JPS61178955A - Production of threo-3-amino-2-hydroxy-4-phenylbutyric acid - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a synthetic intermediate for bestatin and analog compounds thereof useful as a carcinostatic agent, etc., by reducing thereo-3-amino-2-hydroxy-4-oxo-4-phenylbutyric acid or an ester thereof. CONSTITUTION:A compound expressed by formula I (R1 is H or hydroxyl; R2 is protected amino; R3 is H or ester residue) or an ester thereof is reduced in a solvent, e.g. acetic acid or methanol, in the presence of palladium or Raney- nickel, etc. in hydrogen atmosphere at 40-100 deg.C to give the aimed compound. The compound expressed by formula I is obtained by reacting an acetophenone derivative expressed by formula III with glyoxylic acid or an ester thereof expressed by formula IV. EFFECT:The method has improved economic advantage and safety and is suitable for mass-production without problems in equipment, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing intermediates useful for producing bestatin and its analogues, which are useful as anticancer agents.

[Conventional technology]

Conventionally, for example, (28,3R)-3-amino-2-hydroxy-4-phenylbutyric acid derivatives were prepared using (3) CHs O ■ (R)-phenylalanine (1) 'fi = benzyloxycarbonyl derivative ( 2) and then condensation using 3,5-dimethylpyrazole and dicyclohexylcarboside. The obtained benzyloxycarbonyl-(3,5-dimethylpyrazole (3) of the same phenylalanine) was reduced with lithium albanium hydride to convert it to benzyloxycarbonyl-(R)-phenylalaninal (4), and this is reacted with sodium bisulfite to form its adduct (5), and further reacted with a cyanide compound to form a cyanohydrin derivative (6).This is hydrolyzed with acid to form (2R8,3R)-3-amino -2-Hydroxy-4-phenylbutyric acid (7), benzyloxycarbonylated again, (2Rs, 3FL)-3
-penzyloxylponylated 2-hydroxy-
4-phenylbutyric acid (8) was fractionally crystallized using brucine to obtain (28,3R)-3-penzyloxyphenol 2-hydroxy-4-phenylbutyric acid (
9) has been created.

[Problems to be solved by the present invention]

However, although this method can be carried out without any problems on a laboratory scale, when considering large-scale production, it is necessary to use (t)-phenylalanine, which is a non-natural amino acid and is very expensive, as a raw material. Economic problems arising from
Safety and equipment problems arising from reduction with highly flammable lithium aluminum hydride at low temperatures below -20°C, and health and safety issues arising from the use of highly toxic cyanide compounds when synthesizing cyanohydrin. Due to the above problems, it is by no means a desirable method for mass production.

[Means for solving problems]

Therefore, we conducted intensive research to find a method that does not have these drawbacks and is suitable for mass production, and as a result, we completed the present invention.

That is, the present invention relates to the general formula (wherein R1 is a hydrogen atom or a hydroxyl group, R7 is a protected A-i) group, Rs [a hydrogen atom or an ester residue]. ) threo-3-amino-2-hydroxy-4
-threo-3-amino-2-hydroxy-4-phenylbutyric acid or The ester is obtained.

The compound of general formula (1) of the present invention has a general formula (in the formula, R1 is a hydrogen atom, a hydroxyl group, and an RJ-protected ai) group. It can be obtained by reacting an acetophenone derivative represented by the following with glyoxylic acid or an ester thereof represented by the general formula % (where R3 represents a hydrogen atom or an ester residue).

For example, the final compound represented by the general formula (U) below can be obtained from the compound of general formula (U) obtained in the present invention in the following manner.

That is, if necessary, removal of the abano-protecting group or (and) ester residue of the compound of general formula (II), (bJ optical resolution, and when a salt is formed with the resolving agent, the resolving agent or (and) (if cJ ester residues remain, perform the step of removing ester residues, and convert the general formula (where R is the same as above, R'2 is (2S,3R)-3-abino-2-hydroxy-4-phenylbutyric acid represented by (2S,3R,)-3-amino-2-hydroxy −
A functional group that does not participate in the reaction between 4-phenylbutyric acid and the amine acetic acid represented by the general formula % (in the formula, R4 represents an alkyl group having 3 to 4 carbon atoms or a 3-guanidinoglobin group) is necessary. After protection according to the formula, condensation is performed by a conventional method for forming a peptide bond, and then the protecting group of the functional group is removed to obtain (28.3R)- It can be 3-amino-2-hydroxy-4-2enylbutanoyl azunoacetic acid.

To explain the present invention in more detail, in the aceto2dinone derivative represented by the general formula ff1l, which is the raw material of the present invention, R + 'tl may be substituted at any of the ortho, para, or meta positions; Protecting groups for the amine group in the protected amine group of R2 include formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, bromoacetyl group, and 2-chloroglobionyl JL2-70.
Acyl groups such as muglobionyl group and benzoyl group: methoxycarbonyl group, ethoxycarbonyl group, ingloviroxycarbonyl group, isobutyloxycarbonyl group
I, t-butyloxycarbonyl group, -amyloxycarbonyl group, 2,2.2-t-IJ chloroethoxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group group, p
-Oxycarbonyl groups such as halogenobenzyloxycarbonyl group and p-nitrobenzyloxycarbonyl group:
Examples include carboxyl groups such as carbamyl, methylcarbamyl, ethylcarbajal, propylcarbamyl, butylcarbamyl, phenylcarbamyl, and phthalyl groups. In addition, the protective groups such as the acyl group, oxycarbonyl group, carbamyl group and phthalyl group may have substituents such as alkyl groups, phenyl groups, and phenylene groups that do not interfere with the reaction.

In addition, 113 in the compound represented by the general formula (Ml)
Examples of ester residues include lower alkyl groups having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, butyl group, amyl group, and hexyl group. It may have a substituent such as phenyl, chloro, etc.

