JPH0316946B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides racemic or optically active -threo-N-
The present invention relates to a method for producing carbobenzoxy-3-(3,4-dihydroxyphenyl)serine.

For more details, see the general formula [] (In the formula, R ¹ and R ² mean a hydrogen atom or a methyl group, and at least one of them means a methyl group.) Racemic or optically active -threo-N
-By treating a carbobenzoxy-3-(3,4-dihydroxyphenyl)serine derivative with a Lewis acid, the formula [] racemic or optically active -threo-N represented by
- A method for producing carbobenzoxy-3-(3,4-dihydroxyphenyl)serine.

Racemic or optically active -threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine that can be produced by the method of the present invention is useful as a pharmaceutical intermediate. Namely, a therapeutic agent for Parkinson's disease (Japanese Patent Application Laid-Open No. 58-52219), a therapeutic agent for peripheral orthostatic hypotension (Japanese Patent Application Laid-Open No. 56-1988)
-104815) or antidepressants (Japanese Patent Application Laid-open No. 104815-
Racemic or optically active threo-3-(3,
4-dihydroxyphenyl)serine (DOPS)
It is extremely useful as an intermediate in the production of

Conventionally, as a method for producing racemic or optically active -threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine, racemic-DOPS is produced in advance, and then carbobenzoxy chloride and The reaction produces racemic-threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine, followed by optical resolution using quinine to produce optically active -threo-N.
A method for producing -carbobenzoxy-3-(3,4-dihydroxyphenyl)serine is known. (Japanese Unexamined Patent Publication No. 51-32540) In the above-mentioned known method, racemic DOPS is once produced, and then racemic and optically active -threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine is produced. It has the disadvantage of requiring complicated operations to produce optically active DOPS.

Furthermore, in the production of racemic DOPS, which is the raw material compound in the above method, industrially, the formula () obtained by removing the methyl group or methylene group of veratryl aldehyde, vanillin, or piperonal is used. A general formula in which the catechol moiety of protocatechyaldehyde represented by is protected with an easily removable ethoxycarbonyl group or benzyl group [] (In the formula, R ³ means an ethoxycarbonyl group or a benzyl group.) It is produced through a method of condensing a benzaldehyde derivative represented by the following formula with glycine or a glycine derivative. [Chem. Ber. 52 , 1734 (1919),
J.Chem.Soc., 658 (1947), Chem.Ber., 87 , 892
(1954), J.Am.Chem.Soc., 76 , 1322 (1954)] That is, before producing racemic DOPS, a complicated operation of changing the protecting group of the catechol moiety of the benzaldehyde derivative, which is the raw material compound, is necessary. It has the disadvantage that.

On the other hand, various methods are known for removing the methyl group or methylene group from a compound having a methoxy group or methylenedioxy group to form a catechol group. As an example, 3-
(3,4-methylenedioxyphenyl)alanine or its N-acetyl derivative was treated with hydroiodic acid and acetic anhydride in the presence of red phosphorus to produce 3-
Example of obtaining (3,4-dihydroxyphenyl)alanine (Chem.Pharm.Bull., 10 , 693 (1962)) and 2-methyl-3-(3,4-dimethoxyphenyl)alanine with 47.5% odor. Heat treated with hydrochloric acid 2
-Methyl-3-(3,4-dihydroxyphenyl)
Example of obtaining alanine (J.Am.Chem.Soc., 77 , 700
(1955)) is known. However, the method using such reaction conditions could not be applied to the demethylation reaction of the compound represented by the above general formula [].

Under these circumstances, the present inventors have intensively investigated an economical method for producing racemic or optically active DOPS.

As a result, racemic or optically active -threo-N-carbobenzoxy-3-(3, Producing racemic or optically active -threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine [] by treating a 4-dihydroxyphenyl)serine derivative [] with a Lewis acid. The present invention was completed based on the knowledge that this can be done.

That is, by the method of the present invention, the general formula []
Racemic or optically active -threo-
Although N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine derivatives have hydroxyl, carbamate, and carboxyl groups in addition to methoxy groups, they can be treated with Lewis acids under mild conditions. By doing so, the methyl group is removed and the racemic or optically active -threo-N-carbobenzoxy-3-
It was found that it gives (3,4-dihydroxyphenyl)serine. In this reaction, it is preferable to add mercaptans in addition to the Lewis acid.

The starting compound [ ] of the present invention is known or can be easily produced according to a known method or the method described below. For example, US Pat. No. 3,723,514 describes a process for preparing racemic or optically active -threo-N-carbobenzoxy-3-(3-methoxy-4-hydroxyphenyl)serine. In addition, for example, by condensation of veratrylaldehyde and glycine, the formula [] Threo-3-(3,4-dimethoxyphenyl)serine represented by is obtained, followed by the so-called Schotten-Baumann reaction with carbobenzoxy chloride to give racemic-threo-N-carbobenzoxy-3. -(3,4-dimethoxyphenyl)serine can be obtained.
Further, if necessary, by performing an optical resolution operation using an optically active amine, a corresponding optically active substance can be obtained.

Racemic or optically active -threo-N-carbobenzoxy-3-(3,
Conversion of 4-dihydroxyphenyl)serine to the corresponding racemic or optically active -DOPS can be carried out, for example, by catalytic reduction in a solvent in the presence of palladium on carbon.

The above-mentioned series of methods for producing DOPS does not require changing the protective group of the catechol moiety as seen in conventional methods, and provides an economical method for producing DOPS.

Among the above-mentioned series of methods for producing DOPS, the present invention is directed to producing a corresponding racemic or optically active threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine derivative (). -N-carbobenzoxy-3-(3,
The present invention relates to a method for producing 4-dihydroxyphenyl)serine ().

The method of the present invention will be specifically explained below.

Racemic or optically active -threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)
Treatment of the serine derivative () with a Lewis acid in a suitable solvent provides the corresponding racemic or optically active -threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine ().

Preferred examples of Lewis acids include aluminum chloride, aluminum bromide, ferric chloride, stannic chloride, boron chloride, and boron bromide. A complex of Lewis acid and dimethyl sulfide may be used as the Lewis acid.

The Lewis acid is used in an amount of 1 to 20 times, preferably 2 to 10 times, the amount of the threo-3-(3,4-dihydroxyphenyl)serine derivative.

In order to obtain favorable results, in addition to the Lewis acid, mercaptans having 1 to 20 carbon atoms such as methyl mercaptan, ethyl mercaptan, butyl mercaptan, octyl mercaptan, dodecanyl mercaptan, and octadecanyl mercaptan are added to the reaction solution. It can be added 1 to 5 times as much.

As the reaction solvent, any solvent may be used other than the solvent that inhibits the progress of the reaction, but preferred solvents are:
Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and chlorobenzene, aromatic hydrocarbon solvents such as toluene and benzene, ester solvents such as ethyl acetate and butyl acetate, and nitrated hydrocarbons such as nitromethane, nitroethane, and nitrobenzene. solvents, ketone solvents such as acetone and methyl ethyl ketone, pyridine, etc.
Or a mixed solvent thereof can be mentioned.

Although the reaction temperature can be carried out in the range of -40 to 80°C, it is preferably carried out in the range of -10 to 30°C.

The reaction is completed within a range of 10 minutes to 4 hours, but the reaction time may be longer.

Among the raw material compounds used in the method of the present invention, for example, the aforementioned racemic or optically active -threo-N-
Carbobenzoxy-3-(3,4-dihydroxyphenyl)serine can be produced as follows.

That is, in a solvent such as methanol or ethanol,
By reacting glycine with twice the molar amount of veratrylaldehyde and twice the molar amount of a base such as sodium hydroxide or potassium hydroxide relative to glycine, and then treating with aqueous acetic acid, the product is expressed as a crystal by the above formula [V]. racemic threo-3-(3,4-dimethoxyphenyl)serine can be obtained.
If a large amount of erythro isomer is contained depending on the conditions at this time, it is possible to remove the erythro isomer by recrystallizing from water to obtain racemic threo-3-(3,4-dimethoxyphenyl)serine (). can. Subsequently, racemic-threo-N-carbobenzoxy-3-(3,4
-dimethoxyphenyl)serine is obtained.

If necessary, this racemate is treated with an optically active amine to form a diastereomer salt, and an amine salt of D-threo-N-carbobenzoxy-3-(3,4-dimethoxyphenyl)serine and L- After separation into amine salt of threo-N-carbobenzoxy-3-(3,4-dimethoxyphenyl)serine, the optically active (D and L) Threo-N-
Carbobenzoxy-3-(3,4-dimethoxyphenyl)serine can be obtained.

Next, the method of the present invention will be explained by way of examples. The present invention is of course not limited to this.

Reference Example 1 9.0 g of Cerami-threo-3-(3-methoxy-4-hydroxyphenyl)serine was added to 150 ml of an aqueous solution containing 2.73 g of sodium hydroxide at 5°C or below, and after dissolving, 7.02 g of carbobenzoxy chloride was added. 5
It was added dropwise at a temperature below ℃. During this time, a 30% aqueous sodium hydroxide solution was simultaneously added dropwise to adjust the pH to 8.5 to 9.5. After continuing stirring for 2 hours, the pH was adjusted to 2 by adding concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was crystallized from ethyl acetate to obtain 6.2 g of racemic-threo-N-carbobenzoxy-3-(3-methoxy-4-hydroxyphenyl)serine. mp147~
149℃.

Example 1 A solution of 2.0 g of racemic-threo-N-carbobenzoxy-3-(3-methoxy-4-hydroxyphenyl)serine obtained in Reference Example 1, 3 ml of ethyl mercaptan, and 60 ml of dry dichloromethane was heated below 5°C. 6.0 g of anhydrous aluminum bromide was added. After stirring at room temperature for 15 hours, add 3 ml of ethyl mercaptan.
Then, 6.0 g of anhydrous aluminum bromide was added and stirred at room temperature for 72 hours. Furthermore, 3 ml of ethyl mercaptan and 6.0 g of anhydrous aluminum bromide were added and stirred for 15 hours. This reaction mixture was added dropwise to 200 ml of 5% oxalic acid water at 20°C or lower, and then extracted three times with 100 ml of ethyl acetate. The ethyl acetate layer was washed three times with 100 ml of saturated brine, dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to give racemic threo-N
-Carbobenzoxy-3-(3,4-dihydroxyphenyl)serine 0.04 g was obtained.

mp 147℃ (decomposition) Reference Example 2 0.035 g of racemic-threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine obtained in Example 1 above was dissolved in 0.5 ml of methanol, and 10% 0.005 g of palladium on carbon (50% water content) was added and catalytic reduction was carried out at normal pressure. After no longer absorbing hydrogen, add 0.015 g of concentrated hydrochloric acid, stir, remove insoluble matter, and PH the mother liquor with diethylamine.
It was set as ≒5.5. Remove the precipitated crystals and prepare racemic threo-3-(3,4-dihydroxyphenyl)serine.
0.019g was obtained.

mp 222-224℃ Reference Example 3 4.0 g of racemic-threo-N-carbobenzoxy-3-(3-methoxy-4-hydroxyphenyl)serine obtained in Reference Example 1 was added to 120 g of 10% aqueous ethanol.
ml and add 4.36g of quinine trihydrate to 60ml.
It was heated to ℃ to dissolve it. After standing for 8 days, the precipitated crystals were collected to obtain 2.6 g of L-threo-N-carbobenzoxy-3-(3-methoxy-4-hydroxyphenyl)serine quinine salt.

