JPS58216146A - Preparation of optical active-threo-3-(3,4- dihydroxyphenyl)serine - Google Patents

Abstract

PURPOSE:To obtain the titled compound easily without requiring a specific separating operation, by reacting glycine with piperonal, reacting it with carbobenzoxy chloride, optical active amine, and Lewis acid, followed by subjecting the reaction product to catalytic reduction. CONSTITUTION:Glycine is reacted with piperonal in the presence of a base, acetic acid is added to the reaction product, which is reacted with carbobenzoxy chloride to give racemic-threo-N-carbobenzoxy-3-(3,4-methylenedioxyphenyl)serine shown by the formula I . It is subjected to optical resolution operation with an optical active amine such as ephedrine, quinine, etc., and treated with Lewis acid to give optical active threo-N-carbobenzoxy-3-(3,4-dihydroxyphenyl)serine shown by the formula II, which is reduced catalytically to give the desired substance shown by the formula III. USE:Useful as a remedy for peripheral orthostatic hypotension and an antidepressant.

Description

[Detailed description of the invention] The present invention is based on the formula [I] H (The formula represents an optically active substance, *C represents an asymmetric carbon.

) The present invention relates to a method for producing optically active threo-8-CB, 4-dihydroxyphenyl)serine represented by:

More specifically, by reacting glycine in the presence of piperot-fz base and adding acetic acid, racemic threo-8-(8, 4-methylenedioxyphenyl)serine is prepared as acetate salt, and this is reacted with carbobenzoxy chloride to obtain racemic-threo-N-carboxylate represented by the formula [I] Benzoxy-8-(8,4
-methylenedioxyphenyl)serine, and carry out an optical resolution operation by treating this with one of the optically active amines selected from ephedrine, quinidine, quinine, and 2-amino-1,1-diphenylpropanol, Optically active -threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl)serine and then treated with a Lewis acid to form an optically active threo-N-carbobenzoxy-
8-(8,4-dihydroxyphenyl)serine or racemic threo-N represented by the above formula [■]
-Carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine is treated with a Lewis acid to give racemic-threo-N-carbobenzoxy-8-CB,4-dihydroxyphenyl)serine, which is converted to cinchonidine. , brucine, ephedrine, and 2-amino-1,1-diphenylpropanol.
Optically active threo-N-carbobenzoxy-
8-(8,4-dihydroxyphenyl)serine was obtained, and the thus obtained optically active threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine was catalytically reduced to give the formula The present invention relates to a method for producing optically active threo-8-(3,4-dihydroxyphenyl)serine represented by [I].

(6) Optically active -threo- obtainable by the method of the present invention
8-(8,4-dihydroxyphenyl)serine [■] (
DOP8 (hereinafter abbreviated as DOP8) is known to be useful as a therapeutic agent for peripheral orthostatic hypotension (ff@Kokai No. 56-104815) or an antidepressant (Japanese Unexamined Patent Publication No. 55-20747). It is a drug that is

Conventionally, methods for producing optically active DOP8rl have been disclosed in JP-A-50-49252 (method A) and JP-A-54-86.
No. 288 (D method), JP-A-56-29551 (C-method), and JP-A-51-12540 (D method)
method is known.

Methods A, B, and C use as a starting material vanillin or piperonal in which the catechol moiety of protocatechualdehyde represented by formula [V] is protected with two methyl or methylene groups, and the methyl or methylene group is removed. By doing so, L old style [
After obtaining pro-1 catechualdehyde represented by the formula [■], the catechol moiety was protected with a benzyl group again and
This benzaldehyde derivative is condensed with glycine to form a threo and erythro 8-(8) represented by the formula [■] (the formula represents the threo isomer and 1970 isomer).

obtain a mixture of 4-dibenzyloxyphenyl)serine,
Threo form of this compound or its derivative, 1970
In this method, optically active DOP 8 [I] is produced by separating the molecules and then removing the protecting group through an optical resolution operation.

Method D uses threo-3-(8,4-
Once E-DOPS is produced from phosphorus (dibenzyloxyphenyl) [■], it is reacted with carbobenzoxy chloride to form racemic-threo-N-carbobenzoxy-8.
-(8,4-dihydroxyphenyl)serine [W] is obtained, and optically active DOPS [I] is produced by removing the protecting group through an optical resolution operation.

That is, any known method for producing optically active DOPS,
This method has the drawback of requiring a complicated operation of changing the protecting group of the catechol moiety of the benzaldehyde derivative serving as the starting compound. Furthermore, in the method -Husej-DO
There is a drawback that a complicated operation of reintroducing and removing a protecting group is required after producing P8.

Under these circumstances, the present inventors have intensively investigated a method for producing optically active DOPS (9) that does not require changing the protective group of the catechol moiety. As a result, 1 racemic and optically active -threo-N-carbobenzoxy-8-(3゜4-methylenedioxyphenyl)serine [m] that can be produced from biperonal without changing the protecting group. The present invention was completed based on the finding that optically active POPS can be easily produced by using as an intermediate.

That is, in the method of the present invention, (1) the acetate of racemic threo-8-(8,4-methylenedioxyphenyl)serine [I[] can be obtained by condensation of glycine and biperonal without any special separation operation.

■ When racemic or optically active threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine [■] is treated with a Lewis acid, despite the presence of carboxyl, carbamate, and hydroxyl groups, Only the methylene portion of the methylenedioxy group can be removed.

