JPH0570614B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing an optically active drug, a pesticide, or an intermediate for a drug or agrochemical.

(Prior art and problems to be solved by the present invention) The conventional method of simultaneously performing lamicization and preferential crystallization involves crystallization from a large amount of organic solvent, resulting in high equipment costs associated with solvent recovery. There were problems such as side reactions originating from the solvent and constraints originating from the boiling point and freezing point of the solvent. In addition, this method is accompanied by operational complexity, as it requires precise determination of the amount of solvent and crystallization temperature in consideration of solubility.

(Means for Solving the Problems) The present inventors investigated methods to solve these problems and complications, and found that there are no other solvents, or even if there are solvents, it is difficult to perform optical resolution. In a state where not all of the compound is dissolved,
It has been found that preferential crystallization is possible while undergoing racemization.

In other words, a racemic form of a compound that can be optically resolved by preferential crystallization and racemized by a base, or a mixture in which one optically active form is present in excess over the other, is promoted by racemization. The inventors have discovered a method in which they are brought into a molten state in the presence of a base, then cooled to a supercooled state, and one of the optically active substances is added to grow and solidify.

Examples of compounds that can be optically resolved by preferential crystallization and can be racemized with a base, which can be subjected to this production method, include the following compounds.

Alkyl esters, especially lower alkyl esters, methyl esters or ethyl esters of α-(6-methoxy-2-naphthyl)propionic acid;
α-phenylpropionate p-nitrophenyl; α-phenylpropionate β-naphthyl;
α-phenylpropionic acid 2-(β-naphthyl)
Ethyl; pantolactone; N-acetyl-2-phenylalanine alkyl ester; N-(substituted phenylmethylidene)-phenylalanine alkyl ester, etc.

Usually, no solvent is used, but when used, preferred solvents include methanol, ethanol, isopropanol, toluene, benzene, hexane, isopropyl ether, etc., or a mixed solvent of two or more of these solvents. Furthermore, a solvent that does not directly participate in the reaction can also be used.

The amount of solvent to be added is less than the amount that completely dissolves the compound to be optically resolved at the melting temperature, and is within the range of forming a two-layer liquid or an emulsion.

Examples of bases used for racemization include the following.

The active hydrogen at the α-position of the alkyl α-(6-methoxy-2-naphthyl)propionate is an alkali metal,
For example, salts substituted with sodium or potassium (hereinafter referred to as salts); alkali metal hydrides (e.g., sodium hydride, potassium hydride) or alkali metal (e.g., sodium, potassium); alkali metal alkoxides (e.g., lower alkoxides of sodium, potassium); alkaline earth metal alkoxides (e.g., lower alkoxides of calcium); diazabicyclononene (DBN); diazabicycloundecene (DBU ); quaternary ammonium alkoxide, etc.

When using an alkoxide among the above bases, it is not necessary to use an alkoxide corresponding to the alkyl of the alkyl ester to be optically resolved, but since transesterification may be involved, use an alkoxide corresponding to the alkyl of the alkyl ester. is desirable.

When heated to a molten state, it becomes a transparent or translucent liquid, and in some cases, upon standing, a two-layered liquid mixture is obtained.

Next, one of the optically active substances is added, and the same optically active substance is grown and solidified.

As for the optically active substance to be added, it is preferable to use one having an optical purity of 90% or more, since the optical purity of the crystallized crystal will be higher if a crystal with high optical purity is used. It is possible to add the material as long as the addition temperature is below the melting temperature, but if it is too close to the melting temperature, the melting temperature may be exceeded, and even the added crystals may melt, increasing the possibility of racemization. Furthermore, if the temperature is too far away from the melting temperature, crystallization will proceed rapidly, solidification will occur without sufficient racemization in the melted portion, and the optical purity of the resulting crystal will tend to be low.

Furthermore, when a solvent is used, there is a tendency for the melting temperature to be lower than when a solvent is not used, and a tendency for the difference (width) between the melting temperature and the temperature at which it is almost completely solidified to be wider.

