CA1221097A - Asymmetrically modified boron hydride type compound, a production method thereof, and a method for producing an optically active alcohol derivative by the use thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:
The present invention relates to an asymmetrically modified borohydride type compound obtained by reacting an optically active amino alcohol represented by the formula, wherein R1 represents an aryl, alkyl, cycloalkyl or aralkyl group, R2 represents an aryl, alkyl, aralkyl or alkoxycarbonyl group, R3 represents a hydrogen atom or an alkyl or aralkyl group, and a mark * means an asymmetric carbon, or its salt with an acid with a borohydride compound; its production method; and a method for producing an optically active alcohol derivative which is useful as fungicides, herbicides or plant growth regulators, represented by the formula, wherein R4 represents an alkyl, cycloalkyl or cycloalkenyl group, or a phenyl group which may be substituted with at least one of halogen, alkyl, haloalkyl, cyano, alkoxyl, phenoxy or phenyl, R5 represents an imidazol-1-yl or 1,2,4-triazol-1-yl group, R6 represents a tert-butyl group, or a 1,1-dimethyl-2-phenylethyl group wherein benzene ring may be substituted with at least one of halogen atom, and a mark * has the same meaning as above, by carrying out the asymmetric reduction of a ketone compound represented by the formula,

Description

g7 1 The present invention relates to a novel asymmetrically modified boron hydride type compound, its production and a method for producing an optically active alcohol derivative using the compound. More particularly, it relates to an asymmetrically modified boron hydride type compound obtained by reacting an optically active amino alcohol represented by the formula (I), * *
R - CH - CH - R~
1 1 1 ,. (I) wherein Rl represents an aryl, alkyl, cycloalkyl or aralkyl group, R2 represents an aryl, alkyl, aralkyl or alkoxy-carbonyl group, R3 represents a hydrogen atom or an alkylor aralkyl group, and a mark * means an asymmetric carbon, or its salt with an acid, with a boron hydride compound; its production method; and a method for producing an optically active alcohol derivative represented by the formula (III), OH
R -CH = C - CH - R6 (III) wherein R4 represents an alkyl, cycloalkyl or cycloalkenyl group, or a phenyl group which may be substituted with at ~Z2~9~

1 least one of halogen, alkyl, haloalkyl, cyano, alkoxyl, phenoxy or phenyl, R5 represents an imidazol-l-yl or 1,2,4-triazol-1-yl group, R6 represents a tert-butyl group, or a l,l-dimethyl-2-phenylethyl group wherein benzene ring may be substituted with at least one of halogen atom, and a mark * has the same meaning as above, by carrying out the asymmetric reduction of a ketone compound represented by the formula (II), R4 - CH = C - C - R6 (II) wherein R4, R5 and R6 have the same meanings as above, with said asymmetrically modified boron hydride type compound.
The alcohol derivative represented by the above formula (III), i.e. an azole type ~ unsaturated alcohol derivative is known to be useful as an active ingredient for fungicides, plant growth regulators or herbicides, as represented for example by 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-l-yl)-4,4-dimethyl-1-penten-3-ol, 1-(4-chloro-phenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol and l-cyclohexyl-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol [Japanese Patent Application Kokai (Laid-open) u~ . ~ 0~ ~s"
Nos. 124,771/1980, 10054~/1979 and 111,477/1980]. And, it is also well known that there is a remarkable difference in the activity between the optical isomers, and that, for example, with reference to the foregoing 1-~2,4 )97 1 dichlorophenyl)-2~(1,2,4 triazol-1-yl)-4,4-dimethyl-l-penten-3-ol and 1-(4-chlorophenyl)-2-~1,2,4-triazol-l-yl)-4,4-dimethyl-1-penten-3-ol, the (-)-isomer has a strong activity as fungicides, while the (+)-isomer has a strong activity as plant growth regulators and herbicides [Japanese ~ Q,l d ~,' Patent Application Kokai (~ -open) Nos. 99575/1982 and 106669/1982].
For this reason, there is a great demand for the development of a method to produce either one of the (-)-or (+)-optical isomer according to intended uses and yet with a good efflciency in industry.
As the conventionally well-known common reducing agent for reducing the carbonyl group of ketone compounds into alcohol compounds, there are various reagents represented by lithium aluminum hydride and sodium boro-hydride. -The reduction product produced when these reagents are used is an optically inactive, i.e. racemic compound, and when these reagents are used for the reduction of ketone compounds having an unsaturated bond, particularly ~ conjugated unsaturated ketones like the material used in the method of the present invention, reduction of the double bond in addition to the carbonyl group is easy to occur, and besides there also comes out a possibility that the steric configuration correlated with the double bond is isomerized.
C~h l/e,n~o>q~
As the ~e=~e~ r~f employed method for '~ ~ producing optically active alcohol derivatives by asymmetric reduction, there are the following methods to carry out ~Z;~i()97 1 the asymmetric reduction of ketone compounds with lithium aluminum hydride modified with an optically active compound:
A method of using an optically active N-methylephedrine [I. Jacquet, et al., Tetrahedron Letters, 1974, 2065; J.P.
Vigneron, et al., Tetrahedron, 32, 939 (1976); J.P.
Vigneron, et al., Tetrahedron Letters, 1979, 2683; idem, ibid., 1980, 1735; and Japanese Patent Application Kokai (Laid-open) Nos. 99575/1982 and 106669/1982]; a method of using an optically active proline derivative [M. Asami, et al., Heterocycles, 12, 499 (1979)] and a method of using an optically active binaphthyl derivative [R. Noyori, et al., J. Am. Chem. Soc., 101, 3129 (1979); R. Noyori, et al., ibid., 101, 5843 (1979)].
These methods, however, may not always be said to be satisfactory in industry, for example, in the following points: (1) Since lithium aluminum hydride is used, there is a danger such as ignition by contact with moisture, and

(2) in order to obtain an alcohol compound having a higher optical purity~ additives such as N-substituted aniline are required in large amounts.
Also, in asymmetric reduction, the following methods are reported as a method for producing optically active alcohols using an asymmetrically modified boron hydride-reducing agent:
~ A method of using sodium borohydride and the onium salt of optically active ephedrine [described in S.
Colona, et al., J. Chem. Soc., Perkin Trans I, 371 (1978)], ~2~ 9~

