JP2682129B2 - Reducing agent, method for producing the same, and method for producing optically active alcohol using the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a reducing agent and a method for producing an optically active alcohol using the reducing agent, and more specifically, to sulfides, cyclic ethers or ethers of monohydric alcohols. In the presence of the specific compound, the compound of the general formula (I) (In the formula, R ¹ is an aryl group, R ² is a lower alkyl group, R ³
Represents hydrogen or a lower alkyl group. * Represents an asymmetric carbon. The present invention relates to an optically active amine-boron-based reducing agent obtained by reacting an acid and a metal borohydride with an optically active amino alcohol represented by the formula (4), and a method for producing an optically active alcohol using the same.

<Prior Art and Problems to be Solved by the Invention> The present inventors have added optically active amino alcohol (I) to
We have found that an optically active amine-boron-based reducing agent obtained by reacting an acid with a metal boron hydroxide is useful as an asymmetric reducing agent for ketones, and have already proposed it (for example, JP-A-59). -184168, 61-68471, 61-18722,
No. 62-10024).

Then, the present inventors further studied the optically active amine-boron-based reducing agent, and as a result, obtained by reacting the optically active amino alcohol with an acid and a metal borohydride in the presence of a specific compound. Optically active amine
The present inventors have found that the boron-based reducing agent exhibits a remarkably high activity, and further completed various studies to complete the present invention.

<Means for Solving the Problems> (1) In the presence of sulfides, cyclic ethers or ethers of monohydric alcohols, the compound represented by the general formula (I) (In the formula, R ¹ is an aryl group, R ² is a lower alkyl group, R ³
Represents hydrogen or a lower alkyl group. * Represents an asymmetric carbon. ) An optically active amine-boron asymmetric reducing agent obtained by reacting an acid and a metal borohydride with an optically active amino alcohol represented by the formula (2), and (2) the above optically active amino alcohol (I) with a sulfide. (3) The method for producing an optically active amine-boron-based reducing agent, which comprises reacting an acid with a metal borohydride in the presence of a group, a cyclic ether, or a monohydric alcohol ether. ) Optically active amine-boron-based reducing agent and general formula (II) [In the formula, R ⁴ and R ⁵ are lower alkyl groups, aryl groups, or the formula (III) (In the formula, R ⁶ represents a phenyl group which may be substituted with a halogen or haloalkyl group, or a cycloalkyl group.) Represents a 2-substituted-1-triazoleethylene group, and is the same. Absent. ] The general formula (IV) characterized by reacting with a ketone represented by (Wherein R ⁴ and R ⁵ have the same meanings as described above, and * represents an asymmetric carbon), and a method for producing an optically active alcohol is provided.

 Hereinafter, the present invention will be described in detail.

The asymmetric reducing agent of the present invention uses an optically active aminoalcohol (I) as a raw material, and the substituent R ¹ is, for example, a halogen atom, an alkyl group having 1 to 5 carbon atoms,
A phenyl group which may be substituted with an alkoxyl group having 1 to 5 carbon atoms, an aralkyloxyl group having 7 to 10 carbon atoms, an aryloxyl having 6 to 10 carbon atoms or an alkoxycarbonyl group having 1 to 6 carbon atoms, a halogen atom , Carbon number 1
And naphthyl groups which may be substituted with an alkyl group having 5 to 5 carbon atoms, a cyano group, an alkoxyl group having 1 to 5 carbon atoms, or an alkoxycarbonyl group having 1 to 5 carbon atoms.

