JP4919421B2 - Process for producing (R) -3-morpholine carboxylic acid - Google Patents

Description

  The present invention relates to a method for producing (R) -3-morpholine carboxylic acid having high optical purity useful as a pharmaceutical raw material and an intermediate from L-4-oxalidine.

L-4-oxalidine and (R) -3-morpholinecarboxylic acid are compounds that can be represented by the following chemical formula.

  In the creation of a compound having pharmacological activity, there are many examples in which a compound containing 3-morpholine carboxylic acid is used in the molecule or 3-morpholine carboxylic acid is used as a synthetic intermediate or a raw material (Non-patent Document 1, Patent) Therefore, optically active 3-morpholine carboxylic acid having a particularly high optical purity is an important compound as a raw material for synthetic pharmaceuticals.

  As a conventional method for producing optically active (R) -3-morpholine carboxylic acid, an optically active aziridine-2-carboxylic acid derivative is used as a starting material, and a three-step chemical reaction (addition of 2-chloroethane, benzyl group) There is only known a production method through elimination and a cyclization reaction using triethylamine as a cyclizing agent (see Non-Patent Documents 2 and 3).

  In addition, as a method for producing optically inactive racemic 3-morpholine carboxylic acid, a method for producing racemic 3-morpholine carboxylic acid by organic synthesis using N-acetylmorpholine as a starting material (non-patent document) 4), 2-acetamido-2- (β-chloroethoxymethyl) malonic acid ester or methyl 2-bromo-3- (β-chloroethoxy) -propionic acid in an organic synthesis by racemic 3-morpholinecarboxylic acid There is known a method for manufacturing (see Non-Patent Document 5).

In addition, as a similar technique of the present invention, (1) by using L-lysine as a starting material, diazotization of an α-position amino group with sodium nitrite and cyclization reaction using barium hydroxide or sodium hydroxide as a cyclizing agent (2) A method of synthesizing active pipecolic acid (see Non-patent Documents 6 and 9), (2) L-oxalidine is used as a starting material, and an α-amino acid is oxidized by an enzyme and a reduction reaction by the enzyme is performed (S)- A method for synthesizing 3-morpholinecarboxylic acid (see Patent Document 10) is known.
International Publication No. 02/83624 Pamphlet International Publication No. 02/85860 International Publication No. 2004/74291 International Publication No. 2004/92167 International Publication No. 2005/108359 US Pat. No. 7,169,780 US Patent Application Publication No. 2002/99047 US Patent Application Publication No. 2004/152745 JP 2004-51606 A JP 2005-95167 A J. et al. Med. Chem. , 1995, Vol. 38, p. 1853-1864 Bull. Chem. Soc. Jpn. , 1987, Vol. 60, p. 2963-2965 Peptide Chemistry, 1986, p. 153-156 Tetrahedron Letters. , 1981, Vol. 22, p. 141-144 American Chemical Society, 1957, Vol. 79, p5593-5696 Chem. Pharm. Bull. , 1976, Vol. 24, p. 621-631 Antimicrobial Agents and Chemotherapy, 1967, p. 401-406

  The method of synthesizing optically active (R) -3-morpholine carboxylic acid from optically active aziridine-2-carboxylic acid derivatives as described in Non-Patent Documents 2 and 3 is a method in which an intermediate is used as a reaction solution at the end of each reaction. This requires a process for taking out the product, and has a problem that the production cost is high because the operation is complicated, which is not suitable industrially.

  Further, Non-Patent Document 6 of the similar technique (1) does not describe synthesizing optically active 3-morpholine carboxylic acid using L-4-oxalidine as a starting material. When applied as it is, the following problems arise. For example, in the similar technique of Non-Patent Document 6, a process for purifying pipecolic acid by tosylation and further removing the tosyl group is described in the purification method. However, there is a problem that the operation becomes complicated and the production cost increases. In addition to that, the optical purity itself is low.