1 ~ a method of using an optically active amine-borane complex [described in R.F. Borch, et al., J. Org.
Chem. 37, 2347 (1972~], ~ a method of using an ~-amino acid ester-borane complex [described in M.F. Grundon, et al., Tetrahedron Letters, 295 (1976)], and a method of the asymmetric reduction of aromatic ketones with an optically active amino alcohol and borane ~described in A. Hirao, et al., J. Chem. Soc., Chem.
Comm., 315 (1981); S. Itsuno, et al., ibid., 469 (1983); and S. Itsuno, et al., J. Chem. Soc. Perkin Trans I, 1673 (1983)].
But, the methods ~ , ~ and ~ are too low in optical yield to say that they are a practical method.
Also, the method ~ may not always be said to be satisfactory to carry it out in industry because, in order to attain high optical purity t borane of two times by mole, as converted to boron basis, as much as amino alcohol is required.
In view of the situation like this, the present inventors extensively studied a method for obtaining the optically active alcohol derivative represented by the formula (III) by the asymmetric reduction of the ketone compound represented by the above formula (II), and as a result, found that, by using an asymmetrically modified boron hydride compound (hereinafter referred to as present compound) obtained by reacting the optically active amino alcohol represented by the above formula (I) or its ~Zl~g7 1 salt with an acid ~ith a boron hydrlde compound, only the carbonyl group is selectively reduced into the objective optically active alcohol derivative with safety as well as good efficiency.
Next, the present invention will be illustrated.
In the optically active amino alcohol represented by the above ~ormula (I), a material for the present compound, specific examples of a substituent Rl include a Cl-C10 alkyl, C5-C10 cycloalkyl and C7-C16 aralkyl groups, a phenyl group which may be substituted with at least one of halogen, alkyl, cyano, alkoxyl or alkoxycarbonyl, and a naphthyl group which may be substituted with at least one of halogen, alkyl, cyano, alkoxyl or alkoxycarbonyl.
Specific examples of R2 include a C6-C16 aryl, Cl-C10 alkyl and C7-C16 aralkyl groups and an alkyloxycarbonyl group in which the number of carbon atoms constituting the alkyl group is 1 to 10. Specific examples of R3 include a hydrogen atom, a Cl-C6 alkyl and C7-C16 aralkyl groups.
More specifically, as the optically active amino alcohol represented by the formula (I), there may be given norephedrine, norpseudoephedrine, threonine ester, 1,2-diphenyl-2-amino-1-ethanol, 1~(2,5-dimethylphenyl)-2-amino-1-propanol and l-~-naphthyl-2-amino-1-propanol. These optical-ly active amino alcohols are produced, for example, by the methods described in M.J. Kalm, J. Org. Chem., 25, 1929-37 (1960); W.H. Hartung, et al., J. Am. Chem. Soc., 52, 3317-22 (1930); W.H. Hartung, et al., J. Am. Chem. Soc., 51, 2262-6 (1929); M.C. Kloetzel, et al., J. Org. Chem., 11, 12~ 7 1 390-4 (1946), and the like.
In the present invention, the halogen atom represents fluorine atom, chlorine atom or bromine atom.
Next, reference will be made to a method for producing the present compound.
The present compound, when the boron hydride compound is a metal borohydride, is obtained by reacting a salt, as obtained from the optically active amino alcohol represented by the formula (I) and an acid, with the metal borohydride in a solvent, or when the borohydride compound is a borane, it is obtained by directly reacting the optically active amino alcohol represented by the formula (I) with the borane in a solvent. As the foregoing acid which is a material for producing the salt of the optically active amino alcohol, there are given mineral acids (e.g.
hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carboxylic acids (e.g. acetic acid), organic sulfonic acids (e.g. p-toluenesulfonic acid) and the like. Said salt may be used as such or may be produced, in situ, from the optically active amino alcohol and the acid in the reaction system for producing the present reducing agent.
As the metal borohydride described above, there are given for example sodium borohydride, potassium boro-hydride, lithium borohydride, zinc borohydride, etc.
Generally, however, the object of the present invention can sufficiently be achieved by using easily available sodium borohydride. As the borane, for example diborane, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, ~2~9~

1 etc. may be given.
In production of the present compound, the molar ratio of the borohydride compouncl to the optically active amino alcohol is, when said compound is a metal borohydride, 0.7 : 1 to 2 : 1, preferably 0.7 : 1 to 1.3 : 1, more preferably 1 to 1, as converted to boron basis, and when said compound is a borane, said molar ratio is 0.7 : 1 to 1.3 : 1, preferably 1 to 1.
The solvent used in producing the present compound is not particularly limited, so long as it does not take part in the reaction. For example, however, there are given aromatic hydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene), halogenated hydrocarbons (e.g. methylene chloride, 1,2-dichloroethane, chloroform, carbon tetra-chloride~, and mixtures thereof. When the metal borohydrideis used, in order to solve it, for example dimethyl sulfoxide, diglyme, dimethylformamide, 1,3-dimethyl-2-imidazolidinone or the like may be used in combination.
The reaction temperature is generally within a range of -78 to 100C, preferably -40 to 100C. The reaction is generally carried out in an inert gas atmosphere such as nitrogen, argon, etc.
Also, by decomposing the present compound with an aqueous alkali solution, a compound represented by the formula (V), )g7 * *
R - CH - CH - R2 (V) 1 wherein Rl, R2, R3 and a mark * have the same meanings as above, is obtained.
The present compound thus obtained may be used for the subsequent reduction after separated from the reaction solution, but generally, it is used as the solution without being separated therefrom.
Next, re~erence will be made to a method for producing the optically active alcohol derivative of the above formula tIII) by reduction of the ketone compound represented by the above formula (II) using the present compound thus obtained.
The amount of the present -compound used in the reduction is not less than 0.5 mole, generally within a range of 1 to 5 moles, as converted to boron basis, based on 1 mole of the ketone compound represented by the formula (II), and even the range of 1 to 2 moles can sufficiently achieve the object.
Also, the solvent used in the foregoing reduction is not particularly limited, so long as it is an inactive solvent. Preferably, however, organic solvents such as aromatic hydrocarhons (e.g. benzene, toluene, xylene, chlorobenzene), halogenated hydrocarbons (e.g. methylene chloride, ~,2-dichloroethane, chloroform, carbon :~2:~9'~

1 tetrachloride), ethers ~e.g. diethyl ether, tetrahydrofuran, dioxane, diglyme) and mi~tures thereof are used. Also, the solvent used in producing the present compound may be used as it is or in mixture with the solvents described above. The reduction is generally carried out in an inert gas atmosphere as described above. The temperature of the reduction is generally within a range of -30 to 100C, and industrially within a range of -10 to 50C.
The foregoing reduction may be carried out in the presence of an acid, and particularly when sodium boro-hydride is used as a material for the present compound, isomerization between the E form and Z form of the ketone compound represented by the above formula (I) is inhibited, whereby the yield of the objective optically active alcohol derivative can be increased. As the acid, there are given for example Iewis acids (e.g. titanium tetrachloride, boron trifluoride etherate, aluminum chloride), carboxylic acids (e.g. acetic acid, chloroacetic acid, propionic acid) and mineral acids ~e.g. hydrochloric acid, sulfuric acid, phosphoric acid). The molar ratio of these acids to the ketone compound is generally within a range of 0.01 : 1 to 1 : 1, preferably 0.01 : 1 to 0.5 : 1.
After the reduction is carried out in this way, the aqueous solution of a mineral acid (e.g. hydrochloric acid, sulfuric acid) is generally added to the reaction solution, the organic layer is separated from the aqueous layer, washed with water and dried, and then the organic solvent is removed by evaporation. By this procedure, the (J 97 1 objective aforementioned optically active alcohol deri~ative represented by the formula (III) is obtained in a high yield.
The optical purity is obtained by measuring the optical rotation of the product obtained, or directly measuring the enantiomer ratio by high performance liquid chromatography with optically active packing materials.
Hereupon, the optically active amino alcohol used can easily be recovered, with its steric configuration maintained, by adding an aqueous alkali solution to the aqueous layer after the reaction and extracting with an organic solvent. The recovered optically active amino alcohol can be re-used.

Example 1 In a nitrogen atmosphere, 0.338 g of (+)-norephedrine hydrochloride was suspended in 5 ml of deutero chloroform, and after cooling to -30C, a solution of 0.0681 g of sodium borohydride in 1 ml of dimethylformamide was added. On raising the temperature of the resulting 20 mixture from -30C to room temperature over 2 hours, 87 ml of hydrogen gas was generated to obtain a solution of the present compound. llB nuclear magnetic resonance spectrum (standard, BF3~OEt2) of this solution was as follows:
-20.95 ppm, +7.21 ppm.
Thereafter, this solution was de~omposed with 2.5N aqueous sodium hydroxide solution, and the organic layer was washed with water and purified by column 1 chromatography on silica gel with a n-hexane/ethyl acetate (1 : l) mixture as a developing solvent to obtain 0.112 g of a crystal.
llB nuclear magnetic resonance spectrum (standard, BF3~OEt2): -20-5 ppm m.p. 93 -95C (dec.) This crystal, as a result of X-ray diffraction analysis, was identified to be a borohydride compound having the following structure:

CH - CH - CH3 [~]D + 49 7 (c - 1.0, THF) OH N-~BH3 Example 2 ~ eaction was carried out in the same manner as in Example l except that dimethylformamide was replaced by deutero dimethylformamide, to obtain a solution of the present compound having the following physical property:
H nuclear magnetic resonance spectrum [CDCl3-DMF-d7, ~(ppm)]: 0.97(d), 1.04(d), 2.75-3.15(m), 3.1-3.5(broad), 4~2-4.7(broad), 5.18(d), 7.31(s) Examples 3 and 4 Reaction was carried out in the same manner as in Example 2 except that (+)-norephedrine hydrochloride was replaced by (+)-l-(2,5-dimethylphenyl)-2-amino-l-propanol hydrochloride and (-)-l-~-naphthyl-2-amino-l-propanol ~L~Z2~ 7 1 hydrochloride, to obtain a solution of the present compound having the physlcal property shown in Table 1.

