JP2009242288A - METHOD FOR PRODUCING N-ALKOXYCARBONYL-tert-LEUCINE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find a method for efficiently and stably producing an N-alkoxycarbonyl-tert-leucine of high quality by a simple operation. <P>SOLUTION: The N-alkoxycarbonyl-tert-leucine is produced by causing an N-alkoxycarbonylation agent in an amount of at least 0.90 molar time and at most 1.00 molar time the amount of tert-leucine to react with tert-leucine in the presence of water while controlling the pH of the solution within the range of 9-13 by using a basic reagent. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a process for producing N-alkoxycarbonyl-tert-leucine useful as an intermediate for pharmaceuticals or agricultural chemicals.

As a method for producing N-alkoxycarbonyl-tert-leucine, the following two methods are already known.
1) A method for producing N-alkoxycarbonyl-tert-leucine using an excess of an N-alkoxycarbonylating agent while maintaining pH = 11-13. (Patent Document 1).
2) By adding 1.00 equivalent of N-alkoxycarbonylating agent to a strongly basic aqueous solution of tert-leucine to which an excess amount of sodium hydroxide has been added in advance, N-alkoxycarbonyl-tert-leucine How to manufacture. (Patent Document 2).
JP 2004-175703 A Special table 2001-501216

  The N-alkoxycarbonylation reaction is a reaction that proceeds under basic conditions. However, as the reaction proceeds, the amino group is protected, and an acidic compound such as hydrochloric acid or carbonic acid is by-produced. The pH of the reaction solution tends to decrease. Therefore, in order to maintain the reactivity of the amino group, it is necessary to control the reaction pH by using a base together.

  As a method for producing N-alkoxycarbonyl-tert-leucine while carrying out pH control, for example, the method of Patent Document 1 is known, but in this Patent Document 1, it is controlled in a narrow range of pH = 11-13. It is said that the yield and quality are drastically lowered when the pH is exceeded.

  However, it is not easy to perform pH control in a narrow range, and this is a major issue in stable production in fields requiring high quality such as pharmaceuticals or agricultural chemicals.

  On the other hand, an excessive amount of base reported in Patent Document 2 is added in advance to keep the pH of the solution strong, while using a theoretical equivalent of an N-alkoxycarbonylating agent, N-alkoxycarbonyl- Regarding the method for producing tert-leucine, according to the study by the present inventors, although the operation method is simple, the reaction is completely completed by the decomposition of the N-alkoxycarbonylating agent under strongly basic conditions. Therefore, it was found that the yield was low and it was not necessarily an efficient production method.

  As a result of intensive studies on these technical problems, the present inventors have found that in the production of N-alkoxycarbonyl-tert-leucine, the amount of N-alkoxycarbonylating agent used is closely related to the by-product of impurities. In addition, the present inventors have surprisingly found that the effect of the amount of the N-alkoxycarbonylating agent used is exhibited when the pH range of 9 to 13 is maintained by adding a basic reagent. That is, by controlling the amount of N-alkoxycarbonylating agent used to the theoretical equivalent and controlling the pH in the range of 9 to 13 with a basic pH adjuster, high yield and high quality can be achieved with a simple operation. It has been found that N-alkoxycarbonyl-tert-leucine can be produced.

  That is, the present invention provides an N-alkoxycarbonylating agent having a molar ratio of 0.90 times to 1.00 times moles with respect to tert-leucine while controlling the pH of the solution within a range of 9 to 13 using The present invention relates to a process for producing N-alkoxycarbonyl-tert-leucine, which is characterized by reacting in the presence of water.

  According to the method of the present invention, N-alkoxycarbonyl-tert-leucine can be produced with high yield and high quality by a simple operation. Therefore, the method according to the present invention can be suitably used for industrial production.

  The optical purity of tert-leucine used in the present invention is not particularly limited, and may be an optically active form, a racemic form, or a mixture of L form and D form in any ratio. In addition, according to the method concerning this invention, the optical purity of the N-alkoxycarbonyl-tert-leucine obtained is normally hold | maintained.

  The N-alkoxycarbonylation reaction in the present invention is not particularly limited as long as it is carried out in the presence of water, only water, a mixed system of water and an organic solvent compatible with water, an organic solvent not compatible with water and water. Any of these two-phase systems can be suitably used.

