HU206505B - Process for producing optically active amine-borane compounds of optically qctive hydroxy-benzyi-amine derivatives - Google Patents

Abstract

The present invention relates to novel asymmetric reducing agents comprising optically active hydroxybenzylamine derivatives of formula (I) as ligands, for example, optically active amine borane compounds. In formula (I), R1 is hydrogen, C1-C4 alkyl or C1-C4 alkoxy, R2 is C1-C5 alkyl, * is asymmetric carbon, and the hydroxy group on the phenyl group is ortho or meta- is in a position. EN 206 505 B Scope of the description: 10 pages (including 2 sheets)

Description

The present invention relates to novel optically active amine borane compounds having novel optically active hydroxybenzylamine derivatives of formula (I) as ligands. In the formula (I), R ¹ is hydrogen, C 1-4 alkyl or C 1-4 alkoxy,

R ² is C 1 -C 5 alkyl, * is asymmetric carbon, and the hydroxy group is ortho or meta on the phenyl as compared to the asymmetric carbon.

The compound of formula (I) may be used as a ligand to prepare an optically active amine borane compound.

Other optically active compounds can be prepared using the optically active amine borane compound.

Optically active benzylamine derivatives are known, including α-phenethylamine and α-para-hydroxyphenylamine, wherein the hydroxyl group is in the para position on the phenyl ring. It is also known that the first compound can be used as an asymmetric ligand for asymmetric reductions and the second compound can be used as a resolving agent [J. Chem. Soc. Perkin Trans., I, 371 (1988); J. Chem. Soc., 99, 416 (1911)].

To date, the optically active hydroxybenzylamine derivative of formula I wherein the hydroxyl group is ortho or meta in the phenyl ring is not known.

When using the above-mentioned optically active α-phenethylamine (as ligands for the asymmetric reducing agent), the optical yield of the optically active compounds resulting from the reduction is very low or the product of the reduction cannot be easily separated from the ligand.

Various optically active benzylamine derivatives have been synthesized and it has surprisingly been found that an optically active benzylamine derivative wherein the hydroxyl group is at a particular position, namely ortho or meta, is used as the asymmetric ligand of the reducing agent as an asymmetric reducing agent. very high optical yield and very easy to separate from the reaction product. Based on this discovery, the present invention has been prepared after further thorough investigation.

The present invention therefore relates to a process for the preparation of novel amine borane compounds having a novel optically active hydroxybenzylamine derivative of formula (I) as a ligand. In the general formula (I)

R ¹ is hydrogen, C 1-4 alkyl or C 1-4 alkoxy,

R ² is C 1 -C 5 alkyl, * is asymmetric carbon, and the hydroxyl group is ortho or meta on the phenyl as compared to the asymmetric carbon.

Preferred compounds of formula I used as starting materials are those in which the hydroxyl group is ortho to the asymmetric carbon substituent.

The substituent designated by R 'may be, for example, hydrogen, C 1-4 alkyl such as methyl, η-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, and may also represent 1- C4 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, η-butoxy, isobutoxy, sec-butoxy.

Preferred compounds of formula (I) are: optically active 1- (2-hydroxy-3-methylphenyl) ethylamine, 1- (2-hydroxy-3-methylphenyl) ethylamine, 1- (2) -hydroxy-3-methoxyphenyl) ethylamine, 1- (2-hydroxy-3-ethoxyphenyl) ethylamine, 1- (2-hydroxy-5-methoxyphenyl) ethylamine, 1- (2-hydroxyphenyl) ethylamine, 1- (2-hydroxy-5-ethoxyphenyl) ethylamine, 1- (2-hydroxyphenyl) propylamine, 1- (3-hydroxyphenyl) ethylamine, 1- (2-hydroxy-3-ethylphenyl) propylamine, 1- (2-hydroxy-3-methylphenyl) propylamine, 1- (2-hydroxy-3- methylphenyl) propylamine, 1- (2-hydroxy-3-ethylphenyl) propylamine, 1- (2-hydroxy-3-methoxyphenyl) propylamine, 1- (2-hydroxy) 3-ethoxyphenyl) propylamine, 1- (2-hydroxy-5-methylphenyl) ethylamine, 1- (2-hydroxy-5-ethylphenyl) ethylamine, 1- (2-hydroxy5-) methoxyphenyl) propylamine, 1- (2-hydroxy-5-ethoxyphenyl) propylamine, 1- (2-hydroxy-4-methylphenyl) ethylamine, 1- (2- hydroxy-4-methoxyphenyl) ethylamine, 1- (2-hydroxy-4-methylphenyl) propylamine, 1- (2-hydroxy-4-methoxyphenyl) propylamine, 1- (3) hydroxy-phenyl l) -propylamine, 1- (2-hydroxy-6-methylphenyl) ethylamine, 1- (2-hydroxy-6-methoxyphenyl) ethylamine, 1- (2-hydroxy-6-) methylphenyl) propylamine, and 1- (2-hydroxy-6-methoxyphenyl) propylamine.