Some of the acetophenone derivatives of the general formula (VJ) used as raw materials of the present invention are new compounds, but like the known compounds, the acetophenone represented by the general formula (■) (R+ is the same as above) can be converted to bromine. Synthesized by reacting the corresponding phenacyl bromide obtained by the reaction with hexamethylenetetramine, then hydrolyzing it to convert it into the corresponding phenacylamine, reacting with an appropriate acylating agent, and acylating the ada 7 group. be done.

Give a typical example of the compound of general formula (Vl).
(2-oxo-2-phenylethyl)acetamide, N-
(2-oxo-2-phenylethyl)benzamide, N
-(2-oxo-2-7dynylethyl)phthalide,
2-Methoxyluponyla danoacetophenono, 2-t
-Butyloxyluponylbanoacetophenone, N-
[2-oxo-2-(4'-hydroxyphenyl)ethyl]acetavide, N-[2-oxo-2-(4'-hydroxyphenyl)ethyl]chloracetide, 2-ethoxycarponylbano 4'- Hydroxyacetophenone, N-[2-okino-2-(3'-hydroxyphenyl)ethyl]penzado, 2-tert-butyloxyphenone, 3'-hydroxyacetophenone, N
-(2-oxo-2-phenylethyl)chloracetaζ
N-[2-oxo-2-(2'-hydroxyphenyl]ethyl]acetamide, N-[2-oxo-2-(4
'-Hydroxyphenyl)ethyl] penzuabad, N-
(2-oxo-2-(3'-hydroxyphenyl)ethyl) acetagodo and the like.

Examples of the compound of general formula (Vll) include glyoxylic acid, methyl glyoxylate, ethyl glyoxylate, and benzyl glyoxylate.

The reaction of the acetophenone derivative of the general formula (Vl) of the present invention with the glyoxylic acid or its ester of the general formula (Vll) is usually carried out in water, an organic solvent, or a mixed solvent of water and an organic solvent in the presence of a base. There are no particular restrictions on the organic solvent used as a mixed solvent with water, as long as it is soluble in water, but lower alcohols such as methanol, ethanol and propatool, ketones such as acetone and methyl ethyl ketone, acetonitrile, tetrahydrofuran,
Dioxane, dimethylformamide, dimethylacedeamide, dimethylsulfoxide and the like are preferred.

In addition, there are no particular restrictions on the organic solvent used in the reaction as long as the raw materials can be dissolved in it, but in addition to the above-mentioned solvents,
Preferred are esters of methyl acetate and ethyl acetate, ethers such as diethyl ether and diisopropyl ether, and halogenated hydrocarbons such as chloroform and carbon tetrachloride.

In addition, as bases, potassium hydroxide, sodium hydroxide,
Examples include inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, and ammonia, and organic bases such as potassium acetate, sodium acetate, pyridine, trimethylagon, and triethylamine. When carrying out the reaction, inorganic bases, especially potassium hydrogen carbonate and sodium hydrogen carbonate, are preferred;
When carrying out the reaction in an organic solvent or a water-containing organic solvent, an organic base, particularly triethylane, is preferred, and there is no particular restriction on the amount used, as long as the liquid property of the reaction solution remains weakly acidic or alkaline. 1 to glyoxylic acid or its ester represented by the general formula (Vll)
Preferably it is 2 equivalents.

The reaction temperature can be from 0°C to the boiling point of the solvent, but it is preferably carried out at room temperature to about 70°C.
The reaction is usually completed by reacting for 3 to 24 hours.

There is no particular restriction on the amount of glyoxylic acid or its ester of general formula (Vll) used in the present invention, and for example, it may be used in a wide range of 0.2 to 10 equivalents relative to the acetophenone derivative represented by general formula (Vl). The amount of H used is practically 5 to 5 equivalents, preferably 1 to 2 equivalents.

In the case of glyoxylic acid in which R3 is a hydrogen atom in general formula (vIl), an inexpensive aqueous solution may be used without any problem.

In this way, a compound of general formula (VT) and a compound of general formula (V
The compound of general formula (1) can be obtained by reacting the compound of formula (1). Isolation of this compound from the reaction solution is carried out, for example, as follows.

(a> When R3 is a hydrogen atom, ■ When water is used as a reaction solvent, by adding an acid to the reaction solution to make it acidic, precipitating crystals, and collecting this crystal tP, ■ water and organic When the reaction is carried out using a mixed solvent of solvents, first remove the organic solvent under total vacuum, then add acid to make it acidic and precipitate crystals.
f1f”.

In cases (1) and (2) above, if crystallization does not occur even after acidification by adding an acid, extract with ethyl acetate, etc., and perform the same procedure as described below (bl) to isolate crystals.

(When R,s is an ester residue, an organic solvent or a water-containing solvent is usually used as the reaction solvent, so after the reaction, the reaction solution is concentrated under reduced pressure to remove all the organic solvent, water is added, and ethyl acetate is added. The product is extracted with water, washed with water, dehydrated and dried by adding anhydrous sodium sulfate, etc., the solvent is distilled off under reduced pressure, n-hexane, etc. is added to the residue, and the precipitated crystals tf' are collected.