  As an organic solvent that can be used by mixing with water, from the viewpoint of chemical properties, it is preferable that the reactivity with tert-leucine or an N-alkoxycarbonylating agent is poor under basic conditions. There are no particular restrictions on the physical properties such as the melting point. Whether or not it can be used can be easily determined by a simple experiment. Examples of usable solvents include acetonitrile, acetone, tetrahydrofuran, and toluene.

  There is no restriction | limiting in particular about the amount of solvent to be used, either, it may react from the state which tert-leucine completely melt | dissolved, or it may react from the state which is not melt | dissolved completely. In addition, it is not always necessary to use an amount of solvent that can completely dissolve the produced N-alkoxycarbonyl-tert-leucine. However, in order to obtain suitable reactivity, production efficiency, and fluidity of the liquid, the amount of the solvent is preferably 1.0 to 20.0 times the weight of tert-leucine, Preferably, it is 2.0 times weight or more and 15.0 times weight or less.

  Further, from the viewpoint of coexisting substances, inorganic salts may coexist in addition to the organic solvent. Examples of inorganic salts that can coexist include sodium sulfate, sodium chloride, sodium hydrogen carbonate, sodium sulfate, and ammonium chloride, but are not limited to these. You can judge.

  Although it does not restrict | limit especially as reaction temperature, Generally, it selects in the range of the freezing point of a solution-boiling point, Preferably it is 0 to 30 degreeC. The boiling point of the solution generally depends on the pressure, but the pressure during the reaction can be selected from reduced pressure and increased pressure other than normal pressure. These can be easily set by a simple experiment.

  The N-alkoxycarbonylating agent used in the reaction is not particularly limited as long as it is a compound capable of N-alkoxycarbonylating an amino group of an amino acid, but is preferably an alkyl ester of chloroformate or a dialkyldicarbonate, more preferably Is a chloroformate alkyl ester having 1 to 10 carbon atoms in the alkyl group or a dialkyl dicarbonate. Specific examples of the compound include methyl chloroformate, ethyl chloroformate, benzyl chloroformate, di-tert-butyl- Examples include dicarbonate and dimethyl-dicarbonate. The N-alkoxycarbonylating agent may be used as it is or as an organic solvent solution.

  In the present invention, high yield and high quality N-alkoxycarbonyl-tert-leucine can be achieved by suppressing the amount of N-alkoxycarbonylating agent used to the theoretical equivalent and controlling the pH between 9-13. Is the most important factor to manufacture. Details will be described below.

  In the method according to the present invention, the pH during the reaction is controlled in the range of 9-13. When the pH is lower than 9, not only the reactivity of tert-leucine is remarkably lowered and the reaction is not completed, but also the side reaction proceeds remarkably even if the amount of N-alkoxycarbonylating agent is limited. This is because the yield and quality of N-alkoxycarbonyl-tert-leucine are reduced. On the other hand, even when the reaction pH is maintained at 9 or more, when the pH exceeds 13, the decomposition of the N-alkoxycarbonylating agent becomes remarkable and the reaction is not completed. From the viewpoint that a more stable product is easily obtained, the pH is preferably 9 to 11. In commercial scale production, it is preferable to control the pH around 10-11, and even if it is out of the range, the quality and yield will not be affected under the conditions of the present invention. Therefore, stable production is possible.

  As a basic agent used for pH adjustment, an inorganic base or a tertiary amine is used, but an inorganic base is particularly preferably used from the viewpoint of versatility.

  When using an inorganic base, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate, etc. Examples of usable compounds include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate from the viewpoint of basic strength. On the other hand, when a tertiary amine is used, triethylamine, triisopropylamine, pyridine and the like can be mentioned.

  These bases may be used as they are or dissolved in water or an organic solvent. However, in order for the added base to be quickly dispersed in the reaction solution, it may be used in a solution state. Preferably, the solid basic agent is preferably dissolved in water or an organic solvent. Needless to say, a liquid basic agent can be dissolved in water or an organic solvent and used.

  From the viewpoint of chemical properties, the organic solvent that dissolves the basic reagent may not react with the basic reagent, and may have poor reactivity with the tert-leucine or N-alkoxycarbonylating agent under basic conditions. Although preferred, there are no particular restrictions on physical properties such as boiling point and melting point. Whether or not it can be used can be easily determined by a simple experiment. Examples of usable solvents include acetonitrile, acetone, tetrahydrofuran, and toluene.

