JPS62906B2 - - Google Patents

Description

[Detailed description of the invention] The present invention provides (2S, 3R) or (2S, 3S)-3-
This invention relates to a method for producing amino-2-hydroxypropionic acid derivatives.

(2S, 3R) or (2S, 3S)-3-amino-
2-Hydroxypropionic acid derivatives have many physiological effects, such as inhibiting aminopeptidase B, and are especially effective against the compound bestatin (2S,
3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(S)-leucine and related substances (for example, JP-A-51-7187, JP-A-52-
136118, JP-A-52-117435)).

Traditionally, (2S, 3R) and (2S, 3S) are useful as raw materials for the production of bestatin and similar substances.
-3-Amino-2-hydroxy-4-phenylbutyric acid has been derived from D-phenylalanine and L-phenylalanine, respectively, but (2R,
3R) and (2R, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid are always produced as by-products.

However, the optical isomers of bestatin obtained by reacting these compounds with L-leucine, namely (2R,3R) and (2R,3S)-3-amino-2
-Hydroxy-4-phenylbutanoyl- (S)
-Leucine has almost no enzyme inhibitory effect, so
These compounds have been discarded.

This is extremely disadvantageous for production methods using expensive phenylalanine, especially non-natural D-phenylalanine, as a starting material.

Therefore, the present inventors proposed (2R, 3R) and (2R, 3S)-3-amino-2-hydroxy-4-
As a result of intensive research to find a way to convert phenylbutyric acid into the effective (2S, 3R) and (2S, 3S) forms, respectively, the general formula () [In the formula, R ₁ represents a lower alkyl group or an unsubstituted or substituted benzyl group, R ₂ represents a lower alkyl group or an unsubstituted or substituted phenyl group, and R ₃ represents an ester residue. ] The (2R, 3R) form or (2R, 3S) form of the 3-amino-2-hydroxypropionic acid ester derivative represented by is reacted with thionyl chloride, arylsulfonyl chloride or lower alkylsulfonyl chloride, and then the resulting reaction By hydrolyzing the product with acid or alkali, the general formula 3- represented by [wherein R ₁ is the same as above]
It has been found that the (2S,3R) or (2S,3S) form of amino-2-hydroxypropionic acid derivatives can be obtained.

The present invention was completed based on the above findings. The manufacturing method of the present invention will be explained in detail below.

(2R, 3R) or (2R,
As the 3S)-3-amino-2-hydroxypropionate derivative, in the general formula ()
R ₁ is (1) a lower alkyl group such as methyl, ethyl, propyl, butyl, (2) a benzyl group, (3) a halogen,
Lower alkyl group, lower alkyloxy group, lower alkyloxycarbonyloxy group, benzyloxy group, benzyloxycarbonyloxy group, nitro group, benzyloxycarbonylamino group, lower alkyloxycarbonylamino group, arylsulfonylamino group, phthalimino group, etc. , and R ₂ is (1) a lower alkyl group such as methyl, ethyl, or propyl, (2) a phenyl group, (3) a lower alkyl group, a lower alkyloxy group, a halogen, a nitro group, etc. is a phenyl group substituted with , and R ₃ is (1) a lower alkyl group such as methyl, ethyl, propyl, butyl, (2) a phenyl group, (3) a halogen, nitro group, lower alkyl group, or lower alkyloxy group. Examples include compounds such as a phenyl group substituted with (4) a benzyl group, (5) a benzyl group substituted with a halogen, a nitro group, a lower alkyl group, or a lower alkyloxy group.

In the production method of the present invention, the reaction between the compound of the general formula () and thionyl chloride is carried out in the (2R, 3R) or (2R, 3S) form of the 3-amino-2-hydroxypropionic acid derivative represented by the general formula (). Add 1 equivalent or more of thionyl chloride to 1 equivalent, preferably 5 to 10 equivalents of the solvent, and add at room temperature or below, preferably -10 to
It is carried out by reacting at 10°C.

The reaction usually completes within several hours or overnight. Note that an inert solvent that does not participate in the reaction, such as chloroform, benzene, or toluene, may be added as a solvent. To isolate the reaction product from the reaction solution, thionyl chloride is distilled off under reduced pressure below room temperature, and an inert solvent such as ether is added to the residue.
This is done by collecting the precipitated crystals.

