JPH0549659B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the formula [] The present invention relates to a method for producing erythro-3-(3,4-dihydroxyphenyl)serine represented by For more details, see the general formula [] (In the formula, one of R ¹ and R ² means a methyl group and the other a hydrogen atom, or both R ¹ and R ² mean a methyl group, or when R ¹ and R ² racemic or optically active -erythro-
By treating N-phthaloyl-3-(3,4-dihydroxyphenyl)serine derivative with Lewis acid, the formula [] Erythro-N-phthaloyl-3-
(3,4-dihydroxyphenyl)serine,
If this is a racemate, optical resolution is further carried out as necessary by the action of one of the optically active amines selected from cinchonidine, quinidine, norephedrin, and 2-amino-1,1-diphenylpropanol. The racemic or optically active -erythro-N-phthaloyl-3-(3,4-
By subjecting dihydroxyphenyl)serine to a defthaloylation reaction, racemic or optically active erythro-3-(3,4
The present invention relates to a method for producing -dihydroxyphenyl)serine. Racemic and optically active erythro-3-(3,4-dihydroxyphenyl)serine [] which can be obtained by the method of the present invention is known to have antihypertensive activity (Japanese Patent Application Laid-Open No. 50-49252). There is. Conventionally, methods for producing racemic or optically active threo- or erythro-DOPS (DOPS: 3-(3,4-dihydroxyphenyl)serine) include:
General formula [] (In the formula, R ¹ and R ² have the same meanings as above.) A method using an aldehyde derivative represented by the following as a starting material is known. That is, a compound represented by the above general formula [] is used as a starting material for vanillin, veratryl aldehyde, or piperonal, and the formula [] is obtained by removing the methyl group or methylene group that is the protective group of the catechol moiety. After obtaining protocatechyaldehyde represented by the formula, the catechol moiety is protected with an ethoxycarbonyl group or a benzyl group to obtain the formula [] [In the formula, R ³ means an ethoxycarbonyl group or a benzyl group. ] This benzaldehyde derivative is condensed with glycine or a glycine derivative to form threo- and erythro-
Racemic or optically active -DOPS is produced by obtaining a mixture of 3-(3,4-dihydroxyphenyl)serine derivatives and removing protective groups through threo and erythro separation and optical resolution operations as necessary. method is used. [Chem.Ber.,
52, 1724 (1919); J.Chem.Soc., 658 (1947);
Chem.Ber., 87 , 892 (1954); J.Am.Chem.Soc.
76, 1322 (1954); Helv.Chim.Acta., 58 , 147
(1975)] Such conventional methods required a complicated operation of changing the protecting group of the catechol moiety. Under such circumstances, the present inventors have developed erythro-N- expressed by the above general formula [], which is obtained by using vanillin, veratrylaldehyde, piperonal, etc. as a protecting group without removing the methyl group or methylene group. From phthaloyl-DOPS derivatives, erythro-
We discovered that DOPS can be produced efficiently and completed the present invention. That is, the present invention has the general formula [] (In the formula, R ¹ and R ² have the same meanings as above.) By reacting the erythro-DOPS derivative represented by the above with a phthaloylating agent, the erythro-N-phthaloyl-DOPS represented by the general formula [] When the erythro-N-phthaloyl-DOPS derivative represented by the general formula [], which can be obtained in good yield, is treated with a Lewis acid, despite the presence of carboxyl group, hydroxyl group, and imide group in the same molecule, When racemic or optically active erythro-N-phthaloyl-DOPS of the general formula [], in which only the methyl group or methyl group of the catechol moiety can be removed, is treated with hydrazine, the corresponding racemic or optically active erythro-DOPS is obtained. You can get it easily. The