JP2524814B2 - Method for producing α-hydroxy-β-amino acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention provides a compound represented by the general formula (I): (In the formula, R is an amino-protecting group)
Nitromethane is allowed to act on an aminoaldehyde derivative in the presence of a base catalyst to give a compound of general formula (II) (In the formula, R is a protecting group for an amino group)
Formula (III) consisting of obtaining an amino-2-hydroxy-1-nitrobutane derivative, followed by acid treatment. And a method for producing an α-hydroxy-β-amino acid derivative represented by: The compound represented by the general formula (III) has excellent human renin inhibitory activity and is useful as an orally administrable antihypertensive drug of the formula (IV) (In the formula, His is an L-histidyl group) and is an important starting material for producing a compound (see JP-A-62-234071).

[Conventional technology]

The compound represented by the general formula (III) is a compound represented by the general formula (I) derived from 2-phenylalanine. A compound represented by the formula (wherein R is a protecting group for an amino group) is subjected to an addition reaction with sodium cyanide, potassium cyanide or the like in the presence of an acid to give cyanohydrin, which is then hydrolyzed with an acid such as hydrochloric acid. Can be obtained (JP-A-62-234071).

[Problems to be solved by the invention]

The above-mentioned conventional method is generally performed for producing a substance represented by the formula (III),
It includes operations such as solvent extraction, washing, and drying. These operations increase the amount of waste, but in the case of a cyanide compound, it becomes an element that complicates the post-treatment, so a simple method without using a cyanide compound is required.

[Means for solving problems]

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

The compound of formula (I) used as a raw material in the present invention is
It can be easily induced from L-phenylalanine methyl ester hydrochloride (see the reference example below).

The compound of the general formula (I) thus prepared is an optically active substance, and its configuration is (2S). Further, the nitro compound represented by the general formula (II) obtained from the compound of the general formula (I) can be easily treated with an acid to form α of the formula (III).
-A key intermediate that can be derivatized to hydroxy-β-amino acids. The configuration of the compound of general formula (II) is (2R, 3S)
It is a mixture of the body and the (2S, 3S) body. The configuration of the compound represented by formula (III) is preferably the (2R, 3S) configuration, but
Even a mixture of (3S) body and (2S, 3S) body can be used.

First Step In this step, after applying a protecting group represented by R to the amino group of L-phenylalanine methyl ester hydrochloride represented by the formula (V), the ester portion is reduced to an alcohol form,
Then, the phenyl group is reduced and the hydroxyl group is oxidized.

The protecting group for the amino group represented by R may be any group that can be removed under acidic conditions, and examples thereof include formyl group, acetyl group, i-propylcarbonyl group, t-butylcarbonyl group, dimethylaminocarbonyl group, ethoxycarbonyl group. , I-propyloxycarbonyl group, t-butyloxycarbonyl group and the like. Further, these protecting groups can be introduced by a known method (TW Greene, “Protective Groups in Organic Synthe
sis ", John-Whiley ＋ Sons, New York, 1980, pp 218-287
reference).

Reduction of the ester moiety can be carried out by allowing sodium borohydride to act as a suitable reducing agent, for example, in the presence of lithium chloride.

Further, the reduction of the phenyl group can be easily carried out by catalytic hydrogenation, and platinum, rhodium or the like can be used as the catalyst.

Next, for the oxidation of the hydroxyl group, for example, a method of using a sulfur trioxide-pyridine complex and triethylamine in dimethyl sulfoxide can be exemplified as a suitable method (see the above reference examples).

Second Step This step is a base-catalyzed presence of the aldehyde of formula (I).
Nitromethyl adduct by acting nitromethane under
(II) is obtained. Base catalyst used in this step
As lithium hydroxide, sodium hydroxide,
Alkali metal hydroxides such as lithium, calcium hydroxide, etc.
Alkaline earth metal hydroxide, sodium amide, etc.
Lucari metal amides, sodium carbonate, potassium carbonate, etc.
Alkali metal carbonate, potassium methoxide, potassium
Alkali metal alkoxides such as -t-butoxide,
Liethylamine, diazabicycloundecene (DBU), etc.
Amines, potassium fluoride, or amberlite
IRA 400 (OH^-) Anion exchange resins such as
Wear. The amount of base is 0.01 to 0.5 with respect to aldehyde (I).
The amount may be equivalent, but it is preferable to use about 0.05 equivalent.
The amount of nitromethane added is based on the aldehyde (I)
1.0 equivalent is enough, but for smooth reaction,
It is preferred to use 1.5 equivalents.

The solvent used is methanol, ethanol, i
-Propyl alcohol, t-butyl alcohol, ethyl ether, tetrahydrofuran, dioxane, toluene, benzene, acetonitrile and the like can be used, but nitromethane can also be used as a solvent. These solvents are appropriately selected according to the base catalyst used.

The reaction temperature may be -10 ° C to 50 ° C, but 0 ° C
~ Conveniently performed at room temperature. After completion of the reaction, the nitrobutane derivative (II) can be isolated by solvent extraction or filtration, but when the compound of the formula (III) is obtained, it does not particularly need to be purified and can be immediately used in the next step.

Third Step In this step, the nitrobutane derivative represented by the general formula (II) is hydrolyzed with an acid to obtain an α-hydroxy-β-amino acid (II
I) is what you get.

Examples of the acid used include hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and the like. When hydrochloric acid is used, the product (II
It is preferable because it has an advantage that I) can be crystallized as a hydrochloride. After completion of the reaction, the hydrochloric acid solution is filtered to remove insoluble matter, and then the solvent is distilled off to obtain the compound of formula (III) as a hydrochloride. At this time, the product (II
I) is a mixture of (2R, 3S) and (2S, 3S) isomers,
If the (2R, 3S) form is desired alone, the concentration is stopped at the point where crystals start to precipitate, and the (2R, 3S) form crystallizes if left to stand to cool, which can be obtained by filtration.

A more detailed description will be given below with reference examples and examples.