Further, the reaction between the (2R, 3R) or (2R, 3S) form of the compound of general formula () and the arylsulfonyl chloride or lower alkylsulfonyl chloride compound is represented by the general formula (). To 1 equivalent of the (2R, 3R) form or (2R, 3S) form of the 3-amino-2-hydroxypropionic acid derivative, 1 equivalent or more of pyridine, preferably in an amount that dissolves the derivative, is added, or pyridine such as benzene or toluene is added. An inert solvent and 1 equivalent or more, preferably 1.1 to 1.5 equivalents of an organic tertiary base are added, and the temperature is at room temperature or below, preferably from -10 to
Add 1 equivalent or more, preferably 1.1 to 1.5 equivalents of a sulfonyl chloride compound to react at 10°C, add an organic solvent that does not mix with water such as ethyl acetate or ether, and wash with water. It can also be obtained by dehydrating with a dehydrating agent such as sodium and distilling off the solvent under reduced pressure.
Furthermore, this product is dissolved in a lower alcohol, and 1 equivalent or more, preferably 1.1 to 2.2 equivalents of sodium acetate,
It is better to add a mild base such as potassium acetate or pyridine, heat preferably above room temperature, and conduct the reaction again under reflux of the solvent. In this case, isolation of the reaction product from the reaction solution can be carried out using, for example, ethyl acetate,
This is carried out by extraction with an organic solvent such as ether, washing with water, dehydration, and then distilling off the solvent.

Arylsulfonyl chlorides include benzenesulfonyl chloride, toluenesulfonyl chloride, etc., and lower alkylsulfonyl chlorides include methanesulfonyl chloride, ethanesulfonyl chloride,
Examples include arylsulfonyl chloride.

By hydrolyzing the reaction product obtained as above with acid or alkali (2S,
3R) or (2S,3S)-3-amino-2-hydroxypropionic acid derivatives are obtained.

Next, this hydrolysis will be described. The acid for hydrolysis may be either an inorganic acid or an organic acid, and the type is not particularly limited. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, etc., and examples of organic acids include benzenesulfonic acid, Toluenesulfonic acid and the like are preferred. When using an alkali, it may be either inorganic or organic, but inorganic hydroxides, particularly alkali metal and alkaline earth metal hydroxides, are preferred.

In addition, during hydrolysis, if the reaction product is difficult to dissolve in an acid or alkali aqueous solution, use a hydrophilic organic solvent such as tetrahydrofuran, dioxane, etc. to increase solubility and promote hydrolysis.
Lower alcohols, ethylene glycol, methyl cellosolve, diglyme, acetone, methyl ethyl ketone, dimethyl sulfoxide, etc. may be added. The reaction temperature is not particularly limited as long as it is room temperature or higher, but in order to quickly carry out the reaction, it is preferable to carry out the reaction under heating and reflux.

To isolate the hydrolyzate from the reaction solution, a conventional method for isolating amino acids may be applied. For example, when the reaction solution is hydrolyzed with an acid, it is neutralized with an alkali, and when the reaction solution is hydrolyzed with an alkali, it is neutralized with an acid. The (2S, 3R) or (2S, 3S)-3-amino-2-hydroxypropionic acid derivative can be easily isolated by elution with aqueous ammonia and concentration.

The (2R, 3R) or (2R, 3S) form of the 3-amino-2-hydroxypropionic acid derivative represented by the general formula () used as a raw material in the present invention can be prepared by a conventional method, for example, the (2R, 3R) form, respectively. ) or (2R,3S)-3-amino-2
-Hydroxypropionic acids are acylated with an acylating agent and then esterified, or (2R,3R) or (2R,3S)-3-amino-
Esterifying 2-hydroxypropionic acids,
It can then be obtained by acylation with an acylating agent.

The present invention will be specifically explained below using Examples.

Example 1 (2R,3R)-N-benzoyl-3-amino-
6.15 g (19.6 mmol) of 2-hydroxy-4-phenylbutyric acid methyl ester was added little by little to 14.3 ml (196 mmol) of thionyl chloride cooled to 0°C.
Let it react overnight. The reaction solution was concentrated under reduced pressure at room temperature,
When 300 ml of ether is added to the residue, crystals are precipitated. If you take this crystal and wash it with ether,
mp130~131℃, [α] ²⁵ ₅₇₈ +57.0゜(c=3.3
，
A reaction product exhibiting AcOH) is obtained.

50 ml of 6N hydrochloric acid is added to 3.00 g (9.1 mmol) of the obtained reaction product, and the mixture is heated under reflux for 6 hours for hydrolysis. The reaction solution is returned to room temperature, 100 ml of ether is added and shaken, the ether layer is separated, and the aqueous layer is concentrated to dryness under reduced pressure. The residue is dissolved in 300 ml of water, passed through a column packed with 50 ml of Dowex 50x4 (50-100 mesh), washed with water until the liquid becomes neutral, and then the adsorbed amino acids are eluted with 2N aqueous ammonia. The eluate was concentrated under reduced pressure to dryness, and acetone was added to the residue to collect crystals, resulting in (2S,3R)-3
-Amino-2-hydroxy-4-phenylbutyric acid
1.62g is obtained.

[α] ²⁶ ₅₇₈ +30.0° (c = 1, NHCl), optical rotation of standard [α] ²⁵ ₅₇₈ +29.5° (c = 1, NHCl) [J.Med.Ch
em.
, 20 , 510 (1977)] The infrared absorption spectrum and thin layer chromatography of this compound matched that of the standard product, and high performance liquid chromatography showed that (2R, 3R)-3
- It was confirmed that it did not contain any amino-2-hydroxy-4-phenylbutyric acid.

Example 2 (2R,3S)-N-benzoyl-3-amino-
1.88 g (6.0 mmol) of 2-hydroxy-4-phenylbutyric acid methyl ester was added little by little to 4.8 ml (60 mmol) of thionyl chloride cooled to 0°C.
Let it react overnight. The reaction solution was concentrated under reduced pressure at room temperature,
Add 100 ml of ether to the residue, collect the precipitated crystals, and then perform silica gel column chromatography using chloroform:ethyl acetate = 1:1 as a developing solvent. MP139-140℃, [α] ³⁰ _57
8
-97.1° (c=1.32, AcOH) reaction product
391 mg is obtained.

Add 10 ml of 6N hydrochloric acid to 200 mg (0.6 mmol) of the obtained reaction product, and heat under reflux for 6 hours to perform hydrolysis. The reaction solution is returned to room temperature, 50 ml of ether is added and shaken, the ether layer is separated, and the aqueous layer is concentrated under reduced pressure to dryness. Dissolve the residue in 50 ml of water, pass through a column packed with 10 ml of Dowex 50x4 (50 to 100 mesh), and wash with water until the liquid becomes neutral.
The adsorbed amino acids are then eluted with 2N aqueous ammonia. The eluate was concentrated under reduced pressure to dryness, and acetone was added to the residue to collect the crystals. (2S, 3S) -
3-Amino-2-hydroxy-4-phenylbutyric acid
94.8mg is obtained.

[α] ³⁰ ₅₇₈ -5.1° (c = 1.57, NHCl) Optical rotation of standard [α] ²⁸ ₅₇₈ -5.5° (c = 1, NHCl) [J.Med.Che
m.
, 20 510 (1977)] The infrared absorption spectrum and thin layer chromatography of this compound matched that of the standard product, and high performance liquid chromatography revealed that (2R,3S)-3-
It was confirmed that it contained no amino-2-hydroxy-4-phenylbutyric acid.

Example 3 (2R,3R)-N-benzoyl-3-amino-
1.0 g (3.58 mmol) of 2-hydroxy-5-methylhexanoic acid methyl ester is added little by little to 2.58 ml (35.8 mmol) of thionyl chloride cooled to 0°C, and the mixture is allowed to react at 0°C overnight. After the reaction is completed, thionyl chloride is distilled off under reduced pressure to obtain an oily reaction product.

Add 10 ml of 6N hydrochloric acid to the obtained reaction product,
Heat to reflux for an hour. After cooling to room temperature, ether 20
ml was added, the ether layer was removed, and the aqueous layer was concentrated under reduced pressure to dryness. The residue is dissolved in 50 ml of water, passed through a column packed with 10 ml of Dowex 50x4 (50-100 mesh), washed with water until the liquid becomes neutral, and then the adsorbed amino acids are eluted with 2N aqueous ammonia. The eluate was concentrated under reduced pressure to dryness, acetone was added to the residue, and the crystals were collected to give (2S,3R)-3
-450 mg of amino-2-hydroxy-5-methylhexanoic acid are obtained.

[α] ²⁵ ₅₇₈ −24.8° (c=2.0, AcOH) This product also matched the standard product in infrared absorption spectrum and thin layer chromatography.

Example 4 (2R,3R)-N-benzoyl-3-amino-
Dissolve 3.1 g (10 mmol) of 2-hydroxy-4-phenylbutyric acid methyl ester in 50 ml of pyridine and add 0.
Cool to ℃. This includes methanesulfonyl chloride 1.26
g (11 mmol) and reacted at 0 to 5°C for 7 hours. The reaction solution was added to ice water containing 100 ml of concentrated acid, and the precipitated oil was extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed with water until the washings became neutral, dried over anhydrous magnesium sulfate, and filtered. Concentrate the liquid under reduced pressure, dissolve the resulting oil in 50 ml of ethanol, and add 2.06 g of potassium acetate.
(21 mmol) was added, heated under reflux for 2.5 hours, and then ethanol was distilled off under reduced pressure. Dissolve the residue in 30 ml of dioxane and 30 ml of concentrated hydrochloric acid, and heat under reflux for 8 hours.

After the reaction is completed, the solvent is distilled off under reduced pressure, 100 ml of ethyl acetate and 100 ml of water are added to the residue, shaken, and the aqueous layer is concentrated to dryness. Dissolve the residue in 200 ml of water, pass through a 50 ml Dowex 50x4 (50-100 mesh) column, and wash with water until the liquid becomes neutral. Next, the adsorbed (2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid was eluted with 2N ammonia water, concentrated under reduced pressure and dried, and acetone was added to the residue to collect the precipitated crystals. 2S, 3R) - 3
-Amino-2-hydroxy-4-phenylbutyric acid
1.13g is obtained.

[α] ²⁰ ₅₇₈ +30.3゜(c=2,NHCl) It was confirmed by liquid chromatography that this product does not contain any (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid. In addition, the infrared absorption spectrum and thin layer chromatography were consistent with the standard product.

Reference example 1 N-benzoyl-(2R,3R)-3-amino-
Synthesis of 2-hydroxy-4-phenylbutyric acid methyl ester (2R,3R)-3-amino-2-hydroxy-
Dissolve 5 g (25.6 mmol) of 4-phenylbutyric acid in 25.6 ml of 1N caustic soda and add benzoyl chloride under ice cooling.
4.33g (30.8mmol) and 30.8ml of 1N caustic soda in 40
Drip in minutes. After completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 2 hours, excess benzoyl chloride in the reaction solution was extracted and removed with 50 ml of ethyl acetate, 3N hydrochloric acid was added to the aqueous layer to adjust the pH to 2, and the precipitated oil was extracted with 200 ml of ethyl acetate.
Extract twice.

The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. When ethyl acetate-petroleum ether is added to the residue and crystallized, (2R,3R)-N-benzoyl-3-amino-
4.98 g of 2-hydroxy-4-phenylbutyric acid are obtained.

The obtained (2R,3R)-N-benzoyl-3-
Amino-2-hydroxy-4-phenylbutyric acid 4.90
Dissolve g in 100 ml of methanol, and add an ethereal solution of diazomethane at room temperature until the solution turns yellow. Next, acetic acid is added to decompose excess diazomethane, and the solvent is distilled off under reduced pressure. Add ether to the obtained solid and collect the crystals.
(2R,3R)-N-benzoyl-3-amino-2-
Hydroxy-4-phenylbutyric acid methyl ester
4.67g is obtained.

mp188-189℃, [α] ²⁸ ₅₇₈ +33.6゜(c=0.66
，
AcOH) The following compound was synthesized in the same manner.

(2R,3S)-N-benzoyl-3-amino-
2-Hydroxy-4-phenylbutyric acid methyl ester mp132 -3℃, [α] ³⁰ ₅₇₈ -121.7゜(c=2
，
AcOH) (2R,3R)-N-benzoyl-3-amino-
2-Hydroxy-5-methylhexanoic acid methyl ester mp155-156℃, [α] ²⁵ ₅₇₈ +7.8゜(c=0.9
，
AcOH) Reference example 2 (2R, 3R) and (2S, 3R)-3-amino-
Synthesis of 2-hydroxy-5-methylhexanoic acid (2RS, 3R)-N-benzyloxycarbonyl-3-amino-2-hydroxy-5-methylhexanoic acid 21.4g (72.4mmol) and brucine 2
31.1g (72.4mmol) of hydrate in isopropanol
Dissolve with heat in 200 ml, cool to room temperature, leave overnight, and collect the precipitated crystals. The liquid is used in the production of (2R,3R)-3-amino-2-hydroxy-5-methylhexanoic acid as described below.

When the obtained crystals are recrystallized twice from isopropanol, 29.2 g of optically pure (2S,3R)-N-benzyloxycarbonyl-3-amino-2-hydroxy-5-methylhexanoic acid brucine salt is obtained. mp106−107°C, [α] ²⁵ ₅₇₈ +14.8° (c=1.6, AcOH).

29.0g of the obtained brucine salt was added to 500ml of ethyl acetate.
and 50 ml of 1N hydrochloric acid, shake, and remove the aqueous layer containing brucine. The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained oily (2S,3R)-N-benzyloxycarbonyl-3-amino-2-hydroxy-
1.0g of 5-methylhexanoic acid, 30ml of methanol,
Dissolve in 10 ml of acetic acid and catalytically reduce with palladium black for 4 hours. Next, the catalyst was removed, and the liquid was concentrated under reduced pressure to dryness. 30 ml of acetone was added to the residue and the precipitated crystals were collected. (2S,3R)-3-amino-2
430 mg of -hydroxy-5-methylhexanoic acid is obtained.

[α] ²⁵ ₅₇₈ −25.0° (c=1.3, AcOH).

Elemental analysis value (as C ₇ H ₁₅ NO ₃ ) C% H% N% Actual value 51.86 9.42 8.60 Calculated value 52.13 9.38 8.69 On the other hand, the first crystalline liquid above was concentrated under reduced pressure, and 200 ml of ethyl acetate and 50 ml of 1N hydrochloric acid were added to the residue. is added, shaken, and the aqueous layer containing brucine is removed. After washing the ethyl acetate layer with water and drying with anhydrous magnesium sulfate,
The liquid was concentrated under reduced pressure, and the resulting solid was recrystallized twice with a mixed solvent of ether and n-hexane to obtain optically pure N-benzyloxycarbonyl-
(2R,3R)-3-amino-2-hydroxy-5-
3.40 g of methylhexanoic acid are obtained.

mp120.5−121.5℃, [α] ³⁰ ₅₇₈ +11.1゜(c
=
1, AcOH).

Dissolve 1.00 g of this crystal in 30 ml of methanol and 10 ml of acetic acid, and catalytically reduce it with palladium black for 4 hours. After removing the catalyst and concentrating the liquid under reduced pressure to dryness, 50ml of acetone was added to the residue to remove the crystals.
(2R,3R)-3-amino-2-hydroxy-5-
580 mg of methylhexanoic acid are obtained.

[α] ²⁵ ₅₇₈ +27.4° (c=1.5, AcOH).

Elemental analysis value (as C ₇ H ₁₅ NO ₃ ) C% H% N% Actual value 51.98 9.53 8.71 Calculated value 52.13 9.38 8.69

Claims (1)

[Claims] 1 General formula () [In the formula, R ₁ represents a lower alkyl group or an unsubstituted or substituted benzyl group, R ₂ represents a lower alkyl group or an unsubstituted or substituted phenyl group, and R ₃ represents an ester residue. ] 3
The (2R, 3R) or (2R, 3S) form of the -amino-2-hydroxypropionic acid ester derivative is reacted with thionyl chloride, arylsulfonyl chloride or lower alkylsulfonyl chloride, and then the resulting reaction product is treated with an acid or General formula characterized by hydrolysis with alkali 3- represented by [wherein R ₁ is the same as above]
A method for producing the (2S, 3R) or (2S, 3S) form of an amino-2-hydroxypropionic acid derivative.