mp140-142℃, [α] ²⁰ _D -92゜ (C=1, ethanol) Add this salt to 100ml of N-hydrochloric acid and 200ml of ethyl acetate.
After drying with anhydrous sodium sulfate, ethyl acetate was distilled off to obtain 1.25 g of L-threo-N-carbobenzoxy-3-(3-methoxy-4-hydroxyphenyl)serine. mp143~145℃,
[α] ²⁰ _D -21.0° (C=1, methanol) Example 2 1.1 g of L-threo-N-carbobenzoxy-3-(3-methoxy-4-hydroxyphenyl)serine obtained in Reference Example 3 , ethyl mercaptan 1.65ml,
A solution of 33 ml of dry dichloromethane was cooled to below 5°C and 3.3 g of anhydrous aluminum bromide was added. After stirring at room temperature for 24 hours, 1.65 ml of ethyl mercaptan and 3.3 g of anhydrous aluminum bromide were added, and the mixture was stirred at room temperature for 70 hours. Furthermore, ethyl mercaptan
1.65 ml and 3.3 g of anhydrous aluminum bromide were added and stirred for 12 hours. The reaction mixture was added dropwise to 100 ml of 5% oxalic acid water at below 20°C, and 50 ml of ethyl acetate was added.
Extracted three times. The ethyl acetate layers were combined and washed three times with 50 ml of saturated brine. This ethyl acetate layer was dried with anhydrous sodium sulfate and the solvent was distilled off, leaving L as an oil.
-threo-N-carbobenzoxy-3-(3,4
-dihydroxyphenyl)serine 0.025 g was obtained.
[α] ²⁰ _D -26.8° (C=1, methanol) Reference example 4 0.025 g of L-threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine obtained in Example 2 was added to methanol. The solution was dissolved in 0.5 ml, 0.005 g of 10% palladium on carbon (50% water content) was added, and catalytic reduction was performed at normal pressure. After hydrogen was no longer absorbed, 0.011 g of concentrated hydrochloric acid was added, and after stirring, insoluble matter was removed, and the mother liquor was adjusted to pH≈5.5 with diethylamine. The precipitated crystals were collected and L-threo-3-(3,4
-dihydroxyphenyl)serine 0.013 g was obtained.
mp223~225℃, [α] ²⁰ _D -38.0° (C=1, N-hydrochloric acid) Reference example 5 Add 3.0 g of racemic threo-3-(3,4-dimethoxyphenyl) serine hydrochloride to sodium hydroxide. It was added to 50 ml of an aqueous solution containing 0.86 g at below 5°C, and after dissolving, 2.2 g of carbobenzoxy chloride was added dropwise at below 5°C. During this time, a 30% aqueous sodium hydroxide solution was simultaneously added dropwise to adjust the pH to 8.5 to 9.5. After 2 hours, pH≒ by adding concentrated hydrochloric acid.
2 and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was crystallized from ethyl acetate and the crystals were collected to give racemic threo-N-carbobenzoxy-3-(3,4-dimethoxyphenyl).
1.37 g of serine was obtained. mp121-125℃ Example 3 Racemic-threo-N-carbobenzoxy-3-(3,4-dimethoxyphenyl) obtained in Reference Example 5
A solution of 1.0 g of serine, 1.5 ml of ethyl mercaptan, and 18 ml of dry dichloromethane was cooled to below 5°C, 1.4 g of anhydrous aluminum chloride was added, and after stirring at room temperature for 15 hours, 1.5 ml of ethyl mercaptan and 2.8 g of anhydrous aluminum bromide were added. . After stirring at room temperature for 72 hours, 1.5 ml of ethyl mercaptan and 2.8 g of anhydrous aluminum bromide were further added, and the mixture was stirred for 15 hours. The reaction mixture was added dropwise to 100 ml of 5% oxalic acid water at below 20°C, and extracted three times with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed three times with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain racemic-threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine.
0.04g was obtained. mp148℃ (decomposition) Reference example 6 Racemic-threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl) obtained in Example 3
Dissolve 0.035g of serine in 0.5ml of methanol, 10%
0.005 g of palladium on carbon (50% water content) was added and catalytic reduction was carried out at normal pressure. After hydrogen was no longer absorbed, 0.015 g of concentrated hydrochloric acid was added, and after stirring, insoluble matter was removed, and the mother liquor was adjusted to pH≈5.5 with diethylamine. The precipitated crystals were collected and racemic threo-3-(3,
0.02 g of 4-dihydroxyphenyl)serine was obtained. mp222~225℃.

Claims (1)

[Claims] 1 formula racemic or optically active -threo-N represented by
- In producing carbobenzoxy-3-(3,4-dihydroxyphenyl)serine, the formula (In the formula, R ¹ and R ² mean a hydrogen atom or a methyl group, and at least one of them means a methyl group.) Racemic or optically active -threo-N
- Racemic or optically active carbobenzoxy-3-(3,4-dihydroxyphenyl)serine derivative characterized by treatment with a Lewis acid -Threo-N-carbobenzoxy-3-(3,4-dihydroxy Method for producing phenyl)serine.