Threo-(
2R3)-3-adano-2-hydroxy-4-oxo-
Typical examples of 4-phenyl acid or its ester include threo-(2R8)-3-phthalino-2-hydroxy-4-oxo-4-phenylbutyric acid, threo-(2R8)-3-phthalino-2-hydroxy-4-oxo-4-phenylbutyric acid,
8) Ethyl ester of -3-acetylamino-2-hydroxy-4-oxo-4-phenylbutyric acid, threo-(2Rs)-3-chloroacetylamino-2-hydroxy-4-oxo-4-phenylbutyric acid and its methyl esters, threo-(2R8)-3-methoxycarbonylated 2-hydroxy-4-oxo-4-phenylbutyric acid, threo-(2as)-3-t-butoxycarbonylated 2-hydroxy- 4-oxo-4-phenylbutyric acid, threo-(2Rs)-3-penzoylamino-
2-Hydroxy-4-oxo-4-phenylbutyric acid, threo-(2R8)-3-acetylagono 2-hydroxy-4-oxo-4-(4'-hydroquinophenyl)butyric acid, threo-(2R8)- 3-pensylated 2-hydroxy-4-oxo-4-(4'-hydroxyphenyl)butyric acid, threo-(2R8)-3-acetylamino-
2-Hydroxy-4-oxo-4-(3'-hydroxyphenyl)butyric acid, threo-(2R8)-3-pensoylagono 2-hydroxy-4-oxo-4-(3'-hydroxyphenyl)butyric acid, threo -(2R8)-3-Ethoxycarbonylated 2-hydroxy-4-okino-4-(4'-hydroxyphenyl)butyric acid, threo-
(2R8)-3-1-butyloxycarbonylamino-
2-Hydroxy-4-oxo-4-(3'-hydroxyphenyl)butyric acid, threo-(2R8)-3-chloroacetylagono 2-hydroxy-4-(4'-hydroxyphenyl)butyric acid, threo-(2R8) )-3-acetylagono-2-hydroxy-4-(2'-hydroxyphenyl)butyric acid and the like.

Thus obtained threo-
(2as)-a-Amino-2-hydroxy-4-oxo-4-phenylbutyric acid or its ester can be prepared by reducing the threo-3-amino-2 represented by the general formula (Ill).
-Hydroxy-4-phenylbutyric acid or its Nisdel. In addition, in some cases, the racemate of general formula (1) obtained as described above is optically resolved,
The optical isomer of the (28,3R) form is isolated, and if an optical resolving agent is bound, it is removed if necessary, and the (28,3R) optical isomer is isolated.
The 8,3J form of the compound of general formula (I) may be reduced, in which case (2S.

3R) form of the compound of general formula (II) is obtained.

The reduction method used here is not particularly limited as long as it can convert the carbonyl group directly connected to the aromatic ring into a methylene group, but palladiums such as palladium black, palladium carbon, palladium barium sulfate, Raney nickel, etc. Catalytic reduction with lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, etc. and anhydrous aluminum chloride, reduction with zinc or tin and acid, reduction with metallic sodium or metallic lithium in liquid anomonia, etc. Although reduction may be used, contact reduction with palladiums such as palladium black and palladium carbon, and Raney nickel is particularly preferred.

To carry out reduction using palladium or Raney nickel, threo-3-adano-2-hydroxy-4=okino-4-phenylbutyric acid represented by general formula (1) or its ester is dissolved or suspended in a solvent. , Palladium or Raney nickel is added to this, and the process is carried out in a hydrogen atmosphere. The hydrogen pressure may be normal pressure or increased pressure, and the reaction will proceed quickly if carried out under increased pressure.

The reaction solvent is not particularly limited as long as it can dissolve even a small amount of threo-3-ano-2-hydroxy-4-oxo-4-phenylbutyric acid or its ester represented by the general formula (rJ), but acetic acid or methanol can be used. Alternatively, a solvent containing them is preferable, and the reaction temperature is 15°C or higher than room temperature.
Although it can be used up to 0°C, it is preferably carried out at 40-100°C in an acetic acid- or methanol-containing solvent.

The thus obtained 3-agono-2-hydroxy-4-phenylbutyric acid represented by the general formula (II) or its ester is prepared by removing the catalyst from the P, concentrating the liquid f, and adding an appropriate solvent to the residue. It can be easily isolated from the reaction solution by precipitating the crystals and collecting the precipitated crystals by F.

Furthermore, if mild reduction is performed, the intermediate 3-amino-2,4-dihydroxy-4-
Phenyl butylene m-q can also produce and isolate its ester, which can be further reduced to lead to the compound of general formula +10.

In the compound represented by general formula (II), R2 is a chloroacetyl group, a dichloroacetyl group, a t-butyloxycarbonyl group, a t-adaloxycarbonyl group, 2,
2.2-Trichloroethoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phthalyl, etc.-protected adano group compounds are optically resolved and then directly reacted with leucine to produce bestatin and hydroxypestatin. It is suitable because it can be used as and analogues thereof.

A typical example of the 3-avino-2-hydroxy-4-phenylbutyric ester represented by the general formula (II) is threo-(2R8)-3-acetylagono-2-hydroxy-4- Phenylbutyric acid, threo-(2R
8) -3-acetylamino-2-hydroxy-4-phenylbutyric acid noethyl ester, threo-(2R8)-3-
Benzoylamino-2-hydroxy-4-phenylbutyric acid, threo-(2R,8)-3-chloroacetylagono-2-hydroxy-4-phenylbutyric acid, threo-(2as
)-3-Methoxycarbonylamino-4-phenylbutyric acid, threo-(2R8)-3-t-butyloxycarbonylamino-4-phenylbutyric acid, threo-(2R8)-3
-phthalimino-4-phenylbutyric acid, threo-(2R8
)-3-acetylamino-2-hydroxy-4-(4'
-hydroxyphenyl) butyric acid, threo-(2R8)-
3-pencilylamine 2-hydroxy-4-(4'-
Hydroxyphenylinolibutyric acid, threo-(2R8)-3
-Acetylamino-2-hydroxy-4-(3'-hydroxyphenyl)butyric acid, threo-(2R,5)-3-pensylyladanor 2-hydroxy-4-(3'-hydroxyphenyl)butyric acid, threo-( 2R,5)-3-acetyl abinol 2-hydroxy-4-(2'-hydroxyphenyl)butyric acid, threo-(2R8)-3-pensyylabino 2-hydroxy-4-(2'-hydroxyphenyl)butyric acid and their (2S, 3R) type optical isomers.

The compound of general formula (II) is optionally subjected to the steps of (a) removal of the amino protecting group or (and) ester residue of the obtained compound, and (b) optical resolution, and then combined with a resolving agent and a salt. Removal of splitting agent and/or during forming (
C) If ester residues remain, a step of removing the ester residues is carried out to remove the ester residues (2S, 3R
)-3-amino-2-hydroxy-4-phenylbutyric acid.

(2S of the general formula (1) thus obtained.

