JPH0339069B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the formula () racemic or optically active -threo-N represented by
-Carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine. According to the invention, the formula () By reacting racemic-threo-3-(3,4-methylenedioxyphenyl)serine represented by formula (2) with carbobenzoxy chloride, racemic-N-carbobenzoxy-threo-3-( 3,4 methylenedioxyphenyl) serine, optionally followed by ephedrine, quinidine, quinine, 2-amino-1,
D or L-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine is made into an amine salt by reacting with one of the optically active amines selected from 1-diphenylpropanol, and the solubility Utilizing the difference in -methylenedioxyphenyl)serine and the amine salt of serine, and then by treating each salt with an acid, the optically active (D or L)-threo-N-carbobenzoxy-3-(3, 4-methylenedioxyphenyl)serine can be obtained. Racemic or optically active -threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl) represented by formula (), which is a compound of the present invention
Serine is a new compound that has not been described in any literature, has antibacterial activity, and is useful as a pharmaceutical in itself.
104815) or antidepressants (Japanese Unexamined Patent Publication No. 104815-
It is an extremely useful compound as an intermediate in the production of racemic or optically active threo-3-(3,4-dihydroxyphenyl)serine (hereinafter abbreviated as DOPS), which is useful as a compound (No. 20747). Conventionally, the method for producing racemic or optically active DOPS is based on the formula () By using vanillin or piperonal in which the catechol moiety of protocatechyaldehyde represented by is protected with two methyl groups or methylene groups as a starting material and removing the methyl group or methylene group, the product represented by the above formula () is obtained. After obtaining protocatechyaldehyde, the catechol moiety is protected with an ethoxycarbonyl group or a benzyl group and the formula () [In the formula, R ₁ means an ethoxycarbonyl group or a benzyl group. ] This benzaldehyde derivative is condensed with glycine or a glycine derivative to form threo- and erythro-
A method is used in which racemic or optically active -DOPS is produced by obtaining a mixture of 3-(3,4-dihydroxyphenyl)serine derivatives and removing the protecting group through optical resolution operations as necessary. There is. [Chem.Ber., 52 , 1724 (1919); J.
Chem., 658 (1947); Chem. Ber., 87 , 892
(1954); J.Am.Chem.Soc., 76 , 1322 (1954);
Helv. Chim. Acta., 58 , 157 (1975)] That is, in producing DOPS, there is a drawback that it requires a complicated operation of changing the protecting group of the catechol moiety of the benzaldehyde derivative serving as the raw material compound. Under these circumstances, the present inventors have intensively investigated a method for producing racemic and optically active DOPS that does not require changing the protective group of the catechol moiety. As a result, the racemic and optically active -threo-N-carbobenzoxy-3-(3,4-methylenedioxyfluoride) compounds of the present invention, which can be produced from piperonal without changing the protecting group, are undescribed in the literature. The present invention was completed based on the finding that racemic and optically active DOPS can be easily produced by using enyl)serine () as an intermediate. That is, the racemic and optically active compounds of the present invention
threo-N-carbobenzoxy-3-(3,4-
After treating methylenedioxyphenyl)serine () with a Lewis acid such as aluminum chloride to form racemic and optically active -threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine, Racemic or optically active by catalytic reduction reaction using palladium/carbon etc.
You can get DOPS. Therefore, racemic and optically active -threo-N-carbobenzoxy-3-(3,
4-methylenedioxyphenyl)serine ()
is an important intermediate for the economical production of racemic and optically active DOPS. The present invention will be specifically explained below. Racemic-threo-N-carbobenzoxy-3-
(3,4-methylenedioxyphenyl)serine () is a so-called Schotten Baumann combination of racemic-threo-3-(3,4-methylenedioxyphenyl)serine () and carbobenzoxy chloride.
It can be obtained by reaction. That is, it can be carried out by dissolving racemic-threo-3-(3,4-methylenedioxyphenyl)serine () in an alkaline aqueous solution having a pH of 7 or higher and adding carbobenzoxy chloride. Carbobenzoxy chloride is racemic-threo-
It is sufficient to use 1 to 2 times the mole of 3-(3,4-methylenedioxyphenyl)serine () and to react at a reaction temperature of 0 to 30°C for several minutes to 20 hours. It is preferable to keep the pH of the liquid between 7 and 10. To maintain the pH of the reaction solution at 7 to 10, add alkaline water dropwise depending on the pH change, or add salt to the reaction solution in advance, such as sodium bicarbonate or borax, which has a pH of 7 to 10 when made into an aqueous solution. I'll keep it. Examples of the alkali used as alkaline water include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and the like. The reaction proceeds satisfactorily in an aqueous solution, but aromatic hydrocarbon solvents such as toluene and benzene, aliphatic hydrocarbon solvents such as hexane and heptane, ether solvents such as diethyl ether, tetrahydrofuran, and dioxane, acetone, methyl ethyl ketone, etc. Ketone solvents, chloroform, dichloromethane,
Halogenated alkyl solvents such as dichloroethane,
Ester solvents such as ethyl acetate and butyl acetate and mixtures thereof can also be added. To obtain optically active (D or L)-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine (), racemic-threo-N-carbobenzoxyphenyl)serine D and L-threo-N-carbobenzoxy -3-(3,4-methylenedioxyphenyl)serine is salted with an optically active amine, and using the difference in solubility, D-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl) oxyphenyl)
Optically active amine salt of serine and L-threo-N-
Carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine is separated into an optically active amine salt, and then each salt is treated with an acid to decompose the salt. The temperature at which salts are formed and separated can be 0 to 80°C, but it can also be heated to around the boiling point of the solvent and then cooled to 0 to 30°C. A few minutes is sufficient for forming the salt, but there is no particular restriction, and it may take several hours. The optically active amine can be used in a molar amount of 0.5 to 1 times that of racemic-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine. Preferred examples of the solvent used for the formation and fractionation of the salt include alcohol solvents such as methanol, ethanol, and 2-propanol, ether solvents such as tetrahydrofuran and dioxane, acetonitrile, water, and mixed solvents thereof. . The optically active (D or L)-threo-
By adding an acidic aqueous solution to the salt of N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine with an optically active amine, the salt is decomposed, and by extraction with an organic solvent, the optically active ( D or L)-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine can be obtained. Examples of the acid in this acidic aqueous solution include mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and the amount used is 1% per salt.
~10 times the molar amount can be used. Organic solvents used for extraction include ethyl acetate,
Examples include chloroform, dichloroethane, dichloromethane, diethyl ether, and the like. Racemic threo-3, which is a raw material in the present invention
-(3,4-methylenedioxyphenyl)serine () is already known to have an unknown three-dimensional structure (threo, erythro) [Pharmaceutical Journal,
67, 218 (1947), Can.J.Chem., 42 , 1901
(1964)], was the first threo isomer isolated and identified by the present inventors. That is, after reacting glycine with 2 times the mole of piperonal and 2 times the mole of glycine with a base such as sodium hydroxide or potassium hydroxide, by adding acetic acid water to the reaction solution, racemic threo/erythro 3-( 3,
Racemic threo-3
-(3,4-methylenedioxyphenyl)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 61.1 g of potassium hydroxide and 1055 ml of methanol were dissolved with stirring, and 33.05 g of glycine was added and dissolved. Furthermore, 145 g of piperonal was added and stirred at 62°C to 65°C for 30 minutes. After the reaction, it was concentrated under reduced pressure. Add 315ml of methanol to the residue, then add 308g of acetic acid.
was added and stirred at 40°C to 45°C for 30 minutes. more water
Add 135g and 1000g of toluene to 40°C to 45°C for 2 hours.
After stirring at 0.degree. C., the mixture was further stirred at 0 to 5.degree. C. for 1 hour.
The precipitated crystals were collected and dried to obtain 87.0 g of threo/erythro-3-(3,4-methylenedioxyphenyl) serine acetate (yield:
69.3%). The melting point is 162℃ (decomposition point), and the HPLC analysis results under the following conditions are Threo:Erythro = 85:15
The ratio was . HPLC analysis conditions column: Licromosorb RP
-18, 10μ4mm×30cm Mobile phase solvent: 0.005M PIC B-7/acetonitrile (9:1) Flow rate: 1.0ml/min Detection: UV (254mm) Elution time Erythro form: 7.5 minutes Threo form: 8.5 minutes , 88g of piperonal was obtained by separating the toluene layer from the mother liquor from which the above salt was removed and concentrating it.
was able to be recovered. -1 Threo/Erythro-3-(3,
85 g of 4-methylenedioxyphenyl) serine acetate was added and heated to reflux with stirring to dissolve, cool, and stir at 0 to 5° C. for 1 hour. When the precipitated crystals are collected and dried, Threo-3
48.37 g of -(3,4-methylenedioxyphenyl)serine was obtained. (Yield 72.1%). The melting point was 193° C. (decomposition point), and the analysis results under the above HPLC conditions showed that the compound was 100% threoform. -2 Threo/Erythro-3-(3,
1 g of 4-methylenedioxyphenyl) serine acetate was added, and the mixture was stirred at room temperature for 30 minutes. When the precipitated crystals are collected and dried, threo-3-
0.45 g of (3,4-methylenedioxyphenyl)serine was obtained (yield 57.0%). The melting point is 188°C (decomposition point), and the analysis results under the above HPLC conditions are Threo: Erythro = 98.7:
It was 1.3. Example 1 11.3 g of racemic-threo-3-(3,4-methylenedioxyphenyl)serine was added to 160 ml of an aqueous solution containing 4.0 g of sodium hydroxide at 5°C or below, and after dissolution, carbobenzoxy chloride was added at 5°C or below. 9.4g was dropped. At the same time, 30% sodium hydroxide was added dropwise to adjust the pH to 8.5 to 9.5. 2 hours later
The mixture was adjusted to pH≒2 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from toluene and the crystals were collected to give racemic-threo-N-carbobenzoxy-3-(3,
17.3 g of 4-methylenedioxyphenyl)serine was obtained. mp.136-138℃ IR (Nujol) ν (cm ^-1 ); 3500, 3250, 1750,
1655, 1505, 1340, 1255, 1220, 1160 Example 2 Carbobenzoxy chloride in Example 1
Carbobenzoxy chloride 9.4g instead of 9.4g
A reaction was carried out in exactly the same manner as in Example 1 using a solution of 22 g of toluene and 22 g of toluene. After the reaction, the pH was adjusted to 9.0, 100 ml of toluene was added, and toluene extraction was performed.
The aqueous layer was adjusted to pH≒2 with concentrated hydrochloric acid, extracted, washed with water, dried, and concentrated in the same manner as in Example 1, crystallized with toluene, and racemic-threo-N-carbobenzoxy-3-(3, 4-methylenedioxyphenyl)
16.9 g of serine was obtained. mp137-139℃ Example 3 Racemic-threo-N-carbobenzoxy-3-
(3,4-methylenedioxyphenyl)serine
10.0g was dissolved in 100ml of acetonitrile, and 9.02g of quinidine was added to make a homogeneous solution. The mixture was cooled with ice water for 5 hours, and the precipitated crystals were collected to obtain 9.0 g of L-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine quinidine salt. mp161-163℃ [α] ²⁰ _D +119.5゜ (c=1.0, methanol) After adding 50 ml of 3% hydrochloric acid to 2.0 g of a portion of the above salt, extracting with ethyl acetate, L-threo- N-
0.98 g of carbobenzoxy-3(3,4-methylenedioxyphenyl)serine was obtained as an amorphous powder. IR (Nujol) ν (cm ^-1 ); 3500~3580 (broad),
1740-1670 (broad), 1390, 1440, 1040, 930 [α] ²⁰ _D -24.5° (c = 1.0, methanol) A portion of 6.0 g of the above salt was recrystallized twice with methanol to obtain 4.4 g of salt ( mp162-163.5℃, [α] ²⁰ _D +122.6゜ (c=1.0, methanol)), then 4.0g of this salt