In order to efficiently operate the method of the present invention, it is important to adjust the racemization rate, solidification rate, and crystallization rate. If the racemization rate is slower than the solidification rate and crystallization rate, crystallization of optically active substances opposite to the seed crystals will increase, so in this case, to increase the racemization rate, increase the amount of racemization agent or change the solidification initiation temperature In order to reduce the rise and/or solidification rate, it is necessary to moderate the cooling rate and the degree of supersaturation.

The amount of the racemizing agent used may be an amount that can change the melting and solidification of the racemate within the system.

The molar ratio of the racemizing agent to the compound to be optically resolved is, for example, α-(6-methoxy-2
- When alkyl naphthyl propionate is racemized with sodium alkoxide, [racemizing agent]/[compound to be optically resolved) = 0.01~
A range of 10 is preferred.

(Effects of the present invention) Since melting-solidification is used, operation at a higher temperature is possible and racemization is faster than when melting-crystallization is used. For this reason, compared to the conventional method of preferential crystallization by dissolution-crystallization in the presence of a racemizing agent, which uses a large amount of solvent, it is possible to reduce the amount of racemizing agent used, shorten operating time, and reduce the amount of solvent. It has become possible to improve volumetric efficiency and reduce solvent recovery costs.

(Example) Examples are shown below to explain the method of the present invention in more detail. Note that the method of the present invention is not limited to these Examples.

Example 1 Sodium methoxide under an argon atmosphere
0.77g and dl-α-(6-methoxy-2-naphthyl)
4.62 g of methyl propionate was heated to 70° C. and molten into an emulsion in 15 minutes. The temperature of the bath was lowered to 67°C, and after stirring for 5 minutes, d-α-(6-methoxy-2-
Naphthyl) methyl propionate 0.10g {[α] ²⁵ _D +
77.2° (c = 1.0, CHCl ₃ ) 98.3%ee)
It was slowly cooled down to 60°C over a period of time. The pale yellow content that solidified throughout was further cooled to 0°C.
After dropping 12 g of water at ℃, 30 g of toluene was added and the liquid was separated.

After washing with dilute hydrochloric acid and water, distill off the toluene.
4.62 g of almost colorless crystals were obtained.

{[α] ²⁵ _D +35.8° (c=1.19, CHCl ₃ ) 45.6%e.
e.)}. The yield of methyl d-α-(6-methoxy-2-naphthyl)propionate excluding the added crystal content was 43.5% (however, ±78.5° was taken as 100% ee). Yield: 87.0 based on methyl -(6-methoxy-2-naphthyl)propionate
It was %.

Example 2 Sodium methoxide under argon atmosphere
1.54g and dl-α-(6-methoxy-2-naphthyl)
9.24 g of methyl propionate at 70 to 72°C for 15
The mixture was melted into an emulsion over a period of minutes. The temperature of the bath was lowered to 67°C, and after stirring for 5 minutes, 0.20 g of methyl d-α-(6-methoxy-2-naphthyl)propionate was added.
{[α] ²⁵ _D +77.2° (c=1.0, CHCl ₃ ) 98.3%ee)
} was added and slowly cooled to 60°C over 7 hours.
After cooling to 0℃ for another 10 hours, 0℃
20 g of water was added dropwise, 120 g of toluene was added, and the liquid was separated.

After washing with dilute hydrochloric acid and water, distill off the toluene.
9.00 g of nearly colorless crystals were obtained.

{[α] ²⁵ _D +50.7° (c=1.04, CHCl ₃ ) 64.6%e.
e.)}. The yield of methyl d-α-(6-methoxy-2-naphthyl)propionate excluding the added crystal component was 60.7% (however, ±78.5° was taken as 100% ee).
Yield based on methyl d-α-(6-methoxy-2-naphthyl)propionate in the starting material
It was 121.4%.