  When the basic agent is dissolved in water or an organic solvent and used, its concentration is not particularly limited, but it is preferably a high concentration from the viewpoint of production efficiency. In particular, sodium hydroxide, potassium hydroxide, and potassium carbonate are readily soluble in water and can be used as a high-concentration aqueous solution. In this case, it is preferably used at a concentration of 30% by weight to 50% by weight. .

  About the method of adding a basic agent in order to maintain pH, there is no restriction | limiting in particular, For example, maintaining a pH within the range by adding a basic agent each time from the start of addition of N-alkoxycarbonylating agent. Even when the reaction is complete, the N-alkoxycarbonylating agent and the basic agent may be added alternately, or the N-alkoxycarbonylating agent and the basic agent may be added simultaneously.

  The amount of the N-alkoxycarbonylating agent used as another factor requiring control will be described below.

  In the method according to the present invention, the N-alkoxycarbonylating agent has a ratio of 0.90 to 1.00 mol, more preferably 0.95 to 0.99 mol, relative to tert-leucine. The reaction is performed using If the N-alkoxycarbonylating agent is present in excess of tert-leucine, the side reaction proceeds even if the reaction pH is controlled within the above range of 9 to 13, and the N-alkoxy-tert-leucine is recovered. Rate and quality are reduced. In addition, an excessive N-alkoxycarbonylating agent or a decomposition product of the N-alkoxycarbonylating agent is mixed as an impurity. On the other hand, if the amount of N-alkoxycarbonylating agent used is small, the by-production of these impurities is suppressed, but if the amount is extremely smaller than the theoretical equivalent, the yield decreases. In addition, this decrease in yield leads to contamination of unreacted tert-leucine, which is disadvantageous in terms of quality.

  The addition rate of the N-alkoxycarbonylating agent is not particularly limited as long as the pH can be controlled, but from the viewpoint of production efficiency, it is preferably within 50 hours, more preferably within 1 hour to 20 hours. .

  As a stirring speed at the time of reaction, it is sufficient that the N-alkoxycarbonylating agent and the basic reagent are stirred to such an extent that they do not become excessive locally.

  The stirring time after addition of the N-alkoxycarbonylating agent is not particularly limited as long as a sufficient time is set for completion of the reaction, but is preferably within 50 hours, more preferably from the viewpoint of production efficiency. Is between 1 hour and 20 hours.

  The reaction solution containing N-alkoxy-tert-leucine thus obtained is subjected to an extraction operation with an organic solvent under an appropriate pH, if necessary, so that inorganic salts and tert in the reaction solution can be obtained. -Leucine and water-soluble organic compounds can be removed. Moreover, N-alkoxy-tert-leucine can be isolated as a high-purity crystal | crystallization by using for the well-known crystallization operation the obtained reaction liquid or extract. Examples of the operation for isolating as crystals include, for example, a method in which the produced N-alkoxy-tert-leucine is extracted into an aromatic hydrocarbon solvent under acidic conditions and then concentrated and cooled and crystallized. Is mentioned.

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

Example 1
To an aqueous solution (72.4 g) containing L-tert-leucine (13.2 g, 0.10 mol), a 15 wt% sodium hydroxide aqueous solution was added to adjust the pH to 13.0, and then controlled to 25 ° C. or lower. Methyl chloroformate (9.52 g, 0.10 mol, 1.00 equiv) was added slowly. At this time, the pH decreased as methyl chloroformate was added, but the pH of the solution was maintained at 10.0-12.8 by adding a 15 wt% aqueous sodium hydroxide solution in parallel. After completion of the addition of methyl chloroformate, the mixture was stirred for 2 hours, and then analyzed for yield and quality using HPLC.
Yield: 98%, reaction selectivity: 100%

In the examples, the yield was calculated using the following calculation formula.
Yield (%) = (total amount of produced N-alkoxycarbonyl-L-tert-leucine) × 100 / (total amount of L-tert-leucine used).

On the other hand, the reaction selectivity is the ratio of the obtained N-alkoxycarbonyl-L-tert-leucine to the L-tert-leucine consumed in the reaction. The higher the reaction selectivity, the more the reaction selectivity is derived from tert-leucine. It represents that impurities are suppressed, and was calculated using the following calculation formula.
Reaction selectivity (%) = (yield) × 100 / ((total amount of L-tert-leucine used) − (residual L-tert-leucine amount))

  In addition, the quantitative analysis of N-alkoxycarbonyl-tert-leucine was performed using HPLC. As a column, Waters Symmetry C18 (3.5 μm, 150 mm × 4.6 mm id) was used, and as a mobile phase, 0.1 wt% aqueous phosphoric acid solution was used as solution A, and acetonitrile was used as solution B. Used in ratio. The analysis was performed using a flow rate of 1 ml / min, a column temperature of 35 ° C., and a UV (210 nm) detector as the detector.