3 The condensation of J-3-adano-2-hydroxy-4-phenylbutyric acid with the aminoacetic acid of general formula (IV) can be carried out using conventional methods for peptide bond formation, protecting functional groups that do not participate in the reaction as necessary. Yoji is done.

After the completion of the condensation reaction, the protective group of the functional group is removed to obtain the final target compound of the present invention, which is represented by the general formula (28.3R)-3-agono-2-hydroxy-4-
Phenylbutanoylaminoacetic acid can be obtained.

Protection of functional groups that do not participate in the reaction, such as the amine group in general formula (1), may be carried out by conventional methods.

The final compound thus obtained is (2S,3R)-
3-adano2-hydroxy-4-phenylbutanoyl-(S)-leucine (bestatin), (2S, aR,
) -3-amino-2-hydroxy-4-(2'-hydroxyphenyl)phthanoyl-(S)-leucine (0-
hydroxybestatin), (28,3R)-3-ano-2-hydroxy-4-(3'-hydroxyphenyl)
Butanoyl-(S)-leucine (m-hydroxybestatin), (28,3R)-3-amino-2-hydroxy-4-(4'-hydroxyphenyl)butanoyl-(S
) - Leusif.

(28,3R)-3-adano-2-hydroxy-4-phenylbutanoyl-(S)-valine, (28,3R)-
3-Adanor2-hydroxy-4-phenylbutanoyl-(81-norvaline, (2S,3R,)-3-Adanor2-hydroxy-4-phenylbutanoyl-(S)
-fulginine and (2S,3R)-3-avanor2
-Hydroxy-4-(4'-hydroxyphenyl)butanoyl-(S)-arginine and physiologically non-toxic salts thereof, such as hydrochloride and acetate.

Next, the present invention will be specifically explained using examples.

Example 1゜(1) Production of threo-(2R8)-3-acetylamino-2-hydroxy-4-oxo-4-phenylbutyric acid N-(2-oxo-2-phenylethyl)acetamide 4
．． 439” (0,025 mol) and sodium hydrogen carbonate 4.20 P (0,05 mol) t 2
5% glyoxylic acid aqueous solution 135' (0,044m
ol) and 25 mg of water, dissolve in 50-60
The reaction is completed by reacting overnight at °C. The reaction solution was cooled on ice, adjusted to pH 1-2 with dilute hydrochloric acid, and the precipitated crystals were
The sample was taken, washed with water, and dried under vacuum over phosphorus pentoxide to give 4.07 P of threo-(2R8)←-3-acetylamino-2-hydroxy-4-oxo-4-phenylbutyric acid (yield 64.9%). ) is obtained.

Melting point 151-152°C (decomposed).

NMR, x, vector (DMSO-de) δ=2.
0 (s, 3H: CH3) 4.6 (d, H, J = 3H
z:eu-OH), 5.9(dd, H:CH-
NH), 7.7 (multi, 5H:a)).

In addition, NH, OHK-based broad
The absorption is between 6.6 and 8.0 and disappears by adding heavy water.

(21threo-(2R8)-3-acetylagono2-
Production of hydroxy-4-phenylbutyric acid Threo-(2R8
)-3-acetyl abanor 2-hydroxy-4-oxo-4-phenylbutyric acid3. OOS' (0,012mo
1) in 251 nl of acetic acid, 5tipalladium carbon 0
．． When 30 P is added and hydrogen is flowed at 60°C and normal pressure, the reaction is completed in about 6 hours.

The catalyst was separated from F, the P solution was concentrated under reduced pressure, and ethyl acetate 2 was added to the residue.
Add Qrnl, collect the precipitated crystals, wash with ethyl acetate, vacuum dry over phosphorus pentoxide,
LS)-3-acetylaino-2-hydroxy-4-phenylbutyric acid 2,33P (yield 82.3%) is obtained. Melting point 174-176°CO NMR, <vector (DMSO-d6) δ=1.
8 (s, 3H:C:H3).

2.7.2.8 (d, d, H, H, J=5Hz
:CH2), 3.9(d, H, J=3Hz :eu
-OH), 4.3 (multi, H:CH-
NH), 7.2(s, 5H:○-), 7.6
(d, H, J = 9Hz:NH) In addition, O
Broad absorption based on H is 7.0-8
．． It has 0 K and loses itself by adding heavy water.

(Production of 31(28,3R)-3-acetylamino-2-hydroxy-4-phenylbutyric acidThreo-(2R8)-3-acetylamino-2-hydroxy-4-phenylbutyric acid 10.87SL (0,046m
ol) and S(@-1-phenylethyl ε)5.5
Add 5P (0,046 mol) to ethanol gOmt and heat to dissolve. Next, it is allowed to cool to room temperature, and the precipitated crystal tf' is collected, washed with a small amount of ethanol, and dried to obtain crystal 6.375'.

[α]I)′. +16.8° (C=1.methanol).

This crystal 6.30P is ethanol 100mA! In addition to
Dissolve it by heating, let it cool to room temperature, collect the precipitated crystal 'tP, wash it with a small amount of ethanol, and dry it (28,3
R)-3-acetylamino-2-hydroxy-phenylbutyric acid 8(-1-1-phenylethylamine salt 3.45
9- is obtained.

Melting point 194-195°C0 [α]I)'. + 29.0° ((=l, methanol)
Optical rotation of a salt separately prepared from (28,3R)-3-acetylamino-2-hydroxy-4-phenylbutyric acid and S(-1-phenylethyl aban).

[αV. +29.1° (C=1.methanol).

(4) (2S, 3R)-3-amino-2-
Production of hydroxy-4-2-enylbutyric acid (28,3R)-3-acetylamino-2-hydroxy-4-phenylbutyric acid with 8H-1-phenylethyl aban salt 4.25 fi' (0,0119 mo+) Sodium hydrogen carbonate A 1.49 fl (0,0178mo+
) was added to 80 ml of water, and 8(-)-1-phenylethylagon was extracted three times with 5 Q ml of ethyl acetate each time.

