JPS588390B2 - Method for producing optically active ω↓-cyano↓-α↓-acyl amino acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active ω-cyano α-acylamino acid derivatives.

More specifically, the present invention relates to a method for producing an optically active ω-cyano α-acylamino acid derivative by subjecting an α-cyano-acylamino-acrylic acid derivative to catalytic asymmetric hydrogenation.

Optically active ω-cyano-α-acylamino acids and their derivatives are useful as intermediates for pharmaceuticals and agricultural chemicals.

In addition, further reduction can lead to optically active α/ω and diamino acid derivatives.

For example, if the optically active N-acetyl-δ-cyanonorvaline derivative obtained by the method of the present invention is further reduced, an optically active lysine derivative, which is important as an essential amino acid, can be obtained (Acta. Chimica, Ac
ademiae Scientificarum Hungar
icae Tomus, 7 7, 341 (1973
)) In order to obtain an optically active ω-cyano α-acyl amino acid derivative, it is possible to obtain it by a complicated resolution operation or by a method in which it is obtained from an optically active raw material through multiple steps in a low yield (see the above-mentioned literature). However, it is difficult to say that either method is advantageous.

Therefore, it is generally desired to develop a method for obtaining optically active compounds all at once by catalytic asymmetric synthesis, and research is being actively carried out (for example, Knowlestal., Ch.
em Tech 5 9 0 (1 9 7 2)
, Morrison et al., J. Am. C
hem, Soc, 9 31301 (1971)
, Kagam et at. J. Am. Chem.
Soc, 94 6429 (1972)).

The present inventors have conducted intensive studies on a new method for producing optically active ω-cyano α-acyl amino acid derivatives, and as a result, have discovered the following asymmetric synthesis method and have completed the present invention.

The present inventors have already discovered a method for producing a new compound, an α-acylamino-acrylic acid derivative, and have disclosed it in a separate patent application (Japanese Patent Laid-Open Publication No. 133905/1982).

In the present invention, optically active ω-cyano α-acylamino acid derivatives are enhanced by catalytic asymmetric hydrogenation of the novel α-acylamino-acrylic acid derivatives in the presence of a rhodium complex having an optically active phosphine ligand. This product was successfully obtained in high yield and high optical purity.

The present invention uses a new compound as a raw material and provides a new and advantageous method for producing the desired optically active ω-cyano α-acylamino acid with a higher optical yield.

That is, the present invention relates to the general formula (I) [wherein R1 is hydrogen, an alkyl group, or an aralkyl group, R2 is an alkyl group, an aralkyl group, or an aryl group, and n is 0 to 3] is an integer.

] The α-acylamino-acrylic acid derivative represented by the general formula (II
I) [In the formula, * represents an asymmetric carbon, and R1, R2, and n have the same meanings as above] A method for producing an optically active ω-cyano α-acylamino acid derivative.

According to the method of the present invention, the ω-cyano-α-acylamino acid derivative is obtained as a mixture of enantiomers in which either the R or S enantiomer is present in excess.

Whether the configuration of the excess enantiomer is R or S is determined by the absolute configuration of the optically active phosphine used.

The substituents of the α-acylamino-acrylic acid derivative, which is the raw material of the present invention, will be explained.

The substituent R1 is hydrogen, a lower alkyl group, a cycloalkyl group, or an aralkyl group, and specific examples thereof include hydrogen, methyl, ethyl, probyl, butyl, cyclohexyl, and benzyl groups.

The substituent R2 is a lower alkyl group, a cycloalkyl group, an aralkyl group, or an aryl group, and specific examples include methyl, ethyl, proyl, butyl, cyclohexyl, benzyl, and phenyl groups.

Typical compounds that are raw materials for the present invention include, for example, 2-
ethyl acetylamino-3-cyano-2-propenoate,
Ethyl 2-acetylamino-4-cyano-2-butenoate, 2-acetylamino-5-cyano-2-pentenoic acid,
Examples include ethyl 2-acetylamino-5-cyano-2-pentenoate, isoprobyl 2-acetylamino-5-cyano-2-pentenoate, and ethyl 2-acetylamino-6-cyano-2-hexenoate.