racemic form of the erythro-N-phthaloyl-DOPS derivative represented by the general formula [] and the racemic form of the erythro-N-phthaloyl-DOPS derivative represented by the general formula [] are optically active amines that are commercially available. This method was completed based on the knowledge that optical resolution can be carried out using a resolving agent and that corresponding compounds can be obtained as each optically active form (D-form or L-form). The present invention provides an industrial and economical method for producing Ramesh or optically active erythro-DOPS. The present invention will be explained in more detail below. Erythro represented by the above general formula []
DOPS derivatives can be produced, for example, according to the method described in JP-A No. 58-216146 or a method similar to such a known method, and the DOPS derivative can be produced using a phthaloyl compound such as phthalic anhydride or N-ethoxycarbonylphthalimide. By treatment with a curing agent, a racemic form of the erythro-N-phthaloyl-DOPS derivative represented by the general formula [] can be obtained. Optically active forms of erythro-N-phthaloyl-DOPS derivatives [] can be obtained by treating racemic forms with optically active amines such as strychnine, cinchonidine, and 2-amino-1,1-diphenylpropanol. N-phthaloyl-
Using the difference in solubility, the amine salt of D-erythro-N-phthaloyl-DOPS derivative and L-erythro-N-phthaloyl-
It can be obtained by separating DOPS derivatives into amine salts and then treating each salt with an acid. Racemic or optically active erythro-N-phthaloyl-DOPS derivatives [ ] to the corresponding erythro-
Until now, no method of obtaining N-phthaloyl-DOPS has been known. In general, various methods are known for removing the methyl group or methylene group from a compound having a methyl group or methyl group in the catechol moiety to form a catechol group. -(3,4-methylenedioxyphenyl)alanine or its N-acetyl derivative is treated with hydroiodic acid and acetic anhydride in the presence of red phosphorus to produce 3-(3,4-dihydroxyphenyl)alanine. Example of obtaining (Chem.
Pharm.Bull., 10 , 693 (1962)), 2-methyl-3
-(3,4-dimethoxyphenyl)alanine
Treated with 47.5% hydrobromic acid under reflux to give 2-methyl-
Example of obtaining 3-(3,4-dihydroxyphenyl)alanine (J.Amer.Chem.Soc., 77 , 700 (1955))
However, these conditions could not be applied to the demethylation reaction or demethyleneation reaction of the catechol moiety in the method of the present invention. On the other hand, the present inventors investigated various economical methods for producing threo-DOPS, and treated threo-3-(3,4-methylenedioxyphenyl)serine or its N-carbobenzoxy derivative with a Lewis acid. Method of removing methylene groups (JP-A-58-121258
(Japanese Patent Application Laid-open No. 183664/1983). The present inventors have taken into account the above findings and have
As an economical method for producing DOPS, the corresponding racemic or optically active erythro The conversion to -N-phthaloyl-DOPS [] is
It was found that the process progresses efficiently when treated with Lewis acid under mild conditions. In this reaction, it is preferable to add mercaptans or alkali metal iodides in addition to the Lewis acid. Racemic-erythro-N-phthaloyl-DOPS
[] can be converted into optically active (D and L)-erythro-N-phthaloyl-DOPS [] by optical resolution operation using an optically active amine. That is, racemic erythro-N-phthaloyl-
DOPS [] is treated with optically active amines such as cinchonidine, quinidine, norephedrine, and 2-amino-1,1-diphenylpropanol to produce D- and L-erythro-N-phthaloyl-
Using the amine salt of DOPS and utilizing the difference in solubility,
Optically active erythro-N is obtained by separating the amine salt of D-erythro-N-phthaloyl-DOPS and the amine salt of L-erythro-N-phthaloyl-DOPS, and then treating each salt with an acid.
