JPS59216858A - Preparation of threo-3-(3,4-dihydroxyphenyl)serine - Google Patents

Abstract

PURPOSE:To obtain the titled compound economically, by carrying out optical resolution in each process in case of necessity, treating a threo-N-phthaloyl-3- (3,4-dihydroxyphenyl)serine derivative with a Lewis acid, subjecting it to a reaction to remove phthaloyl group. CONSTITUTION:A racemic modification shown by the formula I (R<1>, and R<2> are H, methyl, etc.; but not H simultaneously) or optically active substance is subjected to optical resolution process, and, in case of the racemic modification, it is treated with an optically active amine (e.g., ephedrine), to give optical active substances, each of them treated with a Lewis acid (e.g., aluminum chloride) to give a racemic modification shown by the formula II or an optical active substance, and, in case of the racemic modification, it is similarly subjected to optical resolution process, to give an optical active substance. The racemic modification shown by the formula II or the optical active substance is subjected to a reaction to remove phthaloyl group, to give the desired compound of a racemic modification shown by the formula III or an optical active substance. Substitution of protecting group at catechol part is not required and the desired compound is obtained inexpensively.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the formula CI) 0 represents a racemate or an optically active form, and * represents an asymmetric carbon. ) Racemic or optically active threo-3-(8,
The present invention relates to a method for producing 4-dihydroxyphenyl)serine.

More specifically, the general formula (IT) 0■ (The formula represents a racemate or an optically active form, * indicates an asymmetric carbon, 6R and R each mean a hydrogen atom or a methyl group, or R and 几 and means a methylene group. However, R and R2 do not mean a hydrogen atom at the same time.) When is a racemate, if necessary, an optical resolution operation can be carried out by reacting with one of the optically active amines selected from ephedrine, cinchonidine, and 2-amino-1,1-diphenylpropanol. .

(5) Optically active -threo-N represented by the above general formula (II)
-phthaloyl-8-(8,4-dihydroxyphenyl)
A serine derivative is obtained, racemic or optically active -threo-N-phthaloyl-8-(8,
A 4-dihydroxyphenyl) serine derivative is treated with a Lewis acid to form a racemic or optically active compound represented by the formula [■] (The formula represents a racemic or optically active form, and * indicates the same meaning as above.) -N-phthaloyl-8-(8,4-dihydroxyphenyl)serine, if it is racemic, cinchonine, cinchonidine, (6) quinine, ephedrine, 2-amino-1,1-diphenyl An optical resolution operation is performed by reacting with one of the optically active amines selected from propanol, and the formula (m
) Optically active threo-N-phthaloyl-8-
(3,4-dihydroxyphenyl)serine obtained, racemic or optically active -threo-N- represented by the above formula [■]
The above formula [■
] Racemic or optically active -threo-8-(
The present invention relates to a method for producing 8,4-dihydroxyphenyl)serine.

Racemic and optically active threo-8-(8,4-dihydroxyphenyl)serine (r:) (hereinafter abbreviated as DOPS) that can be obtained by the method of the present invention is a therapeutic agent for peripheral orthostatic hypotension ( JP-A-56-104815), antidepressants (JP-A-55-20747), or therapeutic agents for Parkinson's disease (JP-A-F) 8-5221
It is a pharmaceutical drug known to be useful as (Japanese Publication No. 9).

Conventionally, as a method for producing racemic or optically active DOPS, a method using an aldehyde derivative represented by the general formula Cry (wherein R and R have the same meanings as above) as a starting material is known. .

That is, a compound represented by the above general formula [■], such as vanillin, veratryl aldehyde or hyheronal, is used as a starting material, and the methyl group or methylene group, which is a protective group of the catechol moiety, is removed to obtain the formula [
After obtaining the protocatechualdehyde represented by
The catechol moiety is again protected with an ethoxycarbonyl group or a benzyl group to give the formula [vT] [wherein R8 means an ethoxycarbonyl group or a benzyl group]. ] This benzaldehyde derivative is condensed with glycine or a glycine derivative to obtain a mixture of threo and erythro 8-(8,4-dihydroxyphenyl)serine derivatives, and if necessary protected by optical resolution operation. By removing the group,
A method of producing racemic or optically active DOPS is used. (C!hem, Ber,, 52
.

1724 (1919): J, Chem, Boa
,, 658 (1947): (!hem, Ber,
, 87, 892 (1954): J. Am.
Chem.

Soc, 76, 1822 (1954): He
1v, Chim, Acta,.

(9) 58. 157 (1975)] i.e. DOP
In producing No. 8, 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, they discovered a method of the present invention in which the methyl group or methylene group of a compound represented by the general formula (TV), such as vanillin, veratrylaldehyde, or biperonal, is used as is as a protecting group for catechol, and the present invention was completed.

That is, the method of the present invention comprises (1) an aldehyde derivative represented by the general formula [rv];
For example, the general formula [■] obtained by using vanillin, veratrylaldehyde, biperonal, etc. as is without removing the methyl group or methylene group [■] (10) OH (The formula represents a racemic form or an optically active form, *, R and R have the same meanings as above.) By reacting the waxy semi- or optically active -threo-8-(8,4-dihydroxyphenyl)serine derivative represented by the formula with a phthaloylating agent, the general formula [■ A racemic or optically active -threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine derivative represented by the following formula can be obtained in good yield.