Next, the pH of the aqueous layer was adjusted to 1-2 with 36% hydrochloric acid, and the pH was adjusted to about 401.
Concentrate under reduced pressure at 11't to obtain 1.7 mt of 36-thihydrochloric acid (0,
02moI)? The reaction is then completed by heating and refluxing for 2 hours.

The reaction solution is concentrated to dryness under reduced pressure, 10 ml of water is added to the residue, concentrated to dryness under reduced pressure, and this operation is repeated once again.

Finally, the residue was dissolved in 4Qmi of water, the pH was adjusted to 5-6 with a 2N aqueous sodium hydroxide solution, and after cooling with water, the precipitated crystals fF were collected, washed with cold water, and dried (28,3R).
-3-amino-2-hydroxy-4-phenylbutyric acid 1.
48 P is i. Yield: 63.8 cm [α)5:,;' + 32.5° (C=0.76.
NHCI).

Literature value (J, Med, ehem, 20. 51
0 (1977)).

[α) +29.5° (c = l, NHCl
)(51(28,3R)-3-Benzyloxycarbonyl 7<No Production of 2-hydroxy-4-phenylbutyric acid (28,3R)-3-Ano 2-hydroxy-4-phenylbutyric acid 1.45 P C7 , 44 mmol), triethylagon 1-13'? (11,2rrmo and benzyl S-4,6-cyphthylpyridine-2=
Ilthiol carbonate 2.24 F (8,20m
mol) to a mixed solvent of 7 ml of water and 77 mA of dioxa.

The reaction is completed by stirring at room temperature for 3 hours.

Add 2Qml of water to the reaction solution, and wash twice with 25ml of ethyl acetate each time. Add dilute hydrochloric acid to the aqueous layer to adjust the pH to 1-2. The precipitated oil is extracted twice with 3 Qml each of ethyl acetate, the extracts are combined, washed three times with 3Qml each of brine, and dehydrated and dried over anhydrous sodium sulfate.

(2S, 3R)-3-penzyloxycarbonyl alcohol 2-Hydroxy-4-phenylbutyric acid2.
10 P is obtained. Yield 85.7%. Melting point 154-1
55°C0 [α), 8+ 82.5° (c=1.acetic acid)
Literature value (Unexamined Japanese Patent Publication No. 52-136118 Example 1 (2
)) Melting point 154.5°C0 [α), 8+ 83.5° (c=1.34.acetic acid) (6
) (2S,3R,)-3-benzyloxycarbonylamine-2-hydroxy-4-phenylbutanoyl-
(S)-Leucine pendyl ester production (28,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyric acid 2.00 F! −
(6,00 mmol), (S)-0i'/7(7) benzyl ester p-toluenesulfonate 2.63
P (6,60 rrrm and 0.97 mmol of 1-hydroxype7zotriazole were added to 20 ml of tetrahydrofuran, cooled with salt and ice, triethyl ai] 0.67 F (6,6 mmof) and then dicyclo Hexyl carboxylate 1.49 P(7,2
0 mmol) and allowed to react overnight without changing the water bath.

The precipitated dicyclohexyl urea was separated by P, the liquid f was concentrated under reduced pressure, and 5Qmlf of ethyl acetate was added to the residue to remove the insoluble matter kP.
Separate and wash with ethyl acetate.

Combine the F solution and the washing solution, wash twice with 0.5 N hydrochloric acid, three times with saline, twice with 5% sodium bicarbonate aqueous solution, and three times with saline, and dehydrate and dry with anhydrous sodium sulfate. .

Sodium sulfate was separated from P, concentrated under reduced pressure, n-hexane was added to the residue, the precipitated crystals (kW) were collected, washed with n-hexane, and dried to give (28,3R)-3-penzyloxycarbonylano-2-hydroxy. -4-phenylphtanoyl-(81-leucine benzyl ester 3.19
I can get Pka and be happy. Yield: 99.4 cm. Melting point 122-123°
C0 [α), 8 + 15.2° (C = 1. acetic acid) Literature value (Unexamined Japanese Patent Publication No. 52-136118 Example 2 (3))
Melting point 122°C8 [α]s7s +15.1° (C=Q, 77, acetic acid) (
7) Bestatin ((28,3R,)-3-avanor2-
Preparation of hydroxy-4-phenylphtanoyl-(S)-Leucif)
Loin/benzyl ester 3, OO! i' (5,
60 mmol) t Dissolved in 50 ml VC of 95% acetic acid,
Add the amount of palladium black tm medium and completely introduce hydrogen at normal pressure.

Since the catalytic reduction is completed in 2 hours, the palladium black is separated and the F solution is thoroughly concentrated under reduced pressure. Add 3Qm of acetone to the residue.
1, the precipitated crystals were collected and dissolved in IN hydrochloric acid,
Add a small amount of activated carbon to separate insoluble matter, adjust the pH of the r solution to 5-6 with dilute aqueous ammonia, collect the precipitated crystals, wash with acetone, and dry. (2S,3FL)-3-amino-2-hydroxy-4-phenylbutanoyl-(S)-leucine], 1
．． 479- is obtained. Yield 85.0%.

Cα]5□8-21.1' (C=1, acetic acid) Literature value (
JP-A-52-136118 Example 2 (J) [α]5□8-21.8° (c=0.45.acetic acid) Example 2° (4) Threo-(2R8)-3-pencyl Amino-2
-Production of hydroxy-4-oquino-4-phenylbutyric acid N-(2-oxo-2-2enylethyl)benzamide 16.7 P (0,07 mol) and sodium bicarbonate 13.0 P (0,155 mol)'i25%
Dissolve 37.5 P (0.13 mos) of glyoxylic acid aqueous solution in 10 IJ of water and 250 ml of methanol and react overnight at 50-'60°C.