These optically active benzylamines of formula I can be prepared, for example, according to Scheme 1.

For example, a ketone of formula VI and a benzyl halide can be converted to the benzyl compound of formula VII by Williamson synthesis. The compound of formula (VII) is then reacted with hydroxylamine or alkoxylamine in a solvent such as pyridine to give the oxime of formula (VIII). From this compound, an optically active amine of formula (IX) can be obtained by asymmetric reduction. Said asymmetric reduction can be carried out, for example, according to J. Chem. Soc. Perkin Trans. I, 2039 (1985). The compound of formula I can also be used as an asymmetric ligand.

The optically active amines of formula (IX) may also be prepared by catalytically hydrogenating an oxime of formula (VIII). This may be accomplished by the use of a hydrogenation catalyst such as palladium, platinum or Raney nickel or by reduction of said oxime compound with a metal hydride such as lithium aluminum hydride, sodium borohydride, borane tetrahydrofuran complex or borane dimethyl. Thus, the amine of formula (IX) is prepared as a racemic mixture and then subjected to optical separation.

The optically active benzene derivatives of formula (I) may then be prepared by hydrogenolysis of the optically active amine of formula (IX).

This hydrogenolysis can be carried out in a known manner. For example, a catalyst such as palladium, platinum or Raney nickel can be used.

HU 206 505 Β

The optically active amines of formula (IX) may also be used in the form of salts with mineral acids such as hydrochloric or sulfuric acid or organic acids such as acetic acid or propionic acid.

There is no particular restriction on the solvent to be used in the reaction, it is important that the solvent does not poison the catalyst. Generally, alcohol, such as methanol, ethanol or isopropanol, or a mixture thereof with water, is used. If a catalyst other than Raney nickel is used, the reaction may also be carried out in the presence of inorganic acids such as hydrochloric or sulfuric acid or organic acids such as acetic acid or propionic acid. The reaction can be carried out at a temperature of -50 to +60 ° C and a pressure of less than ¹⁷ bar. In general, it can be performed properly at room temperature and normal pressure.

The following is a detailed description of the process according to the invention for the preparation of an aminoborane compound containing an optically active benzylamine derivative of the formula (I) as a ligand.

The process for the preparation of the amine borane compounds according to the invention is carried out, for example, by reacting a compound of formula I with a borohydride compound such as diborane, borane tetrahydrofuran complex or borane dimethylsulfide complex. The molar ratio of the borohydride compound to the compound of the formula I is 1-5, preferably 2-3, in the wine.

There is no particular limitation on the solvent if the solvent is not involved in the reaction. Solvents include ethers or thioethers such as diethyl ether, tetrahydrofuran, diglime, and dimethyl sulfide. Also mentioned are aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, as well as halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chromoform and carbon tetrachloride. Mixtures of these solvents may also be used.

The reaction is usually carried out at a temperature of from -78 ° C to + 100 ° C, preferably from -40 ° C to + 50 ° C. Generally, an inert gas dipstick, such as nitrogen or argon, is used.

Thus, the amine borane compound containing the compound of formula (I) as a ligand is prepared by the process of the present invention. This compound is very suitable as an asymmetric reducing agent. For example, by reacting asymmetric ketoximes or asymmetric ketones with such compounds, optically active amines can be prepared from ketoximes and optically active alcohols from ketones can be obtained in high optical yield. A further advantage is that the reduction product can be separated from the ligand by simple operation, pH adjustment and liquid layer separation.

The optically active benzylamine derivatives of formula (I) are useful as an asymmetric ligand for an asymmetric reducing agent. The optically active amine-borane complexes of the present invention provide optically active reduction products in extremely high optical yields, and in addition, the reaction products and the asymmetric ligand are easily separated and recovered.

The following examples illustrate the invention in more detail.