Specific examples include phenyl, p-tolyl, and m.
-Tolyl, o-tolyl, 1-naphthyl, 2,5-dimethylphenyl, 2,5-diethylphenyl, 2,4,5-trimethylphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-propoxyphenyl, 2 -Iso-propoxyphenyl, 2-butoxyphenyl, 2-sec-butoxyphenyl, 2-cyclopentyloxyphenyl, 2-cyclohexyloxyphenyl, 2-benzyloxyphenyl, 2-phenoxyphenyl, 2,4-dimethoxyphenyl, 2, 4-dipropoxyphenyl, 2,4-dibutoxyphenyl, 2,5-dimethoxyphenyl, 2,5-diethoxyphenyl, 2,5-diisopropoxyphenyl, 2,5-dibutoxyphenyl, 2,4, 6-trimethoxyphenyl, 2-methyl-5-methylphenyl, 2-ethoxy-5-ethylphenyl, 2-methoxy-5-isopro Pyrphenyl,
2-methoxy-5-t-butylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2
-Ethoxy-5-methylphenyl, 2-ethoxy-5-
Ethylphenyl, 2-methoxy-5-isopropylphenyl, 2-ethoxy-5-t-butylphenyl, 2-propoxy-5-methylphenyl, 2-propoxy-5-.
Ethylphenyl, 2-isopropoxy-5-methylphenyl, 2-isopropoxy-5-isopropylphenyl, 2-isopropyl-5-t-butylphenyl, 5-
Chloro-2-methoxyphenyl, 5-chloro-2-ethoxyphenyl, 5-chloro-2-propoxyphenyl,
5-chloro-2-isopropoxyphenyl, 2-methoxycarbonylphenyl, 2-ethoxycarbonylphenyl and the like can be mentioned.

Examples of the substituent R ² include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and the like.

Examples of R ³ include, in addition to hydrogen, a lower alkyl group similar to R ² .

Specific examples of the optically active amino alcohol (I) include, for example, optically active 2-amino-1-phenyl-1-
Propanol, 2-amino-1- (2,5-dimethylphenyl) -1-propanol, 2-amino-1- (2-methoxyphenyl) -1-propanol, 2-amino-1
-(2,5-dimethoxyphenyl) -1-propanol,
2-Amino-1- (2,5-diethoxyphenyl) -1-
Propanol, 2-amino-1- (2-ethoxyphenyl) -1-propanol, 2-amino-1- (2-methoxy-5-methylphenyl) -1-propanol, 2-
Amino-1- (α-naphthyl) -1-propanol, 2
-Amino-1- (2-phenoxyphenyl) -1-propanol, 2-amino-1- (2-iso-propoxyphenyl) -1-propanol, 2-amino-1- (2-
Propoxyphenyl) -1-propanol, 2-amino-1- (2-benzyloxyphenyl) -1-propanol, 2-amino-1- (2,4-dimethoxyphenyl)
-1-propanol, 2-amino-1- (5-chloro-
2-Methoxyphenyl) -1-propanol, 2-amino-1- (2,5-dipropoxyphenyl) -1-propanol, ephedrine and the like can be mentioned.

Examples of the acids include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carboxylic acids such as acetic acid, organic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid. The amount used is usually equivalent to the optically active amino alcohol (I).

Examples of the metal borohydride include sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride and the like, and sodium borohydride, which is easily available, is usually used. The amount used thereof is usually 0.7 to 1.3 mol times, preferably 1 mol times, in terms of boron, with respect to the optically active amino alcohol (I).

The reducing agent of the present invention is obtained by allowing an acid and a metal borohydride to act on the above optically active amino alcohol (I) in the coexistence of sulfides, cyclic ethers or ethers of monohydric alcohols. Examples of the sulfides include dimethyl sulfide, diethyl sulfide, dipropyl sulfide, diisopropyl sulfide, dibutyl sulfide, di-sec-butyl sulfide, di-t-butyl sulfide, dipentyl sulfide, dihexyl sulfide, dicyclohexyl sulfide, and dicyclohexyl sulfide. Dodecyl sulfide, distearyl sulfide and other monosulfides, tetrahydrothiophene, thiophene and other thiophenes, dimethyl disulfide, diethyl disulfide, dipropyl disulfide, diisopropyl disulfide Dibutyl disulfide, di -se
Disulfides such as c-dibutyl sulfide, di-t-butyl disulfide, dipentyl disulfide, dihexyl disulfide, dicyclohexyl disulfide, didodecyl disulfide, distearyl disulfide and the like can be mentioned.