The insoluble matter eF in the reaction solution was separated, the P solution was concentrated under reduced pressure, the methanol was distilled off, the pH was adjusted to 1 to 2 with dilute hydrochloric acid, the precipitated crystals were collected, washed with water, and phosphorus pentoxide. Vacuum drying above gives 17.65' of crude crystals. This was recrystallized from ethyl acetate to obtain 13.5 PCs of f-(2R8)-3-benzoylamino-2-hydroxy-4-oxo-4-phenylbutyric acid (yield: 61.8%).

Melting point 174-176°C (decomposition) NMR spectrum (DMSOda) δ = 4.6 (
d, H, J = 4Hz:eH-OH), 5.9
(dd, H:CH-NH), 7.7(mul
ti, IOH:Q- and ()-).

8.5 (d, H, J=9Hz:NH).

(2) Production of threo-(2R,5)-3-benzoylazeno-2-hydroxy-4-phenylbutyric acid
R,5)-3-benzoylamino-2-hydroxy-4
-Okino 4-phenylbutyric acid 5.00! −(0,01
6 mol) and 0.50 P' of 10-thipalladium on carbon are added to 9 Q ml of acetic acid, and hydrogen is introduced at 700 C1 at normal pressure, and the reaction is completed in about 8 hours.

Separate the catalyst from P, concentrate if"l' under reduced pressure, add 1 liter of petroleum ether (boiling point 30-70°C fraction) to the oily residue, stir well, remove the supernatant by deca/tissue, When fresh petroleum ether is added, cooled, and the glass wall is rubbed with a glass rod, it crystallizes.After being left at room temperature for 1 hour, it is removed, washed with petroleum ether, and dried.
8) -3-Benzoylamino-2-hydroxy-4-phenylbutyric acid 4.61y- is obtained. Yield 96.4%.

Melting point 144-145 °C NMR spectrum (DMSO-da) δ = 2.9 (d, 2H, J = 7Hz: CH2),
4.0 (d, )L J =3Hz: CH-OH
), 4.55 (multi, H: CH-NH
).

7.25. 7.5(s, multi, IOH:○-
and 〇−).

7.95 (d, H, J = 8Hz, NH) Example 3゜(1) Threo-(2R,5)-2-hydroxy-4
-Production of oxo-4-phenyl-3-7thalinobutyric acid N-(2-, d-so-2-phenylethyl)phthalimide 10.0 fi' (0,0377 mole and sodium bicarbonate 9.00 y-(0,107 mol
) to 25 tiglyoxylic acid aqueous solution 20. IL? (0
,068mo! ) and ethanol (2Qm/), dissolve it and react at 5o-6o'e for 24 hours.

The reaction solution was concentrated under reduced pressure, ethanol was distilled off, and 100 ml of ethyl acetate and 5% hydrogen carbonate were added to the remaining liquid. The precipitated crystals were collected, washed with water, and dried under vacuum over phosphorus pentoxide to give threo-(2R8)-2-hydroxy-4-oxo-
1.97 P of 4-phenyl-3-phthaliminobutyric acid is obtained.

(Yield 15.4%). Melting point 168-170°C (decomposed) NMR spectrum (DMSO-da) δ=4.55 (d, H, J=4Hz: C!1-0
H), 5.8 (dd.

(2) Threo-(2R8)-2-hydroxy-4-
Production of phenyl-3-phthaliminobutyric acid
8) -2-hydroxy-4-oxo-4-phenyl-3
-phthaliminobutyric acid 1,00? (2,90 mmol
), 10% Radium Black 0.10. P'r acetic acid 2Qm
In addition to i, hydrogen was introduced at 70°C and normal pressure, and catalytic reduction was carried out for 5.5 hours.

The reaction solution was concentrated under reduced pressure, and the residue was mixed with petroleum ether (boiling point 30
-70°C fraction) and then ethyl acetate is added little by little until the oil crystallizes. The precipitated crystals are P
After removing, washing with petroleum ether and drying, threo-(
0.55 P of 2R8)-2-hydroxy-4-phenyl-3-phthaligonobutyric acid is obtained. Yield: 57 cm.

Melting point 97-103°C (foaming).

NMR spectrum (DMS Oda) δ = 2.9 (
d, 2H, J = 7Hz: e) 12), 3.9(
d, H, J=3Hz: CH-OH), 4.4
(Multi, H: CH-NH).

7.3+ 7.5 (s, multi, 9) (:○- and "f:)) Example 4゜(1) Threo-(7R8)-3-chloroacetylamino-2-hydroxy-4-oxo- Production of 4-phenylbutyric acid N-(2-oxo-2-phenylethyl) chloracetamide 1.60? (7.60 mmol), sodium hydrogen carbonate 1.92 P (22.8 mmol and 20
%f! j oxy/l/acid aqueous solution 5.609” (
15,2rrmol) in methanol/l/5Q ml
and 10 ml of water, and reacted at 650C for 10 hours.

Hereinafter, when the process is carried out in the same manner as in (1) of Example 1, the thread (
1.06 P of 2R8)-3-chloroacetylamino-2-hydroxy-4-oxo-4-phenylbutyric acid is obtained.

Yield 48.9%, melting point 141-142°C (decomposition) NI
't4B spectrum (DMSOda) δ=4.2(s,
2H, eH, ), 4.5 (d, H, J = 4Hz: CH
-OH), 5.7 (dd, H:CH-NH), 7.8 (
multi.

5H: Q -), 8.4 (d, H, J = 9
Hz:NH).

(2) Production of threo-(2as)-3-chloroacetylamino-2-hydroxy-4-phenylbutyric acid threo-(2R8)-3-chloroacetylamino-2-
Hydroxy-4-oxo-4-phenylbutyric acid 400m9
(1,40rnDl) and 10tipalladium carbon 4
0 ml of acetic acid was added to 10 ml of acetic acid, hydrogen was introduced at 650C under normal pressure, and catalytic reduction was carried out for 14.5 hours.

