JPH0168A - Tertiary amino alcohol compound and method for producing optically active secondary alcohol using the same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] [Field of Application of Nara Tojo] The present invention relates to a method for producing an optically active secondary alcohol by using a tertiary amino alcohol as a catalyst in the asymmetric addition of dialkylzinc to an aldehyde. It is something.

[Conventional technology]

Optically active secondary alcohols are useful as raw materials for medicines, liquid crystals, etc., but there are currently only a few substances available, and those that are available are expensive because they can be obtained by means such as optical resolution. be.

Conventionally, the following method is known as a method for producing an optically active secondary alcohol by asymmetrically adding dialkylzinc to an aldehyde using a catalyst.

■ Tetrahedron Lett by T@Omi et al.
ers 25 2823 (1984) using a 2-amino alcohol as a catalyst.

(2) A method using a combination of L-7 engineered nylalanine derivative and dialkylzinc as a catalyst, as described in K., ITO et al., 52nd Spring Annual Meeting of the Chemical Society of Japan, Audience Collection 4YO6.

■ R, N0YORI et al. J aArn*chom++s
There was a method described in oc* 108 6071 (1986) in which (→-3-exo(dimethylamino)isobutaneol) was used as a catalyst.

[Problem that the invention seeks to solve]

However, the above-mentioned method (■■) has a low optical yield and cannot be said to be a practical method. In addition, in the method (2) above, there were problems such as difficulty in synthesizing the catalyst and low optical yield when producing optically active secondary alcohols from aliphatic aldehydes. .

[Means to solve the problem]

As mentioned above, optically active secondary alcohols can be produced in good yields.
Furthermore, there is no known method for producing it with high optical purity.

The present inventor added dialkylzinc to an aldehyde,
In addition to producing secondary alcohols, various methods of using catalysts were investigated and the present invention was completed.

That is, the present invention is based on the following general formula (1) (where R4 is an alkyl group having 1 to 6 carbon atoms, and ReR is a hydrogen atom, a phenyl group, or a phenyl group substituted with 1 to 5 halogen or nitro groups. , 2 is hydrogen atom Li
Indicates either e Na or K e -ygc2H5. * indicates an optically active carbon atom. ) and a dialkyl zinc are asymmetrically added to an aldehyde by the following general formula Ql) (However, R1 is an alkyl group having 1 to 12 carbon atoms, * is an optically active carbon R is an alkyl group having 1 to 12 carbon atoms or a functional group represented by the following general formula (III).

(However, X is a hydrogen atom,) ・Represents either a rogone, a nitro group, or a cyano group, and m and n are o, 1. Or 2.

α and β are single bonds, -COO-1-OCO-1-0CH
2-1-CH20-1-〇-, and R3 represents an alkyl group having 1-16 carbon atoms. )) In the method for producing an optically active secondary alcohol represented by the following general formula (1) (where R4 is an alkyl group having 1 to 6 carbon atoms, R5 and R6 are a hydrogen atom, a phenyl group, a halogen, a nitro group) is 1-5
Any of the individual phenyl groups, 2 is a hydrogen atom,
Indicates either Li w Na s K or -MgC2H5. * indicates an optically active carbon atom. ) is a method for producing an optically active secondary alcohol, which is characterized by using a tertiary amino alcohol compound represented by the following as a catalyst.

The tertiary amino alcohol compound used as a catalyst in the present invention can be easily synthesized from a proline derivative by the following method.

After reacting phenylgrinia and substituted phenylgrinia with the noroline ester containing an amino group, it is reduced or a tertiary amino alcohol is produced by alkylating the secondary amino alcohol. Obtainable. Also, by reacting the obtained tertiary amino alcohol with an alkyl metal such as butyllithium, a very strong salt thereof can also be obtained.

These tertiary amino alcohols include the following.

(S) -diphenyl(1-=methylpyrrolidine-2-
IR) methanol and its lithium salt, (IR.

Examples include 2'S)-phenyl(1-methylpyrrolidin-2-yl)methanol and its lithium salt.

As the aldehyde, both aromatic and aliphatic aldehydes can be used, and derivatives thereof may also be used.

Moreover, as the dialkyl zinc, those having 1 to 6 carbon atoms are used.

In the production method of the present invention, it is used as a catalyst. Third
The amino alcohol compound is placed in a solvent such as hexane, toluene, or ether, cooled to around 0°C, dialkylzinc solution is added dropwise, and the mixture is stirred for several hours at 0°C to 120°C at room temperature. be able to.

In this gap, it is sufficient that the amount of catalyst is 5 mo1% or less based on the aldehyde, and the dialkyl zinc is 1 to 2 mole% based on the aldehyde.
．． Use 5 per.

〔Effect of the invention〕

By the method of the present invention, secondary alcohols with high optical purity can be produced in high yield. For example, (S)-diphenyl-
Using lithium salt of (1-methylpyrrolidin-2-yl)-methanol as a catalyst, p/zaldehyde was reacted with diethylzinc to alkylate sult, (S)-1-
7-enylpropanol with 100% yield and optical purity (ee
) obtained at 100%.

Using this catalyst, the yield of (S)-3-nonyl alcohol from n-hexylaldehyde and diethylzinc was 96%.
% optical purity (e.) of 91%.

As described above, the method of the present invention allows optically active secondary alcohols to be obtained in a much better yield and with higher optical purity than in conventional methods.

Example 1 (S) - Preparation of 1-7 enylproΔnol (&) Synthesis of catalyst (S) -N-Hydenyloxycargonylgloline methyl ester 2.63II was dissolved in THF 20 m,
Cool to 0°C. A THF solution of 7-enyl Grignard with a concentration of IM (40 mm) was added dropwise thereto, and the mixture was stirred for 4 hours.

Add ammonium chloride aqueous solution and separate the organic layer. The aqueous layer is extracted with chloroform and the organic layers are combined, dried and concentrated.

3.99% of the concentrate was dissolved in 30dK of THF, 0.76.9% of lithium aluminum hydride was added, and the mixture was refluxed for 2 hours.

After cooling and adding water, make PII3 and extract with ether. The aqueous layer is made alkaline and extracted with dichloromethane. The organic layers were combined, concentrated, and recrystallized from hexane to give (S)-diphenyl(l-methylpyrrolidine-2-
yl)-methanol (Q = 2.21).

Add hexane 5- to (C") 0.01341 (0.05 mmol), add 0.05 mg of ailM hexane solution of butyllithium, stir for a while, and produce (S)-diphenyl (1-methylpyrrolidin-2-yl). Prepare a hexane solution of methanol and lithium salt.

(b) Synthesis of (s)-1-7enylpropanol (,)
Benzaldehyde 0,27
．． Add 9 and stir for a while. Cool to 0°C, concentration I
Add 5.5 liters of a hexane solution of diethylzinc M and stir at 0°C for 15 hours.

Add 1M hydrochloric acid solution, extract with dichloromethane, and condense. By silica gel chromatography
Then, (S)-1-7enylpropanol was obtained with a yield of 100%.

Optical purity is determined using a chiral column (Paker-bound DNBPG).
4.6 order x 250 visits, eluent hexane: isoglobinol = 99.75: 0.25, detection wavelength 254 nm
) was measured.

In the racemic form, 8 forms were detected at 45.2 minutes and 8 forms at 47.4 minutes, but with the newly synthesized (S)-1-phenylpurpanol, only the peak at 45.2 minutes was detected. It wasn't done.

In this way, by this method, (8)-
1-7 enylpropanol was obtained.

