JPS584707B2 - Method for producing optically active phenylglycines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active phenyl or substituted phenylglycines from optically active N-carbamoyl (phenyl or substituted phenyl)glycines without changing their steric configuration.

One of the inventors of the present invention first catalytically acted on 5-(phenyl or substituted phenyl)hydantoins with a microorganism capable of asymmetrically cleaving and hydrolyzing the hydantoin ring. Discovered a method for producing glycine (phenyl or substituted phenyl) (Patent application 1983)
-011575 and Japanese Patent Application No. 51-145748).

If the carbamoyl group of these D-N-carbamoyl (phenyl or substituted phenyl) glycines can be hydrolyzed without changing their optical activity, D-N-carbamoyl (phenyl or substituted phenyl) glycines can be used as important raw materials for semi-synthetic penicillins and semi-synthetic cephalosporins. - phenyl or substituted phenylglycines may be advantageously prepared.

As an example of a method for converting optically active N-carbamoyl phenylglycines to the corresponding optically active phenylglycines, JP-A-51-127003 describes a cation exchange resin (
A method is disclosed in which D-N-carbamoylphenylglycine is reacted with sodium nitrite in the presence of H10).

However, even if such a method is attempted to be implemented industrially, there are problems with losses due to mechanical damage to the ion exchange resin, and the process of transferring the ion exchange resin to another container in order to elute the D-phenylglycine produced. There are many difficulties, such as problems that require

The present inventors conducted various studies on the method of reacting optically active N-carbamoyl (phenyl or substituted phenyl) glycines with nitrous acid, and found that it is industrially practicable and yields optically active phenyl or substituted phenyl glycines. The present invention has been completed by discovering reaction conditions that can obtain a high yield.

That is, the present invention is based on the general formula (wherein R1, R2, R3 and R4 are each a hydrogen atom,
Represents a halogen atom, hydroxy group, lower alkoxy group or lower alkyl group.

) is reacted with approximately the same amount of nitrous acid in an aqueous medium in which a strong mineral acid with a concentration of 0.4N or more is present. do.

General formula (wherein Rl, R2, R3 and R4 are the same as in the above formula.

) is a method for producing optically active phenyl or substituted phenylglycines.

This reaction can be expressed as follows.

The optically active N-carbamoyl (phenyl or substituted phenyl) glycine used in the present invention is usually in the D form for the purpose stated at the beginning.

However, it is naturally possible to apply the method of the present invention to L-form N-carbamoyl (phenyl or substituted phenyl) glycines to produce L-phenyl or substituted phenyl glycines.

Optically active N-carbamoyl (phenyl or substituted phenyl) glycines include N-carbamoyl phenylglycine, in which the phenyl nucleus is a halogen atom, a hydroxy group, a lower alkoxy group (having 1 to 4 carbon atoms), or a lower alkyl group. Various derivatives substituted with (1 to 4 carbon atoms) are included.

By applying the method of the present invention to these optically active N-carbamoyl (phenyl or substituted phenyl) glycines, the carbamoyl group is eliminated without racemization, and the corresponding optically active phenyl or substituted phenyl Glycines can be obtained.

The optically active phenyl or substituted phenylglycines that can be produced by the method of the present invention are phenylglycine and various substituted phenylglycines having the above-mentioned substituents.

Specific examples of these substituted phenylglycines include mono-substituted ones such as 2=chlorophenylglycine, 3
-chlorophenylglycine, 4-chlorophenylglycine, 2-fluorophenylglycine, 3-fluorophenylglycine, 4-fluorophenylglycine, 2-iodophenylglycine, 3-iodophenylglycine,
4-iodophenylglycine, 2-hydroxyphenylglycine, 3-hydroxyphenylluglycine, 4-hydroxyphenylglycine, 2-methoxyphenylglycine, 3-methoxyphenylglycine, 4-methoxyphenylglycine, There are 2-methylphenylglycine, 3-methylphenylglycine, 4-methylphenylglycine, etc., and di-substituted substances include 2,4-dichlorophenylglycine, 3,4-dichlorophenylglycine, 3,5
-dichlorophenylglycine, 2,4-dihydroxyphenylglycine, 2,5-hydroxyphenylglycine, 3,4-dihydroxyphenylglycine, nylglycine, 2,4-
Dimethoxyphenylglycine, 2,5-dimethoxyphenylglycine, 34-dimethoxyphenylglycine, 3
・5-dimethoxyphenylglycine, 3-chloro4-
Hydroxyphenylglycine, 5-chloro2-hydroxyphenylglycine, 3-chloro4-methoxyphenylglycine, 2-hydroxy-4-methoxyphenylglycine, 2-hydroxy-5-methoxyphenylglycine, 4 -Hydroxy-3-methoxyphenylglycine, 4-hydroxy=3-ethoxyphenylglycine, 4
-Hydroxy=2-methylphenylglycine, 4-hydroxy-3-methylphenylglycine, etc. Tri-substituted products include 3,5-dichloro-2-hydroxyphenylglycine, 3,5-dichloro-4-hydroxyphenylglycine, etc. Examples include enylglycine and 3,5-dimethyl-4-methoxyphenylglycine.