Example 3 Under an argon atmosphere, 3.50 g of a methanol solution of sodium methoxide (24%, w/w) and dl-α
11.00 g of methyl -(6-methoxy-2-naphthyl)propionate was brought to a molten state at 68-70°C for 5 minutes. This product was an emulsion when stirring, but became a two-layered liquid when stirring was stopped. The temperature of the bath was cooled to 60℃, and after stirring for 5 minutes, d-α-
Methyl (6-methoxy-2-naphthyl)propionate 0.40 g {[α] ²⁵ _D +77.2° (c=1.0, CHCl ₃ )
98.3%ee)} and leave it at 54℃ for 12 hours.
Cooled to . The completely solidified pale yellow content was cooled to 0℃, poured into 10g of ice water, and then toluene.
After adding 65 g and stirring thoroughly, the liquid was separated.

After washing with dilute hydrochloric acid and water, distill off the toluene.
11.2 g of colorless crystals were obtained.

{[α] ²⁵ _D +59.1° (c=1.39, CHCl ₃ ) 75.3%e.
e.)}. The yield of methyl d-α-(6-methoxy-2-naphthyl)propionate excluding the added seed crystals was 73.2% (however, ±78.5° was taken as 100% ee).
Yield based on methyl d-α-(6-methoxy-2-naphthyl)propionate in the starting material
It was 146.4%.

Example 4 Under an argon atmosphere, 2.50 g of a methanol solution of sodium methoxide (24%, w/w) and dl-α
10.80 g of methyl -(6-methoxy-2-naphthyl)propionate was heated to 70°C and brought to a molten state in 10 minutes. The two-layered liquid was cooled to 60°C with stirring, and after 5 minutes, 0.40 g of methyl d-α-(6-methoxy-2-naphthyl)propionate {[α] ²⁵ _D +
77.2° (c = 1.0, CHCl ₃ ) 98.3% ee)},
The mixture was stirred at 60°C for 30 minutes and slowly cooled to 56°C over an additional 2 hours. The completely solidified, almost colorless contents were cooled to 0° C. and treated in the same manner as in Example 3 to obtain 11.2 g of colorless crystals.

{[α] ²⁵ _D +61.3° (c=1.43, CHCl ₃ ) 78.1%e.
e.)}. The yield of methyl d-α-(6-methoxy-2-naphthyl)propionate excluding the added seed crystals was 75.9% (however, ±78.5° was taken as 100% ee).
Yield based on methyl d-α-(6-methoxy-2-naphthyl)propionate in the starting material
It was 151.8%.

In addition, 10.0g of the obtained crystals was added to ethanol.
Recrystallization was performed using 54.0 g of the crystals to obtain 7.74 g of fine flaky colorless crystals. This one is {[α] ²⁵ _D +76.1°(
c.
= 1.12, CHCl ₃ )97%ee)}, d−α−(6−
Methyl methoxy-2-naphthyl)propionate was obtained with a recrystallization yield of 99.1%.

The physical property values such as nmr and MS were consistent with those of the standard product.

Example 5 Under an argon atmosphere, 2.00 g of a methanol solution of sodium methoxide (24%, w/w) and dl-α
6.29 g of methyl -(6-methoxy-2-naphthyl)propionate was heated to 70°C and brought to a molten state in 10 minutes. The two-layered liquid was cooled to 60°C with stirring, and after 5 minutes, 0.23 g of methyl d-α-(6-methoxy-2-naphthyl)propionate {[α] ²⁵ _D +77.2°
(c=1.0, CHCl ₃ ) 98.3%ee)} and heated to 60°C.
The mixture was stirred for 1 hour and 15 minutes. The completely solidified colorless contents were cooled to 0°C, 10g of water at 0°C and then 52g of toluene were added dropwise, stirred thoroughly, and then separated.

After washing with dilute hydrochloric acid and water, distill off the toluene.
6.53 g of colorless crystals were obtained.

{[α] ²⁵ _D +48.3° (c=1.70, CHCl ₃ ) 61.5%e.
e.)}. The yield of methyl d-α-(6-methoxy-2-naphthyl)propionate excluding the added seed crystals was 60.2% (±78.5° was defined as 100% ee).
Yield based on methyl d-α-(6-methoxy-2-naphthyl)propionate in the starting material
It was 120.4%.