In addition, the similar technique of Patent Document 9 describes that (S) -pipecolic acid is generated from the starting material L-lysine, and the absolute configuration of the chiral center is maintained. The difference is that the absolute configuration is reversed. In addition, Patent Document 9 has a problem that there is no specific description of a purification method and purification cannot be performed at low cost.
Patent Document 10 of the similar technique (2) is a method for producing (S) -3-morpholinecarboxylic acid by an enzymatic method, using the same L-4-oxalidine as that of the present invention as a starting material.

  The present invention has been made to solve the conventional problems, and an object of the present invention is to provide a simple and inexpensive method for producing (R) -3-morpholinecarboxylic acid having high optical purity.

  The present inventors have conducted intensive research to solve the above problems. As a result, by using a production method in which L-4-oxalidine is used as a starting material, L-4-oxalidine is diazotized with a diazotizing agent, and cyclized with a cyclizing agent without isolation and purification, The problem of purifying and synthesizing the intermediate from the reaction solution as described in Patent Documents 2 and 3 was solved.

Further, as a purification method, adsorption / desorption of (R) -3-morpholine carboxylic acid to strong acid cation exchange resin (H ⁺ type), strong acid cation exchange resin (NH ₄ ⁺ type) and strong acid cation A simple method of removing impurities using an exchange resin (Ca ²⁺ type) was newly found. As a result, problems relating to purification were solved, and an industrial production method of (R) -3-morpholinecarboxylic acid with high optical purity was completed.

Therefore, the present invention provides the following Steps A to C: (1) A method in which L-4-oxalidine is diazotized with a diazotizing agent in an acidic solvent, and the diazonium salt solution is adjusted to pH 7.0 with an alkaline agent. Process;
(2) To the solution obtained in step A, 0.5 to 1.2 molar equivalents of sodium hydroxide, potassium hydroxide or barium hydroxide are added to L-4-oxalidine to carry out a cyclization reaction, (B) Step B for producing a 3-morpholinecarboxylic acid solution;
(3) Step C, in which the pH of the crude (R) -3-morpholine carboxylic acid solution obtained in Step B is adjusted to 6.5 to 7.0 and then purified using an ion exchange resin;
The present invention relates to a process for producing (R) -3-morpholine carboxylic acid having high optical purity.

  The production method of the present invention does not require a complicated operation such as taking out the intermediate from the reaction system, and enables the reaction operation to be performed in the same solution. In addition, the present invention provides an industrially producible method in which purification can be performed entirely in an aqueous solvent system and a step such as derivatization of (R) -3-morpholine carboxylic acid is unnecessary. be able to. Therefore, by carrying out the production method of the present invention, (R) -3-morpholine carboxylic acid having high optical purity can be produced efficiently and simply at low cost.

The production method of the present invention will be described in detail below.
L-4-oxalidine, which is a starting material of the present invention, can be purchased from commercially available L-4-oxalidine monohydrochloride (manufactured by Wako Pure Chemical Industries, Ltd. and Aldrich). Moreover, it can also manufacture from the fermentation product by microorganisms by a well-known method. For example, as described in Non-Patent Document 7, it is possible to cultivate actinomycetes belonging to Streptomyces chartreusis or Streptomyces erythrochromogenes, and to isolate and purify L-4-oxalidine as monohydrochloride from the culture solution. . Moreover, you may isolate | separate newly L-4-oxalidine production microorganisms from the natural world, and may use for manufacture. By producing L-4-oxalidine by fermentation production, L-4-oxalidine as a starting material can be easily obtained at low cost.

Step A of this method of diazotizing L-4-oxalidine with a diazotizing agent in an acidic solvent can be performed as follows.
The solvent that can be used in the diazotization reaction is not particularly limited as long as L-4-oxalysine is dissolved and diazotization proceeds, but water is particularly preferable in consideration of the solubility of the reagent.
As the acid of the acidic solvent, a mineral acid, an organic acid, or the like can be used, and hydrochloric acid, sulfuric acid, and hydrobromic acid are preferable, and hydrochloric acid is particularly preferable.
The concentration of hydrochloric acid when diazotizing is preferably 1 to 13 N. More preferably, it is the range of 6-12 regulation.
As the diazotizing agent to be used, a nitrite reagent capable of diazotizing an amino group can be used, and examples thereof include sodium nitrite and potassium nitrite. Of these, sodium nitrite is preferred.
The addition amount of the diazotizing agent is between 0.5 and 5 molar equivalents, more preferably 1 to 2 molar equivalents with respect to L-4-oxalidine.
After completion of the diazotization reaction, neutralization is performed using an alkali agent. At this time, it is necessary to strictly neutralize to pH 7.0 using a pH meter or the like. Outside this range, there arises a problem that the optical purity is significantly lowered or the yield is lowered. The alkali agent used is preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide.