(2) Even though racemic or optically active -threo-N-phthacarboxyl, hydroxyl, and imide groups are present in the same molecule, only the methyl or methylene group of the catechol moiety can be removed.

■ Racemic or optically active -threo-N-phthaloyl-
8-(8,4-dihydroxyphenyl)serine [1■]
Treatment with hydrazine gives the corresponding racemic or optically active -DOP8 in good yield.

■ Racemic-threo-N-phthaloyl-3-(8,4-
dihydroxyphenyl)serine derivative r■] and racemic-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine [■] using an industrially available optically active amine as an optical resolving agent. can be optically resolved, and the corresponding compounds can be obtained as optically active forms (D-form or L-form).

This was completed based on this knowledge. The present invention provides an industrial and economical method for producing optically active DOP8.

The method of the present invention will be explained in more detail below.

Racemic or optically active -threo-8-(8,4-dihydroxyphenyl)serine derivative [■] lt-hydrophthalic acid N
-Lase 2 or optically active -Threo-N by treatment with a phthaloylating agent such as ethoxycarbonylphthalimide
-phthaloyl-8-(8,4-dihydroxyphenyl)
A serine derivative [■] is obtained.

To obtain racemic threo-N-phthaloyl-8-(8゜4-dihydroxyphenyl)serine derivative (II) as an optically active form by optical resolution, ephedrine, cinchonidine, 2-amino-1,1- D- and L-threo-N-phthaloyl-8-(3,
Using the difference in solubility, the amine salt of D-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine derivative and L-threo-N-phthaloyl- 8-(8,
It can be obtained by fractionating the amine salt of 4-dihydroxyphenyl)serine derivative (18) and then treating each salt with an acid.

Racemic or optically active threo-N-phthaloyl-8-(
Until now, no method has been known to obtain the corresponding threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine (m') from the 8,4-dihydroxyphenyl)serine derivative [■].

Generally, various methods are known for removing the methyl group or methylene group from a compound having a methyl group or hamethylene group in the catechol moiety to form a catechol group. −
(8,4-Methylenedioxyphenyl)alanine or its N-acetyl derivative was treated with hydroiodic acid and acetic anhydride in the presence of red phosphorus to obtain 3-(R,4-dihydroxyphenyl)alanine. Examples (Chem, Ph
arm, Bull, 10, 698 (196
2)), 2-Methyl-8-(8,4-dimethoxyphenyl)alanine was dissolved in 47.5% hydrobromic acid under reflux (14
) to obtain 2-methyl-8-(8,4-dihydroxyphenyl)alanine (J, Amer, Chem.

Soc, 77, 700 (1955)), but these conditions could not be applied to the demethylation reaction or demethyleneation reaction of the catechol moiety in the method of the present invention.

The present inventors have discovered that racemic or optically active threo-N-phthaloyl-8-
(8,4-dihydroxyphenyl)serine derivative (II
] to the corresponding usicami or optically active threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine [■]. I discovered that I could achieve my goal. In this reaction, it is preferable to add mercaptans in addition to the Lewis acid.

Racemic-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine (III) was obtained by optical resolution operation using an optically active amine. (4-dihydroxyphenyl) decaphosphorus (m).

i.e., racemic-threo-N-phthaloyl-8-(8,4
D- and L-threo-N
-phthaloyl-8-(8,4-dihydroxyphenyl)
Using the difference in solubility, the amine salt of D-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine and the amine salt of L-threo-N-phthaloyl-8-(8° 4-dihydroxyphenyl)serine was fractionated into amine salts, and each salt was then treated with acid to form an optically active threo-N-phthaloyl-8-/(8,
4-dihydroxyphenyl)serine can be produced.

Racemic or optically active threo-N-phthaloia 1/-8
The method for producing optically active Do, ps(r) from -(8,4-dihydroxyphenyl)serine [m] is a conventional method,
This may be carried out by a defthaloylation reaction using hydrazine or the like.

When the above-mentioned matters are summarized and shown in a reaction process formula, it is as follows.

[■] (racemic form) [■] (optically active form) (17) Each step will be explained below.

(1) Human process and B process The difference between the human process and B process is whether the starting compound is a racemate or an optically active compound, and the reactions are exactly the same.

Threo-8-(8,4-dihydroxyphenyl)serine derivative [■] (racemic or optically active form) is reacted with a phthaloylating agent such as phthalic anhydride or N-carboethoxyphthalimide to produce threo-N -Phthaloyl-8-(8,4-dihydroxyphenyl)serine derivative [■] (racemic or optically active) 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 an amine salt of an α-amino acid.

(2) Step C This step is racemic-threo-N-phthaloyl-8-(8
, 4-dihydroxyphenyl) serine derivative [■] (racemic form) was subjected to optical separation/1G) to obtain optically active CD and L)-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl). This is a step to obtain a serine derivative [■] (optically active substance).

Racemic-threo-N-phthaloyl-3-(8,4-dihydroxyphenyl)serine derivative [■] (racemic form) is converted into an optically active amine selected from ephedrine, cinchonidine, and 2-amino-1,1-diphenylpropanol. 1
D and L-threo-N-phthaloyl-3-(8,4-dihydroxyphenyl)serine derivatives are reacted with the optically active amine in an appropriate solvent, and the difference in solubility is utilized. D-threo-N-phthaloyl-8-(
8,4-dihydroxyphenyl)serine derivative and an optically active amine salt of L-threo-N-phthaloyl-8-(B
, and an optically active amine salt of a 4-dihydroxyphenyl)serine derivative, and then each salt is treated with an acid to decompose the salt.

The temperature for forming and fractionating salts can be 0 to 80°C, but it can be carried out at 0 to 30°C after heating near the boiling point of the solvent.
It can also be cooled down to 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 is racemic-threo-N-phthaloyl-8
-(8,4-dihydroxyphenyl)serine derivative [■
] (racemic form) using 0.5 to 1 times the molar amount.

Preferred examples of the solvent used for the formation and fractionation of the salt include alcohol-based HtM such as methanol, ethanol, and isopropyl alcohol, ether-based solvents such as tetrahydrofuran and dioxane, ar-1-tonitrile, water, and mixed solvents thereof. I can do it.

The optically active -threo-N-phthaloyl-8-(8
,4-dihydroxyphenyl)serine derivative [■] (optically active form) by adding an acidic aqueous solution to the salt with an optically active amine to decompose the salt, and extracting with an organic solvent to obtain optically active -threo-N- Carbobenzoxy-8
-(8,4-dihydroxyphenyl)serine derivative [■
] (optically active substance) 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 amount of the salt.

Examples of the organic solvent used for extraction include ethyl acetate, chloroform, dichloroethane, dichloromethane, diethyl ether, and the like.

(8) Steps D and E Steps D and E differ depending on whether the starting compound is a racemate or an optically active compound, and the reactions are exactly the same.

Racemic or optically active -threo-N-phthaloyl-8-
(8,4-dihydroxyphenyl)serine derivative [■]
(racemic or optically active form) is treated with a Lewis acid in an appropriate solvent to produce the corresponding racemic or optically active -threo(21) -N-phthaloyl-8-(8,4-dihydroxyphenyl)serine [■] (racemic form). or optically active form).

Preferred examples of Lewis acids include aluminum chloride, aluminum bromide, ferric chloride, stannic chloride, boron chloride, and boron bromide, and complexes of Lewis acids and dimethyl sulfide can be cited as Lewis acids. [
It can be carried out by using 1 to 20 times the mole, preferably 2 to 10 times the mole of I[). In order to obtain favorable results, in addition to Lewis acid, methyl mercaptan, ethyl mercaptan, butyl mercaptan,
Mercaptans having 1 to 20 carbon atoms such as octyl mercaptan, dodecanyl mercaptan, and octadecanyl mercaptan may be added in moles of 1 to 5 times the Lewis acid.

As the reaction solvent, any solvent other than the solvent (22) that inhibits the progress of the reaction may be used, but preferred solvents include halogenated alkyl solvents such as dichloromethane, chloroform, dichloroethane, and chlorobenzene, and aromatic solvents such as toluene and benzene. Hydrocarbon solvents, ester solvents such as ethyl acetate and butyl acetate, nitrated hydrocarbon solvents such as nitromethane, nitroethane, and nitrobenzene, acetone solvents such as acetone and methyl ethyl ketone, pyridine, etc., or mixed solvents thereof. can,
Although the reaction temperature can be carried out in the range of -40 to 80°C, it is preferably carried out at -10 to 80°C.

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

(4) Step F from racemic-threo-N-phthaloyl-3-(8,4-dihydroxyphenyl)serine [■] (ra!!mi form) to optically active -threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine -dihydroxyphenyl)serine [■] (optically active form)
D and 4-dihydroxyphenyl)serine (m) (racemic form) are treated with one of the optically active amines selected from cinchonidine, cinchonine, quinine, ephedrine, and 2-amino-1,1-diphenylpropanol. L
-Threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine as an amine salt, and utilizing the difference in solubility, D-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine amine salt and L-threo-
The optically active threo-N-
Can you produce phthaloyl-〇-(8,4-dihydroxyphenyl)serine [■] (optically active form)?

The conditions for this optical resolution, except for the optically active amine used as an optical resolving agent, are those used for the optical resolution of racemic-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine derivative [■] (racemic form). It may be carried out using the same molar ratio, solvent, temperature, time, and conditions as those used for salt decomposition.

(ω G step and ① step 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.

Racemic or optically active threo-N-phthaloyl-8-(
The corresponding racemic or optically active DOP8 can be obtained by reacting 8,4-dihydroxyphenyl)serine [■] (racemic or optically active) with hydrazine.

Hydrazine can be used in either anhydrous or hydrated form, and is preferably 1 to 20 times the mole of threo-N-phthaloyl-3-(8,4-dihydroxyphenyl)serine [■], preferably 2 (25) It may be carried out using ~5 times the molar amount. As the solvent, water, alcohol solvents such as methanol, ethanol, and isopropyl alcohol, ether solvents such as dioxane and tetrahydrofuran, halogenated alkyl solvents such as chloroform and 1,2-dichloroethane, and mixed solvents thereof may be used. You can do it. 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, the compounds represented by the internal formula [■] and (IID) included in the method of the present invention are all new, synthesized for the first time by the present inventors, and have shown their usefulness as intermediates for DOP8 synthesis. It is something.

Furthermore, among the compounds represented by the general formula [■], the compound in which R1 is a hydrogen atom and R2 is a methyl group is known in both racemic form and optically active form (US Patent No. 8.728.514). , compounds in which both ■ and 几 in the general formula [■] are methyl groups, and compounds in which R and R represent methylene groups are already known (Pharmaceutical Journal 67.218 (1947): Ca
n, J, Ohem, 42, 19001964
).

Z, Naturforsch, BQQ-588 (19
75) Texas Repts, Biol, a
nd Med, 18, 195 (1955))
The three-dimensional structure of threo and erythro bodies is completely unknown, but the inventors have revealed that the three-dimensional structure is a threo body.
It is isolated.

In other words, the racemic compound of the compound represented by the general formula [2], in which R and R represent methylene groups, is prepared by combining glycine and piperonal in an organic solvent such as methanol in the presence of an inorganic base such as potassium hydroxide. After the reaction, water and acetic acid are added to the reaction solution to decompose the reaction intermediate, and then an organic solvent such as toluene is added to transfer piperonal to the organic layer, and racemic threo-8-CB, 4-methylenedi The acetate of (oxyphenyl)serine is precipitated, and after this salt is boiled to the bottom of a furnace, it can be obtained by recrystallizing from water. threo-N-carbobenzoxy-8-(
After obtaining 8,4-methylenedioxyphenyl)serine, an optical resolution operation is performed, followed by a catalytic reduction. (Japanese Patent Application No. 57-99786) Racemic and optically active compounds of the compound represented by the general formula [■] in which both R1 and R are methyl groups can be obtained by the same method as above. .

The method of the present invention will be specifically explained below with reference to examples and reference examples, but the present invention is not limited to these.
Reference Example 1 Racemic-threo-8-(8,4-methylenedioxyphenyl)serine 20 y, anhydrous sodium carbonate 11.8
1F was dissolved in 200 d of water, and 27, 28 f of N-carbethoxyphthalimide was added to this solution at 5°C or below.

After stirring this mixture at room temperature for 8 hours, concentrated hydrochloric acid was added to make it weakly acidic. The precipitated crystals are heated to the bottom of the furnace to form racemic threo-N.
-Phthaloyl-8-(8,4-methylenedioxyphenyl)serine 80.68 f, mp 124°C was obtained.

Example 1 ■ A solution of racemic-threo-N-□ceftaroyl-(8,4-methylenedioxyphenyl)serine 30f1 ethyl mercaptan 45 Wt1 dry dichloromethane 900 mA obtained in Reference Example 1 above was cooled to -10 to 0°C. Then add 67.5 fl of anhydrous aluminum chloride and mix
The mixture was stirred at 0°C for 4 hours. Drop the mixture of 5% oxalic acid into 600 bottles of ice water at 20°C or below, then boil at 30-40°C.
C and stirred for 80 minutes. After further stirring for 80 minutes at room temperature, the precipitated crystals were collected and racemic-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine 22. Of.

mp180-1B2°C was obtained.

■ Racemic-threo-N-phthaloyl obtained in ■ above?
20.6 fl of '8,4-dihydroxyphenyl)se(29) phosphorus 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. This reaction solution was concentrated under reduced pressure, the filtrate was removed, and the Oki filtrate was diluted with an 80% aqueous sodium hydroxide solution to pH=5.5~
Racemic threo-8-(8,4-dihydroxyphenyl)
Seri:/mP222-224°C, 10, fM' was obtained.

Reference Example 2 ■ Racemic-threo-8-(8,4-methylenedioxyphenyl)serine 59. Add Of to an aqueous solution containing 20f of sodium hydroxide at 5°C or below, and after dissolving at 5°C
Carbobenzoxy chloride 47. Of was added dropwise. At the same time, drop 80% sodium hydroxide, pns,
It was adjusted to be between 5 and 9.5. After 2 hours, the pH was adjusted to #2 with concentrated hydrochloric acid and extracted with ethyl acetate. (30) The organic layer was washed with saturated brine, dried over magnesium myelate, and the solvent was distilled off under reduced pressure. The residue was crystallized from toluene, and the crystals were collected to obtain 89.01 t2-threo-N-carbobenzoxy-8-(8,4-methylenedioxypheni)serine.

racemic-threo-N-carbobenzoxy-8-(8,
4-methylenedioxyphenyl)serine 50. Ofl
was dissolved in 500 ml of acetonitrile, and 45.
11 was added to make a uniform solution. Cool in ice water for 5 hours,
The precipitated product was removed and L-threol N-carbobenzoxy
45.0 g of 8-(8,4-methylenedioxyphenyl)serine quinidine salt was obtained.

mp 161-16 B'C Ca]D+ 119.5° ((+=1.0.methanol) Part s6.oy of the above salt was recrystallized twice with methanol to obtain salt 26.4 II (mp 162 ~16B, 5°
c10 [α)D+122.6° (0=1.0, methanol))
After obtaining this salt 24. 8% hydrochloric acid water was added to Of, extracted with ethyl acetate, and L-threo-N was obtained as an amorphous powder.
-Carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine 10.8F was obtained.

0 [α)D −28,1° (C=1.0, methanol)
This L-threo-N-carbobenzoxy-8-(8,4
After dissolving 10.16 f of -methylenedioxyphenyl)serine in 880 methanol, 10% PD-C (50% water content) 1.04F and 10.16 fl of water were added to perform catalytic reduction at normal pressure. After hydrogen was no longer absorbed, 4.0 g of concentrated hydrochloric acid was added, and after stirring, the insoluble matter was removed and the rice grain liquid was
The pH was adjusted to #5.5 with 0% sodium hydroxide aqueous solution.

Add the precipitated crystals and then recrystallize from water to obtain L-threo-
8-(8,4-methylenedioxyphenyl)serine 4.
16F%mp 196-198°C (decomposition), Ca]
Da 1.8° (e=1.0, N-HCzl was obtained.

■ L-threo-8-(8,4-methylenedioxyphenyl)serine obtained in step (■) above 4. oy.

Dissolve 2.25f of anhydrous sodium carbonate in 50ml of water,
Add 5.45f of N-carboethoxyphthalimide to this solution.
was added below 5°C. After stirring this mixture at room temperature for 8 hours, 50 tons of water was added and the mixture was made weakly acidic with concentrated hydrochloric acid. The precipitated crystals were added to obtain L-threo-N-phthaloyl-8-(8,4-methylenedioxyphenyl)serine 5.95f.

This crystal 2.51 was recrystallized from ethyl acetate to give L-threo-N-phthaloyl-8-(8,4-methylenedioxyphenyl)serine 1.15f, mpH 9 to 124°C1.
(L) D-96,1° (C-1, methanol) was obtained.

Example 2 ■ L-threo-N-phthalate (83) loyl-8-(B,4-methylenedioxyphenyl)serine obtained in Reference Example 2 above1. A solution of Og, 1.5 ml of ethyl mercaptan, and 80 vnL of dry dichloromethane was cooled to -10 to 0°C, and 2.25 f of anhydrous aluminum chloride was added to -10
-Stirred at OoC for 4 hours. This mixture was added dropwise to 2 bottles of 5% oxalic acid ice water at below 20"C, and then stirred at 30-4°C for 30 minutes. The mixture was further stirred at room temperature for 80 minutes, and the precipitated crystals were collected. L-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine 0.76fl, mT) 20'5~208''G
.

Ca) D91.0' (o = 1, methanol) was obtained.

■ L-threo-N-phthaloyl-8-(
0.52f of 8,4-dihydroxyphenyl)serine was dissolved in 50ml of ethanol, and 0.52f of hydrazine hydrate was added to this solution.
11i fl was added and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, methanol (4-) was added to the residue, and the solution was purified with concentrated hydrochloric acid.
After stirring for 80 minutes as H(84) 1, insoluble matter was removed, and the separated liquid was washed with N.
- By adjusting the pH to 5,6 with hydrochloric acid and collecting the precipitated crystals, L-threo-8-(8,4-dihydroxyphenyl)serine m p 228-226 °C, Q,
86 g of [α)D-87,4° (c=l, N-hydrochloric acid) was obtained.

Example 8 ■ Racemic-threo-N- obtained by the same reaction as in Reference Example 1
Phthaloyl-3-(8,4-methylenedioxyphenyl)serine 15. After dissolving Og in 15'Om of ethanol, 9.6 f of 8-2-amino-1,1-diphenyl-1-propatol was added and dissolved. After leaving this solution at room temperature for 15 hours, the precipitated product was added and L-threo-N-phthaloyl-8-(B,4-methylenedioxyphenyl)serine 5-2-amino-1,1-diphenyl- 1-Propatur salt 9.9f, mpHB-125℃, [α]D
-24.1° (e=1.0, methanol) was obtained.

This salt6. 26 ml of IN-hydrochloric acid water was added to Of, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected and L-threo-
N-phthaloyl-8-(8,4-methylenedioxyphenyl)serine 4.1 8 fllm p 9
0 to 100'C.

[α], -87.2° (G=1..0, methanol) was obtained.

■ Racemic-threo-N-phthaloyl-3-(8,4-
Dissolve 0.5f of methylenedioxyphenyl)serine in 5ml of dioxane and add 0.12f of cinchonidine salt to 8-(8,4-methylenedioxyphenyl)serine.
2~207°c120・[α]LJ -81,4° (c = 1, l'p
/ -JL/ ) got it. A part of this salt was added to N-hydrochloric acid 1
The ethyl acetate layer was dried over anhydrous sodium sulfate and the ethyl acetate was distilled off to obtain L-threo-N-phthaloyl-8-(F3.4-methylenedioxyphenyl)serine (pH 8~). 12 "α [α':)D-
112.7° (C=1, methanol) was obtained.