■ Racemic-threo-N-carbobenzoxy-3-(3
,4-X+Tren-o-N-Sif-;ru) Begging〉[Plate](10
) and racemic threo-N-77 report
8,4-dihydroxyphenyl)serine [■] can be optically resolved using an industrially available optically active amine as an optical resolving agent, and the corresponding compound can be separated into an optically active form (D form or It can be obtained as L-form).

The present invention has been completed based on this knowledge, and provides an industrial and economical method for producing optically active DOP 8.

The method of obtaining 8-(8゜4-methylenedioxyphenyl)serine [II] from glycine and biperonal is already known [Pharmaceutical Journal, 67, 218 (1).
947), Can, J., Ohem,, 42.
1901 (1964)], but the three-dimensional structures of threo and erythro bodies were completely unknown, and the present inventors were the first to clarify and isolate the three-dimensional structure of the threo body.

Furthermore, it is used as an intermediate in the production of racemic and optically active DOPS.

As mentioned above, threo-8-(8,4-dibenzyloxyphenyl)serine [■] is obtained as a mixture of threo isomer and erythro isomer from the reaction of glycine and benzaldehyde derivative [V]. body separation is necessary (J, Am, Ohem, Boa, 7
6, 1822 (1954), Japanese Patent Publication No. 50-492
52, JP-A-54-19981), the method of the present invention does not require any special separation operation and can easily produce 8-(8,4-methylenedioxyphenyl)serine CIO, which is a threo isomer. can be obtained.

Racemic-threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl) seri:/ [III] is a new compound, which can be obtained by the reaction of racemic-threo-8-(8,4-methylenedioxyphenyl) phosphorus with carbobenzoxy chloride.

Optically active threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl)serine [m] is racemic-
Threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine is treated with one of the optically active amines selected from ephedrine, quinidine, quinine, and 2-amino-1,1-diphenylpropanol. D and L-threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl)serine as an amine salt,
D-threo-N-carbobenzoxy-g-ca by utilizing the difference in solubility.

4-methylenedioxyphenyl) serine amine salt and L
-Threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine amine salt;
These salts can then be obtained by treating each salt with an acid.

Racemic or optically active threo-N-carbobenzoxy-
8-(8,4-methylenedioxyphenyl)serine [m
] to the corresponding threo-N-carbobenzoxy-8-(
Until now, no method of obtaining 8,4-dihydroxyphenyl)serine [W] has been known.

In general, various methods are known for removing the (18) methylene group from a compound having a methylenedioxy group to form a catechol group. Example of obtaining 8-(8,4-dihydroxyphenyl)alanine by treating 4-methylenedioxyphenyl)alanine or its N-acetyl derivative with hydroiodic acid and acetic anhydride in the presence of red phosphorus (Chero , Pharm, Bull, ,
I.Q.

698 (1962)), and there are no examples of compounds having simultaneously a hydroxyl group, a carbamate group, and a carboxyl group.

The present inventors have discovered that racemic or optically active threo-N-carbobenzoxy-8-(8
, 4-methylenedioxyphenyl)serine [Il[] to the corresponding racemic or optically active threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine [■]. However, it was discovered that the objective (14) could be achieved by treating with a Lewis acid under mild conditions. In this reaction, it is preferable to add a mercaptan in addition to the Lewis acid.

Racemic-threo-N-carbobenzoxy-8-(8,4
-dihydroxyphenyl)serine [31, optically active -threo-N-carbobenzoxy-
The method for obtaining 8-(8,4-dihydroxyphenyl)serine [■] is known from ``(Japanese Unexamined Patent Publication No. 1982-1982).
540).

In the above-mentioned known method, expensive quinine is used as an optical resolving agent. The present inventors investigated an optical resolution method using an optical resolution agent that can be obtained at a lower cost or easily manufactured.

As a result, cinchonidine, brucine, and ephedrine, which can be obtained at a lower cost than the conventionally known optical resolution agent quinine, can be used as an optical resolution agent, or 2-amino-1,1-diphenylpropanol, which can be easily produced, can be used as an optical resolution agent. We found a method to use this as an optical resolution.

That is, racemic-threo-N-carbobenzoxy-8-(
8,4-dihydroxyphenyl)serine [■], cinchonidine, brucine, ephedrine, 2-amino-1,
D and L-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine were made into amine salts by reacting with one of the optically active amines selected from 1-diphenylpropanol to reduce the difference in solubility. D-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine amine salt and L-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)
Optically active -threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine can be produced by fractionating serine into amine salts and then treating each salt with an acid.

Optically active threo-N-carbobenzoxy-8-(8,4
-dihydroxyphenyl)serine (W) to optical activity D
The method for producing OPS [1] involves using ordinary amino acids,
This is carried out using the decarbobenzoxy reaction conditions used in the reaction of peptides, etc.

Formula (17) [[■] (racemic form) [m] (optically active form) Each reaction will be specifically explained below.

The acetate of racemic threo-3-(8,4-methylenedioxyphenyl)serine [I[] can be obtained by subjecting glycine and biperonal to a condensation reaction in the presence of a base, and then adding acetic acid to the reaction solution. be able to. It is preferable to use piperonal in a molar amount 2 to 8 times that of glycine, and to use the base in a molar amount 1.5 to 2.5 times that of glycine. Examples of base binding include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. As the reaction solvent, alcohol-based solvents such as methanol, ethanol, and isopropyl alcohol, ether-based solvents such as tetrahydrofuran and dioxane, and mixed solvents of these and water can be used, and the condensation reaction temperature is -11
The reaction can be carried out at a temperature of 0 to 80°C, but it is preferably carried out at a temperature of -10 to 40°C in order to reduce the production of racemic erythro-8-(8,4-methylenedioxyphenyl)serine.