Add 3% hydrochloric acid to the solution, extract with ethyl acetate,
L-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl) as an amorphous powder
1.8 g of serine was obtained. [α] ²⁰ _D −28.1° (c=1.0, methanol) Example 4 Racemic-threo-N-carbobenzoxy-3-
(3,4-methylenedioxyphenyl)serine
2-propanol 100ml and quinidine 9.02 to 10.0g
g was added to make a homogeneous solution. After standing overnight at room temperature, the precipitated crystals were collected and L-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine quinidine salt 8.3
I got g. mp161-163℃ [α] ²⁰ _D +119.3゜ (c=1.0, methanol) After adding 3% hydrochloric acid water to 4.0g of a portion of the above salt,
Extraction with ethyl acetate gave 1.9 g of L-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine as an amorphous powder. [α] ²⁰ _D −25.3° (c=1.0, methanol) Example 5 Racemic-threo-N-carbobenzoxy-3-
(3,4-methylenedioxyphenyl)serine 5.0
After dissolving g in 50 ml of acetonitrile, 4.5 g of quinine
was added to make a homogeneous solution. After standing at room temperature overnight, remove the precipitated crystals to obtain D-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl) serine quinine salt 5.1
I got g. mp116-118℃ [α] ²⁰ _D -97.3゜ (c=1.0, CH ₂ OH) Add 3% hydrochloric acid water to 4.0 g of a portion of the above salt, extract with ethyl acetate, and extract D-threo-N-carboxylate. 2.0 g of benzoxy-3-(3,4-methylenedioxyphenyl)serine was obtained as an amorphous powder. [α] ²⁰ _D +18.0° (c=1.0, methanol) Example 6 Racemic-threo-N-carbobenzoxy-3-
(3,4-methylenedioxyphenyl)serine
10.0g and R-2-amino-1,1-diphenylpropanol 6.3g were dissolved in 100ml of ethanol,
Cooled in ice water for 4 hours. The precipitated crystals were collected to obtain 7.8 g of L-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine/R-2-amino-1,1-diphenylpropanol salt. . mp170.5℃ (decomposition) [α] ²⁰ _D -23.1゜ (c=1.0, methanol) Add 100 ml of 3% hydrochloric acid to 4.0 g of a portion of the above salt, extract with ethyl acetate, and L-threo-N- 2.3 g of carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine was obtained as an amorphous powder. [α] ²⁰ _D −26.8° (c=1.0, methanol) Example 7 Racemic-threo-N-carbobenzoxy-3-
(3,4-methylenedioxyphenyl)serine
10.0g with 4.6g of l-efedrin and 200g of ethanol
ml was added and dissolved, and then cooled in ice water for 6 hours. After collecting the precipitated salt, this salt was recrystallized twice from ethanol to obtain D-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl).
5.3 g of serine l-ephedrine salt was obtained. mp177-178℃ [α] ²⁰ _D -22.2゜ (c=1.0, methanol) Add 3% hydrochloric acid water to 2.0 g of a portion of the above salt, extract with ethyl acetate, and extract D-threo-N-carbobenzoxy. 1.3 g of -3-(3,4-methylenedioxyphenyl)serine was obtained as an amorphous powder. [α] ²⁰ _D +28.0° (c=1.0, methanol).

Claims (1)

[Claims] 1 formula racemic or optically active -threo-N represented by
-Carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine. 2 formulas Racemic-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl) represented by
In producing serine, the formula Racemic-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine represented by is reacted with carbobenzoxy chloride.
- A method for producing (methylenedioxyphenyl)serine. 3 formulas Optically active (D or L)-threo-
In producing N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine,
Racemic-threo-N-carbobenzoxy-3-
(3,4-methylenedioxyphenyl)serine,
efuedrine, quinidine, quinine, 2-amino-
D and L-
threo-N-carbobenzoxy-3-(3,4-
D-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine amine salt and L-threo -N-
The optically active (D or L) threo- A method for producing N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine.