JPS61251648A - Novel production of threo-3-(3,4-dihydroxyphenyl)serine derivative - Google Patents

Abstract

PURPOSE:To obtain stereoselectively in high yield a compound useful as an intermediate for synthesizing a drug such as a remedy for Parkinson's disease, peripheral orthostatic hypotension, etc., by reducing chemically a keto-amino acid derivative by the use of a metallic hydrogen complex compound. CONSTITUTION:The carbonyl group of a keto-amino acid derivative shown by the formula I (R<1> is benzyl of two R<1> are bonded to form methylene; R<2> is lower alkyl; Bzl is benzyl) is stereoselectively reduced to give the aimed substance shown by the formula II. The compound is chemically reduced by the use of a metallic hydrogen complex compound (e.g., sodium boron hydride) in an inert solvent such as tetrahydrofuran, etc., at room temperature - <=room temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula
together represent a methylene group, R2 represents a lower 7μ kill group, and BzJ represents a benzyl group. ) Threo-8=(8,4-dihydroxy7e=
IL/) Regarding the method for producing a serine derivative, in more detail, a keto-amino acid derivative represented by the general formula (where R'', R'' and Bzl have the same meanings as above) is stereoselectively prepared. When reduced, the general formula according to K [threo-8-(
Examples of the 0 lower a[mu]ky group relating to the method for producing 8,4-dihydroxyphenylene/I/)serine derivatives (hereinafter referred to as threo-DOPS derivatives [gen]) include alkyl[rho] groups having 1 to 4 carbon atoms ( For example, methyl group, ethyl group, n-propyl group, 1so-propyl group, n-butyl group, 1so-butyl group, 5ee-butyl group, tert-butyl group, etc.). Examples include chemical reduction using a metal hydrogen complex compound. By hydrolyzing the ester moiety of the SODOPS derivative obtained according to the present invention, the general formula (2) [°in the formula, R1 and Bzl have the same meanings as above]
[In the formula, nM represents a hydrogen atom or two R1 are combined Represents a methylene group. ] Nureo-DOPS or its derivatives can be obtained from the threo-DOPS derivative represented by the general formula ffVl (where 2.R3 represents a methylene group) using existing methods (for example, JP-A-Sho). No. 58-216146) makes it easy to
DOPS K can be induced.

Nureo D obtained by the method of the present invention with K as described above
OPS derivative [Threo-DOPS that can be induced by υ is
It is known to be useful as a drug for treating Parkinson's disease and for peripheral orthostatic hypotension.
5. (Japanese Unexamined Patent Publication No. 58-52219, etc.) Therefore, the method of the present invention can be used to prepare threo-DO useful as a pharmaceutical.
The objective is to stereoselectively obtain intermediates for PS production.

Conventionally, as a general method for producing threo-DOPS derivatives, for example, glycine and a benzaldehyde derivative are mixed under basic conditions. Condensation into do-ρ type (Pharmaceutical Journal, ■,
218 (1947), etc.) have been known for a long time.Under these circumstances, the present inventors determined that when the keto-amino acid derivative represented by the above-mentioned formula was stereoselectively reduced, K. As a result, the reduction reaction proceeded in a high yield to successfully obtain a threo-DOPS derivative [υ], leading to the present invention. By chemical reduction using complex compounds, the above formula [
The phantom threo isomer can be obtained in high yield.

(2) By hydrolysis of the compound represented by the above formula, the target compound represented by the formula above can be obtained in high yield.

■ Through hydrogenolysis of the compound represented by the formula (8) in the presence of a catalytic reduction catalyst,
DOPS or its derivatives are obtained in high yield.

With this knowledge, we were able to complete the project.

Hereinafter, the present invention will be explained in detail according to the following reaction steps.

Beat-1→[l-→(2)--→■ Process A Process B Process C 0 person process thread, t-DOPS derivative [process] stereoselectively reduces the carbonyl group of the keto amino acid derivative En. You can get good results. Examples of reduction methods include chemical reduction methods using metal hydrogen complex compounds. ◇Chemical reduction methods using metal hydrogen complex compounds are carried out by reacting the compound with the metal hydrogen complex compound in an inert solvent. I can do it.

Preferred metal hydride complexes to be applied include borohydride compounds such as sodium borohydride and sodium cyanoborohydride. Examples of inert solvents include water, methanol, ethanol, and isopropyl.
Cow14 alcoholic solvent, tetrahydrofuran,
A suitable solvent can be used in combination with the metal hydrogen complex compound from among ether solvents such as dioxane, halogen solvents such as carbon tetrachloride, chloroform, and methylene chloride, and solvents such as dimethylformamide.

Although the reaction can be carried out under heated conditions, it generally proceeds sufficiently at room temperature or at a temperature below room temperature.Also, in order to speed up the reaction, the pH may be adjusted to be weakly acidic with ammonium chloride or the like.

(2) Step B The DOPS derivatives y and vi are obtained by hydrolyzing the ester group of the ester compound [η to form the ester group ρ.

As the hydrolysis conditions, it is possible to apply the commonly used hydrolysis conditions for esthetics. For example, sodium hydroxide and
Hydroxylation'+! The reaction is carried out by adding a dilute aqueous solution of a hydroxide of an alkali metal or alkaline earth metal such as barium hydroxide or barium hydroxide, and the reaction proceeds satisfactorily at room temperature or under cooling.

■C process Threo-DOP8 or its derivative ■ is Nureo-DOP8
It is obtained by subjecting a PS derivative to a wide range of hydrolysis in an atmosphere of hydrogen gas in the presence of a catalyst to remove benzyl groups.

As the reduction catalyst, those that deprotect the N-benzyl group can generally be used, but preferred examples include platinum-based catalysts such as platinum oxide, palladium-based catalysts such as palladium-carbon,
Examples of the inert S medium include Nicke μ-based catalysts such as Raney-Nicke μ, rhodium-based catalysts such as Triphe-Rhonuphyl chlororhodium, etc. Examples of the inert S medium include water, methanol, ethanol, alcoholic solvents such as isopropyl alcohol μ, 0 reactions in which ether solvents such as tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as benzene and toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone, or any mixed solvent thereof can be used. As for the temperature, it is preferable to heat the reaction mixture, and as for the hydrogen pressure, although the reaction proceeds satisfactorily at normal pressure, pressure may be applied. After the reaction is completed, the target product can be isolated and purified using conventional organic chemistry techniques.

Furthermore, since the target compound of the method of the present invention is an amino acid, if desired, a salt of an amino group, an acid addition salt of an inorganic acid such as sulfuric acid, an organic acid such as acetic acid or methanesulfonic acid, or an acid addition salt of a carboxy μ group may be added. Alkali metal salts, alkaline earth metal salts,
It can also be an ammonium salt.

The raw material compounds used in the method of the present invention can be produced by known methods, for example, according to the reaction formula shown below.

[In the formula, 11, R2 and Bzz have the same meanings as above, and X represents a leaving group such as a halogen atom.] That is, glycine derivative (b) is metalized with an alkali metal hydride, an alkali metal amide, etc. After that, active esthetics of μ-bonic acid lv
A raw material compound can be obtained by reacting with a molten metal.

The method of the present invention will be specifically explained below by giving examples and reference examples, but the present invention is not limited to these.
, N-dibendi μ glycine methyl ester synthesis N,N-dibendi glycine methyl ester μ (807q
) in a kiln under a stream of dry tetrahydrofuran (5 m
8 mj of a separately prepared solution of lithium diisopropylamide in tetrahydrofuran (1 mol/I) was added while maintaining the liquid temperature at -60°C. Next, this reaction solution was added dropwise to a solution of piperoniy chloride (554-t) in tetrahydrofuran (5mj'') at -60°C.

After the dropwise addition was completed, the temperature was returned to room temperature over 1 hour, and the reaction solution was poured into a large amount of water and extracted with ethyl acetate. Separate the organic layer, dry, shrink, and drain the residue! The desired product (600v) was obtained by purification using Kawomu chromatogram (solvent: methylene chloride/n-hexane = 4) Melting point: 10
8-110°C Reference example 2 8.4-dibenzyloxybenzoyl-N
, Synthesis of N-dibenzylglycine methyl ester 8. 4-Dibenzyloxidipenzoyl chloride (1,
Reference Example 1 was added to the dry tetrahydrofuran solution of 06f).
A metal compound solution of 9N,N-dibendiμglycine methyl ester was prepared in the same manner as above and added under the same conditions as in the previous method. After treatment in the same manner as in Reference Example 1, the crude product was subjected to silica gel cuff chromatography ( Solvent: methylene chloride/n-
The desired product (52
64) was obtained.

Melting point = 127°C (decomposition) Example 1 Synthesis of threo-8-(8,4-methylenedioxypheny/I/)-N,N-dibenzylserine methylester μ8.4-methylenedioxyphenylene /k
-N.

N-Dibenzylglycine methyl ester/' (100 Misaki)
was dissolved in methanol/k (5 mJ), and sodium borohydride (20 capes) was added under water cooling. After cooling to room temperature, the mixture was poured into a large amount of water and extracted with methylene chloride. After drying, the solvent was distilled off to obtain the desired product (Cape 79).

Melting point: 96-970 Example 2 Synthesis of threo-8-(8,4-methylenedioxyphenylene/L/)-N,N-dibenzylserine methyl ester 8.4-methylenedioxyphenylene/L'
-N.

N-dibenzylglycine methyl ester/' (800 Misaki)
was dissolved in 70% aqueous ethanol-μ (80 mJ). After adding and dissolving ammonium chloride (881 inches), sodium borohydride (27-F) was added under water cooling and stirred for 80 minutes. After the reaction, the solvent was distilled off under reduced pressure and 121I acid (
8 ml> and water (25 ml) were added, and the mixture was extracted with ethyl acetate. The desired product (290 Misaki) was obtained by separating the organic layer, drying and distilling it off. Melting point: 96-97°C! l! Example 8 Synthesis of threo-8-(8,4-dibenzyloxy)-N,N-dibenzylserine methyl ester 8.4-Dibenzyloxybency/L/-N.

N-dibenzylserine methyl ester/I/(4゜q) was dissolved in a mixture of methano-/I/(5mj)-blocked methylene (1 mJ), and sodium borohydride (40v) was dissolved under water cooling.
) was added. The reaction solution was returned to room temperature, and the pH was adjusted to a range of 2 to 8 by adding 10% hydrochloric acid, neutralized with sodium bicarbonate, poured into a large amount of water, and extracted with methylene chloride.

The organic layer was separated, dried, and concentrated to obtain the desired product (8
7-1) was obtained 90 Melting point: 84-87°C Example 4 Synthesis of threo-8-(8,4-dibenzyloxy)-N,N-dibenzylserine methyl ester Following the method of Example 2, 3 .4-dibenzyloxybency/l/-N,N-dibenzylserine methyl ester-v
(585-F) was reduced with sodium borohydride for post-treatment, and then purified with silica gel chromatography to obtain the desired product (454 Misaki). Cooperation with this thing.

Is the IR consistent with that obtained in Example 8? “ゝ′Reference 8
Synthesis of threo-8-(8,4-methylenedioxyphenyl-N,N-dibenzylserine)Threo-8-(8,4-methylenedioxypheny/l/)-N,N synthesized in Example 1 -dibenzylserine methyl ester/' (500 cape) ometano/' (27
mJ) and water (8 ml), and potassium hydroxide was added to make a solution of about 0.5 N.After standing overnight,
After adjusting the pH to a range of 2 to 3 with 10% hydrochloric acid, water was added to the concentrated 0 residue and extracted with ethyl acetate. After drying the organic layer and distilling off the solvent, the residue was dissolved in a small amount of ethyl acetate and methylene chloride was added to obtain the desired hydrochloride (4
Melting point (hydrochloride): 178-180
°C (Decomposition) Reference Example 4 Synthesis of threo-8-(8,4-dibenzyloxyphenyl-N,N-dibenzylserine) Threo-8-(8,4-dibenzyloxy)- synthesized in Example 8 N,N-dibenzylserine methyl ester/I
/ (454-f) methanol-methylene chloride-water (
50:40:10) The mixture was dissolved in 100 mJ, and potassium hydroxide was added to bring the mixture to 0.8N and left overnight. After 6 hours, potassium hydroxide was added to the mixture to make it 0.5N, and the reaction solution was neutralized with concentrated hydrochloric acid and extracted with methylene chloride. After the solvent was distilled off, the raw material was recovered by silica gel column chromatography purification (methylene chloride followed by ether) and the desired product (152-v) was obtained.

Melting point: Approximately 68°C (sublimation) NMR (CDCJ3), δ (p p m) ” 8
．． 45 (d - IH, J = 9Hz) e8.59 (d
, 2H, J=18Hz), 4.04(d, 2H, J=1
8Hz).

4.94 (d, IH, J=9Hz), 5.00 (d, 2
H, J=8Hz), 5.10 (s, 2H), 6.7-6
．． 9(m,8H)e7.2-7-4(2-7-4(Reference Example 5) Synthesis of svt-B-(B, 4-methylenedioxyphenylserine) Threo-8 synthesized in Reference Example 8 -(8,4-methylenedioxyphenylene/u) -N,N-dibenzylserine (2
00v) to 95g 6 ethanol (20mJ) and 5
% bafdium-carbon (2 (lv) was added and heated under a stream of hydrogen.
The mixture was stirred at 0°C for 2 hours.

After the precipitate was dissolved by adding several drops of concentrated hydrochloric acid, palladium-carbon was removed. Furthermore, after washing the badge ram carbon with methanol/L' (5mj), the F solution was adjusted to pH = 5.7 with an aqueous sodium hydroxide solution, and the desired product (79-F) was removed to collect the precipitated crystals. Obtained: 90 Melting point: 175-180°C (decomposed) As a result of analysis by HPLC, it was found that this target product contained almost 100% of the threo isomer.

HPLC analysis conditions column: Licromoso/I/7@RP-1s, t
oμe 4mx80m mobile phase mixture: 0. OQ 5M
PIC-B-7 Niacetonitrile-9:1 flow rate:
1. OmJ/min Detection: UV (254 nm) Elution time Threo form = 7.7 minutes Erimolinia, 0 minutes Therefore, it was confirmed that the reduction reactions in Examples 1 and 2 proceeded in a threo specific manner.

Reference Example 6 Synthesis of Threo-8-(8,4-dihydroxyphenylv)serine synthesized in Reference Example 4
Oxyphenylene/L/)-N,N-dibenzylserine (150 capes) was dissolved in 95*ethano-(15 mj), 5g6 palladium-carbon (20 capes) was added, and hydrogenated under the same conditions as Reference Example 5. After the reaction, add a few drops of concentrated hydrochloric acid to the catalyst and adjust the pH of the liquid to 5.7.The desired product (20 capes) precipitated out from K was obtained.0 IR (KB r ) cm -': 8400-815
0 * 2900-1660゜1590, 1510
, 1450 , 1400° 1850.1280.122
0.1110°1060, 1010, 920.82
As a result of HPLC analysis of the p solution and the target product after 0 tactile experiments, it was found that the threo form was approximately 10 (l).

HPLC analysis "Conditional force? A: !J zicro/#7@RP-18,1
0/J, 4mX80an mobile phase mixture: 0.005M
PICB-7/methano-/L'mi1171 solution adjusted to pH=188 with phosphoric acid Solution flow rate: 1 mJ/mln Detection: trv (254 nm) Open during elution Threo form = 9.2 minutes Erimolinia, 7 minutes

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a benzyl group or two R
^1 together represent a methylene group, R^2 represents a lower alkyl group, and Bzl represents a benzyl group. ) The general formula is characterized by the stereoselective reduction of the keto-amino acid derivative represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. A method for producing a threo-3-(3,4-dihydroxyphenyl)serine derivative represented by: