JPH03133958A - Production of optically active pyridyl carbinol - Google Patents

Abstract

PURPOSE:To efficiently produce the subject compound by using optically active norephedrine derivative as a new catalyst and performing asymmetric alkylation of unsaturated compound having aldehyde group on pyridine ring with dialkylzinc. CONSTITUTION:Optically active norephedrine derivative expressed by formula I and formula II [R' and R'' are alkyl, phenyl (substitutable with 1-5 pieces of halogen or nitro) and may be bonded with R' and R'')] readily obtainable as a catalyst [e.g. (+)-N,N-dibutyl norephedrine] is used to perform asymmetric alkylation of an unsaturated compound having aldehyde group on pyridine ring (e.g. 3-pyridine carboxyaldehyde) with dialkylzinc to afford optically active secondary pyridyl carbinol expressed by formula III (R ls alkyl; * is optically active carbon atom) [e.g. (-)-1(3-pyridyl) propanol]. Said compound is useful as a raw material of medical drug or agricultural chemical, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application Optically active pyridyl carbinol is an important synthetic raw material for pharmaceuticals, agricultural chemicals, etc. The present invention relates to a method for producing optically active pyridyl carbinol by asymmetrically alkylating pyridyl aldehyde.

Conventional techniques As a method for obtaining optically active pyridyl carbinol,
Conventionally, methods for reducing acetylpyridine biologically or chemically have been known, for example, ■ N. Imuta et al., J. Org. Chem.
-C described in 43,353Q (1978),
Biological method using macerans.

■ Heterocycle by M. Takeshita et al.
5a described in ex 28j051 (1987)
Biological method using ccharosyces cersvisiae.

■ Bull, Chew, Se by A, Ohno et al.
A chemical method for reducing acetylpyridine using a nicotine fused amide salt conductor as a ligand as described in Jpn. 54°3482 (1!181).

■ Chew, Bar by M. Schmidt et al.
113.1891 (198G), a chemical method for reducing acetylpyridine by complexing a chiral diol derivative with sodium lithium hydride.

Furthermore, there is no known method using pyridyl aldehyde as a raw material.

Problems to be Solved by the Invention However, in the above-mentioned biological method, only one optical antipode of the two existing compounds is obtained, and it is difficult to obtain the other optical isomer. It was difficult.

In addition, the chemical method (■■) has the disadvantage that it requires a large stoichiometric amount of an expensive optically active substance as a ligand to bring about optical activity, and the optical yield of the obtained product is also low. It had the disadvantage of being low.

The present invention solves the above problems and provides a method for efficiently producing optically active pyridyl carbinol using pyridyl aldehyde as a raw material and a novel catalyst.

Means for Solving the Problems The present inventor completed the present invention by asymmetrically alkylating pyridylaldehyde with dialkylzinc using an optically active norephedrine derivative as a catalyst.

That is, the present invention involves asymmetric alkylation of an unsaturated compound having an aldehyde group on the pyridine ring with dialkylzinc to produce an optically active secondary pyridyl carbinol represented by -mino CI) below. In the method, (wherein R represents an alkyl group and 0 represents an optically active carbon atom) the following -mino (■a) and (n b) (however, R' and Ro represent an alkyl group, a phenyl group) .

or a phenyl group substituted with 1 to 5 halogen or nitro groups, and Ro and R'' may be the same or different, or may be one group bonded at each end.) This is a method for producing optically active pyridyl carbinol, which is characterized by using an optically active norephedrine derivative represented by the following as a catalyst.

The optically active norephedrine derivative used as a catalyst in the present invention can be easily derived into any optical antipode by, for example, reacting commercially available norephedrine with furkyl halide. This norephedrine derivative has a structure represented by -mino (■a, IIb), where R'R'' represents an alkyl group or a phenyl group, and the alkyl group typically has about 1 to 12 carbon atoms. However, it is not limited to this.

Phenyl groups include unsubstituted ones and those substituted with 1 to 5 halogen or nitro groups.Rl and R'' may be the same or different, or they may be one atomic group bonded at each end Typical examples include the following:

(+)-N,N-dibutylnore7edrin(-)-N
, N-dibutylnorephedrine (+) -N%N-diethylnorephedrine (-) -N,N-diethylnorephedrine The pyridylaldehyde used as a raw material is a compound having an aldehyde group on the pyridine ring, 2.3. Alternatively, those having an aldehyde group at the 4-position are preferably used.

The dialkyl zinc typically has 1 to 6 carbon atoms, but is not limited thereto.