After the condensation reaction, water and acetic acid are added to the reaction solution to decompose the condensation reaction intermediate, and then toluene, benzene, ethyl acetate, diethyl ether, etc. are added to transfer biperonal to the organic layer, and racemic-threo By precipitating -8-(8,4-methylenedioxyphenyl)serine as an acetate, the acetate of racemic threo-8-(8,4-methylenedioxyphenyl)serine [■] can be obtained. can. The amount of water added at this time is at least 2 times the amount of glycine, preferably 3 to 20 times, and the amount of acetic acid added is at least 8 times, preferably 5 to 20 times.

80 times the amount can be used.

In the above reaction, the threo isomer precipitates as acetate, and the erythro isomer remains dissolved.

Racemic-threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl)serine@) is racemic-threo-8-(8,4-methylenedioxyphenyl)serine (m) and carbobenzoxychloride 0) so-called 5
It can be obtained by a chotten Baumann reaction.

That is, it can be carried out by dissolving racemic-threo-8-CB, 4-methylenedioxyphenyl)serine (If) in an alkaline aqueous solution having a pH of 7 or more, and adding carbobenzoxy chloride.

Carbobenzoxy chloride is racemic-threo-8-(8
, 4-methylenedioxyphenyl) serine position)
~2 times the mole is used, and the reaction temperature is 0~80℃ for several minutes~2
It is sufficient to react for 0 hours, and during the reaction, the pH of the reaction solution is kept at 7 to 7.
It is preferable to keep it at 10.

To maintain the pH of the reaction solution at 7 to 10, add alkaline water dropwise depending on the pH change, or add sodium carbonate, borax, etc. to the reaction solution in advance and adjust the pH.
Add 7-10 salt.

Examples of the alkali used as alkaline water include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and the like.

(21) 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, Ketone solvents such as methyl ethyl ketone, halogenated argyl solvents such as chloroform, dichloromethane and dichloroethane, ester solvents such as ethyl acetate and butyl acetate, and mixtures thereof can also be added.

Optically active -threo-N-carbobenzoxy-8-(8,
To obtain 4-methylenedioxyphenyl)serine@), chamithreo-N-carbobenzoxy-8-(8,
4-methylenedioxyphenyl)serine is reacted with one of the optically active amines selected from ephedrine, quinidine, quinine, and 2-amino-1,1-diphenylpropanol in a suitable solvent to form D and L. -Threo-N
-Carbobenzoxy-8-(8゜4-methylenedioxyphenyl)cerinto optics (22) D-threo-N-carbobenzoxy-8-(8゜Separate into optically active amine salt of 4-methylenedioxyphenyl)serine and optically active amine salt of L-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine, and then A method is used to decompose each salt by exposing it to an acid.

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 80°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-8-(8,4-methylenedioxyphenyl)phosphorus.

Preferred examples of the solvent used for the formation and fractionation of the salt include alcohol solvents such as methanol, ethanol, and isopropyl alcohol, ether solvents such as te, trahydrofuran, and dioxane, acetonitrile, water, and mixed solvents thereof. be able to.

Obtained optically active -threo-N-carbobenzoxy-8
- By adding an acidic aqueous solution to the salt of (8,4-methylenedioxyphenyl)serine with an optically active amine, the salt is decomposed, and by extraction with an organic solvent, the optically active -threo-N-carbobenzoxy- 8-(8,4-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 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. 'Racemic and optically active -threo-N-carbobenzoxy-8-(8,4
Treatment of -methylenedioxyphenyl)serine [I[] with a Lewis acid in a suitable solvent yields 1, the corresponding racemic and optically active -threo-N-carbobenzoxy-8-(8,4
-dihydroxyphenyl)serine [■] is obtained.

Preferred examples of the Lewis acid include filled albinium, aluminum bromide, ferric chloride, stannic chloride, boron chloride, and boron bromide. It may also be used as a Lewis acid. Lewis acid is 1 to 1 to threo-8-(8,4-methylenedioxyphenyl)serine rl [[]
This can be carried out by using 20 times the molar amount, preferably 2 to 10 times the molar amount. In order to obtain favorable results, in addition to the Lewis acid, 01 to 02G mercaptans such as methyl mercaptan, ethyl mercaptan, butyl mercaptan, octyl mercaptan, dodecanyl mercaptan, and octadecanyl mercaptan are added to the Lewis acid in the reaction solution. You may add 1 to 5 times the mole amount.

As the reaction solvent, any solvent may be used except those that inhibit the progress of the reaction, but preferred solvents (25) include dichloromethane, chloroform, dichloroethane,
Halogenated alkyl solvents such as chlorobenzene, aromatic hydrocarbon solvents such as toluene and benzene, ethyl acetate,
Ester solvents such as butyl acetate, nitrated hydrocarbon solvents such as nitromethane, nitroethane, and nitrobenzene,
Examples include acetone-based solvents such as acetone and methyl ethyl ketone, pyridine, and mixed solvents thereof.