Examples of cyclic ethers include furans such as tetrahydrofuran, dioxane such as 1,4-dioxane, dioxolanes such as 1,3-dioxolane, pyrans of tetrahydropyrans, crown ethers such as 12-crown-4. Examples of ethers of monohydric alcohols include dimethyl ether, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether and the like.

These sulfides and ethers are usually used in an amount of 0.2 mol times or more, preferably 0.5 to 20 mol times, with respect to the optically active amino alcohol (I).

The reducing agent is usually produced by using a solvent in an atmosphere of an inert gas such as nitrogen or argon.

The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, methylene chloride, 1,2-dichloroethane, chloroform, and four. Examples thereof include halogenated hydrocarbons such as carbon chloride, ether solvents such as diglyme and triglyme, and mixed solvents thereof.

When the acid and the metal borohydride are allowed to act on the optically active amino alcohol (I), usually, the acid is acted on the optically active amino alcohol (I) and then the metal borohydride is acted on. In this case, a salt of an optically active amino alcohol (I) and an acid can also be used, and a metal borohydride is added to a mixture of the salt, solvent, sulfides, ethers and the like with diglyme, triglyme, dimethylformamide, 1, It is usually acted as a solvent solution of 3-dimethyl-2-imidazolidinone.

Further, the acid can be directly reacted with a mixture of the optically active amino alcohol (I), the metal hydride compound, the solvent, the sulfides, the ethers and the like.

The reaction temperature is not particularly limited, but is usually −78 to 100 ° C., preferably −40 to 100 ° C.

Thus, the desired optically active amine-boron reducing agent is obtained. The reducing agent can be isolated and used, but it is usually used as it is without isolation.

The reducing agent of the present invention has extremely high activity, and when it is reacted with asymmetric ketones, for example, it can efficiently produce an optically active alcohol with a small amount and a high optical yield.

Next, the method for producing an optically active alcohol using the reducing agent of the present invention will be described. For example, the above general formula (II)
The optically active alcohol represented by the above formula (IV) can be produced from the asymmetric ketone represented by:

Here, as the substituents R ⁴ and R ⁵ of the asymmetric ketones (II), phenyl, 2-, 3-, 4-pyridyl, o-, m-, p-chlorophenyl, o-, m-, p- Bromophenyl, o-, m
-, P-Fluorophenyl, halogen-substituted phenyl such as 2,3-, 2,4-, 2,5-, 2,6-dichlorophenyl, o-, m
-, P-methylphenyl, o-, m-, p-ethylphenyl,
o-, m-, p-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6
-Phenyl substituted with alkyl having 1 to 5 carbon atoms such as dimethylphenyl, o-, m-, p-methoxyphenyl, o
Phenyl substituted by alkoxy having 2 to 6 carbon atoms such as-, m-, p-ethoxyphenyl, o-, m-, p-propoxyphenyl, o-, m-, p-benzyloxyphenyl, 2-benzyloxy -3-methylphenyl, 2-benzyloxy-4-methylphenyl, 2-benzyloxy-5-methylphenyl, 2-benzyloxy-5-t-butylphenyl, 2-benzyloxy-3-methoxyphenyl,
Benzyloxy-substituted phenyl such as 2-benzyloxy-4-methoxyphenyl, 2-benzyloxy-5-methoxyphenyl, and 2-benzyloxy-3,5-dichlorophenyl, and the total number of carbon atoms such as α- and β-naphthyl is 5 To 17 aryl groups, methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, 1-chloroethyl, 2-chloroethyl, 1-bromoethyl, 2-bromoethyl, 1- Fluoroethyl, 1
Lower alkyl group having 1 to 6 carbon atoms such as -chloropropyl, 3-chloropropyl, 1-bromopropyl, 4-bromopropyl, 1-bromo-1-methylethyl, benzyl, o-, m-, p- Trimethyl, (o-, m-, p-ethylphenyl) methyl, (2,3-, 2,4-, 2,5-, 2,6-dimethylphenyl) methyl, 2-phenylethyl-2- (o
-, M-, p-tolyl) ethyl, (2,3-, 2,4-, 2,5-,
The carbon number of 2,6-dimethylphenyl) ethyl, 3-phenylpropyl, (α-, β-naphthyl) methyl, etc. is 7 to 11
Aralkyl group, a phenyl as a substituent R ^6, chlorophenyl, bromophenyl, dichlorophenyl, dibromophenyl, trifluoromethylphenyl, trichloromethylphenyl, tribromomethylphenyl, 2-substituted-1-benzotriazole ethylene group having a cyclohexyl and It can be illustrated.

