein Boc represents tert-butoxycarbonyl, wherein Boc represents tert-butoxycarbonyl.

5. The production method according to claim 4, characterized in that, further comprising: a step of using tetrahydrofuran and water as solvents and reacting a compound of formula (5) with dimethyl sulfate in the presence of an alkali metal hydroxide to produce a compound of formula (4); wherein Boc represents tert-butoxycarbonyl, wherein Boc is as described above.

6. The production method according to claim 5, characterized in that, further comprising: a step of tert-butoxycarbonylating the amino group of D-serine to produce a compound of formula (5), wherein Boc represents tert-butoxycarbonyl.

7. A crystallization mother liquor containing an amide compound of formula (1) and water in an amount of 2.0 moles or less per mole of the amide compound of formula (1),

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