Example 6 Under an argon atmosphere, 5.00 g of an ethanolic solution of sodium ethoxide (14.4%, w/w) and dl-
5.00 g of ethyl α-(6-methoxy-2-naphthyl)propionate was heated to 57° C. and brought into a molten state for 5 minutes. The two-layered liquid was cooled to 46°C with stirring, and after 5 minutes, 0.20 g of ethyl d-α-(6-methoxy-2-naphthyl)propionate {[α] ²⁵ _D +
48.4° (c=1.0, CHCl ₃ ) 99.6%ee, however, ±48.6°
was set as 100%ee. )} for 3 hours.
It was slowly cooled to 44°C. The nearly fully solidified contents were further cooled to 34°C over a period of 2 hours, and then to 0°C. Drop 15g of water at 0℃,
Next, 25g of toluene was added dropwise to separate the liquids, washed with dilute hydrochloric acid and then with water, and the toluene was distilled off to give 5.21
A pale yellow crystal of g was obtained.

{[α] ²⁵ _D +40.5° (c=1.50, CHCl ₃ ) 83%e.
e.)}. The yield of ethyl d-α-(6-methoxy-2-naphthyl)propionate excluding the added seed crystals was 82.8% (however, ±48.6° was defined as 100% ee).
Yield based on ethyl d-α-(6-methoxy-2-naphthyl)propionate in the starting material
It was 165.6%.

The physical property values such as nmr and MS were consistent with those of the standard product.

Claims (1)

[Claims] 1 α-(6-Methoxy-2-naphthyl)alkyl propionate, N-acetyl-2-phenylalanine alkyl, N-(substituted phenylmethylidene)
- A racemic form of an ester compound selected from alkyl phenylalanine, p-nitrophenyl of α-phenylpropionic acid, β-naphthyl and 2-(β-naphthyl)ethyl, or one optically active form is better than the other optically active form. The mixture present in excess is treated with alkali metal hydride, alkali metal, α-
(6-methoxy-2-naphthyl)alkyl propionate, N-acetyl-2-phenylalanine alkyl, N-(substituted phenylmethylidene)-phenylalanine alkyl, p-nitrophenyl of α-phenylpropionic acid, β-naphthyl and 2-
Salts in which the active hydrogen at the α position of an ester compound selected from (β-naphthyl)ethyl is substituted with an alkali metal, alkali metal alkoxides, alkaline earth metal alkoxides, diazabicyclononene, diazabicycloundecene, quaternary ammonium A method for producing an optically active substance, which comprises bringing it into a molten state in the presence of a base selected from alkoxides, cooling it to a supercooled state, adding one of the optically active substances, and growing and solidifying it. 2 The ester compound is α-(6-methoxy-2
-naphthyl) alkyl propionate. 3 The ester compound is α-(6-methoxy-2
-naphthyl) lower alkyl propionate. 4 α-(6-methoxy-2-naphthyl)alkyl propionate, N-acetyl-2-phenylalanine alkyl, N-(substituted phenylmethylidene)
- A racemic form of an ester compound selected from alkyl phenylalanine, p-nitrophenyl of α-phenylpropionic acid, β-naphthyl and 2-(β-naphthyl)ethyl, or one optically active form is better than the other optically active form. The mixture present in excess is treated with alkali metal hydride, alkali metal, α-
(6-methoxy-2-naphthyl)alkyl propionate, N-acetyl-2-phenylalanine alkyl, N-(substituted phenylmethylidene)-phenylalanine alkyl, p-nitrophenyl of α-phenylpropionic acid, β-naphthyl and 2-
Salts in which the active hydrogen at the α position of an ester compound selected from (β-naphthyl)ethyl is substituted with an alkali metal, alkali metal alkoxides, alkaline earth metal alkoxides, diazabicyclononene, diazabicycloundecene, quaternary ammonium After bringing it to a molten state in the presence of a base selected from alkoxides, cooling it to a supercooled state, adding one of the optically active substances, growing and solidifying it, and then crystallizing it from the solution part. A method for producing a characteristic optically active substance. 5 The ester compound is α-(6-methoxy-2
-naphthyl) propionic acid. 6 The ester compound is α-(6-methoxy-2
-naphthyl)propionic acid (lower alkyl).