Table Example No. llB NMR spectrum [~(ppm)]
_

3 -20.6, +6.5

4 -20.3, +6.4 Example 5 In a nitrogen atmosphere, a solution of 0.272 g (1.8 mmoles) of (+)-norephedrine in 4 ml of 1,2-dichloro-ethane was added dropwise at -78C to a solution comprising 1.8 ml (0.9 mmole) of a 0.50M diborane-tetrahydrofuran solution and 2 ml of 1,2-dichloroethane, and the tempera-ture of the resulting mixture was raised from -78C to room temperature over about 2 hours. 11B nuclear magnetic resonance spectrum of this solution was as follows: -20.7 ppm, +7.7 ppm.

Example 6 In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (+)-norephedrine hydrochloride was suspended in 5 ml of 1,2-dichloroethane, and after cooling to -30~C, a solution of 0.0681 g (1.8 mmoles) of sodium borohydride in 1 ml of dimethylformamide was added. On raising the temperature of the resulting suspension from -30C to room temperature ~Z~ '7 1 over 2 hours, 87 ml of hydrogen gas was generated. There-after, a solution of 0.39 g ~1.2 mmoles~ of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=99.9/0.1) in 4 ml of 1,2-dichloroethane was added to this suspension at room temperature, and then stirring was carried out for 23 hours. Thereafter, 6 ml of 2M hydrochloric acid was added, followed by stirring for 2 hours. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified on a column packed with 2 g of silica gel with a chloroform solvent and then concentrated under reduced pressure to obtain 0.39 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crude crystal. By gas-chromatographic analysis, it was found that the conversion was 96.4%, and the composition of the reaction product was: E-form alcohol, 98.3% and Z-form alcohol, 1.7% (Z-form alcohol was produced through isomerization of the ketone compound to the Z-form, followed by reduction of the carbonyl group).
Optical rotation [~]D -19.93 (c=1.0, CHC13) ~y high-performance liquid-chromatographic analysis using an optically active column, it was found that the enantiomer ratio of the E-form alcohol was:
(-)-isomer, 85.1% and (+)-isomer, 14.9%. The optical yield 25 was 70.2%.

Examples 7 to 10 Reaction was carried out according to Example 6 12Z~97 1 using the reactlon solvents described below in place of 1,2-dichloroethane, to obtain (-)-(E)-1-(2,4-dichlorophenyl)-2~ 2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol.
The results are shown in Table 2. In the table, the solvents in parentheses in the column, "Reaction solvent", are a solvent used for dissolving sodium boro-hydride.

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l Examples 11 to 13 Reaction was carried out according to Example 6 using (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-l-yl)-4,4-dimethyl-l-penten-3-one (E/Z=99.8/0.2) in place of (E)-l-(2,4-dichlorophenyl-2-(1,2,4-triazol-l-yl)-4,4-dimethyl-l-penten-3-one and at varying molar ratlos, 1.0, l.l and 1.2, of sodium borohydride to norephedrine hydrochloride.
The results are shown in Table 3. Hereupon the saturated alcohol of the reaction products means a product obtained by hydrogenation of both the carbonyl group and the carbon/
carbon double bond contained in the ketone compound which is a material.

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~Z ~ ~1 - - --~22~ 97 1 Examples 14 and 15 In a nitrogen atmosphere, a solution of 1.8 mmoles of the following each acid in 1 ml of 1,2-dichloroethane was added to a solution of 0.272 g (1.8 mmoles) of (+)-norephedrine in 4 ml of 1,2-dichloroethane, and after cooling to -30C, a solution of 0.0681 g (1.8 mmoles) of sodium borohydride in 1 ml of dimethylformamide was added.
The temperature of the resulting mixture was raised from -30C to room temperature over 2 hours to prepare the present compound. Thereafter, asymmetric reduction of the ketone compound was carried out in the same manner as in Example 6.
The results are shown in Table 4.

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1 Example 16 Reaction was carried out on a scale of ten times that of Example 6. ~n a nitrogen atmosphere, a solution of 0.681 g (0.018 mole) of sodium borohydride in 9.44 g of dimethylformamide was added dropwise at -20C to a suspension of 3.38 g (0.018 mole) of (+)-norephedrine hydrochloride in 62.8 g of 1,2-dichloroethane, and the temperature of the resulting mixture was raised from -20~C to room temperature over 2 hours. Thereafter, a solution of 3.89 g (0.012 mole) of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=97.6/2.4) in 50.24 g of 1,2-dichloroethane was added, and stirring was carried out at room temperature for 21 hours and then at 40C for 3 hours. The reaction solution was decomposed with addition of 7.22 g of 10% hydrochloric acid and 2.1 g of water, and the organic layer was separated, washed with water and concentrated under reduced pressure to obtain 3.89 ~ of (-) (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-l-yl)-4,4-dimethyl-1-penten-3-ol as a crystal. The conver-sion of 99.9%, and the composition of the product obtainedwas: E-form alcohol, 95.8%; saturated alcohol, 0.2%;
Z-form alcohol, 3.5%; and others, 0.5%. The enantiomer ratio of the E-form alcohol was: (-)-isomer, 85.2% and (+)-isomer, 14.8%. The optical yield was 70.4%.

Example 17 Reaction was carried out in the same manner as in Example 16 except that the amounts of 1,2-dichloroethanep ~z~1~9~

1 a solvent, used were reduced to 13.52 g and 12.2 g from 62.8 g and 50.24 g, respectively. The conversion was 99.9%, and the composition of the product obtained was: E-form alcohol, 88.9%; saturated alcohol, 0.9%; Z-form alcohol, 9.4%; and others, 0.8%. The enantiomer ratio of the E-form alcohol was: (-)-isomer, 84.1% and (+)-isomer, 15.9%. The optical yield was 68.2%.

Examples 18 to 24 Asymmetric reduction of each of (E)-l-(Z,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=97.6/2.4) and (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl~-4,4-dimethyl-1-penten-3-one (E/Z=
98.9/1.1) was carried out according to Example 6 using the hydrochloride of each optically active amino alcohol described below in place of (+)-norephedrine hydrochloride.
The results are shown in Table 5.

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_ _ __ _ 26 --~215)97 1 Examples 25 to 29 Reaction was carried out in the same manner as in Example 6 except that the (E) ancL (Z) forms of l-cyclohexyl-4,4-dlmethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one (the E/Z ratios of the former and the latter were 99.9/0.1 and 0.1/99.9, respectively) were used in place of (E)-l-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-l-penten-3-one, and that the hydrochlorides of the optical-ly active amino alcohols and the solvents (solvents in parentheses are a solvent used for dissolving sodium borohydride) described below were used. The results are shown in Table 6.

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~Wo o~ _, ~ __ . . _, o ~ ~ ~ In ao ~ w __~ ~ ~` ~

~22~)97 ~ o E~ o~

~ 31 --1 Example 30 In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (+)-norephedrine hydrochloride was suspended in 5 ml of 1,2-dichloroethane, and to this suspension was added at -30C a solution of 0.0681 g (1.8 mmoles) of sodium boro-hydride in 1 ml of dimethylformamide. The temperature of the resulting suspension was raised to room temperature over 2 hours. Thereafter, to this suspension was added at room temperature a solution of 0.0108 g (0.18 mmole) of acetic acid and 0.35 g (1.2 mmoles) of (E)-1-(4-chlorphenyl)-2-(1,2,4-triazol-1-yl~-4,4-dimethyl-1-penten-3-one (E/Z=
99.8/0.2) in 4 ml of 1,2-dichloroethane. The subsequent treatment was carried out according to Example 6.
The conversion was 79.4%, and the composition of the product obtained was: E-form alcohol, 92.5%; saturated alcohol, 0.3%; and Z-form alcohol, 7.Z~. The enantiomer ratio of the E-form alcohol was~ isomer, 76.1% and (+)-isomer, 23.9%. The optical yield was ;2.2%.