Reference example 1 25 g of L-phenylalanine methyl ester hydrochloride (116
mmol) under ice-cooling under an atmosphere of argon,
Suspended in 120 ml hydrofuran. Triethylami
16 ml (11.6 g, 11.6 mmol, 1.0 equiv.)
Liethylamine 17.8 ml (12.9 g, 128 mmol, 1.1 eq)
Isopropyl chloroformate 15.6 ml (16.8 g, 128 mmol, 1.1
(Equivalent) was added dropwise at the same time. 2.5 hours under ice cooling, room temperature
After stirring for 2.5 hours at room temperature, the solvent was distilled off under reduced pressure and diethyl ether was added.
200 ml of ether is added and 1N hydrochloric acid and saturated sodium hydrogencarbonate are added.
Sequentially wash with an aqueous solution of sodium and saturated saline, and dry with anhydrous sodium sulfate.
After being dried with helium, the solvent was distilled off under reduced pressure to obtain a clear oily N
-(Isopropoxycarbonyl) -L-phenylalani
32.1 g (quantitative) of methyl ester was obtained.¹ HNMR (CDCl₃) Δ: 1.15 (d, 6H, J = 5.0), 3.05 (d, 2H, J = 3.0), 3.63
(S, 3H), 4.40-5.20 (m, 3H), 7.12 (s, 5H) Reference example 2 N- (isopropoxycarbonyl) -L-phenyla
Ranine methyl ester 32.1 g (116 mmol)
Dissolved in 150 ml of Drofran, 14.9 g of lithium chloride (348 mmo
l, 3 equivalents), sodium borohydride 13.2 g (348 mmol,
3 eq.), Then 300 ml of ethanol, at room temperature
After stirring at rt for 3 h, excess reagent was treated with ethyl acetate.
The solvent was distilled off from the reaction solution under reduced pressure, and water and hydrochloric acid were added to the residue.
PH to 2 and extract with diethyl ether, saturated saline
It was washed with water, the solvent was distilled off under reduced pressure, and white N- (iso
Propoxycarbonyl) -L-phenylalaninol 2
8.1 g (quantitative) was obtained.¹ HNMR (CDCl₃) Δ: 1.19 (d, 6H, J = 6.0), 2.88 (d, 2H, J = 3.5), 3.70〜
4.10 (m, 3H), 4.80 (brs, 1H), 4.95 (sep, 1H, J = 6.0),
7.30 (s, 5H) Reference example 3 N- (isopropoxycarbonyl) -L-phenyla
Laninol 17.2 g (65 mmol) dissolved in 44 ml methanol
Then, add 5% rhodium-alumina 1.72g (10w / w%)
Hydrogen pressure (50kg / cm²~ 60kg / cm²) For 17 hours
Was. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure,
Benzene was further added and dried again under reduced pressure to obtain a transparent oily substance.
2S- {N- (isopropoxycarbonyl) amino} -3
-16.2 g (92%) of cyclohexyl propanol were obtained.¹ HNMR (CDCl₃) Δ: 1.24 (d, 6H, J = 6.5), 0.60 to 1.85 (m, 13H), 2.30 (b
rs, 1H), 3.45 to 3.70 (m, 3H), 4.68 (brs, 1H), 4.88 (se
p, 1H, J = 6.5) Reference example 4 2S- {N- (isopropoxycarbonyl) amino}-
About 1.02 g (4.2 mmol) of 3-cyclohexyl propanol
Place at 18 ℃, 1.5 ml of anhydrous benzene (.31 g, 16.8 mmol, 4
Equivalent), 3.1 ml of anhydrous dimethyl sulfoxide (3.41 g, 43.7
mmol, 10 equivalents), 1.76 ml of anhydrous triethylamine (1.28
g, 12.6 mmol, 3 equivalents), and the internal temperature is 17 ° C with stirring.
At sulfur trioxide-pyridine complex 2.00 g (12.6 mmol, 3
Equivalent) was gradually added. After reacting for 40 minutes, add ice water and
Extract with chilled ether, and then add 1N hydrochloric acid and saturated brine.
Next, wash, dry over anhydrous magnesium sulfate, and dissolve under reduced pressure.
The medium was distilled off to obtain 1.0 g of a crude product. This is silica gel
Rum chromatography (developing solvent hexane / ethyl acetate = 8/1)
The product was purified by 2S- {N- (isopropoxy
Cycarbonyl) amino} -3-cyclohexylpropana
812 mg (80%) was obtained.¹ HNMR (CDCl₃) Δ: 1.26 (d, 6H, J = 6.0), 0.85 to 1.75 (m, 13H), 4.28 (b
rs, 1H), 4.97 (sep, 1H, J = 6.0), 5.03 (brs, 1H), 9.63
(S, 1H) Example 1 2-S- {N- (isopropoxycarbonyl) ami
No} -3-cyclohexylpropanal 528 mg (2.17 mmo
l) is dissolved in 2.2 ml of ethanol and amber light is added. IRA4
00 132mg (25w / w%), Nitromethane 17.5μ (198.7m
g, 3.26 mmol, 1.5 equivalents) and stirred at room temperature for 8 hours
Was. Add 5 ml of ethyl ether to this and add amber light
Is removed by filtration, the solvent is distilled off under reduced pressure,¹By HNMR
After confirming the completion of the reaction, add 8 ml of concentrated hydrochloric acid and at 20 ° C at 100 ° C.
Heated for a while. Then, the reaction solution was concentrated and left at room temperature for precipitation.
The resulting white crystals are collected by filtration, and (2R, 3S) -3-amino-4-
Cyclohexyl-2-hydroxybutyrate 165 mg (32
%).¹All results of HNMR analysis are as standard
Matched. Also, by evaporating and drying the filtrate,
A mixture of 3S-amino-4-cys is a mixture of 2S-forms having a ratio of 1: 2.5.
Chlohexyl-2-hydroxybutyrate hydrochloride 313 mg (61
%).