Representative examples of ketones include acetophenone,
2-chloroacetophenone, 2'-chloroacetophenone, 3'-chloroacetophenone, 4'-chloroacetophenone, propiophenone, 3-chloropropiophenone, butyrophenone, 4-chlorobutyrophenone, 3
-Bromoisobutyrophenone, isobutyrophenone, α
-Acetonaphthone, β-acetonaphthone, phenylbenzyl ketone, phenyl (p-tolylmethyl) ketone, phenyl (m-trimethyl) ketone, phenyl (o-tolylmethyl) ketone, 2-butanone, 2-pentanone, 2
-Hexanone, 3-hexanone, 2-heptanone, 2-
Octanone, 1-phenyl-2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-
On, 1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-one, 1- (2,4-dichlorophenyl)- 2-
(1,2,4-triazol-1-yl) -4,4-dimethyl-
1-penten-3-one, 1-cyclohexyl-2-
(1,2,4-triazol-1-yl) -4,4-dimethyl-
1-penten-3-one, 1- (4-trifluoromethylphenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-one, 1 −
(3-Bromophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-one, 1- (4-fluorophenyl) -2- (1 , 2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-one and the like.

When reducing ketones, the reducing agent is
It is possible to achieve the object sufficiently even if it is used in an amount of 0.5 mol times or more, usually 0.5 to 2 mol times in terms of the optically active aminoalcohol (I), or 0.7 to 1.5 mol times.

The reduction reaction is usually carried out in the presence of a solvent.
The solvent is not particularly limited as long as it does not participate in the reduction reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, etc. Ethers such as halogenated hydrocarbons, diethyl ether, tetrahydrofuran, dioxane, diglyme,
Alternatively, a mixed solvent of these is used. The amount used is 1 to 50 wt times that of ketones.

The reduction reaction is usually carried out in the same inert gas atmosphere as described above, and the reaction temperature is usually -78 to 100 ° C, preferably -40 to 50 ° C.

After the reduction reaction, usually, after the reaction, an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid is added to separate the organic layer and the aqueous layer, the organic layer is washed with water, dried, and then the solvent is distilled off to facilitate the reaction. The desired optically active alcohol (IV) can be obtained.

The progress of the reaction can be monitored by gas chromatography, liquid chromatography or the like. Further, the optical yield can be measured by measuring the degree of light application of the product or by directly measuring the enantiomeric ratio by high performance liquid chromatography using an optically active filler.

The optically active aminoalcohol (I) can be easily recovered while retaining its configuration and reused by adding an alkali to the aqueous layer after the above liquid separation and extracting with an organic solvent.

<Effect of the Invention> The reducing agent of the present invention exhibits extremely high activity, efficiently reduces prochiral compounds even in a small amount, and gives an optically active compound in a high optical yield.

Moreover, the reducing agent of the present invention can be easily produced by adjusting it in the presence of sulfides, cyclic ethers or ethers of monohydric alcohols, which is also advantageous in this respect.

<Examples> Hereinafter, the present invention will be described in more detail with reference to Examples.
The invention is not limited to the examples.

Example 1 (+)-Norephedrine hydrochloride 0.24 under nitrogen atmosphere
After suspending 4 g (1.3 mmol) in 1.4 ml of monochlorobenzene, 0.162 g (2.6 mmol) of dimethyl sulfide was added and cooled to -20 ° C.