-Phthaloyl-DOPS can be produced. The method for producing erythro-DOPS[] from erythro-N-phthaloyl-DOPS[] may be carried out by a conventional defthaloylation reaction using hydrazine or the like. The above-mentioned matters can be summarized in the following reaction process formula. [Table] ↓ ↓
〓〓 (racemic form) 〓〓 (optically active form)
Each step will be explained below. (1) Step A and Step B Step A and Step B differ depending on whether the raw material compound is a racemate or an optically active compound, and the reactions are exactly the same. Erythro-DOPS derivatives [ ] are reacted with phthaloylating agents such as phthalic anhydride and N-carboethoxyphthalimide to produce erythro-DOPS.
N-phthaloyl-DOPS derivative [ ] can be obtained. This reaction may be carried out using reaction conditions such as molar ratio, solvent, reaction temperature, and reaction time that are generally used when phthaloylating the amino group of an α-amino acid. (2) Step C In this step, the racemic erythro-N-phthaloyl DOPS derivative [] is subjected to optical resolution operation,
This is a step of obtaining an optically active (D and L)-erythro-N-phthaloyl-DOPS derivative []. Racemic-erythro-N-phthaloyl-DOPS
The derivative [] is reacted with an optically active amine such as strychnine, cinchonidine, or 2-amino-1,1-diphenylpropanol in an appropriate solvent to obtain optical activity with D and L-erythro-N-phthaloyl-DOPS derivatives. D-erythro-
Optically active amine salt of N-phthaloyl-DOPS derivative and L-erythro-N-phthaloyl-
The DOPS derivative is separated into optically active amine salt and
After that, each salt is treated with an acid to decompose the salt. The temperature for forming and fractionating the salt 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 on the time it takes to form the salt. Optically active amine is 0.5 to 1 for racemic erythro-N-phthaloyl-DOPS derivative []
It can be carried out using twice the molar amount. The solvent used for the formation and fractionation of the above salts is as follows:
Examples include alcohol solvents such as methanol, ethanol, and isopropyl alcohol, ether solvents such as tetrahydrofuran and dioxane, acetonitrile, water, and mixed solvents thereof. The salt of the obtained optically active erythro-N-phthaloyl-DOPS derivative [] with an optically active amine is decomposed by adding an acidic aqueous solution, and the optically active erythro-N-phthaloyl is extracted by an organic solvent. -DOPS derivative [ ] 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 can be 1 to 10 times the mole of the salt. Examples of the organic solvent used for extraction include ethyl acetate, chloroform, dichloroethane, dichloromethane, diethyl ether, and the like. (3) Step D and Step E Step D and Step E differ depending on whether the raw material compound is a racemate or an optically active compound, and the reactions are exactly the same. When a racemic or optically active erythro-N-phthaloyl-DOPS derivative [] is treated with a Lewis acid in a suitable solvent, the corresponding racemic or optically active erythro-N-phthaloyl-DOPS
[] is obtained. Examples of Lewis acids include aluminum chloride, aluminum bromide, ferric chloride, stannic chloride, boron chloride, boron bromide, etc. Also, a complex of a Lewis acid and dimethyl sulfide can be used as a Lewis acid. May be used. Lewis acid is 1 to 20 for erythro-DOPS derivative []
This can be carried out by using twice the molar amount, usually 2 to 10 times the molar amount. 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, or sodium iodide are added to the reaction solution. , an alkali metal iodide such as potassium iodide may be added in an amount of 1 to 5 times the mole of the Lewis acid. As the reaction solvent, any solvent may be used other than those that inhibit the progress of the reaction, such as halogenated alkyl solvents such as dichloromethane, chloroform, dichloroethane, and chlorobenzene, aromatic hydrocarbon solvents such as toluene and benzene, and ethyl acetate. , ester solvents such as butyl acetate, nitrated hydrocarbon solvents such as nitromethane, nitroethane, and nitrobenzene, acetone 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. (4) F process racemic-erythro-N-phthaloyl-DOPS