  The cyclization reaction of the next B step can be carried out in the same solution without isolating the intermediate from the reaction solution obtained in the A step. Examples of the cyclizing agent to be added include basic salts. For example, sodium hydroxide, potassium hydroxide or barium hydroxide can be mentioned. Of these, sodium hydroxide is preferred.

  The added amount of the cyclizing agent is 0.5 to 1.2 molar equivalents relative to L-4-oxalidine, more preferably 1.0 molar equivalents. If the addition amount of the cyclizing agent is more than 1.2 molar equivalents, the optical purity of the (R) -3-morpholine carboxylic acid to be produced is significantly lowered, so the addition amount must be strictly controlled.

  After adding the cyclizing agent, the solution is heated to promote the reaction. The cyclization reaction temperature is not particularly limited as long as it is 25 ° C. or higher, but it is more preferable to perform heating and reflux in a reaction vessel equipped with a cooling pipe. The reaction time is until the completion of the cyclization reaction, but it is about 5 to 30 minutes under heating and reflux conditions.

  After completion of the cyclization reaction, the reaction solution is cooled to room temperature and the pH is adjusted to 6.5 to 7.0. The pH adjuster is not particularly limited as long as the pH can be adjusted to 6.5 to 7.0, but is preferably the same substance as the acid used for the diazotization reaction and the alkali agent used for neutralization, More preferred are hydrochloric acid and sodium hydroxide.

The cationic substance in the reaction solution whose pH has been adjusted may be adsorbed as it is to the strongly acidic cation exchange resin (H ⁺ type) which is the next C step, but in order to reduce the amount of resin used, the reaction solution It is preferable to carry out the ion exchange resin treatment after reducing the amount of salts therein. The principle is precipitation removal of salts using the difference in solubility between the salt and (R) -3-morpholinecarboxylic acid in water.

  The reaction solution is concentrated in order to precipitate salts, but the concentration may be performed up to the amount of water in which (R) -3-morpholinecarboxylic acid does not precipitate, and preferably (R) -3-morpholinecarboxylic acid. 1 to 5 times the amount (w / w).

  The precipitated salts can be separated into solid and liquid by a general method. For example, filtration and centrifugation.

Next, the purification process using an ion exchange resin as the C process will be described. A cationic substance containing (R) -3-morpholinecarboxylic acid in the eluate by adsorbing the cationic substance in the reaction solution obtained in Step B onto a strongly acidic cation exchange resin (H ⁺ type) To release. At this time, the eluent to be used is not particularly limited as long as it can release a cationic substance from the resin, but is preferably aqueous ammonia, aqueous hydrochloric acid or aqueous sodium chloride, and more preferably aqueous ammonia.

The eluate containing the (R) -3-morpholine carboxylic acid is concentrated to remove ammonia in the solution. Thereafter, unreacted L-4-oxalidine is adsorbed on an NH ₄ ⁺ type cation exchange resin and removed from the solution. The ion exchange resin used, may be used, strong acid cation exchange resin (NH ₄ ⁺ type) or weakly acidic cation exchange resin (NH ₄ ⁺ type), a strongly acidic cation exchange resin (NH ₄ ⁺ Type) is preferably used.

Using a column packed with a strongly acidic cation exchange resin (Ca ²⁺ type), the solution removed by adsorbing unreacted L-4-oxalidine to the strong acid cation exchange resin (NH ₄ ⁺ type) was concentrated and packed. Perform chromatography. By this operation, a by-product generated during the synthesis of (R) -3-morpholine carboxylic acid (2-hydroxy-3- (β-aminoethoxy)-, in which the α-amino acid of L-4-oxalidine is hydroxylated) — (R) -3-morpholine carboxylic acid can be separated. The by-product elutes after (R) -3-morpholine carboxylic acid because of its affinity for Ca ²⁺ type strongly acidic cation exchange resin. Therefore, both substances can be easily separated from each other.

Thereafter, the fraction containing (R) -3-morpholine carboxylic acid is collected, decolorized with activated carbon, and after concentration, methanol or ethanol is added to precipitate crystals, and (R) -3-morpholine carboxylic acid is added. It can be recovered.
In this way, (R) -3-morpholine carboxylic acid having high optical purity can be easily produced.

  As mentioned above, although embodiment of this invention was described, this invention can be implemented with another form.

  For example, in the above-described embodiment, the embodiment in which the cation exchange resin is used in the step C has been shown. However, in the present invention, an anion exchange resin can also be used. Furthermore, a purification process using silica gel chromatography is also possible.

  Although the specific example of the manufacturing method by this invention is shown in the following examples, this invention is not limited at all by these Examples.

  In this example, quantitative analysis and optical purity analysis of 3-morpholinecarboxylic acid were performed by the following methods.

Quantitative analysis was calculated by internal standard method using high performance liquid chromatography. The analysis conditions are as follows.
Column: Hydrosphere C18 manufactured by YMC (inner diameter 4.6 mm, column length 25 cm)
Column temperature: 40 ° C
Detector: UV detector Measurement wavelength: 254 nm
Solvent: Acetonitrile: Water (0.025% copper sulfate, 0.025% sodium octanesulphonate) = 13: 87
Flow rate: 1.0 ml / min
Internal standard substance: L-valine Elution time: 3-morpholinecarboxylic acid 5.4 (min)

Optical purity analysis was performed by high performance liquid chromatography using a chiral column. The analysis conditions are as follows.
Column: CHIRALPAK WH manufactured by Daicel (inner diameter 4.6 mm, column length 25 cm)
Column temperature: 50 ° C
Detector: UV detector Measurement wavelength: 254 nm
Solvent: 0.25 mM copper sulfate aqueous solution Flow rate: 0.5 ml / min
Elution time: (R) -3-morpholine carboxylic acid 25.4 (min)
(S) -3-Morpholinecarboxylic acid 30.1 (min)

Unless otherwise indicated, ¹ H- and ¹³ C-NMR were measured with a solution of heavy water (D ₂ O) using a nuclear magnetic resonance apparatus (model JNM-LA300) manufactured by JEOL Ltd.