Examples 31 to 38 Reaction was carried out according to Example 30 using titanium tetrachloride, boron trifluoride etherate, monochloroacetic acid, propionic acid and conc. sulfuric acid in place of acetic acid. The results are shown in Table 7.

~ZZ1~97 O ~ ~~1 1~r~ ~ ~ N
O o~t~ ~r~i 1~co ~ ~I ~ ~
~ --~OCIDIl~ a~~D CO ~ 0 U
_ _ O
. ~ er ~ ~7 ~r ~ c~
o a) s ~ ~ ~ ~ ~ ~D
~ -~ ~ _ _ C) 00 O
a) o ~ In ~ ~ ~ .
.,1 ~ ~ ~ f~ O O O O O U~

` a o _ __ ~ __ _ ,1 _ ~ ~ I_ ~ ~ ~r~ ~ co ~
~_ ~ o ~ ~ ~ ~ ~ o ~~ o ~O O ~ O O O O O
E~ X~ _ . . . . . . .
~ ~C o O O O o O o O
h 'a t) ~ .~ .~ ~ C~
~ ~ o a) .,, .,, rl ~ ~ ~ C~ S~
~ ~0 ~ O ~ 4~
u~ ~ ~,1 S~ a~ o ., .~ ~.C ~ ~ ~ ~ U~
3 ~d,~ ~ t~ S O
a) Z~ ~ :~ s~ ~ .,, .
s~ o a~ o ~a ~ o ~ ~ ~ S ~ rl O ~ ., ,1 0 O ~ O O h O O
~ ~ m a) X ~ _ ~ ~
Q~
~ .
O ~ ~ ~ ~ ~n ~D ~ 0 ~ Z ~ ~ ~ ~ ~ ~7 ~ ~
X _ _ __ v~

- ~o~-c ~v~ ~; ~ - ~ ~ -o l ~ ~ ~ oo ~ co u~ co co ~ ~ ~ ~ ~ ~ ~ ~ ~r u~
o o ~
- - - - - - -+ r~ ~ co i~i~ ~ i~ co a) ~ ~ . . . . . . ~
~ I ~ ~ ~ ~D CO O ~ U~ O
0~ ~ O ~ r~ ~ ~ , .
~ O i ~ ~`~CO ~ ~ ~ ~D
8~9 ~D ~ ~i ~ ,~ ~r a~
~0 ~ ~ _ ~ 00 ~ ~D t` i-~ _ _ ~, ~ r~ ~ ~ N If) ~ CO ~I
~` 00 ~7 _ O _1 C~ O ~ ,0~
~ _ __ .

S~ ~5-Q ~ O ~ _~ ~ ~ ~
. .~ ~0- O
_ _ _ d~
_ ,~ U~ ~ In U~ ~ ~1 ~ a~
O O ~o ~ oo _ ~ a~ o a~
1~1 ~ ~ a~ o~ ~ oo ~ co _ _ 1 Examples 39 to 41 Reaction was carried out according to Example 30 using varying molar ratios of sodium borohydride to norephedrine hydrochloride. The results are shown in 6 Table 8.

Table 8 Example Molar ratio (%) Molar ratio (%) Re~c- Conver- _ acid to amino borohydride to tlon sion No. alcohol norephedrine hr (~) hydrochloride ( ) O
_ _ _ 39 15 _ 1.1 24 90.0 _ 1.2 43 _ 97.8 41* 15 1.1 24 97.2 _ _ _ _ _ Reaction product Enantiomer Optical _ ratio (-/+) yield of E-form Saturated 2-form of E-form E-form alcohol alcohol alcohol alcohol alcohol (%) (%) (%) (%) _ 92.1 _ 7.9 79.0/21.0 58.0 _ 83.6 0.8 13.4 85.0/15.0 70.0 _ 91.2 _ 8.8 75.5/24.5 51.0 _ _ * Chlorobenzene was used in place of 1,2-dichloro-ethane.

Example 42 In a nitrogen atmosphere, 0.393 g 10.0065 mole)of acetic acid was added to a suspension of 8.18 g lZ;~ 397 1 (0.0436 mole) of ~ norephedrine hydrochloride in 62.17 g of chlorobenzene, and then a solution of 1.815 g (0.0480 mole) of sodium borohydride in 9.35 g of dimethylformamide was added dropwise to this suspension at 5 to 10C for 1.5 hours. Thereafter, the resulting mixture was stirred at room temperature for 1 hour, and then a solution of 8.42 g (0.0291 mole; E/Z=99.8/0.2) of (E)~ 4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one in 49.7 g of chlorobenzene was added at room temperature. The resulting mixture was stirred at the same temperature for 18 hours. The reaction solution was decomposed with addition of 17.50 g of 10% hydrochloric acid and 5 g of water, and the organic layer was separated, washed with water and concentrated under reduced pressure to obtain 8.15 g (~)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crystal. The conversion was 99.8%, and the composition of the product obtained was:
E-form alcohol, 90.8%; saturated alcohol, 2.3%; and Z-form alcohol, 6.9~. The enantiomer ratio of the E-form alcohol was: (+)-isomer, 81.0% and (-)-isomer, 19.0%. The optical yield was 62.0~.

Example 43 In a nitrogen atmosphere, a solution of 2.64 g (0.0698 mole) of sodium borohydride in 14.95 g of dimethyl-formamide was added dropwise at -20C to a suspension of 13.07 g (0.0696 mole) of (~)-norephedrine hydrochloride in 52.26 g of 1,2-dichloroethane, and the temperature of the ~Z~1~)97 1 resulting mixture was raised from -20C to room temperature over 2 hours.
Thereafter, 0.35 g of phosphoric acid and then a solution of 16.12 g (0.0497 mole) of (E)-1-(2,4-dichloro-phenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=97.6/2.4) in 49.37 g of 1,2-dichloroethane were added at 20 to 25C, and stirring was carried out at the same temperature for 20 hours. The reaction solution was decomposed with addition of 24.17 g of 20% nitric acid and 4.6 g of water, and the organic layer was separated, washed with water and concentrated under reduced pressure to obtain 15.60 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-l-yl)-4,4-dimethyl-1-penten-3-ol as a crystal. The conversion was 99.8%, and the composition of the product obtained was: E-form alcohol, 95.6%; saturated alcohol, 0.4%; Z-form alcohol, 3.2%; and others, 0.8%. The enantiomer ratio of the E-form alcohol was: (-)-isomer, 85.8% and (+)-isomer, 14.2%. The optical yield was 71.6%.

Example 44 In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (-)-norephedrine hydrochloride was suspended in a mixture comprising 15.4 ~1 (0.27 mmole) of acetic acid and 5 ml of 1,2-dichloroethane, and after cooling to -30C, a solution of 0.0749 g (1.98 mmoles) of sodium borohydride in 1 ml of dimethylformamide was added. The temperature of the resulting suspension was raised from -30C to room tempera-ture over 2 hours. Thereafter, to this suspension was ~.2~C~

1 added at room temperature a solution of 0.31 g (1.2 mmoles) of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl~-1-penten-3-one (E/Z=99.9/0.1) and 10.3 ~1 (0.18 mmole) of acetic acid in 1,2-dichloroethane, and stirring was carried out for 24 hours. The subsequent treatment was carried out in the same manner as in Example 6 to obtain (-)-(E)-l-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol. The conversion was 100%, and the composition of the product obtained was: E-form alcohol, 97.4% and Z-form alcohol, 2.6%. The enantiomer ratio of the E-form alcohol was~ isomer, 77.7% and (+)-isomer, 22.3%.