Then, a solution of sodium borohydride (0.0492 g, 1.3 mmol) in triglyme (1.1 ml) was added, and the temperature was raised from -20 ° C to room temperature over 2 hours, and the suspension was mixed with (E) -1- (2,4
-Dichlorophenyl) -2- (1,2,4-triazole-
1-yl) -4,4-dimethyl-1-penten-3-one
A solution of 0.60 g (1.85 mmol) in 2.25 ml of monochlorobenzene was added, and the mixture was stirred at room temperature for 90 hours. Then 10% hydrochloric acid
After adding 5 ml and stirring, wash the organic layer with water and concentrate under reduced pressure.
0.61 g (-)-(E)-(2,4-dichlorophenyl) -2
Crude crystals of-(1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol were obtained.

When analyzed by gas chromatography, the reaction rate was 97.4% and the composition of the product was alcohol E: 96.9%.
%, Alcohol Z form was 3.1%.

Almost no saturated alcohol compound in which both the carbonyl group and the carbon-carbon double bond were reduced and a saturated ketone compound in which only the carbon-carbon double bond were reduced were produced.

Further, when analyzed by high performance liquid chromatography, the enantiomer ratio of the alcohol E form was (-) form 82.
%, And the (+) form was 18%.

Examples 2 to 6 In Example 1, instead of dimethyl sulfide, tetrahydrothiophene, diethyl sulfide, di-t-
The procedure of Example 1 was repeated except that butyl disulfide, tetrahydrofuran, and thiophene were used, except for those shown in Table 1. The results are shown in Table 1.

Example 7 In Example 1, instead of monochlorobenzene, 1,
The procedure was carried out in the same manner as in Example 1 using 2-dichloroethane. The results are shown in Table 1.

Comparative Example 1 The procedure of Example 1 was repeated except that dimethyl sulfide was not used. The results are shown in Table 1.

Example 8 In Example 1, 0.081 g (1.3%) of dimethyl sulfide was added.
(E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-
Instead of dimethyl-1-penten-3-one, (E)
-1-Cyclohexyl-2- (1,2,4-triazole-
1-yl) -4,4-dimethyl-1-penten-3-one
Using 0.484 g (1.85 mmol), the reduction reaction was carried out in the same manner as in Example 1 except that the reduction reaction was performed for 24 hours, and 0.489 g of crude (+) was used.
-(E) -1-Cyclohexyl-2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-pentene-
I got 3-ol.

The reaction rate is 96.9% and the composition of the product is alcohol E.
Body 89.6%, alcohol Z body 9.8%, saturated alcohol body 0.6
%Met. The enantiomer ratio of the alcohol E isomer was (−) isomer 24.9% and (+) isomer 75.1%.

Example 9 In Example 1, (+)-1- (2,5-dimethoxyphenyl) was used instead of (+)-norephedrine hydrochloride.
0.62 g of 2-amino-1-propanol hydrochloride 0.322 g (1.3 mmol), the procedure of Example 1 was repeated except that 0.4 ml of dimethylformamide was used instead of triglyme.
(-)-(E)-(2,4-dichlorophenyl) -2-
(1,2,4-triazol-1-yl) -4,4-dimethyl-
Crude 1-penten-3-ol crystals were obtained. Table 2 shows the results
It was shown to.

Comparative Example 2 The procedure of Example 9 was repeated except that dimethyl sulfide was not used. The results are shown in Table 2.

Example 10 In Example 1, 0.81 g (1.3%) of dimethyl sulfide was added.
Mmol), and instead of (+)-norephedrine hydrochloride (+)-1- (2,5-dimethoxyphenyl) -2
-Amino-1-propanol hydrochloride 0.322 g (1.3 mmol), (E) -1- (2,4-dichlorophenyl) -2-
(1,2,4-triazol-1-yl) -4,4-dimethyl-
(E) -1- (4- instead of 1-penten-3-one
Chlorophenyl) -2- (1,2,4-triazole-1-
Yl) -4,4-dimethyl-1-penten-3-one 0.536
The procedure of Example 1 was repeated, except that the reduction reaction was carried out using g (1.85 mmol) for 24 hours. The results are shown in Table 2.