In the reaction between N-carbamoyl (phenyl or substituted phenyl)glycines and nitrous acid, a side reaction tends to occur in which the generated phenyl or substituted phenylglycines further reacts with nitrous acid and turns into mandelic acid derivatives. There is a problem in that the yield of the target phenyl or substituted phenylglycines decreases.

In addition, N- in which the phenyl nucleus is substituted with a hydroxy group
In the case of carbamoyl (substituted phenyl) glycines,
There is a side reaction in which nitrous acid reacts with the highly active phenol nucleus to produce a colored substance, which also causes a decrease in the yield of the target product.

As a result of various studies, the present inventors found that when N-carbamoyl (phenyl or substituted phenyl) glycine and nitrous acid are reacted in a strongly acidic medium, the reaction rate of the desired main reaction is increased, and the above-mentioned reaction rate is increased accordingly. It has been found that the undesirable side reactions of phenyl or substituted phenylglycines are suppressed, and as a result, the yield of phenyl or substituted phenylglycines is improved.

That is, in the method of the present invention, it is extremely important to increase the acidity of the reaction system.

In order to increase the acidity of the reaction system, it is appropriate to use a strong mineral acid such as hydrochloric acid or sulfuric acid.

Although it is practical to carry out the reaction in an aqueous medium, a practically desirable yield cannot be obtained unless the concentration of the strong mineral acid present in the aqueous medium is 0.4N or more.

The concentration of the strong mineral acid is preferably in the range of 0.4 to 2.0N, and even if the concentration is 2.0N or more, the yield will not improve.

The optically active N-carbamol (phenyl or substituted phenyl) glycine used as a raw material in the present invention is
It can be used not only in the form of the free acid but also in the form of salts such as sodium salt, potassium salt, ammonium salt, etc. Except for the amount of strong mineral acid, the above-mentioned strong mineral acid concentration must be taken into account.

Furthermore, when nitrous acid, which is another raw material, is generated in the reaction system by a reaction between nitrite and an acid, it is similarly necessary to use an excess of strong mineral acid equivalent to the amount of nitrite.

It is most practical to use an aqueous medium as the reaction medium.

Optically active N=carbamoyl(hydroxyphenyl)glycines have good solubility in water, so even if water is used as the sole solvent, the reaction can be carried out under conditions close to a homogeneous system, and the optical Active hydroxyphenylglycines can be obtained.

However, optically active N-carbamoyl phenylglycine and optically active N-carbamoyl-substituted phenylglycines having substituents other than hydroxy groups used in the present invention have low solubility in acidic aqueous solutions, resulting in a non-uniform reaction system. .

In such cases, a satisfactory reaction can be achieved by increasing the solubility using a mixed aqueous medium of an organic acid such as acetic acid and water, and by adding a strong mineral acid to the above concentration to carry out the reaction. The desired yield can be obtained.

The amount of nitrous acid used in the present invention should be approximately equivalent to the amount of optically active N-carbamoyl (phenyl or substituted phenyl) glycine.

More specifically, it may be used in an amount of 1.0 to 1.1 equivalents to optically active N-carbamoyl (phenyl or substituted phenyl) glycine.

The presence of nitrous acid in an amount greater than this range is undesirable because it promotes the deamination reaction of the produced optically active phenyl or substituted phenylglycine and the oxidation reaction that produces aldehydes.

Nitrous acid is conveniently generated in the reaction solution by reacting a water-soluble salt of nitrous acid, such as sodium nitrite or potassium nitrite, with an acid in the medium.