E~ample 45 In a nitrogen atmosphere, a solution of 0.272 g of (+)-norephedrine in 4 ml of 1,2-dichloroethane was added dropwise at -78C to a mixture comprising 1.8 ml of a 0.500M diborane-tetrahydrofuran solution and 2 ml of 1,2-dichloroethane, and the temperature of the resulting mixture was raised from -78C to room temperature over about 2 hours. Thereafter, to this solution was added dropwise at room temperature a solution of 0.39 g of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl~-4,4-dimethyl-1-penten-3-one (E/Z=99.9/0.1) in 4 ml of 1,2-dichloroethane, and stirring was carried out for 24 hours. Thereafter, 6 ml of 2M hydrochloric acid was added to the reaction solution, followed by stirring for about 2 hours. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

g7 1 The residue was purified on a column packed with 2 g of silica sel using a chloroform solvent and then concentrated under reduced pressure to obtain 0.39 g of (-)-(E)-l-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-S l-penten-3-ol as a crude crystal. The conversion was 98.6%, and the composition of the product obtained was: E-form alcohcl, 98.6~ and Z-form alcohol, 1.4%.
Optical rotation [~]D: -20.7 (c=1.0, CHC13) Optical yield of E-form alcohol: 70 Examples 46 to 50 Reaction was carried out according to Example 45 using the following reac~ion solvents in place of 1,2-dichloroethane, to obtain (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triaæol-1-yl)-4,4-dimethyl-1-penten-3-ol. The results are shown in Table 9.

~2~V~7 o ~ o h ~ _ ~r ~r t:~ co L~
q~ u~ ~ L~ ~D n O '~ ~ ~
~ CO o ~ o o ~) ~ ~~ ,_1 ~1 ~r u~ ut ~1 C~ .~ . . . .
~ ~ ~ ~O ~r ~ o ~0 oO~OU _l ~ ~ ~ l ~ ~'.C
.~ O O
U I 1~ t~l ~ W f'~
~ ~ O ~ o o o 0~0\ ~ OD a~ ~ c7~

d~ --O O ~ O
a~ ~:: 0 ~ cn 10 ~ ~i ,4 _ E~ r ~) ~ a~ ~r _l e s _, '~
_ s~ ~
r~l~ ~ ~a~ o ~ ~ ~ ~ ~ a) ,ra ~ ~
_~ ~ a~ ~ s~ o a~ o :~ x ~ .c o R S-~; ~q .C O ~ ~ ~1 5 .,, o a~
. _ r~ a E~ ~ O U

~ z W ~ ao a~ o 1i3 _ 1 Examples 51 and 52 Reaction was carried out in the same manner as in Example 45 except that toluene was used as reaction solvent in place of 1,2-dichloroethane, the reaction time was changed to 23 hours, and that the molar ratio of diborane to (+)-norephedrine was varied, to obtain (-)-(E)-1-(2,4 dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. The results are shown in Ta~le 10.

~LZ;~ 7 _ _ ~ ~ e ,, ~r '~ 'I ~ ' 117 n ~3 I h O ~ O ~ ~ ~r h ~ O I ~
i` ~D
~0 ~ ~ ~0 (~
.~ _ .
^ Ul o~
~; ~ O ~P ~i O
~ _ ~,C - U~
O O dP
,01 ~ ~ cn R O
E~ ~ ~P ~ ~o ~ _ ~ ~

\ 'S~ O O
\ ~1 ~i ,_1 ~ \ + O ~ r o a _ _ ~ ~3 .

~L221(397 1 Examples 53 to 57 Reaction was carried out in the same manner as in Example 45 except that the optically active amino alcohols described below were used in place of (+)-norephedrine, and that tetrahydrofuran and diethyl ether were used as a reaction solvent. The results are shown in Table 11.

:12~1~97' ~ N N N r O
r~ ~ O O dP ~ ~ O ~ ~
o a) v~ t~l ~ ~. ~ ~, ~rl I r-l 0~
~ + ~ ~ ~ ~ O
~--~ . . . .
~ O I 0~1 er ~ u~ U~
~1 ~ -- -- -- --O I ,C ~r a~ C5~ a~ o O ~ rl q O . . . .
~1t~ ~ U Is~ ~ ~r ~ CD
~ ~0~ _ _ .,1~
O
s~ ~ _ ~ ~ r ~r c~
~0 C~ O O O O ,_ t~1; _ ~ O
h ~ ~ ~ a~ tr7 ~D ~
00 ~ . . . .
_ a~ ~ cr~ c~ co a~ ~ ~
_ _ s~ ~o ~ ~r o~
oP ~o o ~r O ~
o~ ,1 - 0~ O ~` ~ CO
C~
R I ,_ E~ C~ ~ I~ er O
~ O ~ S ,1 ~ ~ ~
~ ~ ~1 ~1 . _ , O O O
~ S~ S~ 5 O ~ ~ ~
~ ~ ~ S~ _~ S
O ~ ~ ~ S S~ ~ ~ S ~ ~ ~
r~ ~1 ~ rd ~ n~ ~ ~ ~ ~ 5~ td ~ O ~ ~ au ~ ~ h ~ S ~ 5~
~n a~ ~ 1 ~~J 3 .rl ~ a~
E~ ~ a) E~ ~ C~ a~ E~
~ ~ ~ ~ l l l a) 'ol '~ ~ .~ ~ ~ ~ ~ol ~ ~ o s o o ~ o ~ ~ a~
.,, ~1 ~ o a) ~ ~ ~ ~ ~ I ~ ~ ~
~ s~ c~ ~ s~ s ~ ^ Q, ~ s O ~ ~1 I S ~ u~ I S ~ tn +-rl I
o ~ ~ ~ ~ ~ , ~ -P O ~ ~r u~ ~D I~
~ Z u~ u~ ~ In U~
~ . _ lz~as~
1 Examples 58 and 59 Reaction was carried out in the same manner as in Example 45 except that (+)-norephedrine was replaced by ~ norephedrine and (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one, and that the following ketone compounds were used. The results are shown in Table 12.

lL~ZlV9~7 a t ~
S~ ~D
~
~_ r o a~ ~lo ~ 5~ =~

~U ; ~3~D
_ _ ~ _ U~ l Z1~9~

. _ ~
CO CO
a)~ a~

,o- o-OI oo O I S _l a~
3 o .
~ ~ ~, U~
,_ C ~ 4~ ,, ~ ~ o Yo _ ~, ~,~
_l ~ ~D
~ ,, ,~o _~

~ ~S- _, o ~ O Od~ .
o ~_ ~ _, ~ ~o~ l ~o~ ~

~=

Examples 60 to 69 Asymmetric reduction was carried out in the same manner as in Example 6 except that (+)-norephedrine hydro-chloride was replaced by an amino alcohol of (+)-2-amino-1-(2,5-dimethoxyphenyl)-1-propanol hydrochloride, (+)-2-amino-l-(2,5-diethoxyphenyl)-1-propanol hydrochloride, (-)-2-amino-1-(2,4-dimethoxyphenyl)-1-propanol hydrochloride, (+)-2-amino-1-(2-methoxyphenyl)-1-propanol hydrochloride or (-)-2-amino-1-(2-ethoxyphenyl)-1-propanol hydrochloride, to asymmetrica~ly reduce a ketone compound of (E)-l-(4~ chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z= 98.9/1.1), (E)-l-cyclohexyl-2-(1,2,4-triazol-l-yl)-4,4-dimethyl-1-penten-3-one (E/Z=99.9/0.1) or (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=97.6/2.4). The results are shown in Table 13.