L-4-oxalidine monohydrochloride 5.52 g was dissolved in water 30.0 ml, concentrated hydrochloric acid 36.0 g was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous sodium nitrite solution in which 2.89 g of sodium nitrite was dissolved in 18.0 ml of water was added dropwise over 1 hour. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, while maintaining the temperature of the solution at 25 ° C. or lower, a 48% (w / w) aqueous sodium hydroxide solution was added to neutralize the reaction solution to pH 7.0. Subsequently, 2.45 g of a 48% (w / w) aqueous sodium hydroxide solution (1.0 molar equivalent with respect to L-4-oxalidine) was added as a cyclizing agent, and the mixture was reacted for 20 minutes under heating and reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in this reaction solution, the amount of 3-morpholine carboxylic acid produced was 3.16 g (reaction yield 80.6%).
The reaction solution was concentrated under reduced pressure using an evaporator until sodium chloride was precipitated, and the crystals were separated from the solution by filtration through filter paper. The crystal was washed with a small amount of cold methanol, and the filtrate and the washing solution were mixed. This operation was performed once again to remove sodium chloride precipitated from the solution.
The mixed solution of the filtrate and the washing solution was concentrated under reduced pressure using an evaporator to remove methanol, and diluted with distilled water to 100 ml. This solution was passed through a column packed with 50 ml of strongly acidic cation exchange resin Duolite C20 (H ⁺ type) to adsorb 3-morpholine carboxylic acid to the ion exchange resin. After 150 ml of ion exchange water was passed through the column, the column was washed with water, and then 250 ml of 2% aqueous ammonia was passed through to release 3-morpholinecarboxylic acid from the ion exchange resin and eluted from the column. The eluate was collected and concentrated under reduced pressure with an evaporator to remove ammonia.
Distilled water was added to the concentrated residue to dilute to 150 ml. This solution was passed through a column packed with 50 ml of strongly acidic cation exchange resin Duolite C20 (NH ₄ ⁺ type) to adsorb unreacted L-4-oxalidine to the ion exchange resin. The column-passing solution containing 3-morpholine carboxylic acid was collected and concentrated under reduced pressure using an evaporator.
Distilled water was added to the concentrated residue to dilute to 100 ml. This solution was passed through a column packed with 100 ml of strong acid cation exchange resin Diaion UBK530 (Ca ²⁺ type), and the by-product generated during synthesis and 3-morpholine carboxylic acid were chromatographed. The 3-morpholine carboxylic acid eluted before the by-product was recovered and concentrated under reduced pressure to about 100 ml with an evaporator. 0.5 g of activated carbon (Fuji activated carbon flower F2) was added to the solution, stirred, and allowed to stand overnight to decolorize the solution. This solution was filtered through a filter paper to remove the activated carbon, and then filtered through a filter having a pore size of 0.2 μm. The filtrate was concentrated under reduced pressure with an evaporator, and ethanol was added to the concentrated solution for crystallization. The crystals were collected by filtration through a glass filter and dried to obtain 1.94 g of 3-morpholinecarboxylic acid white crystals (recovery rate 61.4%).
NMR analysis of this crystal sample gave the following ¹ H-NMR and ¹³ C-NMR chemical shift values.
¹ H-NMR; δ (ppm) 3.98 (1H, dd, J = 2.6, 11.4 Hz), 3.77 (1H, dt, J = 3.6, 13.2 Hz), 3.51 −3.68 (3H, m), 3.17 (1H, dt, J = 3.2, 13.2 Hz), 3.01 (1H, ddd, J = 3.6, 9.9, 13.5 Hz) )
¹³ C-NMR; δ (ppm) 171.3, 66.8, 64.0, 57.7, 42.9
The absolute configuration of the obtained 3-morpholine carboxylic acid is of the (R) type, and the optical purity of the (R) -3-morpholine carboxylic acid is 99.8% e.e. e. Met.

L-4-oxalidine monohydrochloride 5.52 g was dissolved in water 30.0 ml, concentrated hydrochloric acid 36.0 g was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous solution obtained by dissolving 2.89 g of sodium nitrite in 18.0 ml of water was added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 30% (w / w) aqueous potassium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 5.61 g of a 30% (w / w) potassium hydroxide aqueous solution (1.0 molar equivalent with respect to L-4-oxalidine) was added as a cyclizing agent, and the mixture was reacted for 20 minutes under heating and reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in this reaction solution, the amount of 3-morpholine carboxylic acid produced was 2.68 g (reaction yield 68%).
When a part of the reaction solution was purified according to Example 1 and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 98.3% e.e. e. Met.

5.54 g of L-4-oxalidine monohydrochloride was dissolved in 30.0 ml of water, and 36.00 g of concentrated hydrochloric acid was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous solution obtained by dissolving 2.89 g of sodium nitrite in 18.0 ml of water was added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 48% (w / w) aqueous sodium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 4.65 g of barium hydroxide octahydrate (0.5 molar equivalent based on L-4-oxalidine) was added as a cyclizing agent, and the mixture was reacted for 20 minutes under heating and reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in the reaction solution, the amount of 3-morpholine carboxylic acid produced was 2.1 g (reaction yield 54%).
When a part of the reaction solution was purified and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 97.6% e.e. e. Met.

1.84 g of L-4-oxalidine monohydrochloride was dissolved in 10.0 ml of water, and 12.0 g of concentrated hydrochloric acid was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous solution obtained by dissolving 0.83 g of sodium nitrite in 6.0 ml of water was added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 48% (w / w) aqueous sodium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 0.41 g of a 48% (w / w) aqueous sodium hydroxide solution (0.5 molar equivalent based on L-4-oxalidine) was added as a cyclizing agent, and the mixture was reacted for 20 minutes under heating and reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous sodium hydroxide solution. As a result of measuring the amount of 3-morpholine carboxylic acid in this reaction solution, the amount of 3-morpholine carboxylic acid produced was 0.6 g (reaction yield 46%).
When a part of the reaction solution was purified according to Example 1 and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 98.2% e.e. e. Met.

L-4-oxalidine monohydrochloride (0.92 g) was dissolved in 10.0 ml of water, 12.0 g of concentrated hydrochloric acid was added, and the mixture was stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous solution in which 0.48 g of sodium nitrite was dissolved in 6.0 ml of water was added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 48% (w / w) aqueous sodium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 0.48 g of a 48% (w / w) aqueous sodium hydroxide solution (1.2 molar equivalents relative to L-4-oxalidine) was added as a cyclizing agent, and the mixture was allowed to react for 20 minutes with heating under reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in this reaction solution, the amount of 3-morpholine carboxylic acid produced was 0.46 g (reaction yield 70%).
When a part of the reaction solution was purified according to Example 1 and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 97.6% e.e. e. Met.

3.68 g of L-4-oxalidine monohydrochloride was dissolved in 10.0 ml of water, and 12.0 g of concentrated hydrochloric acid was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., 1.93 g of sodium nitrite was dissolved in 6.0 ml of water and added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 48% (w / w) aqueous sodium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 1.92 g of a 48% (w / w) aqueous sodium hydroxide solution (1.2 molar equivalents relative to L-4-oxalidine) was added as a cyclizing agent, and the mixture was reacted for 20 minutes under heating and reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in this reaction solution, the amount of 3-morpholine carboxylic acid produced was 2.04 g (reaction yield 78%).
When a part of the reaction solution was purified according to Example 1 and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 97.6% e.e. e. Met.

Comparative Example 1
1.84 g of L-4-oxalidine monohydrochloride was dissolved in 10.0 ml of water, and 12.0 g of concentrated hydrochloric acid was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous solution obtained by dissolving 0.83 g of sodium nitrite in 6.0 ml of water was added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 48% (w / w) aqueous sodium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 1.23 g of a 48% (w / w) aqueous sodium hydroxide solution (1.5 molar equivalents relative to L-4-oxalidine) was added as a cyclizing agent, and the mixture was reacted for 20 minutes under heating and reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in this reaction solution, the amount of 3-morpholine carboxylic acid produced was 0.93 g (reaction yield 71%).
When a part of the reaction solution was purified according to Example 1 and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 87.1% e.e. e. Met.

Comparative Example 2
1.84 g of L-4-oxalidine monohydrochloride was dissolved in 10.0 ml of water, and 12.0 g of concentrated hydrochloric acid was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous solution obtained by dissolving 0.83 g of sodium nitrite in 6.0 ml of water was added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 48% (w / w) aqueous sodium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 1.64 g of a 48% (w / w) aqueous sodium hydroxide solution (2.0 molar equivalents relative to L-4-oxalidine) was added as a cyclizing agent, and the mixture was allowed to react for 20 minutes with heating under reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in the reaction solution, the amount of 3-morpholine carboxylic acid produced was 0.92 g (reaction yield 70%).
When a part of the reaction solution was purified according to Example 1 and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 65.9% e.e. e. Met.

Comparative Example 3
1.84 g of L-4-oxalidine monohydrochloride was dissolved in 10.0 ml of water, and 12.0 g of concentrated hydrochloric acid was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous solution in which 0.69 g of sodium nitrite was dissolved in 6.0 ml of water was added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 48% (w / w) aqueous sodium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 2.05 g of a 48% (w / w) aqueous sodium hydroxide solution (2.5 molar equivalents relative to L-4-oxalidine) was added as a cyclizing agent, and the mixture was allowed to react for 20 minutes with heating under reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in this reaction solution, the amount of 3-morpholine carboxylic acid produced was 0.66 g (reaction yield 50%).
When a part of the reaction solution was purified according to Example 1 and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 55.0% e.e. e. Met.

Comparative Example 4
1.84 g of L-4-oxalidine monohydrochloride was dissolved in 10.0 ml of water, and 12.0 g of concentrated hydrochloric acid was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous solution in which 0.69 g of sodium nitrite was dissolved in 6.0 ml of water was added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 48% (w / w) aqueous sodium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 4.20 g of a 48% (w / w) aqueous sodium hydroxide solution (5.1 molar equivalents relative to L-4-oxalidine) was added as a cyclizing agent, and the mixture was allowed to react for 20 minutes under heating and reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in this reaction solution, the amount of 3-morpholine carboxylic acid produced was 0.65 g (reaction yield 50%).
When a part of the reaction solution was purified according to Example 1 and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 25.4% e.e. e. Met.

Comparative Example 5
1.84 g of L-4-oxalidine monohydrochloride was dissolved in 10.0 ml of water, and 12.0 g of concentrated hydrochloric acid was added and stirred. While maintaining the temperature of this aqueous solution at 0 to 5 ° C., an aqueous solution in which 0.69 g of sodium nitrite was dissolved in 6.0 ml of water was added dropwise. After completion of dropping, the solution was stirred for about 4.5 hours while keeping the temperature of the solution at 15 ° C. or lower. Next, a 48% (w / w) aqueous sodium hydroxide solution was added while maintaining the temperature of the solution at 25 ° C. or lower to neutralize the reaction solution to pH 7.0. Subsequently, 9.60 g of a 48% (w / w) aqueous sodium hydroxide solution (11.6 molar equivalents relative to L-4-oxalidine) was added as a cyclizing agent, and the mixture was allowed to react for 20 minutes under heating to reflux. After cooling the reaction solution to room temperature, the pH was adjusted to 6.9 with an aqueous hydrochloric acid solution. As a result of measuring the amount of 3-morpholine carboxylic acid in this reaction solution, the amount of 3-morpholine carboxylic acid produced was 0.22 g (reaction yield 17%).
When a part of the reaction solution was purified according to Example 1 and the optical purity was measured, the optical purity of (R) -3-morpholinecarboxylic acid was 8.4% e.e. e. Met.

Table 1 shows the reaction conditions and results of Examples and Comparative Examples.

As is clear from the results in Table 1, when the molar ratio of the added cyclizing agent to oxalidine is 1.5 or more, the optical purity is 97% e.e. e. It turns out that it falls more drastically.
It can also be seen that the optical purity of (R) -3-morpholinecarboxylic acid synthesized with three cyclizing agents is not significantly different among sodium hydroxide, potassium hydroxide and barium hydroxide. .

Claims (2)

Step A to Step C below, that is, (1) Step A in which L-4-oxalidine is diazotized with a diazotizing agent in an acidic solvent and the diazonium salt solution is adjusted to pH 7.0 with an alkali agent;
(2) To the solution obtained in step A, 0.5 to 1.2 molar equivalents of sodium hydroxide, potassium hydroxide or barium hydroxide are added to L-4-oxalidine to carry out a cyclization reaction, (B) Step B for producing a 3-morpholinecarboxylic acid solution;
(3) Step C, in which the pH of the crude (R) -3-morpholine carboxylic acid solution obtained in Step B is adjusted to 6.5 to 7.0 and then purified using an ion exchange resin;
A process for producing (R) -3-morpholine carboxylic acid having high optical purity, comprising: Purification using an ion exchange resin in Step C is a strong acid cation exchange resin (H ⁺ type), a strong acid cation exchange resin (NH ₄ ⁺ type) or a weak acid cation exchange resin (NH ₄ ⁺ type) and a strong acid. The method for producing (R) -3-morpholine carboxylic acid having high optical purity according to claim 1, wherein a cationic cation exchange resin (Ca ²⁺ type) is sequentially used.