The reaction between optically active N-carbamoyl (phenyl or substituted phenyl) glycine and nitrous acid is accompanied by a large amount of heat generation and gas evolution, so when carried out on an industrial scale, N-carbamoyl (phenyl or substituted phenyl) glycine, It is difficult to carry out an operation in which acid and nitrite are simultaneously charged and reacted from the beginning.

Therefore, in practice, a method is employed in which the necessary strong mineral acid is added to an aqueous solution of optically active N-carbamoyl (phenyl or substituted phenyl) glycine or a salt thereof, and an aqueous nitrite solution is gradually added while stirring.

When carried out in this manner, the reaction proceeds in a highly acidic medium, side reactions are suppressed, and a satisfactory yield can be obtained.

Conversely, if a strong mineral acid is gradually added to a solution of optically active N-carbamoyl (phenyl or substituted phenyl) glycine or its salt and nitrite, the acidity of the medium will be insufficient. Desired yield cannot be obtained.

The reaction temperature is usually in the range of 0 to 40°C, but the yield is better when the reaction is carried out at a lower temperature in order to reduce the loss of nitrous acid due to vaporization and to suppress harmful side reactions.

The reaction started as soon as the addition of the nitrite aqueous solution started,
Nitrogen gas and carbon dioxide gas are generated, but 15 minutes to several hours after the entire amount of nitrite has been added, the gas generation stops and the reaction is almost complete.

However, in order to fully complete the reaction, a further post-reaction of about 30 minutes to 15 hours is required after the completion of gas generation.

The time required for the reaction depends on the reaction temperature, and the lower the temperature, the longer the reaction time.

In order to isolate the produced optically active phenyl or substituted phenylglycine from the reaction solution, known methods such as concentration, neutralization, and treatment with an ion exchange resin may be used.

The present invention will be explained in more detail below with reference to Examples.

Example 1 A 500 ml fourth flask equipped with a gas outlet, a stirrer, a thermometer and an inlet tube reaching the bottom of the reaction vessel was charged with D-N.
-Carbamoylphenylglycine {[α]20D=-1
35°(C-1, INNH40H)}5.0g and acetic acid 1
25 ml and 125 mg of water were charged, and 25.2 g of 35% hydrochloric acid was added to this solution.

To this acidic solution, 10.0 g of a sodium nitrite aqueous solution containing 1.85 g of sodium nitrite was introduced into the acidic solution through an inlet tube using a metering pump while stirring.

The charging speed of the sodium nitrite aqueous solution is as follows: the reaction temperature is 2.
It was prepared over 30 minutes so that it was maintained at 0°C.

Stirring was continued for 5 hours after the completion of the charging, and then the reaction solution was concentrated to 100 ml and adjusted to pH 6 with aqueous ammonia to obtain D-phenylglycine as a white precipitate.

Yield 3.5g (yield 90.0%), [α]20D-1
56° (c=1, IN HCl) Example 2 Into a 300 ml four-necked flask equipped with the same apparatus as in Example 1, 5.0 g of D-N monocarbamoyl-2-(4-
hydroxyphenyl) glycine {[α]20=-180
(C=0.5, 5% ethanol)}, 100 ml of water and 0.95 g of caustic soda were charged to prepare a homogeneous solution, and then 19.9 g of 35% hydrochloric acid was added.

A 20% aqueous sodium nitrite solution containing 1.72 g of sodium nitrite was introduced into this acidic solution with stirring using a metering pump through an inlet tube.

The feeding was carried out so that the reaction temperature was maintained at 25°C, and the reaction was completed in 30 minutes.

After the preparation, stirring was continued for another 5 hours, and then the reaction solution was heated to 50C.
Concentrate to pH 5, adjust to pH 5 with aqueous ammonia, and then
By concentrating while heating at 0°C, a white precipitate of D-4-hydroxyphenylglycine was obtained.

Yield: 3.7g (Yield: 92.7%) [α]20D=-1
58° (C=1, IN HCI) Example 3 Same as Example 2, 5.0 g of D-N monocarbamoyl-
2-(4-hydroxyphenyl)glycine and water 100m
29.0 g of 32.3% sulfuric acid was added to 1 of the mixed solution, and then 9.0 g of a 20% aqueous sodium nitrite solution was fed in with stirring using a metering pump over 30 minutes.