~i ~ ~ h ~, ,Q o ~l O
0 10- Co Cl` ~ I I O

~+ O ~ rO
~ , l l _ ~ ~ O` C~ O
+~ ~, r ~ ~ ~ I ~i ~i ~
~ ~J ~ , ~C~0~1 V' ~1 1 l V
~ ~ h 0 I _ ~ eS ~ ~ O`
_ ~ 0 ! - _ ~ ~O` Nl O ! `
~ o~ ~ ~ ! ~ ~ l ~ L
~} ~an o o ~ o ~ o *~ *~--æ
o ~ æ ~ ~ ~ ~
a ~ = = c~ o~ ~ l _ o ~ ~ ~ l +

~æ ~

_ 49 _ ~221~)97 ~ I ~ ~o ~ r .
_ , _ ~ ~ I ~.' ~o ~

V I ~ ~ V V ~

o c~ ~ e o o I oo CY I o o ~
~o ~ ~ ~
O I O O ~O _ C~I
Xl ~ ~ _ 3~ o~
æ >~ I_~*~1 ~ ~ I :r ~

~\0 0 ~ ~-0 = Co~-~
+ ~ + ~ 1 ô ~ w~ ~ ~ ~
o--o z o--~ z ~ o_~ æ J
~z~J ~ æ \c~/\æ
,~
~o ~ ~ ~ ~o 12~097 Example 70 Under a nitrogen atmosphere, 0.4459 g (1.8 mmoles) of (-)-erythro-2-amino-1-(2,4-dimethoxyphenyl)-1-propanol hydrochloride (optical purity, 98.6%) was suspended in 5 ml of 1,2-dichloroethane, the suspension was cooled to -25~C, and af-ter addlng a solution of 0.0681 g (1.8 mmoles) of sodium borohydride in 1 ml of dimethylformamide, the temperature was raised from -25C -to room temperature over 2.5 hours.
Thereafter, to -this suspension was added at 20C a solution of 0.35 g (1.2 mmoles) of (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-l-yl)-4,4-dimethyl-1-penten-3-one (E/Z=98.9/1.1) in 4 ml of 1,2-dichloroethane, and the mixture was stirred for 26 hours. Thereafter, decomposition was carried out at 45C
with stirring with addition of 8 ml of 10% hydrochloric acid.
The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.35 g of a crude crystal of (+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. Gas chromatographic analysis showed that the conversion was 97.8%
and that the product composed 95.7% of the E-form alcohol and 4.3% of the Z-form alcohol. High-performance liquid , chromatography on optically active column showed that the i enantiomer ratio of the E-form alcohol was: (~)-form, 85.0%;
and (-)-form, 15.0~.

Reference Examples 1 to 7 .
Reference Example 1 To a mixture of 8.43 g (0.04 mole) of (-~)-erythro--2-amino-1-(2,4-dimethoxyphenyl)-1-propanol (ery-thro/threo=
98.9/1.1) and 60 ml of water was added 5.21 g (0.04 mole) of D-(-)-pantolactone, and after stirring at 80 to 90 C for 1 hour, the reaction solution was concentrated under reduced pressure. The residue obtained was recrystallized from 50 ml of methanol ethanol (1:4) mixture to obtain 5.44 g of the diasteroemer salt of D-(-)-pantolc acid. [~]D: -16.0 (c=l.0, water). This product was recrystallized once more from 50 ml of ethanol to ob-tain 3.64 y of D~ pantoic acid acid salt of (-)-erythro-2-amino-1-(2,4-dimethoxyphenyl)-1-propanol. [~]D: -19.4 (c=l.0, water). The dias-tereomer salt obtained was decomposed with a solution of 1 g of pot-assium hydroxide in 10 ml of water and extracted with methy-lene chloride to obtain 2.07 g of (-)-etythro-2-amino-1-(2, 4-dimethoxyphenyl)-1-propanol (erythro/threo= 99.6/0.4). m.p. :
92-93C. The optical purity of this product was 98.6% by high-performance liquid chromatographic analysis. By dissol-ving -this arninoalcohol in a mixed solvent of diethyl ether and methylene chloride and passing a hydrogen chloride gas therethrough, 2.36 g of (-)-erythro-2-amino-1-(2,4-dime-thoxy-phenyl)-l-propanol hydrochloride was obtained. m.p. : 183-183.5C (decomp.). [~]D: ~34 0 (c=l.0, water). The optical purity of this product was 98.6% by high-performance liquid chromatographic analysis.
Reference Example 2 A mixture of 14.05 g of (+)-erythro-2-amino-1-(2-methoxyphenyl)-l-propanol (erythro/threo=98.0/2.0), 10.09 g of D-(-)-pantolactone and 100 ml of water was heated for 1 hour with stirring and concentrated under reduced pressure.
The residue obtained was recrystallized from 110 ml of iso-propanol to obtain 5.09 g of the D-(-)-pantoic acid salt of (+)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol. [~]D
` 30 +22.9 (c=0.9, water). This dias-tereomer salt was decomposecL
with a solution of 1.61 g of potassium hydroxide in 20 ml of water and extracted with chloroform to obtain 2.58 g of (+)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol. By dissolv-- ing this aminoalcohol in diethyl ether-chloroform mixture ancL
passing a hydrogen chloride gas therethrough, the hydrochloric ; acid salt of the aminoalcohol was formed. This salt was ;

3L~21~)97 collected by filtration and dried to obtain 2.82 g of (~
erythro-2-amino-1-(2-methoxyphenyl)-1-propanol hydrochloride.
[a~D: +26.5 (c=1.0, water). This product was conver-ted to its sugar derivative (diastereomer) and analyzed by high-performance liquid chromatography to find that i-ts optical purity was 62.6%. The filtra-te after recrystalliza-tion was concentrated under reduced pressure to obtain 20.28 g of the D-(-)-pantoic acid salt of (-)- erythro-2-amino-1-(2-methoxy-phenyl)-l-propanol. [a]D: +1.29 (C=1.0, water). This product was recrystallized from isopropanol, and after filtration, the filtrate obtained was concentrated under reduced pressure, decomposed with a solution of 3.76 g of potassium hydroxide in 47 ml of water and extracted with chloroform to obtain 6.79 g of (-)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol.
This aminoalcohol was converted -to its sugar derivative (dia-stereomer) and analyzed by high-performance liquid chroma-to-graphy to find that its optical purity was 44.6%. ~3y dissolv-ing this aminoalcohol in diethyl ether-chloroform mixture and passing a hydrogen chloride gas therethrough, (-)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol hydrochloride was ob-tained. After recrystallizing this hydrochloride three times from ethanol, 1.75 g of (-)-erythro-2-amino-1-(2-methoxyphenyl)-l-propanol hydrochloride was obtained from the filtrate. Ca]D:
-37.7 (c=1.0, water). The optical purity of this product was 98.0% by high-performance liquid chromatographic analysis.

Reference Example 3 On adding a hot solution of 20.5 g (0.0918 mole) of (+)-erythro-2-amino-1-(2,5-diethoxyphenyl)-1-propanol (erythro/threo=98.4/1.6) in 40 ml of methanol to a hot solu-tion of 13.78 g (0.0918 mole) of L-(+)-tartaric acid in 50 ml of methanol, a crystal was deposited. This crystal was re-dissolved in the solution by additionally adding 140 ml of methanol, and after allowing to cool, the deposited crystal was collected by filtra-tion. The yield of the crystal was ~2~0~

12.43 g- [~]D: +28.0 (c=1.0, water~. This crystal was fur-ther recrys-tallized from 150 ml of methanol to obtain 7.44 g of the I,-(+)-tartaric acid salt of (+)-erythro-2-amino-1-(2,5-diethoxyphenyl)-l-propanol. [~]D +31.8 (c=1.0, water).
This salt was decomposed with a 10% aqueous sodium hydroxide solution and extracted with methylene chloride to obtain 4.75 g of (+)-ery-thro-2-amino-1-(2,5-diethoxyphenyl)-1-propanol (erythro/threo=100/0). By dissolving this product in diethyl ether and passing a hydrogen chloride gas therethrough, 5.40 g of (+)-erythro-2-amino-1-(2,5-diethoxyphenyl)-1-propanol hydrochloride was obtained. m.p.: 136.5-138.5 C. [~]D: +29.i (c=l.0, water). The optical purity of this product was 99.0%
or more by high-performance liquid chromatographic analysis.