[] is treated with an optically active amine such as cinchonidine, quinidine, norephedrine, or 2-amino-1,1-diphenylpropanol to form D- and L-erythro-N-phthaloyl-
Using the difference in solubility, the amine salt of D-erythro-N-phthaloyl-DOPS and the amine salt of L-erythro-N-phthaloyl-
Optically active erythro-N-phthaloyl-DOPS can be produced by separating DOPS into amine salts and then treating each salt with an acid. The conditions for this optical resolution are the same as the molar ratio, solvent, temperature, time, and salt decomposition conditions used for the optical resolution of racemic-erythro-N-phthaloyl-DOPS derivative [], except for the optically active amine used as an optical resolving agent. It can be carried out using the following conditions. (5) G step and H step The G step and H step differ depending on whether the raw material compound is a racemate or an optically active compound, and the reactions are exactly the same. By reacting racemic or optically active - erythro-N-phthaloyl-DOPS [ ] with hydrazine, the corresponding racemic or optically active -
Erythro-DOPS can be obtained. Hydrazine can be used in either anhydrous or hydrated form, and erythro-N-phthaloyl-
1 to 20 times the mole of DOPS [], usually 2 to 20 times
It may be carried out using 5 times the molar amount. As a solvent, water, alcoholic solvents such as methanol, ethanol, and isopropyl alcohol, dioxane,
Ether solvents such as tetrahydrofuran, halogenated alkyl solvents such as chloroform and 1,2-dichloroethane, and mixed solvents thereof can be used. Although the reaction proceeds at room temperature, the temperature may be increased to the boiling point of the solvent to accelerate the reaction. By the way, among the compounds included in the method of the present invention,
The compounds represented by formulas [] and [] are all new, synthesized for the first time by the present inventors,
This demonstrates its usefulness as an intermediate for DOPS synthesis. Furthermore, the optically active form of the erythro-DOPS derivative represented by the general formula [] can be obtained by, for example, reacting the racemic form of the compound [] with carbobenzoxy chloride to obtain the N-carbobenzoxy form, and then optically It can be obtained by splitting and performing catalytic reduction. The method of the present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto. Reference Example 1 20 g of racemic erythro-3-(3,4-methylenedioxyphenyl)serine and 11.31 g of anhydrous sodium carbonate were dissolved in 200 ml of water, and 27.28 g of N-carboethoxyphthalimide was added to this solution at below 5°C. added. The mixture was stirred at room temperature for 3 hours, then made weakly acidic by adding 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 obtained residue was crystallized with 80 ml of methanol,
Racemic erythro-N by taking the crystals
-phthaloyl-3-(3,4-methylenedioxyphenyl)serine was obtained. 29.63g, mp117 _~ 20℃ Elemental analysis (for _C18H13O7N・_CH3OH ) Calculated values: C58.94%, _H4.49 %, N3.62% Actual values: C58.76%, H4. 41%, N3.60% Example 1 Racemic erythro-N- obtained in Reference Example 1 above
A solution of 24.5 g of phthaloyl-3-(3,4-methylenedioxyphenyl)serine, 71.3 g of n-octyl mercaptan, and 740 ml of dry dichloromethane was cooled to -10 to 0°C, and 65.0 g of anhydrous aluminum chloride was added to -10 Stirred at ~0°C for 4 hours. Add this mixture to 430 ml of 5% oxalic acid water for 20 min.
The mixture was added dropwise at a temperature of 30°C to 40°C and stirred for 30 minutes. The mixture was further stirred for 30 minutes at room temperature, and the precipitated crystals were collected to obtain 20.6 g of racemic erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl)serine [mp 93-95°C]. IR: Liquid paraffin (cm ^-1 ) 3400, 1700,
1610, 1510, 1400, 1380, 1190, 1110, 1010 Racemic erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl) obtained above
20.6 g of serine was dissolved in 200 ml of ethanol, and 4.5 g of hydrazine hydrate was added to this solution and heated under reflux for 2 hours. Concentrated hydrochloric acid was added to this reaction solution to make the pH≒1, and after stirring for 30 minutes, insoluble matter was removed, and the supernatant solution was diluted with 30% aqueous sodium hydroxide solution to pH≒5.5.