Reference Example 1

Preparation of benzyl compound

Sodium ethylate solution (200 ml) in ethanol and metal sodium (7.9 g, 0.3435 g) was prepared. To this was added 2-hydroxyacetophenone (0.132 mol, 42.52 g) and benzyl chloride (47.47 g, 0.375 mol). The resulting reaction mixture was stirred at reflux for 4 hours. The reaction mixture was then cooled to room temperature and the formed sodium chloride was filtered off. The filtrate was concentrated in vacuo and extracted with toluene. The toluene extract was washed with water, dried and evaporated in vacuo to give 66.06 g of 2-benzyloxyacetophenone.

Using 2-hydroxypropiophenone, 2-hydroxy-3-methylacetophenone, 2-hydroxy-3-methoxyacetophenone, 2-hydroxy-5-methoxyacetophenone, or 3-hydroxyacetophenone instead of 2-hydroxyacetophenone, suitable benzyl compounds can be prepared.

Table 7 Compounds of Formula VIIa

Song Benzilvegyület Fp. (° C / mm Hg) R ¹ R ² Evade- pro- duction First H ch ₃ 94 140-142 / 0.4 Second H C2H5 90 140-144 / 0.27 Third 3-CH ₃ ch ₃ 80 127-132 / 0.4 4th 3-OCH ₃ ch ₃ 56 160-161 / 0.8 5th 5-OCH3 ch ₃ 75 162-163 / 0.4 6th 3-benzyloxy-acetophenone 91 155 / 0.4

Reference Example 2

Preparation of the oxime compound To 2 ml of pyridine was added 0.0434 mol (9.77 g) of 2-benzyloxyacetophenone prepared in Reference Example 1 (see Compound 1 of Table 1) and 4.35 g (0.0521 mol) of O. methyl-hydroxylamine hydrochloride. The reaction mixture was stirred at room temperature for 2 hours and then at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, water (300 mL) was added and the oily phase was separated. The aqueous phase was extracted with chloroform and the extract was combined with the previously separated oily phase, washed with water, dried and then distilled under vacuum. 10.77 g of 2-benzyloxyacetophenone-O-methyloxime are obtained.

Table 1, Table 2-6. The compound of formula I can be prepared as the benzyl compound to give the corresponding oximes. The results are shown in Table 2.

HU 206 505 Β

Table 2 Compounds of formula (VIIIa)

Song oxime R R ² An- li / color Fp. (° C / mm Hg) Yield (%) First H ch ₃ 88/12 135-141 / 0.27 97 Second H c ₂ h ₅ 80/20 133-140 / 0.27 94 Third 3-CH ch ₃ 87/13 127-132 / 0.4 97 4th 3-OCH ₃ ch ₃ 88/12 150-154 / .53 97 5th 5-OCH ₃ ch ₃ 86/14 155-158 / 0.4 97 6th 3-benzyloxy-aceto- phenone-O-methyl- oxime 96/4 147 / 0.27 95

Reference Example 3

Preparation of optically active α- (benzyloxyphenyl) alkylamine (3-1) (+) - 1- (2-benzyloxyphenyl) ethylamine

A mixture of tetrahydrofuran (THF) (200 mL) and (S) - (-) - 2-amino-3-methyl-1,1-diphenylbutanol (13.79 g, 0.054 mol) was cooled to -78 ° C. At this time, 4.31 g of borane dimethyl sulfide complex was added with stirring and the reaction mixture was allowed to warm to room temperature over about 2 hours. An additional 4.31 g of borane dimethyl sulfide complex was added and the mixture was stirred for 15 minutes.

Then, 9.19 g (0.036 mol) of the 2-benzyloxyacetophenone O-methyl oxime prepared in Reference Example 2 (see

Compound No. 1 of Table 2) and tetrahydrofuran (10 ml) were added to the reaction mixture and stirred at room temperature for 20 hours and then at 60 ° C for 1 hour.

The reaction mixture was then treated with 10% hydrochloric acid (70 ml) and stirred at 51 ° C for 1.5 hours. The reaction mixture was concentrated in vacuo, then made basic by addition of 10% w / w aqueous sodium hydroxide and extracted twice with chloroform. The organic layer was washed with water, dried, concentrated and subjected to silica gel column chromatography using ethyl acetate as eluent.

thus separating the ligand. In this way, 6.08 g of (+) - 1- (2-benzyloxyphenyl) ethylamine were obtained. 1 H NMR (CDCl ₃ ): δ = 1.41 (3H, d), 2.16 (2H, s), 4.43 (1H, q), 5.08 (2H, s), δ 89-7.00 (2H,

m), 7.12-7.23 (1H, m), 7.28-7.44 (7H, m) ppm.