Comparative Example 3 The procedure of Example 10 was repeated except that dimethyl sulfide was not used, and the results are shown in Table 2.

Example 11 In Example 1, (+)-norephedrine hydrochloride was replaced by (−)-norephedrine hydrochloride, trimethylformamide 0.4 ml instead of triglyme, diethyl sulfide instead of dimethyl sulfide, and monochlorobenzene. 1,2-dichloroethane instead of
(E) -1- (2,4-dichlorophenyl) -2- (1,2,4
-Triazol-1-yl) -4,4-dimethyl-1-penten-3-one, except that 0.27 g (1.85 mmol) of phenyl isopropyl ketone was used instead of the one and the reduction reaction was carried out for 18.5 hours. The procedure was followed to obtain 0.27 g of crude (-)-1-phenylisobutyl alcohol.

The reaction rate is 97.3%, and the enantiomeric ratio is (+) form.
36% and (-) form 64%.

Comparative Example 4 The procedure of Example 11 was repeated except that diethyl sulfide was not used.

The reaction rate is 88.7% and the enantiomeric ratio is (+)
The body was 32% and the (-) body was 68%.

Example 12 (+)-Norephedrine hydrochloride 0.65 under nitrogen atmosphere
7 g (3.5 mmol) was suspended in 4.1 g (61.3 mmol) of tetrahydrofuran and cooled to -30 ° C.

Then, a solution of 0.1324 g (3.5 mmol) of sodium borohydride in 0.8 ml of dimethylformamide was added, and the temperature was raised from -30 ° C to room temperature over 2 hours, and (E) -1-
(2,4-Dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-pentene-3-
Onion 1.62 g (5.0 mmol) of monochlorobenzene 5.06 g
The solution was added and stirred at room temperature for 19 hours.

 Hereinafter, post-treatment and analysis were carried out in accordance with Example 1.

The reaction rate is 90.5% and the composition of the product is alcohol E.
The body was 94.9% and the alcohol Z body was 5.1%. Almost no saturated alcohol compound in which both the carbonyl group and the carbon-carbon double bond were reduced and a saturated ketone compound in which only the carbon-carbon double bond were reduced were produced.

The enantiomer ratio of alcohol E form is (-) form 80%,
(+) Body was 20%.

Example 13 A reducing agent was prepared in the same manner as in Example 12, and then concentrated under reduced pressure to distill off about all the tetrahydrofuran used and about half the dimethylformamide, and then 3.3 g of chlorobenzene was added to the concentrate.

(E) -1- (2,4-dichlorophenyl) -2
A solution of 1.62 g (5.0 mmol) of-(1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-one in 5.06 g of monochlorobenzene was added, and the mixture was stirred at room temperature for 15 hours. . Hereinafter, post-treatment and analysis were carried out in accordance with Example 12. The results are shown in Table 3.

Example 14 The procedure of Example 13 was repeated, except that dioxane was used instead of tetrahydrofuran. The results are shown in Table 3.

Example 15 In Example 13, instead of (+)-norephedrine hydrochloride, (+)-1- (2,5-dimethoxyphenyl) -2-amino-1-propanol hydrochloride 0.867 g (3.
The same procedure as in Example 13 was performed except that 5 mmol) was used. The results are shown in Table 3.

Example 16 Under a nitrogen atmosphere, (+)-norephedrine 0.53 g (3.5
0.1324 g (3.5 mmol) of sodium borohydride was suspended in a solution of 3.5 g (49 mmol) of tetrahydrofuran in tetrahydrofuran and 0.182 g (1.8 mmol) of 97% sulfuric acid was added to a solution of 0.88 g (12.3 mmol) of tetrahydrofuran. It took 1 hour and added. Then, this was concentrated under reduced pressure, and about all the amount of tetrahydrofuran used was distilled off.

Then, after adding 1.96 g of monochlorobenzene,
(E) -1- (2,4-dichlorophenyl) -2- (1,2,4
A solution of 1.62 g (5.0 mmol) of monochlorobenzene in 2.42 g of -triazol-1-yl) -4,4-dimethyl-1-penten-3-one was added, and the mixture was stirred at 25 ° C for 15 hours.

