JPH0259545A - 3-amino-2-hydroxy-1-nitrobutane derivative and production of alpha-hydroxy-beta-amino acid - Google Patents

Abstract

NEW MATERIAL:A 3-amino-2-hydroxy-1-nitrobutane derivative expressed by formula I (R is protecting group of amino group). EXAMPLE:3S-Amino-4-cyclohexyl-2-hydroxylactic acid.hydrochloride. USE:The compound expressed by formula I has excellent human renin inhibiting activity and is useful as a raw material for producing a compound expressed by formula II useful as a remedy for hypertension capable of orally administering. PREPARATION:A 2-aminoaldehyde derivative expressed by formula III is reacted with nitromethane in the presence of a basic catalyst to provide the compound expressed by formula I. The compound expressed by formula I is further subjected to acid treatment to simply provide the alpha-hydroxy-beta-amino acid derivative without using a cyan compound. The compound expressed by formula III is synthesized by bonding a protecting group expressed by R to amino group of L-phenylalanine methylester hydrochloride expressed by formula V and then carrying out reduction of ester part, reduction of phenyl group and oxidation of hydroxyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing an α-hydroxy-β-amino acid derivative represented by the general formula (I) H . The compound represented by general formula (I) is
A compound represented by the formula (in the formula, His is a histidyl group) which has excellent human renin inhibitory activity and is useful as an orally administrable antihypertensive drug (JP-A-62-23
4071)) is an important raw material for manufacturing.

[Conventional technology]

The compound represented by the general formula (n) can be obtained by the general formula (IV) derived from 2-phenylalanine (JP-A-62-234071).

[Problem that the invention seeks to solve].

The conventional method is commonly used to produce a substance represented by formula (II), and includes operations such as solvent extraction, washing, and drying. These operations increase the amount of waste, but in the case of cyanide compounds, they complicate post-treatment, so a simple method that does not use cyanide compounds is desired.

[Means for solving problems]

As a result of intensive studies to solve this problem, the present inventors succeeded in developing a simple method shown in the following reaction formula, and completed the present invention.

(In the formula, R is a protecting group for an amino group) is subjected to an addition reaction with sodium cyanide, potassium cyanide, etc. in the presence of an acid to form cyanohydrin, and then hydrolyzed using an acid such as hydrochloric acid. ○H (wherein R is a protecting group for an amino group) The compound of formula (IV) which is a raw material used in the present invention can be easily derived from phenylalanine methyl ester hydrochloride ( (See reference side below).

The compound of general formula (rV) thus prepared is an optically active substance, and its configuration is (2S). Furthermore, the nitro compound represented by the general formula (I) obtained from the compound of the general formula (rV) is a new substance, and is an important compound that can be easily converted to the α-hydroxy-β-amino acid of the formula (n) by acid treatment. It is an intermediate. The steric configuration of the compound of general formula (I) is a mixture of (2R93S) form and (2S, 3S) form. The steric configuration of the compound represented by formula (II) is preferably (2R,3S), but (2R,3S) and (2R,3S) are preferable.
2S, 3S) Even if it is mixed with the body, there is no problem at all.

1st step This step is represented by the formula (V), and after applying a protecting group represented by R to the amino group of monophenylalanine methyl ester hydrochloride, the ester moiety is reduced to form an alcohol, and then the phenyl group is It performs reduction and oxidation of hydroxyl groups.

The protecting group for the amino group represented by R may be any group as long as it can be removed under acidic conditions, such as formyl group, acetyl group, 1-propylcarbonyl group, t-butylcarbonyl group, dimethylaminocarbonyl group, and ethoxycarbonyl group. , l-propyloxycarbonyl group, and t-butyloxycarbonyl group. In addition, these protecting groups can be introduced by known methods (
T. III.

Greene, “Protective Grow”
ps in Organic 5ynthesis”,
John-Whiley + 5oz, Ne
w York, 193Q, pp218-287
reference).

The ester moiety can be reduced by using sodium borohydride as a suitable reducing agent, for example, in the presence of lithium chloride.

Furthermore, the reduction of phenyl groups can be easily carried out by catalytic hydrogenation, and platinum, rhodium, etc. can be used as a catalyst.

Next, a suitable method for oxidizing the hydroxyl group is, for example, a method using a sulfur trioxide-pyridine complex and triethylamine in dimethyl sulfoxide (see reference side above).

2nd step In this step, the aldehyde represented by the formula (rV) is treated with nitromethane in the presence of a base catalyst to form a nitromethyl adduct N
). Base catalysts used in this step include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, and alkali metal amides such as IJ amide. alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alcokinds such as potassium methoxide and potassium t-butoxide, triethylamine, diadibicycloundecene (DB
U), potassium fluoride, or anion exchange resins such as Amberlite' IRA 400 (DH-). The amount of base is the aldehyde (
It is sufficient if the amount is 0.01 to 0.5 equivalent to rV), but it is preferable to use about 0.05 equivalent. The amount of nitromethane added is 1.0 with respect to aldehyde (rV)
An equivalent amount is sufficient, but in order to proceed with the reaction smoothly, 1.
It is preferred to use 5 equivalents.