C₁₄H₂₆N₂O_Five ¹ HNMR (CDCl₃) Δ: 0.96-1.66 (m, 13H), 1.15 (d, 6H), 3.42-3.87 (m,
2H), 4.27 ~ 4.52 (m, 4H), 4.63 ~ 5.05 (m, 1H) IR (neat): 3350,2990,2930,2860,1690,1552,1380cm^-1 C_TenH₁₉NO₃HCl¹ HNMR (D₂O) δ: 0.96-1.02 (m, 2H), 1.13-1.29 (m, 3H), 1.36-1.4
5 (m, 1H), 1.62 to 1.78 (m, 1H), 3.71 (dt, 1H, J = 3.4, 3.
7), 4.37 (d, 1H, J = 3.5) IR (KBr disk): 3360,3260,3040,2940,2870,1730,1494c
m^-1 Example 2 2-S- {N- (isopropoxycarbonyl) ami
No} -3-cyclohexylpropanal 40.0 mg (0.164 m
mol) in 0.1 ml of ethanol and amber light IR
A400 10.0mg (25w / w%), Nitromethane 13.3μ (15.1
(mg, 0.25mmol, 1.5eq) and stirred at room temperature for 6 hours
Was. Add 5 ml of ethyl ether and add amber light Roast
After removal by filtration, the solvent was distilled off under reduced pressure, and concentrated hydrochloric acid was added.
After adding 5 ml and heating at 100 ℃ for 17 hours, black brown oily insoluble matter
The reaction solution by evaporation to dryness,¹Δ4.40 and δ4.45 by HNMR
The integral ratio of the peaks in the vicinity was measured, and the ratio of 2R body and 2S body was 1.5.
3S-amino-4-cyclohexyl-a mixture of 1
35.1 mg (90%) of 2-hydroxybutyric acid hydrochloride was obtained.

Examples 3-10 Amber Light Example 2 and similar using IRA 400 as a catalyst
An example of reactions performed under similar conditions is summarized below.

Example 11 2S- {N- (isopropoxycarbonyl) amino}-
26 mg (0.107 mmol) of 3-cyclohexylpropanal was dissolved in 0.1 ml of ethanol, and 2.5 μ (0.05 equivalent) of 10% sodium hydroxide aqueous solution and 8.7 μ (9.9 m of nitromethane).
g, 0.161 mmol, 1.5 eq) was added and stirred at room temperature for 13 hours. After the reaction, 5 ml of ethyl ether was added, the mixture was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 0.5 ml of concentrated hydrochloric acid was added to this, and after heating at 100 ° C for 17 hours, the black brown oily insoluble matter was removed and the reaction solution was evaporated to dryness to give 3S-amino which is a mixture of the 2R form and the 2S form in a ratio of 1.8: 1. -4-Cyclohexyl-2-hydroxybutyric acid hydrochloride 2
0.2 mg (79%) was obtained.

Examples 12 to 23 Examples of reactions performed in the same manner as in Example 11 except that the base catalyst is changed are shown below.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Hiroshi Harada 8054 Nakagawa, Shiga-mura, Higashichikuma-gun, Nagano Examiner Zenichi Wakimura (56) Reference JP-A-63-22081 (JP, A) JP-A-54- 36226 (JP, A) UK patent application publication 2200115 (GB, A) European patent application publication 22310 (EP, A)

Claims (1)

(57) [Claims] 1. A general formula (In the formula, R is an amino-protecting group)
Aminoaldehyde derivatives are treated with nitromethane in the presence of a base catalyst to give a general formula A 3-amino-2-hydroxy-1-nitrobutane derivative represented by the formula (wherein R is an amino-protecting group),
Then the formula consisting of acid treatment Method for producing α-hydroxy-β-amino acid derivative represented by