Reference Example 4 A hot solution of 11.19 g of (+)-erythro-2-amino-1-(2-ethoxyphenyl)-1-propanol (content of the erythro-form, 99~ or more) in 15 ml of methanol was added to a hot solu-tion of 8.60 g of L-(+)-tartaric acid in 20 ml of methanol, and the resulting solution was allowed to cool. The deposi-ted crystal was collected by filtration to obtain 10.44 g of the L-(-~)-tartaric acid salt of (-)-erythro-2-amino-1-(2-ethoxyphenyl)-1-propanol. [ ~]D: +6-3 (c=1.0, water). This sal-t was recrystallized from methanol to obtain 4.50 g of a crystal. [~JD -16.4 (c=l.0, CHC13). This aminoalcohol was converted to its sugar derivative (diastereomer) and analyzed by high-performance liquid chromatography to find that its optical purity was 63.2%. By dissolving this amino-alcohol in diethyl ether-chloroform mixture and passing a hydrogen chloride gas therethrough, 3.18 g of (-)-erythro-2-amino-1-(2-ethoxyphenyl)-1-propanol hydrochloride was obtained. Recrystallization of this product from isopropanol was repeated four times to obtain 1.02 g of a crystal. [~]D
-43.6 (c=l.0, water). The optical purity of the crystal was 97.8%.

~Z~ 9~

eference Example 5 On adding a solution of 4.56 g (0.0263 mole) of N-acetyl-L-leucine and 1.11 g (0.0263 mole) of 95% sodium hydroxide in 50ml of wa-ter to a solution of 12.17 g (0.0525 mole) of (+)-erythro-2-amino-(2-methoxy-5-me-thylphenyl)-1-propanol hydrochloride (ery-thro-form, 99% or more) in 115 mL
of water, a crystal was deposited. This crystal was re-dissolved in the solution by additionally adding 500 ml of water, and after allowing to cool, the deposited crystal was collected by filtra-tion. The yield of the N-acetyl-L-leucine sal-t of (-)-erythro-2-amino-1-(2-methoxy-5-methyl-phenyl)-l-propanol was 3.63 g. [a]D: -29.2 (c=1.0, water).
This salt was decomposed with a 10% aqueous sodium hydroxide ; 15 solution and extracted with chloroform to obtain 1.94 g of (-)-erythro-2-amino-1-(2-methoxy-5-methylphenyl)-1-pro-panol- [~]D: -22.1 (c=l.l, CHC13)i By dissolving this pro-duct in diethyl ether and passing a hydrogen chloride gas therethrough, 2.13 g of (-)-erythro-2-amino-1-(2-methoxy-5-methylphenyl)-l-propanol hydrochloride was obtained. This salt was recrystallized from isopropanol to ob-tain 1.65 g of the crystal. [~]D: -22.2 (c=1.0, water). The optical purity of this product as sugar derivative (diastereomer) was 97.8% by high-performance liquid chromatographic analysis.
;

Reference Example 6 31 Grams (0.114 mole) of 2-amino--1-(2,5-diethoxy-phenyl)-l-propanone hydrochloride was dissolved in 450 ml of water, and 2.15 g (0.0568 mole) of sodium borohydride was added at 3 to 7C. After maintaining the temperature for 2 hours with stirring, the reaction solution was acidified with conc. hydrochloric acid and washed with chloroform.
The aqueous layer was made alkaline with a 25% aqueous sodium hydroxide solution and extracted with chloroform to obtain 24.1 g of (+)-erythro-2-amino-1-(2,5-diethoxyphenyl)-1-7.

propano] (erythro/threo=93.6/6.4). This product was recrys--tallized from toluene -to obtain 21.0 g of a crystal (erythro/
threo=98.4/1.6).
m.p., 108-109C
NMR spectrum (CDC13):
(ppm): 0.99 (d 3H), 1.37 (t 6H), 1.4-2.2 (broad 2H), 3.24 (m H), 3.98 (q 4H), 4.72 (d H), 6.74 (2H), 6.96 (H) Reference Example 7 20 Grams (0.0938 mole) of 2-amino-1-(2-ethoxy-phenyl)-l-propanone hydrochloride was dissolved in 300 ml of water, and 1.77 g (0.0468 mole) of sodium borohydride was added at 5 to 8C. After maintaining -the temperature for 1 hour with stirring, the reaction solution was allowed -to stand overnight at room temperature. Thereafter, the reac-tion solution was acidified with conc. hydrochloric acid and then made alkaline with a 25% aqueous sodium hydroxide solu-tion. The deposited crystal was collected by filtration, washed with water and dried to obtain 13.40 g of erythro-2-amino-1-(2-ethoxyphenyl)-1-propanol as a crystal (erythro/
threo=98.4/1.6). This crystal was recrystallized from to-; luene to obtain 12.39 g of a crystal (content of the erythro--' 25 form, 99% or more).
m.p., 89-91C
NMR spectrum (CDC13):
~(ppm): 0.99 (d 3H), 1.40 (t 3H), 1.6-2.4 (broad 2H), 3.24 (m E-l), 3.99 (q 2H), 4.76 (d H), 6.7-7.04 (m 2H), 7.05-7.45 (m 2H) ' , .
.,

Claims (54)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An asymmetrically modified boron hydride type compound obtained by reacting an optically active amino alcohol represented by the formula (I), (I) wherein R1 represents an aryl, alkyl, cycloalkyl or aralkyl group, R2 represents an aryl, alkyl, aralkyl or alkoxycarbonyl group, R3 represents a hydrogen atom or an alkyl or aralkyl group, and a mark *
means an asymmetric carbon, or its salt obtained from an acid selected from the group consisting of mineral acids, carboxylic acids and organic sulfonic acids with a borane or a metal borohydride, respectively.

2. A compound according to Claim 1, wherein, in the above formula (I), R1 is a C6-C16 aryl selected for a phenyl group which may be substituted with a least one of halogen, alkyl, cyano, alkoxy and alkoxycarbonyl, and a naphthyl group which may be substituted with a least one of halogen, alkyl, cyano, alkoxyl and alkoxycarbonyl, a C1-C10 alkyl, C5-C10 cycloalkyl or C7-C16 aralkyl group, R2 is a C6-C16 aryl, C1-C10 alkyl or C7-C16 aralkyl group or an alkyloxycarbonyl group in which the number of carbon atoms constituting the alkyl group is 1 to 10, and R3 is a hydrogen atom.

3. A compound according to Claim 1, where, in the above formula (I), R1 is a phenyl group which may be substituted with at least one of halogen, alkyl, cyano, alkoxy or alkoxycarbonyl, or a naphthyl group which may be substituted with at least one of halogen, alkyl, cyano, alkoxyl or alkoxycarbonyl, R2 is a C1-C5 alkyl group, and R3 is a hydrogen atom.

4. A compound according to Claim 1, wherein, in the above formula (I), R1 is a naphthyl group, R2 is a methyl group and R3 is a hydrogen atom.

5. A compound according to Claim 1, wherein, in the above formula (I), R1 is a 2,5-dimethylphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

6. A compound according to Claim 1, wherein, in the above formula (I), R1 is a phenyl group, R2 is a methyl group and R3 is a hydrogen atom.

7. A compound according to Claim 1, wherein the borohydride compound is a metal borohydride.

8. A compound according to Claim 7, wherein the metal borohydride is sodium borohydride, potassium boro-hydride, lithium borohydride or zinc borohydride.

9. A compound according to Claim 7, wherein the molar ratio of the salt of the optically active amino alcohol to the metal borohydride is 1 : 0.7 to 1 : 1.3, as converted to boron basis.

10. A compound according to Claim 1, wherein the borohydride compound is a borane.

11. A compound according to Claim 10, wherein the molar ratio of the optically active amino alcohol to the borane is 1 : 0.7 to 1 : 1.3, as converted to boron basis.

12. A method for producing an asymmetrically modified borohydride type compound characterized in that an optically active amino alcohol represented by the formula (I), (I) wherein R1 represents an aryl, alkyl, cycloalkyl or aralkyl group, R2 represents an aryl, alkyl, aralkyl or alkoxycarbonyl group, R3 represents a hydrogen atom or a C1-C6 alkyl or aralkyl group, and a mark * means an asymmetric carbon, or its salt obtained from an acid selected from the group consisting of mineral acids, carboxylic acids and organic sulfonic acids is reacted with a borane or a metal borohydride, respectively.