Solvents used include methanol, ethanol, 1-
Propyl alcohol, t-butyl alcohol, ethyl ether, tetrahydrofuran, dioxane, tosoleene, benzene, acetonitrile, etc. can be used, but nitromethane can also be used as a solvent.

These solvents are appropriately selected depending on the base catalyst used.

The reaction temperature can be carried out at -10°C to 50°C, but
It is convenient to carry out the reaction at a temperature of ℃ to room temperature. After the reaction is completed, the nitrobutane derivative (I) can be isolated by solvent extraction or filtration, but when obtaining the compound of formula (II), there is no need for particular purification and it can be used immediately in the next step.

3rd step This step is performed by acid hydrolyzing the nitrobutane derivative represented by the general formula (1) to obtain α-hydroxy-β-amino acid (II).
This is what you get.

Examples of acids that can be used include hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, etc. When hydrochloric acid is used, the product (n)
It is suitable because it has the advantage that it can be crystallized as a hydrochloride. After completion of the reaction, the insoluble matter in the hydrochloric acid solution is filtered off, and the solvent is then distilled off to obtain the compound of formula (II) as a hydrochloride. At this time, the product (II)
is a mixture of the (2R, 3S) and (2S, 3S) bodies, but if you want the 2R13S) body alone, stop concentration when crystals begin to precipitate, and leave it to cool (2L). 3S) crystallizes and can be obtained by filtration.

A more detailed explanation will be given below using reference examples and examples.

Reference example 1 L-phenylalanine methyl ester salt 1 salt 25 g (
116 mmol) was cooled on ice under an argon atmosphere and suspended in 120 d of anhydrous ζ tetrahydrofuran. This includes triethylamine 161T+7! (11.8g, H
, 6 mmol, 0 eq.) and then 17.8 mA of triethylamine (12.9 g, 128 mmol).
l, 1.1 equivalents) and isopropoxy chloroformate 15.
6m/! (16.8g, 128 mmol, 1.1
equivalent amount) was added dropwise at the same time. After stirring for 2.5 hours under water cooling and further stirring for 2.5 hours at room temperature, the solvent was distilled off under reduced pressure.

Add 200 d of diethyl ether, wash sequentially with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
32.1 g (quantitative) of N-(isopropoxycarbonyl)-L-phenylalanine methyl ester as a transparent oil was obtained.

') INMR (CDC11> δ: 1.15 (d, 6H, J=5.0), 3.0
5 (d, 2H, J=3.0), 3.63 (s, 3
H), 4. '40~5.20 (m.

311), 7.12 (s, 5H) Reference Example 2 N-(isopropoxycarbonyl)-cyphenylalanine methyl ester 32.1 g (116 mmol)
was dissolved in 150rnI2 of anhydrous tetrahydrofuran,
Lithium chloride 14.9 g (348 mmol, 3 equivalents)
, sodium borohydride 1'3.2 g (348 mm
ol, 3 eq.) was added, followed by 300 g of iteethanol, and after stirring at room temperature for 3 hours, excess reagent was treated with ethyl acetate. The solvent was distilled off from the reaction solution under reduced pressure, and water and
The pH was adjusted to 2 by adding hydrochloric acid, extracted with diethyl ether, washed with saturated brine, and the solvent was distilled off under reduced pressure to obtain 28.1 g of white N-(impropoxycarbonyl)-L-phenylalaninol (quantitated amount). target).

11N! , IR(CDCl2) δ: 1.19 (d, 6H, J=6.0),
2.88 (d, 2N, J=3.5), 3.
70-4.10 (m, 3H), 4.80 (br
s.

1) 1), 4 95 (sep, IH, J=6.
0), 7.30 (s.

5H) Reference example 16.2 g (92%) of 0panol was obtained.

[(NMR (CDC13) δ: 1°24 (d, 6H, J=6.5), 0.60
~1.85 (lt!.

13H), 2.30 (brs, LH), 3.4
5-3.70 (m3H), 4.68 (brs,
IH), 4.88 (sep.

1N, J=6.5) Reference Example 4 17.2 g (65 mmol) of N-(isopropoxycarbonyl)-L-phenylalaninol was dissolved in 44 ml of methanol, and 1.7 g of 5% rhodium-alumina was added.
Add 2 g (10 w/w%) and increase the hydrogen pressure (50 kg/c
m" to 60 kg/cm") for 17 hours. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and benzene was added and dried under reduced pressure again to give a transparent oil of 23-(N-(impropoxycarbonyl)amino)-3-cyclohexylp2S- (N-(Impropoxycarbonyl)amino) 1.02 g (4.2 mmol) of 3-cyclohexylpropatool was placed at about 18°C, and 1.5 ml (1.31 g of anhydrous benzene 15.3
mmol, 4 equivalents), anhydrous dimethyl sulfoxide 3
．． 1 d(3,41g, 43.7+t++nol,
IQ equivalent), anhydrous triethylamine 1.76 ml (1
, 28 g, 12.6 mmol, 3 equivalents) and the sulfur pyridine complex salt 2 at an internal temperature of 17°C without stirring.
．． 00 g (12.6 mmol, 3 eq.) were added slowly. After 40 minutes of reaction, ice water was added, extracted with diethyl ether, washed sequentially with normal hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of crude product. I got it. This was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate = 8/1) to obtain 812 mg (80%) of 23-(N-(isopropoxycarbonyl)amino 13-cyclohexylpropanol) as a pale yellow oil. Ta.