The reaction of the present invention proceeds as shown in the following equation.

In an example of the production method of the present invention, pyridyl aldehyde and an optically active norephedrine rust conductor as a catalyst are mixed with hexane,
After dissolving in a solvent such as toluene or ether and cooling to about 0°C, a dialkylzinc solution is added dropwise. After this, the temperature of the solution is raised to room temperature and stirred for 1 to several hours to carry out the desired reaction. can be completed.

At this time, the amount of catalyst is 2 mo1% based on pyridyl aldehyde.
~120 mo1%, preferably 5 mo1% ~ 75 mo1
Use %. A desired optical yield can be obtained by adjusting the amount added. For example, in order to increase the optical yield, it is sufficient to increase the amount of catalyst, but if the amount is too large, the effect will be saturated.

Example This will be explained below with reference to examples.

Example 1 0.53 mmol of 3-pyridinecarboxaldehyde was added to 0.38 mmol (molar ratio to aldehyde 0.7
5) Hexane solution containing (1, 2 and)-C-)-dibutylnorephedrine (DBNE) 0.5-
After cooling to 0°C, 1.4 molar solution of diethylzinc was added, and the mixture was reacted at room temperature for 1 hour. By extracting the product with ethyl acetate, (-)-1-(3-pyridyl)propertool was obtained with a yield of 89% and an optical purity of 74%.
, e, obtained. The optical rotation of this object is ((α)”o
-28,11” (c 1.411°Meal)
)Met.

Example 2 In Example 1, the reaction was carried out in the same manner as in Example 1 except that only the catalyst DBNE was used at a molar ratio of 0.05 to aldehyde. As a result, the same product was obtained with a yield of 83% and an optical purity of 37% e,e.

Example 3 The same reaction was carried out in Example 1 except that only diethylzinc was replaced with dimethylzinc.

(S)-1-(3-pyridyl)ethanol yield 70%
, with an optical purity of 48%e,e. The optical rotation of this object is [[α)24o -12,25° (Eq. 1.42
, hOH)].

Example 4 In Example 1, only the catalyst (IR12 mutually) -(+)
-DBNH was changed and the reaction was carried out in the same manner. As a result, (+
)-1-(3-pyridyl)propertool yield 95%,
Obtained with optical purity of 71% e,e. The optical rotation of this object is [[α)”o + 2L45@(c 1.41, M
eOH) ) Te was there.

Example 5 In Example 1, only diethylzinc was changed to di-n-butylzinc and the reaction was carried out in the same manner. As a result, 1-(
3-pyridyl)pentanol yield 90%, optical purity 7
Obtained at 1% e,e.

Effects of the Invention ■ By the method of the present invention, optically active pyridyl carbinol can be produced in high yield. For example, (-)-dibutylnorephedrine is used as a catalyst.

Alkylation of pyridylaldehyde with diethylzinc yields (-)-1-(3-pyridyl)propanol in a yield of 8.
S% and optical purity of 74%.

(2) By using an appropriate optical isomer of the norephedrine conductor as a catalyst, it is possible to obtain a product of the desired type of optical isomer. This has been difficult with conventional techniques using biological methods.

■ Unlike conventional chemical methods, the amount of catalyst does not necessarily need to be stoichiometric to the aldehyde.

For example, a medium level of optical purity can be obtained even with only about 5 mo1%, and even higher optical purity can be obtained by increasing the amount of catalyst.

(2) Different alcohols can be obtained from the same aldehyde by changing the alkyl group of the dialkylzinc used.

As described above, the method of the present invention can produce optically active pyridyl carbinol much more efficiently than conventional methods.
Can be synthesized in a wide range of applications.

Claims (1)

[Claims] An unsaturated compound having an aldehyde group on the pyridine ring,
In the method for producing optically active secondary pyridyl carbinol represented by the general formula (I) below by asymmetric alkylation with dialkylzinc, there are ▲mathematical formulas, chemical formulas, tables, etc.▼...(I) (However, R represents an alkyl group. * represents an optically active carbon atom.) The following general formulas (IIa) and (IIb) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼... (IIa) ▲ Mathematical formulas , chemical formulas, tables, etc. ▼...(IIb) (However, R
', R'' represent either an alkyl group, a phenyl group, or a phenyl group substituted with 1 to 5 halogen or nitro groups, and R' and R'' may be the same or different, or It may be one group attached at each end. ) A method for producing optically active pyridyl carbinol, which comprises using an optically active norephedrine derivative represented by the following as a catalyst.