■ Racemic-threo-N-phthaloyl-8-(8,4-
Dissolve 0.5f of methylenedioxyphenyl)serine in 5rnt of acetonitrile, add and dissolve 0.28f of ephedrine, and let it stand at room temperature for 15 hours. (8,4-
methylenedioxyphenyl) serine/ephedrine salt 0
．． 25f, mp178~182°C-(a]n+
42.0° (c=1.0, methanol) was obtained. When a part of this salt is decomposed in the same manner as in ① above, D-threo-N-phthaloyl-8-(8,4-methylenedioxyphenyl) is obtained.
Serine mp 120-124°C, [α]D 72.7° (C=1, methanol) was obtained.

■ L-threo-N-phthaloyl-8-(
8,4-Methylenedioxyphenyl)serine 8f1 Ethyl mercaptan 4.5 nd, A solution of 90 tnL of dry dichloromethane was cooled to -10~0°C, 6.75f of anhydrous aluminum chloride was added, and the solution was cooled to -10~0°C. At 4
Stir for hours.

This mixture was mixed with 5% oxalic acid in 60rr of ice water at 20°C.
The mixture was added dropwise and then stirred at 30-40°C for 80 minutes. The temperature was further stirred for 30 minutes at room temperature, and the precipitated crystals were filtered and L-threo-N-phthaloyl-8-(8,4
-dihydroxyphenyl)sen'J 2.24 Q, m
p200~208°C1[α]D -90,2° (
c=1, methanol) was obtained, ■L-threo-N-phthaloyl-8-(obtained in the above ■)
2.061 of 8,4-dihydroxyphenyl)serine was dissolved in 20 d of ethanol, and 0 hydrazine hydrate was added to this solution.
．． 45 g was added and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, 20 mA of methanol was added to the residue, the pH was adjusted to 1 with concentrated hydrochloric acid, and after stirring for 80 minutes, the insoluble materials were removed, and the pH of the filtered mother liquor was adjusted to pH 5.6 with an 80% aqueous sodium hydroxide solution. When the precipitated crystals are collected, L-threo-8-(8,
4-dihydroxyphenyl)serine, mp228-22
5°C11,07N, (α]D-87.4°(C-1,
N-hydrochloric acid) was obtained.

Example 4 ■ Racemic threo-obtained by the same reaction as in Example 1-■
0.5f of N-phthaloyl-8-(8,4-dihydroxyphenyl)serine was dissolved in 5d of methanol, and 0.46F of quinine was added and dissolved. After standing for 155 hours at room temperature, the precipitated crystals were removed and D-threo-N-phthaloyl-
8-(8,4-dihydroxyphenyl)serine quinine salt 0.41f, mp180-185°C, Cα')D
-82.7° (C=1, methanol) was obtained. When a part of this salt is decomposed in the same manner as Example B-■, D-threo-
N-phthaloyl-8-(8,4-dihydroxyphenyl)serine mp 175°C (decomposed), [α)D +82.1° (C=1, methanol) was obtained.

■ Dissolve 0.59 of racemic-threo-N-phthaloyl-8-di(8,4-=+hydroxyphenyl)serine in methanol am/, and dissolve 0.48 of cinchonidine.
1 was added and dissolved. After standing for 5 hours at room temperature, the precipitated crystals were taken off and D-threo-N-phthaloyl-8-(8,
4-dihydroxyphenyl)serine 0.28N.

0 mp165-172°C1Ca], -41,2° (c=1, methanol) was obtained. When a part of this salt was decomposed in the same manner as in Example 3-■, D-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine mp1
80°C (min 0 solution), [α], +44.7° (C=1, methanol)
I got it.

■ Racemic-threo-N-phthaloyl-8-(8,4-
Dissolve 0.5 g of dihydroxyphenyl serinshi in 6 dioxane, and dissolve 0.5 g of dihydroxyphenyl serinshi in dioxane.
48 fl was added and dissolved. After standing at room temperature for 5 hours, the precipitated crystals were added and D-threo-N-phthaloyl-8-
(8,4-dihydroxyphenyl)serine cinchonidine 0.29 (c=1.methanol) was obtained. When a part of this salt is decomposed in the same manner as in Example 3-■, D-threo-N-
Phthaloyl-8-(8,4-dihydroxyphenyl)serine mp185°C (decomposition)・[α:)D +61.9
° (C=1, methanol) was obtained.

■ Racemic-threo-N-phthaloyl-3-(8,4-
dihydroxyphenyl) serine 0.51 to ethanol 5
trL! , and 0.249 g of ephedrine was added and dissolved. After standing at 0 to 5°C for 155 hours, the precipitated crystals were removed and D-threo-N-phthaloyl-8-(8
, 4-dihydroxyphenyl) serine ephedrine salt 0.8 g, mpH 9°C (decomposition), [α) D -15,
2° (C=1, methanol) was obtained.

Reference Example 3 29.9 g of glycine was added to a solution of 55 g of potassium hydroxide and 1040 g of methanol. 'lf was added to dissolve. 41) Then, 144.5f of Vera Shiba aldehyde was added to this and 62~
After stirring at 65°C for 80 minutes, the mixture was concentrated. 285 tons of methanol was added to this residue to dissolve it, and 725 f of acetic acid was further added and stirred at 40 to 45°C for 80 minutes. 120g of drained water
, 900f of toluene was added, and the mixture was stirred at 40-45°C for 2 hours. The reaction solution was separated, and the aqueous layer containing acetic acid was washed with a mixed solution of 800ml of badluene and 800d of diethyl ether, and after being left for 15 hours, crystals precipitated. When added, racemic threo/erythro 8-(8,4-dimethoxyphenyl)serine (threo/erythro = 7/8) 21
．． 72f, mpH 9°C (decomposed) was obtained.

This crystal 20f was recrystallized from 100 tnL of water to obtain racemic threo-8-(8,4-dimethoxyphenyl)serine 6, Of%mp 190°C (decomposed).

IR; 1) Nujol(z')8B60, 815
0, 1660.

1600, 1510, 1B40.

1240, IIFIo, 1020(42) 8.75(s, 8H), 8.77(s, 8H), 5
．． 05 (d, IH) 6.7-7.1 (m, 8H)■
5.0 g of racemic threo-8-(8゜4-dimethoxyphenyl)serine obtained in the above ①, anhydrous sodium carbonate 2.
3 g was dissolved in 50 ml of water, and 5.1 Bf of N-carboethoxyphthalimide was added to this solution at below 5°C.

This mixture was stirred at room temperature for 15 hours and 200 ml of condensate was added.
Add. After adding concentrated hydrochloric acid to make it weakly acidic, the precipitated crystals were collected at the bottom of the furnace and racemic-threo-N-phthaloyl-8-
(8,4-dimethoxyphenyl)serine 5.84f, m
p97''C (degraded) was obtained.

Example 5 ■ Racemic-threo-N-phthaloyl-8-(8,4-dimethoxyphenyl)serine obtained in Reference Example 8 above.
5 g of ethyl mercaptan, 0.75 ml of ethyl mercaptan, and 15 ml of dry dichloromethane were added with 1.44 f of anhydrous aluminum bromide at below 5°C, and after stirring at room temperature for 2 hours, 0.75 ml of ethyl mercaptan and anhydrous odor were added. 1.44 f of aluminum chloride was added and stirred at room temperature for 72 hours. This mixture was mixed with 5% oxalic acid at 20 °C in 50 fnt of ice water.
After adding dropwise at a temperature below C, extraction was performed 8 times with 50 mt of ethyl acetate, and the ethyl acetate layers were combined and extracted with 50 mt of saturated saline.
Washed twice.

The ethyl acetate layer was dried over anhydrous sodium sulfate, the ethyl acetate was distilled off, and the residue was crystallized from diethyl ether, giving 0.8 g of racemic-threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine, mp 128- 182°C was obtained.

■ Racemic-threo-N-phthaloyl-8 obtained in the above ■
-(8,4-dihydroxyphenyl)serine 0.21N
was dissolved in 2 d of ethanol, and 0.0 ml of hydrazine hydrate was added to this solution. 5 fl of O was added and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, 2 ml of methanol was added to the residue, the pH was adjusted to 1 with concentrated hydrochloric acid, and after stirring for 30 minutes, insoluble materials were removed and the filtered mother liquor was diluted with an 80% aqueous sodium hydroxide solution to pH 5.5-6.
When the precipitated crystals are taken off the surface, racemic-threo-
8-(8,4-dihydroxylephenyl)serine mp22
2-225°C 10.1f was obtained.

Reference example 4 Racemic threo/erythro 8-(8〒hydroxy-4
-Methoxyphenyl)serine 5.011 (8/2 in Threo/Erythro), anhydrous, 2.8 g of sodium carbonate to 5.01 g of water
0 ml, and 6.75 fl of N-carboethokylephthalimide was added to this solution at 5°C or lower. After stirring this mixture at room temperature for 8 hours, concentrated hydrochloric acid was added to make it weakly acidic.
It was extracted 8 times with 500 g of ethyl acetate. This ethyl acetate layer was dried over anhydrous sodium sulfate, and when the ethyl acetate was distilled off, racemic
Threo/erythro N-phthaloyl-8-(8-hydroxy-4-methoxyphenyl)serine 12.1f was obtained as an oil.

By separating and purifying a part of this using silica gel chromatography (45), the
(8-Hydroxy-4-'methoxyphenyl)phosphorus was obtained as an oil. , NMRM8 δODO18 (ppm) 8.6-(s, 8I:T)
4.9(d, IH) 5.22-(d, IH) 6.6-7
．． 0-(m, BH)7.92-(s, 5H) Similarly, by separation and purification by silica gel chromatography, erythro N-phthaloyl-8; (8=-hydroxy-4
-methoxyphenyl)serine was also obtained as an oil.

M8 NMR, δ(3DcLBrpl)m)8.6(s,
8H).

4.7 (d, IH), 5.28 (d, IH
), 6.4-6.8 (m, BH).

7.8 (s, 5H) Example 6 ■ Lacerated ε-threo N-phthaloyl-8-(B-hydroxy-4-methoxyphenyl)serine 1.0f% n-octylmercaptan 8. 5nd
+ 1.41 l of anhydrous aluminum chloride was added to a mixture of 150 l of dry dichloromethane at below 5°C. After stirring at room temperature for 15 (At!) hours, 2.1 f of anhydrous aluminum bromide and 8.5 rnt of n-octyl mercaptan were added.

After stirring for 15 hours, anhydrous aluminum bromide 2.
1 g of n-octyl mercaptan and 8.5 ml of n-octyl mercaptan were added and stirred for 40 hours. This mixture was added dropwise to 200 tons of 5% oxalic acid ice water at 20°C or lower. After extraction with ethyl acetate and drying over anhydrous sodium sulfate, the ethyl acetate was distilled off and the residue was crystallized from diethyl ether at the bottom of the furnace to give racemic-threo-N-phthaloyl-8-(8,4-dihydroxy7 x Ni JL/
) Seri: z0.14g, mp122-1B2°C was obtained.

■ Obtained from above. Racemic-threo-N-phthaloyl-
8-(8,4-dihydroxyphenyl)serine 0.11
f was dissolved in 1 tnL of ethanol, 0.028 g of hydrazine hydrate was added to this solution, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, 1 tnt of methanol was added to the residue, and the pH was adjusted to pH 5 with concentrated hydrochloric acid.
By adding the precipitated crystals adjusted to 5 to 6, old Miethreo-8 (Jj, 4-dihydroxyphenyl)serine mp222-2240C10,0fi I was obtained.

Reference Example 5 Racemic and threo-N-phthaloyl-8-(8,4-
Synthesis of standard specimen of dihydroxyphenyl)-t7 phosphorus ■ Racemic threo-8-(8,4-dihydroxyphenyl)serine 2 og, anhydrous sodium carbonate A11.94F
was dissolved in 2 oofnt of water, and 28.8 g of N-carboethoxyphthalimide was added to this solution at below 5°C. After stirring this mixture at room temperature for 15 hours, insoluble matter was removed,
After making the mother liquor weakly acidic with concentrated hydrochloric acid, 1000W of ethyl acetate was added.
Extracted three times at t. The ethyl acetate layer was dried over anhydrous sodium sulfate, the ethyl acetate was distilled off, and the residue was crystallized from diethyl ether and then added to give racemic-threo-N-phthaloyl-8-
(8゜4-dihydroxyphenyl)detophosphorus 20.9f.

mp181°C (decomposition) was obtained.

■ L-threo-8-(8,4-dihydroxyphe=
JL/) Sen +) 10f, anhydrous sodium carbonate 5.
979 was dissolved in 100 trLL of water, and 14.49 N-carboethoxyphthalimide was added to this solution at below 5°C. This mixture was stirred at room temperature for 3 hours.
1 was added, and then concentrated hydrochloric acid was added to make the mixture weakly acidic, and the mixture was extracted 8 times with 500 ml of ethyl acetate. This ethyl acetate layer was dried over anhydrous sodium sulfate, and then the ethyl acetate was distilled off to obtain residues 1o and 5f, which were crystallized from diethyl ether and L-threo-N-phthaloyl-3-(8,4-dihydroxy phenyl)serine 6.0g, mp187℃ (decomposition), (a]D
-99.9° (C-1, methanol) was obtained.

(49 cheeks

Claims (1)

[Claims] General formula (IF) Formula 1 represents a racemate or an optically active form, and * represents an asymmetric carbon. R and R each represent a hydrogen atom or a methyl group, or R1 and R2 together represent a methylene group. However, R1 and R2 do not mean a hydrogen atom at the same time. ) When the racemic or optically active -threo-N-phthaloyl-8-(8,4-dihydroxyphenyl)serine derivative represented by is racemic, if necessary b, ephedrine, cinchonidine, 2-amino-1, The optically active -threo-N-phthaloyl-8-(8 , 4-dihydroxyphenyl) serine derivative, racemic or optically active -threo-N-phthaloyl-8-(8,4-
dihydroxyphenyl) serine derivative is treated with a Lewis acid to form a racemic or optically active -threo-N- Phthaloyl-8-(8,4-dihydroxyphenyl)serine is obtained, and when it is racemic, cinchonine, cinchonidine, quinine, ephedrine, 2''-
The optically active threo-N-phthaloyl-8-(8゜4-dihydroxyphenyl)serine was obtained, and racemic or optically active -threo-N-phthaloyl-8-(8,
4-dihydroxyphenyl)serine is subjected to a defthaloylation reaction (r) (The formula represents a racemic form and an optically active form, * indicates the same meaning as above.) Racemic or optical form Active-threo-8-(8
, 4-dihydroxyphenyl)serine.