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

The reaction is completed within a range of 10 minutes to 4 hours, but the reaction time may be longer.・ Racemic-threo-N-carbobenzoxy-8-(8,4
-Optical activity from dihydroxyphenyl)serine [V]-
To obtain threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)phosphorus [M] racemic-threo-N-carbobenzoxy-8-(,8,4-dihydroxy(26) phenyl ) Serine, cinchonidine, prusinephedrine, 2-amino-1,1-diphenylpropatur,
D- and L-threo-N-carbobenzoxy-8-(8,4-
Using the difference in solubility, the amine salt of D-threo-N-carbobenzo4C8 (8,4-dihydroxyphenyl)serine and L-threo-N-carbobenzoxy- 8-(8,
The optically active threo-N-carbobenzoxy-8-(8°4
-Dihydroxyphenyl)serine can be produced.

The conditions for this optical resolution are the molar ratios used in the optical resolution of racemic-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine, except for the optically active amine used as an optical resolving agent. It may be carried out using the same solvent, temperature, time, and conditions as the salt decomposition conditions.

The method for producing optically active DOP S [I] is carried out by subjecting optically active threo-N-carbobenzoxy-8-(8°4-dihydroxyphenyl)serine [F/] to a catalytic reduction reaction in the presence of a catalyst. can do.

Palladium, platinum, nickel, etc. are used as catalysts, or barium carbonate, activated carbon, etc. are used as carriers, and optically active threo-N-carbobenzoxy-8-(8,
0 for 4-dihydroxyphenyl)serine [11/]
, 01 to 0.1 weight ratio can be used. As a reaction solvent, alcohol-based methanol such as methanol and ethanol,
Aromatic carbonized ice cream solvents such as benzene and toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone and methyl ethyl ketone, water, and any mixed solvent thereof can be used.

The reaction temperature can be carried out at room temperature, but it may also be cooled or heated from room temperature, and the hydrogen pressure may be normal pressure, or may be pressurized. An acid such as hydrochloric acid or sulfuric acid can also be added to the reaction solution to accelerate the progress of the reaction.

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 thereto.

Reference Example Synthesis of racemic erythro and threo-8-(8°4-methylenedioxyphenyl)serine 145 g of biperonal was added to a solution of 61.1 N of potassium hydroxide, 88.05 f of glycine, and 1055 g of methanol.
It was added below 0°C and then stirred at 62-65°C for 80 minutes. The reaction solution was concentrated and the residue was dissolved in methanol (185 flI).
808 g of acetic acid was added thereto at a temperature below 80°C, and the mixture was further stirred at 40 to 45°C for 80 minutes. water 1851
1 and toluene 1250°C and heated at 40 to 45°C.
After stirring for 1 hour, the precipitated crystals were stirred at 0 to 5°C for 1 hour.
86.98 g (yield: 69.8%) of racemic elimero/threo-8-(8,4-methylene(29) dioxyphenyl) serine acetate was obtained. mP162℃ (decomposition) IR (Nu
jol) v (♂”): 8550-2200 (
broad).

3490, 1720, 1670, 1580, 1
490, 1400.

1290.1050.940 I (PLO analysis result: erymero/threo = 16/84 This mother liquor was left at room temperature for 15 hours and the precipitated crystals were removed, resulting in racemic erythro 8-(8°4-methylenedioxyphenyl)serine. - 2.86f of acetate (yield 4.8%) was obtained.

nnp 188.5℃ (decomposition) IR (Nujol)y(z'): 8490
, 8400~2200 (pro t') + 1695 , 1
590, 1510, 1400, 1240, 10
40.985NMR (DMSO-d6) δ: 1.88
(8H, s), a, 44 (tH, d, J=7Hz),
4.89 (IH, d, J=7Hz), 5.40
(2H,s).

6.74-7.00 (8H, m) HPLC analysis result: Erythro/Threo = 96.8/8.
Racemic Elimero/Threo-8-(8,4-
Methylenedioxyphenylene 9L+-) serine acetate 85
1 was diluted with water and recrystallized from 105 g (80) to obtain racemic threo-8-(8,4-methylenedioxyphenyl)serine 4B, B11 (yield 72.1%). mp19a℃(decomposition)IR(Nujol)ν(cm
1): 8600-2100 (broad).

140013r70 8550.8460.16BQ, 1510.1440.
→Sieve, special sieve.

1250.1040.98O NMR (DM80-ds) δ: 8.84 (IH, d
, J=4H2).

4.97 (IH, d, J = 4fiZ), 5.68 (2H
,8) kLPLC analysis result: Elimero/Threo=0/1
00 [PLO analysis conditions] Column: Licromosorb RP-18, 10μ, 4-X8
0 Secondary mobile phase solvent: Q, 995M PICB-7/acetonitrile (9:1) Flow it: 1.0ml/min Detection:
UV (254-) Elution time: Erythro form (7.5 minutes) Threo form (8.5 minutes) Example 1 <Step A> Race grass - Threo-8-(8,4-methylenedioxyphenyl)serine Synthetic glycine 45.411 Piperonal 208.2f1 Potassium hydroxide 87.79 was dissolved in methanol 838f,
The mixture was stirred at room temperature for 5 hours.

After adding 687 g of acetic acid and stirring at 85° to 45° C. for 30 minutes, 181 g of water was added and stirred at room temperature for 4 hours, then 157 g of toluene was added and stirred for 2 hours.

The precipitated crystals were collected and washed with toluene to give racemic threo-8-(8,4-methylenedioxyphenyl)serine.
e acid m 120.6 g.

rnplf was obtained at 31°C (decomposed).

IR(Nujol)y(cm”): 8460
~2200 (broad), 1705, 1665.161
0.1490.1400.1285°1240.104
0.980.84O NMR (DM80-da) δ: 1.9 (817
18) 18.47 (lR1dlJ=4Hz), 4
．． 99 (IE[, d, J-4Hz), 5.96
(2H.