13. A method according to Claim 12, wherein, in the above formula (I), R1 is a C6-C16 aryl, selected from a phenyl group which may be substituted with a least one of halogen, alkyl, cyano, alkoxy and alkoxycarbonyl, and a naphthyl group which may be substituted with at least one of halogen, alkyl, cyano, alkoxyl and alkoxycarbonyl, C1-C10 alkyl, C5-C10 cycloalkyl or C7-C16 aralkyl group, R2 is a C6-C16 aryl, C1-C10 alkyl or C7-C16 aralkyl group or an alkyloxycarbonyl group in which the number of carbon atoms constituting the alkyl group is 1 to 10, and R3 is a hydrogen atom.

14. A method according to Claim 12, wherein, in the above formula (I), R1 is a phenyl group which may be substituted with at least one of halogen, alkyl, cyano, alkoxy or alkoxycarbonyl, or a naphthyl group which may be substituted with a least one of halogen, alkyl, cyano, alkoxyl or alkoxycarbonyl, R2 is a C1-C5 alkyl group, and R3 is a hydrogen atom.

15. A method according to Claim 12, wherein, in the above formula (I), R1 is a naphthyl group, R2 is a methyl group and R3 is a hydrogen atom.

16. A method according to Claim 12, wherein, in the above formula (I), R1 is a 2,5-dimethylphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

17. A method according to Claim 12, wherein, in the above formula (I), R1 is a phenyl group, R2 is a methyl group and R3 is a hydrogen atom.

18. A method according to Claim 12 , wherein the borohydride compound is a metal borohydride.

19. A method according to Claim 18, wherein the metal borohydride is sodium borohydride, potassium borohydride, lithium borohydride or zinc borohydride.

20. A method according to Claim 18, wherein the molar ratio of the salt of the optically active amino alcohol to the metal borohydride is 1 : 0.7 to 1 : 1.3, as converted to boron basis.

21. A method according to Claim 12 , wherein the borohydride compound is a borane.

22. A method according to Claim 21, wherein the molar ratio of the optically active amino alcohol to the borane is 1 : 0.7 to 1 : 1.3, as converted to boron basis.

23. A method for producing an optically active alcohol derivative represented by the formula (III), (III) wherein R4 represents an alkyl, cycloalkyl or cycloalkenyl group, or a phenyl group which may be substituted with at least one of halogen, alkyl, haloalkyl, cyano, alkoxyl, phenoxy or phenyl, R5 represents a 1,2,4-triazol-l-yl group, R6 repre-sents a tert-butyl group, or a 1,1-dimethyl-2-phenylethyl group wherein benzene ring may be substituted with at least one of halogen atom, and a mark * has the same meaning as above, charac-terized in that the asymmetric reduction of a ketone compound represented by the formula (II), (II) wherein R4, R5 and R6 have the same meanings as above, is carried out in the presence or absence of an acid with an asymmetrically modified borohydride type compound obtained by reacting an opti-cally active amino alcohol represented by the formula (I), (I) wherein R1 represents an aryl, alkyl, cycloalkyl or aralkyl group, R2 represents an aryl, alkyl, aralkyl or alkoxy-carbonyl group, R3 represents a hydrogen atom of a C1-C6 alkyl or aralkyl group, and a mark * has the same meaning as above or its salt obtained from an acid selected from the group consisting of mineral acids, carboxylic acids and organic sulfonic acids with a borane or metal borohydride, respectively.

24. A method according to claim 23, wherein in the above formulae (II) and (III), R4 is a C1-C10 alkyl, C6-C10 cycloalkyl or C6-C10 cycloalkenyl group or a phenyl group which may be substituted with at least one of halogen, C1-C10 alkyl, C1-C10 haloalkyl, cyano, C1-C10 alkoxyl, phenoxy or phenyl.

25. A method according to Claim 23, wherein, in the above formulae (II) and (III), R4 is a 2,4-dichlorophenyl group, R5 is a 1,2,4-triazol-l-yl group and R6 is a tert-butyl group.

26. A method according to Claim 23, wherein, in the above formulae (II) and (III), R4 is a 4-chlorophenyl group, R5 is a 1,2,4-triazol-l-yl group and R6 is a tert-butyl group.

27. A method according to Claim 23, wherein, in the above formulae (II) and (III), R4 is a cyclohexyl group, R5 is a 1,2,4-triazol-l-yl group and R6 is a tert-butyl group.

28. A method according to Claim 23, wherein, in the above formula (I), R1 is a C6-C16 aryl, C1-C10 alkyl, C5-C10 cycloalkyl or C7-C16 aralkyl group, R2 is a C6-C16 aryl, C1-C10 alkyl or C7-C16 aralkyl group or an alkyloxy-carbonyl group in which the number of carbon atoms constitut-ing the alkyl group is 1 to 10, and R3 is a hydrogen atom.

29. A method according to Claim 23, wherein, in the above formula (I), R1 is a phenyl group which may be substituted with at least one of halogen, alkyl, cyano, alkoxy or alkoxycarbonyl, or a naphthyl group which may be substituted with at least one of halogen, alkyl, cyano, alkoxyl or alkoxycarbonyl, R2 is a lower alkyl group, and R3 is a hydrogen atom.

30. A method according to Claim 23, wherein, in the above formula (I), R1 is a naphthyl group, R2 is a methyl group and R3 is a hydrogen atom.

31. A method according to Claim 23, wherein, in the above formula (I), R1 is a 2,5-dimethylphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

32. A method according to Claim 23, wherein, in the above formula (I), R1 is a phenyl group, R2 is a methyl group and R3 is a hydrogen atom.

33. A method according to Claim 23 , wherein the borohydride compound is a metal borohydride.

34. A method according to Claim 33, wherein the metal borohydride is sodium borohydride, potassium borohydride, lithium borohydride or zinc borohydride.

35. A method according to Claim 33, wherein the molar ratio of the salt of the optically active amino alcohol to the metal borohydride is 1 : 0.7 to 1 : 1.3, as converted to boron basis.

36. A method according to Claim 23 , wherein the borohydride compound is a borane.

37. A method according to Claim 36, wherein the molar ratio of the optically active amino alcohol to the borane is 1 : 0.7 to 1 : 1.3, as converted to boron basis.

38. A method according to Claim 33, wherein the asymmetric reduction is carried out in the presence of an acid.

39. A method according to Claim 38, wherein the acid is Lewis acids, organic acids or mineral acids.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE

40. A compound according to claim 1, wherein, in the above formula (I), R1 is a 2,4-dimethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

41. A compound according to claim 1, wherein, in the above formula (I), R1 is a 2,5-diethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

42. A compound according to claim 1, wherein, in -the above formula (I), R1 is a 2,5-dimethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

43. A compound according to claim 1, wherein, in the above formula (I), R1 is a 2-methoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

44. A method according to claim 12, wherein, in the above formula (I), R1 is a 2,4-dimethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

45. A method according to claim 12, wherein, in the above formula (I), R1 is a 2,5-diethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

46. A method according to claim 12, wherein, in the above formula (I), R1 is a 2,5-dimethoxyphenyl group, R2 is a ethyl group and R3 is a hydrogen atom.

47. A method according to claim 12, wherein, in the above formula (I), R1 is a 2-methoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

48. A method according to claim 23, wherein, in the above formula (I), R1 is a 2,4-dimethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

49. A method according to claim 23, wherein, in the above formula (I), R1 is a 2,5-diethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

50. A method according to claim 23, wherein, in the above formula (I), R1 is a 2,5-dimethoxyphenyl group, R2 is an ethyl group and R3 is a hydrogen atom.

51. A method according to claim 23, wherein, in the above formula (I), R1 is a 2-methoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

52. A compound according to claim 1, wherein, in the above formula (I), R1 is a 2-ethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

53. A method according to claim 12, wherein, in the above formula (I), R1 is a 2-ethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.

54. A method according to claim 23, wherein, in the above formula (I), R1 is a 2-ethoxyphenyl group, R2 is a methyl group and R3 is a hydrogen atom.