The reaction temperature was kept at 5°C. After the preparation is completed, 15 more
The reaction solution obtained by continuous stirring for 60 minutes at room temperature was depressurized for 60 minutes to remove trace amounts of N02, adjusted to pH 2 with aqueous caustic soda solution, and passed through a strongly acidic ion exchange resin of IR-120-B (acid type). .

Then, the eluate was eluted with 3% ammonia water, the eluate was concentrated under reduced pressure, and the pH was adjusted to 5 with hydrochloric acid to obtain a white precipitate of D-4-hydroxyphenylglycine.

Yield: 3.1 g (Yield: 95.5%) Example 4 5.0 g of D-N-carbamoyl-2 in the same manner as Example 2
-(4-Hydroxyphenyl)gun and water 100m#
) 25.3 g of mixed solution K32.3% sulfuric acid was added, and then 8.4 g of a 20% aqueous sodium nitrite solution was introduced over 60 minutes while stirring.

The reaction temperature was kept at 20°C.

After the completion of the preparation, stirring was continued for another 4 hours, and the resulting reaction solution was treated with an ion exchange resin in the same manner as in Example 3 to concentrate and adjust the pH.
A white precipitate of D-4-hydroxyphenylglycine was obtained by adjustment.

Yield: 3.6 g (Yield, 90.5%) Example 5 Into a 500 ml four-loaf flask equipped with the same equipment as in Example 1, 5.1 g of D-N-carbamoyl-2-(3-
N lorofenyl) glycine {[α]24D=-124°
(C=0.5, 0.1N NH40H)}, acetic acid 150
1 liter and 150 ml of water, then add 1 liter of 35% hydrochloric acid.
9.4g was added.

Add 20% sodium nitrite aqueous solution 7.85 to this acidic solution.
g was fed over 30 minutes using a metering pump, during which time the reaction temperature was maintained at 15°C.

After the preparation was completed, stirring was continued for another 6 hours.

The reaction solution was adjusted to pH 2 with an aqueous caustic soda solution and filtered, and the solution was treated with an ion exchange resin in the same manner as in Example 3.
Concentration and neutralization were performed to obtain a white precipitate of D-3-chlorophenylglycine.

Yield: 3.7 g (Yield: 91.1%) The optical rotation of D-3-chlorophenylglycine purified by neutralization crystallization with hydrochloric acid and aqueous ammonia is [α]25D=-120° (
C-1, IN HCI).

Example 6 Similar to Example 5, 5.0 g of D-N-carbamoyl-
2-(4-methoxyphenyl)glycine {[α]25D
11142° (C=0.5, 0.1NNH40H)},
Pour 150ml of water and 150ml of acetic acid into a 500ul four-bottle flask, then add 40.6f of 32.3% sulfuric acid.
was added.

Then, while stirring, the reaction temperature was maintained at 15°C for 20°C.
An 8.11% aqueous solution of sodium nitrite was pumped into the reaction via a metering pump over 40 minutes.

After the completion of the preparation, stirring was continued for 8 hours, and then treatment with an ion exchange resin, concentration, and neutralization were performed in the same manner as in Example 3 to obtain a white precipitate of D-4-methoxyphenylglycine.

The yield of D-4-methoxyphenylglycine was 3.64 f (yield: 90.0%) and purified by neutralization crystallization in the same manner as in Example 5. The optical rotation was [α]25D~1146° (C- 1,
IN HCI).

Claims (1)

[Claims] 1 General formula (wherein R1, R2, R3 and R4 are each a hydrogen atom,
Represents a haloken atom, hydroxy group, lower alkoxy group or lower alkyl group. ) is reacted with approximately the same amount of nitrous acid in an aqueous medium in which a strong mineral acid with a concentration of 0.4N or more is present. shall be. A method for producing an optically active phenyl or substituted phenylglycine represented by the general formula (wherein R1, R2, R3 and R4 are the same as the above formula). 2. Claim 1, in which nitrous acid or a salt thereof is gradually added to an aqueous medium in which an optically active N-carbamoyl (phenyl or substituted phenyl) glycine and a strong mineral acid are present.
Manufacturing method described in section. 3. The production method according to claim 1 or 2, wherein the optically active N-carbamoyl (phenyl or substituted phenyl) glycine is D-form.