The catalyst used in the present invention is a rhodium complex having an optically active phosphine as a ligand, as described above.

Any suitable compound can be used as the rhodium source.

A typical rhodium compound is (Rh (olefin)2C1
]2 (Olefins include ethylene, propylene, cyclooctene, etc.), (Rh.
(Diene) CI] 2 (Dienes include ■・5-hexadiene, ■・5-cyclooctadiene, bicyclo[2
・2.1]-hepta-2.5 diene, etc.).

The optically active phosphine used in the present invention can be selected from compounds represented by the following formulas.

[In the formula, R3 is an aryl or substituted aryl group, specifically selected from phenyl, tolyl, xylyl, mesityl, ethyl phenyl, and cyclohexyl phenyl, and R4 is an aryl or substituted aryl group. , specifically, a hale selected from phenyl, tolyl, xylyl, mesityl, ethyl phenyl, cyclohexyl phenyl, or a lower alkyl group.

] [In the formula, R3 and R4 have the same meanings as above.

] When both R3 and R4 are phenyl, the above compound (III) is trans, 4,5-bis-(diphenylphosphinemethyl)-2,2-dimethyl=1,3-dioxolane (DIOP), ( IV) is called neomethyldiphenylphosphine.

To form the rhodium complexes with optically active phosphine ligands used in the present invention, the molar ratio of the base sodium reacted to the optically active phosphine is at least 1:2.

Generally preferred ratios of P/Rh are between about 2:1 and 1021, and most preferably between 2:1 and 4:1.

To prepare the rhodium complex, the above-mentioned Kagan
et al. , J. Am, Chem, Soc,
9 4, 6429 (1972) and Morri's
on et al J. Am. Chem. Soc,
9 3, 1'307 (1971) are used.

The molar ratio of catalyst to substrate is from 0.01 mol% to 100
It is used in an amount of between 0.1 mol% and 10 mol% in practice.

Representative examples of the optically active ω-cyano-α-acylamino acid derivatives obtained by the present invention include N-acetyl-β-cyano-α-alanine, 4-cyano-2-acetylamino-butyric acid, N-acetyl-δ-cyano Examples include nonorvaline, N-acetyl-delta-cyanonorvaline ethyl ester, N-7 cetyl-delta-cyanonorvaline-inglobil ester, and 6-cyano-2-acetylamino-caproic acid.

Next, when carrying out the method of the present invention, it is usually carried out in a solvent.

Preferred solvents can be chosen from lower alkanols or lower alkanols in combination with aromatic hydrocarbons.

Specific examples include methanol, ethanol, gropanol, benzene, and toluene.

The temperature during the reaction can range from -70°C to 150°C, preferably from -30°C to 50°C.

Hydrogen pressure can range from normal pressure to 100 atmospheres,
Preferably the pressure is from normal pressure to 10 atmospheres.

As described in detail above, the method of the present invention allows optically active ω-
The production of cyano α-acyl amino acid derivatives is industrially extremely advantageous.

Hereinafter, the method of the present invention will be explained in more detail with reference to Examples.

In the following examples, the enantiomeric excess (hereinafter abbreviated as ee) was calculated using the following formula.

However, the parameter (R/S) is a suitable chiral reagent, such as Eu Optishift I; (
Willowbrock Laboratory for tris(half-fluoroisopropyl camphorate) coropium(III)
ries (registered trademark)] by the NMR method.

Example 1 A 100 ml two-day flask was equipped with a gas inlet cock and an exhaust cock so that they could be stirred using a boxwood magnetic stirrer.

First, the system was replaced with nitrogen, and in a nitrogen stream, 131n9 of (Rh (cyclooctene) 2C1)2 was charged, 5 ml of dry benzene was added and dissolved, and then 31 mg of (±DIOP) was charged and stirred at room temperature for 15 minutes to prepare a catalyst.