5.6, and the solvent was distilled off. The resulting residue was heated and dissolved in 140 ml of water, left at 0 to 5°C for 15 hours, and the precipitated crystals were collected to obtain 8.33 g of racemic erythro-3-(3,4-dihydroxyphenyl)serine [mp215 ~218℃] was obtained. Elemental analysis (for _C9H11O5N・_H2O ) Calculated values: C46.75%, H5.67%, N6.06 _% Actual values: C46.84%, H5.78%, _N6.06 % Example 2 - Racemic-erythro-N-phthaloyl-3
0.25 g of -(3,4-methylenedioxyphenyl)serine was dissolved in 40 ml of methanol, and 0.19 g of cinchonidine was added and dissolved. After standing at room temperature for 48 hours, the precipitated crystals were collected and L-erythro-N-phthaloyl-3-(3,4-methylenedioxyphenyl)serine cinchonidine salt 0.12
g (mp230~232℃, [α] ²⁰ _D -41.8° (c=1,
DMSO)) was obtained. Part of this salt is N-hydrochloric acid 10
ml and extracted twice with 20 ml of ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain oily L-erythro-N-phthaloyl-3-(3,4-methylenedioxyphenyl). )
Serine ([α] ²⁰ _D −4.5° (c=1, CHCl ₃ )) was obtained. - Racemic erythro-N-phthaloyl-3
0.25 g of -(3,4-methylenedioxyphenyl)serine was dissolved in 20 ml of ethanol, and 0.216 g of strychnine was added and dissolved. at room temperature
After standing for 15 hours, the precipitated crystals were collected and L-erythro-N-phthaloyl-3-(3,4-methylenedioxyphenyl)serine strychnine salt
0.08g [mp144~148℃, [α] ²⁰ _D −1.8° (c=1.0,
CHCl ₃ )] was obtained. Add some of this salt to the above −
When decomposed similarly, oily L-erythro-N-
Phthaloyl-3-(3,4-methylenedioxyphenyl)serine [[α]] ²⁰ _D -2.3° (c=1,
CHCl ₃ )] was obtained. - Racemic erythro-N-phthaloyl-3
- After dissolving 22.0 g of (3,4-methylenedioxyphenyl)serine in 200 ml of ethanol, S-2
-Amino-1,1-diphenyl-1-propanol (12.9 g) was added and dissolved. After leaving this solution at room temperature for 15 hours, the precipitated crystals were collected and L-erythro-N-phthaloyl-3-(3,4-methylenedioxyphenyl)serine S-2-amino-
1,1-diphenyl-1-propanol salt
12.51 g [mp 118-119°C] was obtained. [α] ³⁰ _D −
135.4° (c=1, chloroform) 12.0 g of the salt obtained above was recrystallized from 96 ml of ethanol to obtain 10.98 g of salt (mp118-119°C, [α] ³⁰ _D −
137.6° (c=1, CHCl ₃ )) was obtained. Elemental analysis (for C ₃₃ H ₃₀ N ₂ O ₈ .C ₂ H ₅ OH) Calculated values: C66.87%, H5.77%, N4.46%, Calculated values: C66.91%, H5.85%, N4.44%, 50 ml of 1N hydrochloric acid and 50 ml of ethyl acetate were added to 7.70 g of the salt obtained above, and the mixture was stirred at room temperature for 30 minutes to separate the layers. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain L-erythro-N-phthaloyl-3-.