For quantitative analysis of L-tert-leucine, CAPCELLPAKSCX (250 mm X 4.6 mm id) was used as the column, and phosphate buffer (pH = 3.3) and acetonitrile were used in a volume ratio as the mobile phase. Analysis was performed using a solution mixed at 95: 5, a flow rate of 1.0 mL / min, a column temperature of 35 ° C., and a differential refractometer as a detector.
Similar calculations were performed in the following examples.

(Example 2)
An aqueous solution (303.37 g) containing L-tert-leucine (30.03 g, 0.23 mol) was cooled to 10 ° C., and the pH of the solution was adjusted to 9.0-9. While controlling at 5, methyl chloroformate (21.63 g, 0.23 mol, 1.00 equiv) was added slowly. After completion of the addition, the mixture was subsequently stirred at 10 ° C. for 12 hours, and then the yield and the amount of impurities by-products were analyzed using HPLC.
Yield: 97%, reaction selectivity: 99%

(Examples 3 to 6)
The same procedure as in Example 2 was conducted except that the pH was controlled to 9.5-10.0, 10.0-10.5, 10.5-11.0, 9.0-13.0.

(Example 7)
The same procedure as in Example 6 was performed except that the aqueous solution containing L-tert-leucine was cooled to 20 ° C.
Yield: 97%, reaction selectivity: 99%

(Example 8)
The same procedure as in Example 6 was performed except that D-tert-leucine was used instead of L-tert-leucine.
Analysis of D-tert-leucine was carried out in the same manner as L-tert-leucine.
Yield: 97%, reaction selectivity: 99%

Example 9
The same procedure as in Example 6 was performed except that racemic tert-leucine was used instead of L-tert-leucine.

Racemic tert-leucine was analyzed in the same manner as L-tert-leucine.
Yield: 97%, reaction selectivity: 98%

(Comparative Example 1)
L-tert-leucine (85.0 g, 0.65 mol) was dissolved in a 15% by weight aqueous sodium hydroxide solution (191.7 g), and further maintained at 5 to 15 ° C. while maintaining methyl chloroformate (68.9 g, 0.73 mol). , 1.13 equivalents) was added dropwise to the reaction mixture over 1 hour. In that case, 15 mass% sodium hydroxide was added suitably, and it reacted, keeping the pH of a reaction liquid at 9.0-9.5. After completion of the dropwise addition of methyl chloroformate, the mixture was further stirred at 20 ° C. for 1 hour.
Yield: 90%, reaction selectivity: 90%

(Comparative Example 2)
It carried out similarly to the comparative example 1 except having reacted with pH 10.0-10.5.
Yield: 93%, reaction selectivity: 93%

(Comparative Example 3)
The reaction was performed in the same manner as in Comparative Example 1 except that the reaction was carried out at pH 13.5-14.0.
Yield: 82%, reaction selectivity: 97%

(Comparative Example 4)
After adding 9.1 ml of dioxane to 29.3 g of an aqueous solution containing L-tert-leucine (2.18 g, 0.017 mol) and sodium hydroxide (2.35 g, 0.059 mol), methyl chloroformate ( 1.57 g, 0.017 mol, 1.00 equivalent) was added slowly. After the addition, the temperature was raised to 60 ° C. and stirred for 14 hours. When the obtained solution was analyzed by HPLC, the amount of N-methoxycarbonyl-tert-leucine produced was only 1.0 g. In addition, pH of the obtained solution showed pH13.9 at 30 degreeC. The pH at the start of the reaction also exceeded 14.
Yield: 33%, reaction selectivity: 63%

(Example 10)
An aqueous solution (101.06 g) containing L-tert-leucine (10.36 g, 0.079 mol) was cooled to 5 ° C., and the pH of the solution was adjusted to 9.0-9. While controlling at 5, benzyl chloroformate (13.49 g, 0.079 mol, 1.00 equiv) was added slowly. After completion of the addition, the mixture was subsequently stirred at 20 ° C. for 14 hours, and then the yield and the amount of impurities by-products were analyzed using HPLC.
Yield: 96%, reaction selectivity: 97%

(Examples 11 and 12)
The same procedure as in Example 10 was performed except that the pH during the reaction was controlled to 10.0 to 10.5 and 9.0 to 13.0.