In a separate flask similar to the above, 1.0 ethyl 2-acetylamino-5-cyano-2-pentenoate was added under nitrogen flow.
05g was prepared, and 10ml of dry ethanol was added to dissolve it.

The above complex catalyst was charged therein, the atmosphere was changed to hydrogen, and hydrogenation was carried out at room temperature and pressure.

It stopped after absorbing 110,771 liters of hydrogen in 6 hours.

The solvent was distilled off from the reaction mixture under reduced pressure and purified by silica gel column chromatography to obtain [α)D-20.1 (C=2.
(S)-N-acetyl-δ with 4, ethanol)
-cyanonorvaline ethyl ester o. 924? (
A yield of 90.6% was obtained.

From NMR, the S:R enantiomer ratio is 89:11, 7
8%e, e. Met.

Example 2 In Example 1, the reducing substrate was 2-acetylamino-5-
The reaction was carried out in the same manner except that 1.075 g of isopropyl cyano-2-pentenoate was used [α) D-1 3.2
(S)-N-acetyl-δ-cyanonorvaline isoprobyl ester 1.051' (yield 97.5%) having (C=2, ethanol) was obtained.

The NMR S:R enantiomer ratio was 83:17, 66% e,e.

Example 3 In Example 1, the refluxed substrate was 2-acetylamino-5-
The reaction was carried out in the same manner except that 0.874f of cyano-2-pentenoic acid was used.

After the reaction, the solvent was distilled off, extracted with a dilute aqueous sodium hydroxide solution, the aqueous layer was thoroughly washed with ether, precipitated with acid, the solvent was distilled off to dryness, and extracted with ethanol [α) D- 6.0(
(S)-N-acetyl-δ-cyanonorvaline with (C=1, water) 0.7 6 8 ? (yield 87%)
I got it.

The S/R was 70.5729.5 and 41% e,e.

Example 4 A 100 ml autoclave was equipped with a magnetic stirrer, and the atmosphere was completely replaced with nitrogen. Ethyl acid 1.0
5S', neomenthyl diphenylphosphine 24.5~
, 5 mA of benzene, and 10 ml of ethanol were charged.

Fill with hydrogen to a gauge pressure of 18 atm and heat to 50°C.
Stir for hours.

The solvent was distilled off from the reaction mixture, and it was separated and purified using silica gel column chromatography to obtain (R) 1N-acetyl δ-cyanonorvaline having [α)D=+2.0° (C-2, ethanol). Ethyl ester 1.06L? (yield 10
0%] was obtained.

The S/R was 4 6/5 4 and 8% 6,e.

Example 5 100 ml of ethyl 2-acetylamino-4-cyano-2-butenoate in 100 ml of O-1 crepe under nitrogen.
9, [Rh (cyclooctadiene) CI] 26.7 mg
, (-+3DIOP 1 6.07711 p, benzene 5 ml, and ethanol 10 ml were charged.

Hydrogen at a gauge pressure of 50 kg/crj. The mixture was filled up to 100%, heated to 50°C, and stirred for 10 hours.

The solvent was distilled off from the reaction mixture, and the residue was separated and purified using silica gel column chromatography to obtain 95 m9 of ethyl 4-cyano-2-acetylaminobutyrate.

[α) D-'7.2° (C=0.18, C2H50H)
Example 6 In Example 5, neomenthyl diphenylphosphine (NMDPP) 20.7 m instead of (±DIOP)
I? [α)D+2.7]
90 η of ethyl 4-cyano-2-acetylaminobutyrate having a temperature of (C=0.30, C2H50H) was obtained.

Claims (1)

[Scope of Claims] 1 General formula [wherein R1 is hydrogen, an alkyl group, or an aralkyl group, R2 is an alkyl group, an aralkyl group, or an aryl group, and n is O-3 Any integer. A general formula characterized by catalytic asymmetric hydrogenation of an α-acylaminoacrylic acid derivative represented by . R1, R2, and n have the same meanings as above. ] A method for producing an optically active ω-cyano α-acyl amino acid derivative.