(3,4-methylenedioxyphenyl)serine
4.35 g [[α] ²⁵ _D -172.5° (c=1, CHCl ₃ )] was obtained as an oil. IR: Liquid paraffin (cm ^-1 ) 3500, 1700,
1600, 1240, 1160, 1090, 1020, 910 4.35 g of L-erythro-N-phthaloyl-3-(3,4-methylenedioxyphenyl)serine obtained in - above, n-octyl mercaptan
A solution of 7.5 g in 60 ml of dry dichloromethane -10
Cool to ~0°C, anhydrous aluminum chloride 6.85g
was added and stirred at -10 to 0°C for 4 hours. This mixture was added dropwise to 90 ml of 5% oxalic acid water at a temperature below 20°C, and then stirred at 30-40°C for 30 minutes. The mixture was further stirred at room temperature for 30 minutes and left to stand, and the mixture was separated into an aqueous layer and a dichloroethane layer. The aqueous layer was extracted with 40 ml of ethyl acetate, and the ethyl acetate extract was washed with saturated brine and dried over magnesium sulfate. When the solvent of the obtained washing liquid was distilled off under reduced pressure, L-erythro-N-phthaloyl-3-
(3,4-dihydroxyphenyl)serine 2.27
g ([α] ²⁶ _D −154.7° (c=1, methanol)) of an oil was obtained. IR: Liquid paraffin (cm ^-1 ) 3500, 1700,
1605, 1510, 1270, 1160, 1110, 1030, 930 2.06 g of L-erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl)serine obtained above was dissolved in 20 ml of ethanol and suspended in this solution. 0.45 g of water hydrazine was added and the mixture was heated under reflux for 2 hours. This reaction solution was diluted with concentrated hydrochloric acid at room temperature to pH=1.0.
After stirring for 30 minutes, remove the insoluble matter and remove the concentrated mother liquor.
PH≒5.5-5.6 with 30% sodium hydroxide aqueous solution
The solvent was distilled off. The obtained residue was heated and dissolved in 4.4 g of water.
1.12 g of L-erythro-3-(3,4-dihydroxyphenyl)serine ([α] ²¹ _D +
51.6° (c=1, N-HCl), mp 190-193°C (decomposition)). Elemental analysis (for C ₉ H ₁₁ O ₅ N・2 1/6H ₂ O) Calculated values: C43.04%, H6.11%, N5.54% Actual values: C43.00%, H6.08%, N5 .57% Example 3 - Racemic erythro-N-phthaloyl-3-(3,4-
0.245 g of (dihydroxyphenyl)serine was dissolved in 10 ml of ethanol, and 0.209 g of quinidine was added and dissolved. After standing for 15 hours at room temperature, the precipitated crystals were collected and L-erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl)serine quinidine salt 0.085g [mp230-240℃, [α]
²⁵ _D +69.0° (c=1, DMSO)] was obtained. When a part of this salt is decomposed in the same manner as in Example 2, an oily L-erythro-N-phthaloyl-3-
(3,4-dihydroxyphenyl)serine ([α] ²⁶ _D -3.0° (c=1, CHCl ₃ )) was obtained. - Racemic erythro-N-phthaloyl-3
-(3,4-dihydroxyphenyl)serine
0.245 g was dissolved in 10 ml of ethanol, and 0.190 g of cinchonidine was added and dissolved. 5 at room temperature
After standing for a period of time, the precipitated crystals were collected and L-erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl)serine cinchonidine salt 0.088
g [mp235~40℃ (decomposition) [α] ²⁶ _D −20.2° (c=
1, DMSO)] was obtained. When a part of this salt is decomposed in the same manner as in Example 2-2, an oily L-erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl)serine ([α] ²⁶ _D +12.7°( c.