(Example 13)
The same operation as in Example 12 was performed except that the aqueous solution containing L-tert-leucine was cooled to 20 ° C.
Yield: 97%, reaction selectivity: 98%

(Example 14)
The same procedure as in Example 12 was performed except that D-tert-leucine was used instead of L-tert-leucine.
Yield: 97%, reaction selectivity: 98%

(Example 15)
The same procedure as in Example 12 was performed, except that racemic tert-leucine was used instead of L-tert-leucine.
Yield: 97%, reaction selectivity: 99%

(Comparative Example 5)
The same procedure as in Comparative Example 1 was performed except that benzyl chloroformate was used instead of methyl chloroformate.
Yield: 90%, reaction selectivity: 90%

(Comparative Example 6)
It carried out similarly to the comparative example 5 except having maintained pH at the time of reaction at 10.0-10.5.
Yield: 94%, reaction selectivity: 94%

(Comparative Example 7)
The same procedure as in Example 10 was performed except that the pH during the reaction was maintained at 14.0 or higher.
Yield: 86%, reaction selectivity: 95%

(Example 16)
The same procedure as in Example 6 was performed except that ethyl chloroformate was used instead of methyl chloroformate.
Yield: 97%, reaction selectivity: 98%

(Example 17)
An aqueous solution (250.5 g) containing L-tert-leucine (20.5 g, 0.16 mol) was cooled to 7 ° C., and 16.5 g of 48% by weight sodium hydroxide was added thereto. While maintaining 4-10.8, di-tert-butyl-dicarbonate (34.92 g, 0.16 mol, 1.00 equiv) was added slowly. After completion of the addition, the mixture was subsequently stirred at 20 ° C. or lower for 14 hours, and then the yield and the amount of impurity by-products were analyzed using HPLC.
Yield: 96%, reaction selectivity: 98%

(Example 18)
The same procedure as in Example 17 was performed except that D-tert-leucine was used instead of L-tert-leucine.
Yield: 97%, reaction selectivity: 97%

Example 19
The same procedure as in Example 17 was performed except that racemic tert-leucine was used instead of L-tert-leucine.
Yield: 96%, reaction selectivity: 98%

(Comparative Example 8)
The same procedure as in Comparative Example 1 was performed except that di-tert-butyl-dicarbonate was used instead of methyl chloroformate and the temperature was maintained at 20 to 30 ° C.
Yield: 89%, reaction selectivity: 89%

(Comparative Example 9)
It carried out similarly to the comparative example 8 except having maintained pH at the time of reaction at 10.0-10.5.
Yield: 92%, reaction selectivity: 92%

Claims (7)

While controlling the pH of the solution within a range of 9 to 13 using a basic reagent, 0.90-fold mol to 1.00-fold mol of N-alkoxycarbonylating agent is present in water relative to tert-leucine. A process for producing N-alkoxycarbonyl-tert-leucine, which is characterized by acting under the following conditions. The method for producing N-alkoxycarbonyl-tert-leucine according to claim 1, wherein the pH when the tert-leucine and the N-alkoxycarbonylating agent are allowed to act is 9 or more and 11 or less. The method for producing N-alkoxycarbonyl-tert-leucine according to claim 1 or 2, wherein the N-alkoxycarbonylating agent is an alkyl ester of chloroformate or a dialkyl dicarbonate. 4. The production of N-alkoxycarbonyl-tert-leucine according to claim 3, wherein the N-alkoxycarbonylating agent is a chloroformic acid alkyl ester or dialkyl dicarbonate having 1 to 10 carbon atoms in the alkyl group. Law. The N-alkoxycarbonyl-tert of claim 4, wherein the N-alkoxycarbonylating agent is one of methyl chloroformate, ethyl chloroformate, benzyl chloroformate, and di-tert-butyl-dicarbonate. -Process for producing leucine. The N-- agent according to any one of claims 1 to 5, wherein the basic agent used for adjusting the pH of the reaction solution is any one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Process for producing alkoxycarbonyl-tert-leucine. The method for producing N-alkoxycarbonyl-tert-leucine according to claim 6, wherein the basic reagent is used as an aqueous solution of 30 wt% to 50 wt%.