Examples 2 to 4 In place of the lithium salt (4) of (S)-diphenyl(l-methylpyrrolidin-2-yl)methanol, (S)-diphenyl(1-methylpyrrolidin-2-yl) was used as a catalyst.
yl)methanol (C), lithium salt of (IR,2'8)-phenyl(1-methylpyrrolidin-2-yl)methanol (B), CIR,2'S)-phenyl(1-
Table 1 shows an example in which 1-phenylpropanol was synthesized using methylpyrrolidin-2-yl)methanol (2) in a manner similar to that described in Example 1-(b)K.

Examples 5 to 24 Using either of the various aldehyde raw materials and catalysts in Examples 2 to 4 as a catalyst, diethyl zinc or dimethyl zinc is used as the dialkyl zinc, An optically active secondary alcohol was synthesized in the same manner as in Example 1-(b).
Shown in the table.

Example 25 Synthesis of catalyst (IR, 2'S)-phenyl(pyrrolidin-2-yl)
Methanol (obtained by known methods. Journal Otsu Chemical Society Chemical Comi, Nikage, N. 1986)
412 pages) 0.24711 to 98 thiformic acid 0.41
nt and water and heated to reflux. Add formaldehyde (0.3 m of 37% aqueous solution) and reflux for 4 hours. After making pi (11) with a sodium hydroxide aqueous solution, extracting with dichloromethane. After concentration, distillation (Pulp method pass temperature 140 ° C / 2 wag)
R,2'S)-phenyl(l-methylpyrrolidine-2-
methanol (b) (0,2549) is obtained in 95%.

(IR,2'S)-phenyl(pyrrolidin-2-yl)
To methanol hydrochloride (3 mmol), an aqueous sodium hydroxide solution (1N, 10 m) and ether 5-1 piparoyl chloride (4.5 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours. 3-dimethylaminopropylaquine (2.5 mmol) is added. Add ethyl acetate and wash the organic layer with an aqueous solution of carbon dioxide, water, and diluted salted rice. After concentration, it was dissolved in tetrahydrofuran (10 m) and reduced with lithium aluminum hydride (261Q) (refluxed for 5 hours).

Add dilute hydrochloric acid and further add sodium hydroxide aqueous solution,
pl [10 Kl, filter. The filtrate was extracted with ether, concentrated, and then distilled (pulp method, bath temperature 170°C/
3 mmHg) from cy(IR,2'S)-f;nyl(1-neopentylpyrrolidin-2-yl)methanol(t)87q6.

Structural formula of A-G Prisoner (B) h e C) (b) h e (g) 　　　　　(g) h

Claims (2)

[Claims] (1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, R^4 is an alkyl group with 1 to 6 carbon atoms, R^5, R
^6 represents a hydrogen atom, a phenyl group, or a phenyl group substituted with 1 to 5 halogen or nitro groups, and Z represents a hydrogen atom such as Li, Na, K, or -MgC_2H_5. * indicates an optically active carbon atom. ) A tertiary amino alcohol compound represented by (2) By asymmetrically adding dialkylzinc to aldehyde, the following general formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ (However, R^1 is an alkyl group having 1 to 12 carbon atoms, * is an optically active R^2, which represents a carbon atom, is an alkyl group having 1 to 12 carbon atoms or a functional group represented by the general formula (III) below. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (However, X, Y represents a hydrogen atom, halogen, nitro group, or cyano group, m and n are 0, 1, or 2. α and β are single bonds, -COO-, -OCO-, -OC
Indicates either H_2-, -CH_2O-, or -O-. R_3 represents an alkyl group having 1 to 16 carbon atoms. )), the following general formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, R^4 is an alkyl group having 1 to 6 carbon atoms. ,R^5,R
^6 represents a hydrogen atom, a phenyl group, or a phenyl group substituted with 1 to 5 halogen or nitro groups, and Z represents a hydrogen atom such as Li, Na, K, or -MgC_2H_5. * indicates an optically active carbon atom. 1. A method for producing an optically active secondary alcohol, which comprises using a tertiary amino alcohol compound shown in ) as a catalyst.