= 1, CHCl ₃ )) was obtained. - Racemic erythro-N-phthaloyl-3
-(3,4-dihydroxyphenyl)serine
Dissolve 0.245g in 5ml of ethanol, S-2
-Amino-1,1-diphenyl-1-propanol (0.147 g) was added and dissolved. After standing at room temperature for 5 hours, the precipitated crystals were collected and L-erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl)serine S-2-amino-1,1
-diphenyl-1-propanol salt 0.050g
[mp300℃ or higher, [α] ²⁶ _D +13.1° (c=1,
DMSO)] was obtained. Example of a part of this salt
When decomposed in the same manner as 2,-, oily L-erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl)serine ([α] ²⁶ _D -1.1° (c=
1, CHCl ₃ )) was obtained. - Racemic erythro-N-phthaloyl-3
-(3,4-dihydroxyphenyl)serine
0.245 g was dissolved in 10 ml of isopropyl alcohol, and 0.098 g of norephedrine was added and dissolved. After standing at 0 to 5°C for 15 hours, the precipitated crystals were collected and L-erythro-N-phthaloyl-3
-(3,4-dihydroxyphenyl)serine
Norefedrin salt 0.086g [mp300℃ or higher,
[α] ²⁶ _D +3.4° (c=1, CHCl ₃ )] was obtained. When a part of this salt is decomposed in the same manner as in Example 2, an oily L-erythro-N-phthaloyl-
3-(3,4-dihydroxyphenyl)serine ([α] ²⁵ _D +20.1° (c=1, CHCl ₃ )) was obtained. Reference example 2 Racemic threo/erythro-3-(3,4-
Dimethoxyphenyl) serine (threo/erythro = 4/6) 217.2g and acetic acid 54.3g water 1630ml
In addition, it was recrystallized from this to give racemic erythro-3-(3,4-dimethoxyphenyl)serine.
18.2g (mp 183-5°C) was obtained. IR: Liquid paraffin (cm ^-1 ) 3200, 1600,
1515, 1410, 1315, 1255, 1230, 1130, 1020 NMR: δTMS CF ₃ COOD (ppm) 3.93 (s, 6H), 4.78 (d, 1H, J = 5Hz), 5.17 (d, 1H, J = 5Hz) , 7.07 (s, 3H) Racemic erythro-3-(3,
Dissolve 5.0 g of 4-dimethoxyphenyl)serine and 2.3 g of anhydrous sodium carbonate in 50 ml of water, and add 5.13 g of N-carboethoxyphthalimide to this solution.
was added at below 5°C. This mixture was stirred at room temperature for 3 hours, and then 200 g of water was added.
Added ml. Further, concentrated hydrochloric acid was added to make the mixture weakly acidic, and then 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 to give an oily racemic erythro-N-
5.34 g of phthaloyl-3-(3,4-dimethoxyphenyl)serine was obtained. NMR: δTMS CDCl ₃ (ppm) 3.75 (s, 6H), 5.05 (d, 1H, J = 9Hz), 5.52 (d, 1H, J = 9Hz), 6.67-6.83 (m, 3H), 7.68 (m, 4H) Example 4 Racemic erythro-N- obtained in Reference Example 2 above
Phthaloyl-3-(3,4-dimethoxyphenyl)serine 5.0g and n-octylmercaptan
14.4 g of anhydrous aluminum chloride was added to a mixture of 14.3 g and 150 ml of dry dichloromethane at a temperature below 5°C, and the mixture was stirred at 0 to 10°C for 4 hours. This mixture was added dropwise to 100ml of 5% oxalic acid water at below 20°C.
Thereafter, the temperature was raised to 30-40°C and stirred for 30 minutes. The temperature was further stirred for 30 minutes, the precipitated crystals were collected, and racemic erythro-N-phthaloyl-3-
(3,4-dihydroxyphenyl)serine 4.40
g (mp93-95°C) was obtained. Racemic erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl) obtained above
2.06 g of serine was dissolved in 20 ml of methanol, and 0.45 g of hydrazine hydrate was added to this solution and heated under reflux for 2 hours. Concentrated hydrochloric acid was added to this reaction solution to bring the pH to 1, and after stirring for 30 minutes, insoluble matter was removed, and the concentrated mother liquor was diluted with a 30% aqueous sodium hydroxide solution to a pH of 5.5.