After the reaction, the catalyst was separated, the F solution was concentrated under reduced pressure, and ether was added to the oily residue. was added, the resulting precipitate was collected, washed with ether, and dried to give 3-chloroacetyl-
140 m9 of 2-hydroxy-4-phenylbutyric acid are obtained. Yield 36.8% Melting point 108-110 °C NMR spectrum (CD(,'+3)δ=2.95
(d, 2H, J=7Hz: CH2-〇).

4.0, 4.2 (s, d, H, 2H: CH-
OH, CH2-(,:I).

4.7 (multi, H:CH-NH), 7.
15 (d, H, J=10Hz: NH), 7.
25 (S, 5H+○-) Example 5゜(1) Production of threo-(2R8)-3-1-butyloxycarbonylated 2-hydroxy-4-oxo-4-phenylbutyric acid 2-adanoacetophenone Hydrochloride 4.00P (0,02
33 mol) in dioxane-water (1:1) with t-butyl S-4,6-dimethylpyridin-2-ylthiol carbonate and triethylamine. Luponyla vanoacetophenone, sodium bicarbonate 4.70 P (0
,0559 mol) and 20% glyoxylic acid aqueous solution 13,75 ft (0,037 mol) f methanol 50 ml and reacted overnight at 60-65°C.

After the reaction, the insoluble matter tP was separated, the f solution was concentrated under reduced pressure, 10% saline solution IQmlf was added, the insoluble matter tl-IF was separated, the r solution was extracted twice with 5Qml each of ethyl acetate, and the extracts were combined and saturated. Wash with saline and dehydrate and dry with anhydrous sodium sulfate.

Separate the sodium sulfate tP, concentrate the r liquid under reduced pressure, add ether to the residue, remove the insoluble matter and wash with ether,
When dried, threo-(2Rs)-3-t-butyloxycarbonylated 2-hydroxy-4-oxo-4
-1.18 P of phenylbutyric acid is obtained. Yield: 38.2% from 2-aminoacetophenone hydrochloride, melting point: 14
2-143°C (decomposition) NMR spectrum (DMSO-da) δ=1.35 (S, 9H: ((-”H3)3c)
, 4.3 (d, H, J = 4H2: CH-OH
), 5.35 (dd, H:CH-NH).

6.6 (d, H, J = 10Hz:NH),
7.8 (multi, 5H: low).

(2) Production of threo-(2R8)-3-1-butyloxycarbonylamino-2-hydroxy-4-phenylbutyric acid threo-(2R8)-3-t-butyloxycarbonylamino-2-hydroxy-4-oxo 500 m9 (1,62 mmol) of -4-phenylbutyric acid and 100~ of 10-chipalladium carbon in lQmA of acetic acid! In addition, catalytic reduction is carried out at room temperature and hydrogen pressure of 5 oKy/m.

After the reaction, the catalyst is separated, the liquid is concentrated under reduced pressure, and the solvent is thoroughly distilled off. Dissolve the oily residue in 5Qm/ethyl acetate,
Saline 3 omz, o, s Normal hydrochloric acid 3 (Ml/, saline 3
Wash sequentially with Qml and dehydrate and dry with anhydrous sodium sulfate.

Sulfuric acid (IJ) was separated, liquid F was concentrated under reduced pressure, n-hexane was added to the oily residue, it was thoroughly washed, the n-hexane layer was removed by decantation, and fresh n-hexane was added. Add. By repeating this operation several times, it will eventually crystallize, so the precipitated crystals are collected, washed with n-hexane, and dried. Hydroxy-4-phenylbutyric acid 2611n9 is obtained. Yield 54.6%. Melting point 121-122°C NMR spectrum (CDCl2) δ=1.4(3,9H: (CHs)sC), 2.9(
d-2H, J = 7Hz: CH2), 4.1 (
s, H:C:H-OH), 4.2 (multi.

H: CH-NH), 7.2 (s, 5H:〇-)
.

Example 6゜(1) Threo-(2R8)-3-pensoyl abanor 2-hydroxy-4-(3'-hydroxyphenyl)
-Production of 4-oxobutyric acid
), 3.78L of sodium hydrogen carbonate? (0,0450m
ol) and 7.76 L of 25 tiglyoxylic acid urine solution?
(0,030moJ)'ii 95% ethanol 5Qm
A! Oyobi l Tanur 501111Vc added, 50-
React at 60°C for 24 hours.

The reaction solution was reduced to about 20ml under reduced pressure, and water was added to reduce the volume to about 5ml.
Qmi and add concentrated hydrochloric acid to adjust pH to 1-2.

Next, add 100 ml of ethyl acetate and 501 nt of water, shake well, and separate the liquid. Ethyl acetate toomz in the aqueous layer
The ethyl acetate layers were combined, washed twice with brine, and dehydrated and dried over anhydrous magnesium sulfate.

Magnesium sulfate ftF was separated, the P solution was concentrated under reduced pressure, ether was added to the residue, the precipitated crystals were collected, washed with ether, and dried to give threo-(2R8)-3-benzoylamino-2-hydroxy. 1.96% of -4-(3'-hydroxyphenyl)-4-oxobutyric acid is obtained.

Yield 40.2%, melting point 176-177 °C (decomposition) NM
R, spectrum (DMSOda) δ=4.7 (d,
H, J=4Hz: CH-OH), 5.95
(dd.

It has a strong absorption and disappears by adding heavy water.

(2J threo-(2R8)-3-bensyylamino-2-hydroxy-4-(3'-hydroxyphenyl)
Preparation of butyric acid Threo-(2R8)-3-benzoylamino-2-hydroxy-4-(3'-hydroxyphenyl)-4-oxobutyric acid 1.65 P (5,OOrm'Iol) and 10% palladium on carbon 0. 335”k methanol 3Qm
1 and 3Qml of acetic acid, and reacted at 60°C for 7 hours.

When the reaction solution was treated in the same manner as in Example 4 (2), 0.995 L of threo-(2R8)-3-pencyylamino-2-hydroxy-4-(3'-hydroxyphenyl)butyric acid
is obtained. Yield: 63 cm.

Foaming at melting point 80-90°C, 162-165°C NMR spectrum (DMSO-dd) δ = 2.95 (d, 2H, J = 7Hz: CH2),
4.15 (d, H.

Example 7゜ (1) Threo-(2RJS)-3-acetylamino-.

2-Hydroxy-4-okino-4-(4'-hydroxyphenyl)butyric M H-formation N-[2-oxo-2-(4'-hydroxyphenyl)
Ethyl] acetad 10.0 P C0,052mo!
), sodium bicarbonate 12.4, ? (0,14
8 mol), and 25 tiglyoxylic acid aqueous solution 27
, 61i' (0,093moi) eMeta/-R 5
Add to Qml and react at 50°C for 21 hours.

The reaction solution was concentrated under reduced pressure to remove methanol, and 50% of water was added.
ml, adjust the pH to 1-2 with dilute hydrochloric acid, add rock salt to saturate, and extract 5 times with 200 ml of ethyl acetate each time.

The ethyl acetate layers are combined and dehydrated and dried over anhydrous sodium sulfate. sulfuric acid) was separated, the liquid was thoroughly concentrated under reduced pressure, a small amount of ethyl acetate was added to the residue, and the precipitated crystals were separated.
After removing P, washing with ethyl acetate and drying, threo-(
2RS)-3-acetylamino-2-hydroxy-4-
(4'-Hydroxyphenyl)-47oxobutyric acid 8,0
1% is obtained. Yield 57.7%.

Melting point 179-181°C (decomposed) NMR, spectrum (DMS Oda) δ=1.9
(s, 3H: (-H3), 4.45 (d, H,
J ==3Hz =(,'H-OH), 5.7Cd
d, H:CH-NH), 6.9. 7.9(dd,
2H, 2H, J = 8Hz: h-), 7.9
5 (d, H, J = 8Hz: NH).

(2) Production of threo-<2aS)-3-acetylamino-2-hydroxy-4-(4'-hydroxyphenyl)butyric acid threo-(2R,5)-3-acetylamino-2-hydroxy-4-( 4'-hydroxyphenyl)-4-oxobutyric acid 2.6 Of (9,70 mmol) and 10
% palladium on carbon 0.305” to 45 mA of acetic acid,
Hydrogen was introduced at normal pressure of 70°C, and catalytic reduction was carried out overnight.

After the reaction, the same treatment as in Example 2 (2) was carried out, and the obtained crystals were recrystallized from ethanol and ethyl acetate to give threo-<zRs)-s-acetylano-2-hydroxy-
0.679- of 4-(4'-hydroxyphenyl)butyric acid is obtained. Yield: 27 cm. Melting point 194-197°C (decomposed) NMR spectrum (CF3COOH) δ = 2.3 (s, 3H:CH3), 3.1 (d, 2H,
J=7Hz: CH2), 4.65 (s, H
:CH-OH), 4.85 (multi.

H:CH-NH), 6.9. 7.2(d, d,
2H, 2H, J = 8Hz Knee〇-), 8.6 (
d, H, J = 9Hz: NH).

Example 10゜(1) H-formation glyoxylic acid of methyl ester of threo-(2R8)-3-chloroacetylamino-2-hydroxy-4-oxo-4-phenylbutyric acid 5.60 y-(15.2rrmol)
) instead of glyoxylic acid methyl ester 1.34
F! The reaction was carried out in the same manner as in Example 4 (1) except that -(15.2 mmol) was used. Reaction wave example 5 (
When treated in the same manner as in 1), threo-(2R8)-3-chloroacetylamine-2-hydroxy-4-oxo-4
-Methyl ester of phenylbutyric acid 1,429- is obtained.

Yield 62.5% Melting point 119-121°C NMR spectrum (CDCI,) δ = 3.9 (s, 3H:CH,) + 4.1 (S
, 2H:CH2) 14.6 (d, H, J = 2Hz
:(:H-OH), 5.95 (dd, H:
CH-NH), 7.8 (multi, 5H knee ○) In addition, there is a broad absorption based on NH and OH at 7.0-9.0, which disappears by adding heavy water.

(2) Preparation of methyl ester of threo-(2as)-3-chloroacetylamino-2-hydroxy-4-phenylbutyric acid threo-(2R8)-3-chloroacetylamino-2-
Methyl ester of hydroxy-4-oxo-4-phenylbutyric acid 1.00 f (3,77 rrmol) and 1
Add 0.10 P of 0% palladium on carbon to 2 Qml of acetic acid and react in the same manner as in Example 4 (2).

After the reaction, the catalyst is separated from P and concentrated under reduced pressure. Add 3 QmJ of ethyl acetate to the residue to dissolve it, wash sequentially with 10% brine, 5% sodium bicarbonate solution, and 10% brine, and dehydrate and dry over anhydrous sodium sulfate.

Sulfuric acid) IJum is separated from F and the F solution is concentrated under reduced pressure to obtain oily methyl ester of threo-(2R8)-3-chloroacetylamino-2-hydroxy-4-phenylbutyric acid (0.389-). .

Yield: 40 cm.

NMR, spectrum/l/ (CDCI,) δ=2.95
(d, 2H, J=7Hz: CH, -〇)13.
7 (s.

3H:(,'H3), 3.95(S, 2H:CH2
-CI), 4.15 (d, H, J=2Hz: CH
-OH), 4.6 (multi, H:(, H7
NH), 6.9 (d, H, J=9Hz:NH
), 7.3 (s.

5H: Q).

IR spectrum νFi"'(z-') = 3400 and 3300 (b
road) ax 1740 (broad), 1660 (broad)
), 1605.

Claims (1)

[Claims] 1. (A) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 is a hydrogen atom or a hydroxyl group, R_
2 represents a protected amino group, and R_3 represents a hydrogen atom or an ester residue. ) threo-3-amino-2-hydroxy-4
-It is characterized by reducing oxo-4-phenylbutyric acid or its ester. A method for producing threo-3-amino-2-hydroxy-4-phenylbutyric acid represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1, R_2, and R_3 are the same as above.)