S'), 6.76-6.97 ((H,l1l)
The mother liquor and washing liquor were combined, 500 g of water was added, and the separated toluene layer was washed with 5% sodium hydroxide solution, then washed with water, and then concentrated under reduced pressure to obtain Biperonal 87.2 II.
I got it.

<Step B> Racemic-threo-N-carbobenzoxy-8
-Synthesis of (8,4-methylenedioxyphenyl)serine (Synthesis Example 1) Racemic-threo-8-(8,4-methylenedioxyphenyl)serine acetate 108.61N in water 1217.8N
and 80.41 g of sodium hydroxide, and then 102 g of a 70% toluene solution of carbobenzoxy chloride was added dropwise under ice cooling. At the same time, 80% aqueous sodium hydroxide was added dropwise to adjust the pE [#] to 8.5 to 9.5.

After the dropwise addition, the pH was adjusted and the reaction was continued for 4 hours under cooling with ice water.

After adding concentrated hydrochloric acid 120II to make the pH≠1, toluene 85
Add 0F and stir at 40-45℃ for 1 hour, then 5-45℃.
The mixture was stirred at 15°C for 2 hours. The precipitated product was separated, washed with water and toluene, and racemic-threo-N-carbobenzoxy-8-(8,4-methylenedioxy(88) 5-Jl/) serine 847.41, mp 1
A temperature of 86-188°C was obtained.

IR(Nujol)ν(z 1)': 8500.
8250.1750.1655°1505.1B40.
1255.1220.1160 (Synthesis Example 2) Racemic-threo-8-CB, 4-methylenedioxyphenyl)serine 11.8N was added with sodium hydroxide 4. In addition to the aqueous solution containing 160 ml of 160% of carbobenzoxy chloride, 9.41 g of carbobenzoxy chloride was added dropwise at 5° C. or lower after dissolution. At the same time, 80% sodium hydroxide was added dropwise to pH 8.5-9.
I adjusted it to be 5. After 2 hours, the pH was adjusted to 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 residual liquid was crystallized with toluene and the crystals were separated to give racemic-threo-N-carbobenzoxy-8-(8
,4-methylenedioxyphenyl)serine (17.89%) was obtained.

mP186-138°C (84) IR(Nujol)l'(crrt): 8500.
8250.1750.1655゜1505.1B40,
1255.1220゜160 Step C〉Optically active -threo-N-carbobenzoxy-
Synthesis of 8-(8,4-methylenedioxyphenyl)serine (Synthesis Example 1) Racemic-threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl)serine 10. Dissolve Of in 100 - of acetonitrile, add 9.02 fl of quinidine
was added to make a homogeneous solution. After cooling in ice water for 5 hours, the precipitated crystals were collected and L-threo-N-carbobenzoxy-8-
9.0 g of (8,4-methylenedioxyphenyl)serine quinidine salt was obtained.

mpH6-118℃ [α];; +119.5° (0=1.0, )1ri)-
JL/) Part of the above salt 2. After adding 50% of 8% hydrochloric acid to Og, the mixture was extracted with ethyl acetate to obtain 0.98f of L-threo-N-carbobenzoxy-8(8,4-methylenedioxyphenyl)serine as an amorphous powder. obtained as.

IR (Nujol) ν (cm”): 8500~
3250 (bou-do).

1740-1670 (Broad).

1B90 , 1440 , 1040 , 980 [α]j
'-24,5° (cm1.0, methanol) Part of the above salt 6. Recrystallize Og twice from methanol to obtain salt 4.4
fl (mP 162-168.5℃, [α] also' +
After obtaining 122.6' ((+ = 1.0, methanol)), 8% hydrochloric acid water was added to 4.0 g of this salt, extracted with ethyl acetate, and L-threo-N was obtained as an amorphous powder. -Carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine 1.81 was obtained.

[α]; -28,1° (cm1.0, Meta/-JL/)
(Synthesis Example 2) Racemic-threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl)serine io, ol was added with 100% of isopropyl alcohol and 9.029% of quinidine to form a homogeneous solution.

After standing overnight at room temperature, the precipitated product was counted, and L-Threo-N-
Carbobenzoxy-8-(8.

4-methylenedioxyphenyl) serine quinidine salt 8
．． I got 8f.

mp 161-168℃ [α]j' +119.8° (cm1.0,) evening) −
Jl/) Part of the above salt4. (After adding 8% aqueous hydrochloric acid to l, extracting with ethyl acetate, L-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)-
1.91% of 1F phosphorus was obtained as an amorphous powder.

[α element'-25,8° (cm1.0, methanol) (Synthesis Example 8) Racemic-threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl)serine5. After dissolving Of in 50% of acetonitrile, 4.5 g of quinine was added to form a homogeneous solution.

After standing overnight at room temperature, the precipitated product was separated into D-Threo-N.
-Carbobenzoxy-8-(8°(87) 4-methylenedioxyphenyl)serine quinine salt5.
Get 1g.

mpH 6 to 118°C [α120-97.8° (0 = 1.0, methanol) 3% hydrochloric acid water was added to 4.0 g of a portion of the above salt, extracted with ethyl acetate, and D-threo-N-carbo Benzoxy-8-(
8,4-methylene di; i Ki', t phenyl) serine 2. Of was obtained as an amorphous powder.

[a] 20+ is, o' c c = i, o, methanol] (Synthesis Example 4) Racemic-threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl)serine 10. Og and R-
2-Amino-1,1-diphenylpropatol 6.8g
was dissolved in 100% ethanol and cooled in ice water for 4 hours.