5.6, and the solvent was distilled off. The obtained residue was heated and dissolved in 13 ml of water, and the
Racemic erythro-3-(3,4
-dihydroxyphenyl)serine 0.83g
(mp215-218℃) was obtained. Reference example 3 Racemic threo/erythro-3-(4-hydroxy-3-methoxyphenyl)serine, 5.0
g (threo/erythro≒3/2), 2.8 g of anhydrous sodium carbonate was dissolved in 50 ml of water, and 6.75 g of N-carboethoxyphthalimide was added to this solution at 5°C.
Added below. The mixture was stirred at room temperature for 3 hours, made weakly acidic by adding concentrated hydrochloric acid, and extracted three times with 500 ml of ethyl acetate. After drying this ethyl acetate layer with anhydrous sodium sulfate and distilling off the ethyl acetate, racemic threo/erythro-N-phthaloyl-
3-(4-hydroxy-3-methoxyphenyl)
12.1 g of serine was obtained as an oil. A portion of this was separated and purified using silica gel chromatography to obtain racemic erythro-N-phthaloyl-3-(4-hydroxy-3-methoxyphenyl)serine as an oil. NMR: δTMS CDCl ₃ (ppm) 3.6 (s, 3H), 4.7 (d, 1H), 5.28 (d, 1H), 6.4-6.8 (m, 3H), 7.8 (s, 5H) Example 5 Reference example above Racemic erythro-N- obtained in 3.
Anhydrous aluminum chloride in a mixture of 0.5 g of phthaloyl-3-(4-hydroxy-3-methoxyphenyl)serine, 1.43 g of n-octyl mercaptan, and 15 ml of dry dichloromethane at below 5°C.
1.44 g was added and stirred at 0 to 10°C for 4 hours. This mixture was added dropwise to 10 ml of 5% oxalic acid water at a temperature below 20°C, and then stirred at 30-40°C for 30 minutes. The crystals precipitated by further stirring for 30 minutes at room temperature were collected, and racemic erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl)
0.44 g of serine (mp93-95°C) was obtained. Racemic erythro-N-phthaloyl-3-(3,4-dihydroxyphenyl) obtained above
0.206 g of serine was dissolved in 4 ml of methanol, and 0.045 g of hydrazine hydrate was added to this solution, followed by heating under reflux for 2 hours. Add concentrated hydrochloric acid to this reaction solution and pH≒1
After stirring for 30 minutes, insoluble matter was removed, and the concentrated mother liquor was diluted with a 30% aqueous sodium hydroxide solution to pH≒5.5.
~5.6 and the solvent was distilled off. The obtained residue was heated and dissolved in 1.3 ml of water, and the
Racemic erythro-3-(3,4
-dihydroxyphenyl)serine 0.08g
(mp215-218℃) was obtained.

Claims (1)

[Claims] 1 formula Erythro-N-phthaloyl-3-
A formula characterized by subjecting (3,4-dihydroxyphenyl)serine to a defthaloylation reaction A method for producing erythro-3-(3,4-dihydroxyphenyl)serine represented by 2 General formula (In the formula, one of R ¹ and R ² means a methyl group and the other a hydrogen atom, or both R ¹ and R ² mean a methyl group, or when R ¹ and R ² racemic or optically active -erythro-
By treating N-phthaloyl-3-(3,4-dihydroxyphenyl)serine derivative with Lewis acid, the formula Erythro-N-phthaloyl-3-
(3,4-dihydroxyphenyl)serine,
If this is a racemate, optical resolution is further carried out as necessary by the action of one of the optically active amines selected from cinchonidine, quinidine, norephedrin, and 2-amino-1,1-diphenylpropanol. The racemic or optically active -erythro-N-phthaloyl-3-(3,4-
A formula characterized by subjecting dihydroxyphenyl)serine to a dephthaloylation reaction A method for producing erythro-3-(3,4-dihydroxyphenyl)serine represented by