HN! J R (CD Cl s ) δ: 1.26 (d, 6H, J=6.0), 0.
85-1.75 (m.

13) 1), 4.28 (brs, 1ll), 4.
97(set), ILJ=6.0), 5.03(b
rs, LH), 9.63 (s, 1) 1) Example 1 H 2-3-(N-(impropoxycarbonyl)amino)
3-cyclohexylpropanal 528 mg (2,
Dissolve 17 mmol) in ethanol 2.2+n1 and add Amberlite IRA 400132 mg (2
5w/w%>, nitromethane 175, 5 copies (198,7
mg, 3.26 mmol, 1.5 eq.) and stirred at room temperature for 8 hours. After adding ethyl ether 5d and removing amberlite by filtration, the solvent was distilled off under reduced pressure, the completion of the reaction was confirmed with 'flNMH, and concentrated hydrochloric acid 3
mN was added and heated at 100°C for 20 hours. Next, the reaction solution was concentrated, left at room temperature, and the precipitated white crystals were collected by filtration.
(2R,3S)-3-amino-4-cyclohexyl-2
-Hydroxybutyric acid hydrochloride 165 mg (32%) was obtained. ' All the results of analysis by HNMH were consistent with the standard product. In addition, by evaporating the filtrate, the 2N and 2
3S-amino-4, which is a mixture of g-isomers in a ratio of 1:2.5
-Cyclohexyl-2-hydroxyacetic acid hydrochloride 313
mg (61%) was obtained.

C,4flzsNzOs'HNMR (CDC13) δ: 0.96-1.66 (m, 13H),
1.15 (d, 6H).

3.42~3.87 (m, 2H), 4.27~
4.52 (m.

411), 4.63-5.05 (m, III)
IR(neat): 3350. 2990. 293
0. 2860. 1690°1552; 1380
cm-'C+oH+5NOJcl'HNMR (D□0) δ: 0.96-1.02 (m, 2H), 1.
13-1.29 (m.

3H), 1.36-1.45 (m, IH),
1.62-1.78 (m, IH), 3.
71 (dt, DI, J=3.4°3.7),
4.37 (d, IH, J = 3.5) IR (KBr
disk): 3360. 3260. 3040.
2940°2870, 1730. 1494c
m Example 2 2-3- (N, -(impropoxycarbonyl) amino) ~ 3-cyclohexylpropanal 40.0 m
g (0,164 mmol) in 0.1 m ethanol
Dissolved in N, Amberlite IRA 40010. O
mg (25 w/w%), nitromethane 13,3Ii (1
5.1 mg, 0.25 mmol, 1.5 equivalent)
was added and stirred at room temperature for 6 hours. Ethyl ether 5n+
j! was added, Amberlite was removed by filtration, the solvent was distilled off under reduced pressure, 0.5 ml of concentrated hydrochloric acid was added, and 1
After heating at 00°C for 17 hours, the reaction solution was evaporated to dryness after removing the blackish brown oily insoluble matter, and was found to be δ4.40 and δ4.4.
The integral ratio of the peak around 45 was measured, and 35.1 mg of 3S-amino-4-cyclohexyl-2-hydroxybutyric acid hydrochloride, which is a mixture of 2H form and 2S form at a ratio of 1.5:1.
(90%).

Examples 3 to 10 Reaction examples conducted using Amberlite/IRA 400 as a catalyst under conditions similar to those in Example 2 are summarized below.

Example The reaction solution was evaporated to dryness except for the dark brown oily insoluble matter, and 2R
3S-amino-4-cyclohexyl-2-hydroxyacetic acid hydrochloride 2, which is a mixture of the isomer and the 2S isomer in a ratio of 1.8:1.
0.2 mg (79%) was obtained.

Examples 12 to 23 Reaction examples performed in the same manner as in Example 11 except that the base catalyst was changed are shown below.

Claims (3)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is a protecting group for the amino group) 3-
Amino-2-hydroxy-1-nitrobutane derivative (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is a protecting group for the amino group) 2-
A general formula consisting of the action of nitromethane on an aminoaldehyde derivative in the presence of a base catalyst ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 3- expressed as (in the formula, R is a protecting group for the amino group)
Method for producing amino-2-hydroxy-1-nitrobutane derivative (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is a protecting group for the amino group) 2-
By reacting nitromethane with an aminoaldehyde derivative in the presence of a base catalyst, 3-amino-2-hydroxy expressed by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R is a protecting group for the amino group) -obtain a 1-nitrobutane derivative,
A method for producing an α-hydroxy-β-amino acid derivative represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, which is then treated with an acid.