The precipitated crystals were collected by F' and L-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine.
R-2-amino-1,1-diphenylpropanol m7
．． 8g is fl.

(88) mp 170.5°C (decomposed) [α] D-28,1° (0 = 1.0, methanol) Add 100 - 3% hydrochloric acid solution to 4.01 part of the above salt and dissolve in ethyl acetate. L-threo-N-carbobenzoxy-8
-(8,4-methylenedioxyphenyl)serine 2.8
g was obtained as an i-form powder.

[a] D-26,8° (C=1.0, methanol) (Synthesis Example 5)
-methylenedioxyphenyl)serine 10. Og to t-
After adding and dissolving 4.6 g of ephedrine and 200 g of ethanol, the mixture was cooled with ice water for 6 hours. After the precipitated salt was separated, this salt was recrystallized twice from ethanol to obtain D-threo-N-carbobenzoxy-8-(8°4-methylenedioxyphenyl)serine/l-ephedrine salt5. I got 89.

mp 177-178°C [α]9°-22°2° (C=1.0, methanol) Part of the above salt 2. 3% hydrochloric acid water was added to Of, extracted with ethyl acetate, and D-threo-N-carbobenzoxy-8-(
1.3 g of 8,4-methylenedioxyphenyl)serine was obtained as an amorphous powder.

[α], +28.0° (C=1.0, methanol)
<Step 1> Racemic-threo-N-carbobenzoxy-3-
Synthesis of (8,4-dihydroxyphenyl)serine (Synthesis Example 1) Racemic-threo-N-carbobenzoxy-B-(8,4
Add 500 g of dichloromethane and 80 g of ethyl mercaptan to 1111 of -methylenedioxyphenyl) serine.
The mixture was cooled to ℃ and stirred. Add 27% of aluminum chloride to this solution.
．． After adding 6f and reacting at below 5°C for 4 hours, 250fnl of 10% hydrochloric acid solution was added and the dichloromethane layer was separated.
The aqueous layer was extracted with ethyl acetate.

The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.14. 'fl residue was obtained. This was transferred to a silica gel column chromatograph (eluent solvent acetonitrile/benzene/acetic acid = 4.5/4.5
/1) to obtain 12.8 g of racemic-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine as an amorphous powder, which was then crystallized with ethyl acetate to obtain crystals. 1016g was obtained.

mP 145-146℃ (decomposition) IR (Nujol) ν (cyn): 8520,84
90.88B0, 8270°1720, 1700,
1610, 15B5.

1290, 1175, 1080, 1055.

90 (Synthesis Example 2) Racemic-threo-N-carbobenzoxy-8-(8,4
-methylenedioxyphenyl)serine 18g, ditalolomethane 500tnt% n-octadecylmercaptan 1
After performing the reaction and post-treatment in the same manner as in Synthesis Example 1 using 18 g of aluminum chloride and 27.61 g of aluminum chloride, the product (41
) 19.5 g of the residue was crystallized from ethyl acetate to obtain racemic-threo-N-carbobenzoxy-B-(8,4-dihydroxyphenyl)serine 11,'ll.

mP 145-146°C (decomposition) (Synthesis Example 3) Using toluene 500-in place of dichloromethane 50- -carbobenzoxy-8-(814-dihydroxyphenyl)71? I got phosphorus 9, Of.

rnp144-146°C (decomposition) Step E> Optically active -threo-N-carbobenzoxy-
Synthesis of 8-(8,4-dihydroxyphenyl)serine [optically active-threo-N-carbobenzoxy-8-(8
,4-methylenedioxyphenyl)serine] (42) (Synthesis Example 1) L-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine [[α]D- 27.9
(C=1.0.methanol)] 250 g of dichloromethane and 14 g of ethyl mercaptan were added to 8.0 g, and the mixture was cooled to 5° C. While stirring, 18.0 g of aluminum chloride was added and reacted for 4 hours. After repulsion, post-treatment and purification were performed in the same manner as in Synthesis Example 1 to obtain L-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine 5.
．． 11 was obtained as an amorphous powder.

IR (Nujol) ν (crn): 8500~B
250 (broad).

1740-1670 (broad).

1B90,1440.1040.980[α]2f'-
27.4° (0 = 1.0.methanol) (Synthesis Example 2) D-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)sery [α older 0 + 28.0°
((1=1.0. methanol)) To 1.0 g were added 25 rnt of methylene chloride and 8.4 g of n-octyl mercaptan, and while cooling to 5° C., 1.59 g of aluminum chloride was added and stirred.

After 6 hours, post-treatment and purification were performed in the same manner as in Synthesis Example 1 to obtain D-threo-N-carbobenzoxy-8-(8,,4
-dihydroxyphenyl)serine was obtained as an amorphous powder.

IR(Nujol)vCcm'): 8500~8
250 (broad).

1740-1670 (Broad).

1B90, 1440, 1040, 980[α]D
+27.8° (e=1.0.methanol) (Synthesis Example 8) L-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine [[α]20-27.
9° (C=1.0.methanol)18. O1, dichloromethane 259mj, n-dodecylmercaptan 86.8
f, Synthesis Example 1 using aluminum inide 12.8N
Perform the reaction, post-treatment, and purification in the same manner as L-threo-
N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine 6.21 was obtained as an amorphous powder.

[α]D-27.5°((3=1.0.methanol)(
Synthesis Example 4) L-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine [[α]D-27,
9° (C=1.0.methanol) 110. After dissolving Of in 200 g of methylene chloride, 81 g of pyridine and 46 g of aluminum chloride were added at room temperature, and the mixture was stirred for 8 hours. After adding 200 g of 8% hydrochloric acid water under cooling with ice water, the mixture was separated, and the aqueous layer was extracted with ethyl acetate. After washing the organic layer with water, it was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain a residue, which was subjected to silica gel column chromatography (eluent solvent acetonitrile/benzene/acetic acid = 4.5/4.5).
/1) to obtain II-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine 2
．． 8f was obtained as an amorphous powder.

[αID-27,0° (Q=1.0, methanol) (
45) (Synthesis Example 5) L-threo-N-carbobenzoxy-3-(8,4-methylenedioxyphenyl)serine [[α]D-26.8
°(Q=1.01 methanol)11. To Of, 50 mm of dichloromethane and 2.7 mm of ethyl mercaptan were added, and 1.5 f of 771/E nium bromide was added and reacted for 80 minutes at 5° C. or lower under cooling with ice water.

After completion of the reaction, 50% of 8% aqueous hydrochloric acid was added and post-treatment and purification were carried out in the same manner as in Synthesis Example 4 to obtain 0.0% of L-threo-N-carbobenzoxy-8-(8°4-dihydroxyphenyl)phosphorus. 58N was obtained as an amorphous powder.

[α]I) -25,7° ((+=1.0.methanol)
(Synthesis Example 6) L-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine [[α]D-26,
8° (e=1.0.methanol)]1. Of was dissolved in dichloromethane (50°C), and 2.2 g of titanium tetrachloride was added at 5°C or lower under cooling with ice water (46).The mixture was reacted at room temperature for 1 hour. After cooling with ice water, 50% of 8% hydrochloric acid was added to the reaction mixture to separate the layers, and the aqueous layer was extracted with ethyl acetate (
7. After washing with water and drying, the solvent was distilled off to obtain a residue, which was purified by silica gel column talomadography to obtain L-
0.221 of threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine was obtained as an amorphous powder.

[α]D-26.8° ((+=1.0, methanol)
Step F> Optically active -threo-N-carbobenzoxy-8
Synthesis of -(8,4-dihydroxyphenyl)serine (synthesis from racemate) (Synthesis Example 1) Racemic-threo-N-carbobenzoxy-8-(8,4
-dihydroxyphenyl)serine was dissolved in 400 g of methanol and 250 g of water at room temperature, 41.8 g of cinchonidine was added thereto, stirred, and heated to 50° C. after 20 minutes.

After that, it was gradually cooled to 20℃ over 2 hours, and then 15℃~
The mixture was stirred at 20°C for 8 hours.

The precipitated crystals were collected and L-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)phosphorus cinchonidine! 40.2IImp140℃ (decomposition), [
α]D-64.0° (C=1.0° methanol) was obtained.

This salt 221 was decomposed by adding 80 g of 3% hydrochloric acid and extracted with 240 g of ethyl acetate to form an amorphous powder of L-threo-N.
-Carbobenzoxy-8-(8,4-dihydroxyphenyl)-1? Phosphorus 11.8g, [α]D-25.9° (
C-1,0, methanol) was obtained.

IR(NujOI)ν(cm'): 8600
~8100 (broad).

1660-1760 (broad).

1600, 1520, 1840, 1270.

050 Methanol was distilled off from the mother liquor from which the salts had been removed under reduced pressure, and 8%
After adding 120% of aqueous hydrochloric acid, extraction was performed with ethyl acetate to obtain D-threo-N-carbobenzoxy-8 as an amorphous powder.
-(8゜4-dihydroxyphenyl)detophosphorus 29.8f
[α], +17.4° (0=1.0.methanol) was obtained.

IR(Nujoiν(3-'): 8600~8
100 (Boo-o-F).

1760-1660 (Broad).

1600.1520,1840,1270°050 The above D-threo N-carbobenzoxy-8-(8,4
8.9 g of -dihydroxyphenyl)serine was dissolved in 260 g of ethyl acetate, and 2.7 g of benzylamine was added at room temperature. The precipitated crystals were counted, and D-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine benzylamine mIO, 9 fl, mp 145°C (
decomposition), [α]D −5,8° (C=11 methanol)
I got it.

(Synthesis Example 2) Racemic-threo-N-carbobenzoxy-8-(8,4
0.62 g of brucine was added to a solution of 0.51 -dihydroxyphenyl)serine and 5-dioxane, and the mixture was stirred at room temperature for 15 hours. The precipitated crystals were prepared in a furnace and D-threo-N-carboben (49) dixy-8-(8,4-dihydroxyphenyl) serine brucine salt Q, 2111, mp 189°C (decomposition), [α]D-1 , 9° (C=1.0.methanol) was obtained.

A portion of 0.2 g of this salt was decomposed with 8% aqueous hydrochloric acid and extracted with ethyl acetate to obtain D-threo-N-carbobenzoxy-8-(8) as an amorphous powder.

4-dihydroxyphenyl) serine o, o sy [
α], +25.5° (0=1.0.methanol) was obtained.

(Synthesis Example 8) Racemic-threo-N-carbobenzoxy-8-(8,4
-Dihydroxyphenyl)serine 0.51 and isopropyl alcohol 5-8. -2-amino-1,1-
Diphenylpropertool o, ay were added and stirred at room temperature for 1 hour. The number of precipitated crystals was L-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine S-amino-1,1-diphenylpropanol salt 0.801, mp 167°C (decomposition), [α], +
81.5° ((1=1.0.methanol to 8A) was obtained.

A portion of 0.2 g of this salt was decomposed with 8% hydrochloric acid and extracted with ethyl acetate to form an amorphous powder, L-threo-N-carbobenzoxy-8-(!3°4-dihydroxyphenyl).
Serine 0.121[α]D-26.8° (e=l, Q,
Methanol] was obtained.

(Synthesis Example 4) Racemic-threo-N-carbobenzoxy-8-(8,4
-dihydroxyphenyl)serine (0.51 g) and acetonitrile (10 g) was added t-ephedrine (0.489 g) and stirred at room temperature for 10 days. The number of precipitated crystals was 0.241 D-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine-ephedrine salt,
mp 104℃ (decomposition) [α] 0-21.5° (C=
1.0. methanol) was obtained.

A portion of this salt was decomposed with 8% hydrochloric acid and extracted with ethyl acetate to obtain an amorphous powder of D-threo-N-carbobenzoxy-8-(3,4-dihydroxyphenyl)serine.
I Q [α], +20.5° (C=1.0.methanol) was obtained.

<Step G> Synthesis of optically active threo-8-(8,4-dihydroxyphenyl)serine (Synthesis Example 1) L-threo-N-carbobenzoxy-3-(8,4-dihydroxyphenyl)serine 2, 861 r [α]D
-27,4° (e=1.Q, meta/-Jl/)) 5% palladium-carbon (50% water content > 0.241) was added to a mixture of 24-1 methanol and 2.4 liters of water under a hydrogen stream. Catalytic reduction was carried out. After the reaction was completed, concentrated hydrochloric acid O and SY were added and stirred for 20 minutes. Insoluble matter was separated from P and washed with methanol, and the furnace washing liquid was diluted with 80% sodium hydroxide aqueous solution to pH 5.5 to 6.0.
When adjusted to , crystals precipitated. The leached product stirred for 2 hours at 0 to 5°C was heated to 1.88F L-Threo-8-
(8,4-dihydroxyphenyl)serine was obtained. (Yield 91.9%) [α]D-89.7° (c=1.0.I
N-HCz), mp 215°C (decomposition) When this L-threo-8-(8,4-dihydroxyphenyl)serine 1.2f is recrystallized with water 76 containing 0.01g of L-ascorbic acid, 0.96g is obtained. Pure threo-8-C,8,4-dihydroxyphenyl)serine was obtained.

(Yield 80.0%) [α]D-40.7° ((1=1.
0°IN -Hot) mp 226°C (decomposition) (Synthesis Example 2) L-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine 8, Of/C[α]D-2
7.1'5° ((1 = 1.01 methanol)) Add 5% palladium-carbon (50% water content > o, sy) to a mixture of 15-1 methanol, 15-1 ethyl acetate, 15-1 water, and contact under a hydrogen stream. After the reaction was completed, 1.Of concentrated hydrochloric acid was added and 2.
Stirred for 0 minutes. Insoluble matter was separated from P and washed with methanol.
The P washing solution was diluted with 80% sodium hydroxide aqueous solution to pI'f 5.
．． When the value was adjusted to 5 to 6.0, crystals precipitated.

The leached product was stirred at 0 to 5°C for 2 hours and counted.1.
679 of L-threo-8-(8,4-dihydroxyphenyl)serine was obtained. (Yield (58) rate 90.5%) [α]D-87.8° (c = 1.0
, I N-HC/-).

mP214°C (decomposition) When 1.5 g of this L-threo-8-(8,4-dihydroxyphenyl)serine is recrystallized with 96% of water containing 0.02N of L-ascorbic acid, 1.2 g of pure threo-8 is obtained.
-(8,4-dihydroxyphenyl)serine was obtained.

(Yield 80.5%) [α]”-40.4° (e=1.0
, IN-HOt) mp 226℃ (decomposition) (54 complete)

Claims (1)

[Claims] After reacting glycine and piperonal in the presence of a base,
By adding acetic acid, the acetate of racemic threo-8-(8,4-methylenedioxyphenyl)serine represented by formula [■] is obtained, and this is reacted with carbobenzoxy chloride to obtain the acetate salt of racemic threo-8-(8,4-methylenedioxyphenyl)serine represented by formula [11]. racemic-threo-N-carbobenzoxy-
By using 8-(8,4-methylenedioxyphenyl)serine and treating it with one of the optically active amines selected from ephedrine, quinidine, quinine, and 2-amino-1,1-diphenylpropanol, By performing a splitting operation, the optically active -threo-N-carbobenzoxy-
After forming 8-(8,4-methylenedioxyphenyl)serine, the optically active threo-N-carbobenzoxy- represented by the formula [■] is obtained by treatment with a Lewis acid.
8-(8,4-dihydroxyphenyl)serine or treated with racemic-threo-N-carbobenzoxy-8-(8,4-methylenedioxyphenyl)serine Lewis acid of formula CIII above; Racemic-threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine is used as an optically active amine selected from cinchonidine, brucine, fethrin, and 2-amino-1,1-diphenylpropanol. The optical splitting operation is performed by applying one of
] to obtain optically active threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine,
Optically active threo-8- represented by formula [I] H characterized by catalytic reduction of the optically active threo-N-carbobenzoxy-8-(8,4-dihydroxyphenyl)serine obtained in this way. Method 73r for producing (8,4-dihydroxyphenyl)serine.