Hereinafter, post-treatment and analysis were carried out in accordance with Example 1.
The results are shown in Table 3.

Example 17 In Example 16, instead of using (+)-norephedrine and sulfuric acid, (+)-norephedrine sulfate.
Using 7 g (3.5 mmol) of this and tetrahydrofuran
4.4 g (61 mmol) and sodium borohydride 0.1324 g
The procedure of Example 16 was repeated except that the mixture (3.5 mmol) was stirred for 6 hours and then concentrated under reduced pressure. The results are shown in Table 3.

Example 18 The procedure of Example 13 was repeated, except that 3.6 g of diethyl ether was used instead of tetrahydrofuran. The results are shown in Table 3.

Comparative Example 5 The procedure of Example 12 was repeated, except that monochlorobenzene was used instead of tetrahydrofuran. The results are shown in Table 3.

Comparative Example 6 The procedure of Example 13 was repeated except that monochlorobenzene was used instead of tetrahydrofuran in Example 13. The results are shown in Table 3.

Example 19 (+)-Norephedrine hydrochloride 0.48 under nitrogen atmosphere
After suspending 8 g (2.6 mmol) in 3 ml of monochlorobenzene, 0.323 g (5.2 mmol) of dimethyl sulfide was added and cooled to -20 ° C.

Then, d ₇ sodium borohydride 0.0984g (2.6 mmol) - dimethylformamide 1ml was added -20 ° C.
It took 2 hours to reach room temperature. 1 ml of deuterated chloroform was added to this product, and the ¹¹ B nuclear magnetic resonance spectrum was measured. The area percentage is shown below (BF ₃ · OEt ₂ standard).

-19.4 ppm (85.7%), -11.0 ppm (1.2%) -7.4 ppm (0.5%) 7.8 ppm (12.5%) Example 20 (+)-norephedrine 1.495 g (9.
9 mmol) was dissolved in a solution of 5.61 g of monochlorobenzene and 3.57 g of tetrahydrofluorane, and then 0.374 g (9.9 mmol) of sodium borohydride was suspended. Then, 0.514 g (5.1 mmol) of 97% sulfuric acid was added over 1 hour, and the mixture was further stirred for 1.5 hours.

Hereinafter, the ¹¹ B nuclear magnetic resonance spectrum was measured in the same manner as in Example 19 and shown in area percentage (BF ₃ · OEt ₂ standard).

-20.4ppm (92.9%), 1.7ppm (0.5%) 5.2ppm (1.3%), 13.2ppm (2.4%) 19.0ppm (2.9%)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 33/18 9155-4H C07C 33/18 C07F 5/02 C07F 5/02 D // C07D 249 / 08 520 C07D 249/08 520 C07M 7:00

Claims (3)

(57) [Claims] 1. A compound of the general formula (I) in the presence of sulfides, cyclic ethers or ethers of monohydric alcohols. (In the formula, R ¹ is an aryl group, R ² is a lower alkyl group, R ³
Represents hydrogen or a lower alkyl group. * Represents an asymmetric carbon. ) An optically active amine-boron-based reducing agent obtained by causing an acid and a metal borohydride to act on the optically active amino alcohol represented by 2. The optically active amino alcohol (I) according to claim 1, wherein the acid and the metal borohydride are allowed to act in the presence of sulfides, cyclic ethers or ethers of monohydric alcohols. Optically active amine
Method for producing boron-based reducing agent. 3. The optically active amine-boron reducing agent according to claim 1 and the general formula (II). [In the formula, R ⁴ and R ⁵ are lower alkyl groups, aryl groups, or the formula (III) (In the formula, R ⁶ represents a phenyl group which may be substituted with a halogen or haloalkyl group, or a cycloalkyl group.) Represents a 2-substituted-1-triazoleethylene group, and is the same. Absent. ] The general formula (IV) characterized by reacting with a ketone represented by (In the formula, R ⁴ and R ⁵ have the same meanings as described above, and * represents an asymmetric carbon.)