The resulting amine hydrochloride has an optical rotation of [α] D + 13.45 ° (c 1.05, water).

The hydrochloride was recrystallized from isopropanol to give 4.64 g of crystals, [α] D +16.44 ° (c = 1.09, water). Part of the crystal is reacted with 3,5-dinitrophenyl isocyanate to convert it to its urea derivative. This urea derivative is then analyzed by high performance liquid chromatography using an optically active column. The optical purity was found to be 87.2%.

Preparation of (3-2) (+) - 1- (2-benzyloxyphenyl) propylamine in 140 ml of tetrahydrofuran and 9.3 g (0.0364 mol) of (S) - (-) - 2- The mixture of amino-3-methyl-1,1-diphenylbutanol was cooled to -78 ° C and 2.90 g of borane-dimethylsulfide complex was added with stirring. The temperature of the mixture was raised to room temperature over 3 hours. An additional 2.90 g of borane-dimethylsulfide complex is added and the mixture is stirred for 15 minutes. A mixture of 7.0 g (0.026 mol) of the 2-benzyloxypropiophenone-O-methyloxime prepared in Reference Example 2 (see Table 2, Compound 2) and 10 ml of tetrahydrofuran was then added and the resulting mixture was stirred at room temperature for 20 minutes. and then at 50 ° C for 1 hour. The reaction mixture was then worked up in the same manner as in Reference Example 3-1, i.e., 10% hydrochloric acid was added, concentrated in vacuo, neutralized with alkali, extracted with chloroform and purified by column chromatography. 4.5 g of (+) - 1- (2-benzyloxyphenyl) -propylamine were obtained in an oil of 49.6% optical purity.

1 H NMR (CDCl ₃ ): δ = 0.89 (3H, t), 1.58 (2H, s), 1.67-1.98 (2H, q), 4.12 (H, t) , 5.08 (2H, s),

6.8-7.35 (4H, m), 7.39 (5H, s) ppm.

Dissolve 5.17 g of the above amine hydrochloride in 170 ml of water and add 3.23 g of N-acetyl-L-leucine

18.6 ml of a solution of IN in NaOH. The precipitated crystals were filtered to give 3.40 g of the (+) - 1- (2-benzyloxyphenyl) propylamine N-acetyl-L-leucine salt.

[α] D +12.1 ° (c 0.5, water).

Aqueous sodium hydroxide solution is then added to the salt prepared above to liberate the amine, which is then extracted with chloroform. 1.95 g of (+) - 1- (2-benzyloxyphenyl) propylamine are obtained in the form of an oil with an optical purity of 97.0%.

[α] D + 14.86 ° (c 1.0, water) (hydrochloride).

Preparation of (3-3) (-) - 1- (2-benzyloxy-3-methyl-phenyl) -ethylamine

A mixture of 15.83 g (0.062 mol) of (S) -2-amino-3-methyl-1,1-diphenylbutanol and 260 ml of 1,2-dichloroethane was cooled to -30 ° C. 4.95 g of borane dimethylsulfide complex are added and the temperature of the reaction mixture is raised to + 10 ° C over 2 hours. An additional 4.95 g of borane-dimethylsulfide complex is added and the temperature is raised to room temperature over 1 hour.

Subsequently, 11.93 g (0.0443 mol) of the 2-benzyloxy-3-methylacetophenone-O-methyloxime prepared in Reference Example 2 (see compound 3 of Table 2) and 15 ml

A mixture of 1,2-dichloroethane was added, the resulting mixture was stirred at room temperature for 21 hours, then at 50 ° C for 1 hour, and finally 120 ml of 10% hydrochloric acid was added.

The (S) - (-) - 2-amino-3-methyl-1,1-diphenylbutanol hydrochloride thus precipitated is filtered off. The filtrate was basified with aqueous sodium hydroxide solution, and the organic layer was separated and concentrated in vacuo.

The concentrate was then purified by silica gel column chromatography using ethyl acetate as the eluent. This separates the ligand and other minor contaminants. Such is the case

GB 206,505 Β Don 5.2 g of (-) - l- (2-benzyloxy-3-methylphenyl) ethylamine, [j ^ ⁰ -4.8 (c 1.4, methanol) , the product has an optical purity of 79.8%.

1 H NMR (CDCl ₃ ): δ = 1.36 (3H, d), 1.62 (2H, s), 2.35 (3H, s), 4.47 (H, q), 4, 85 (2H, s),

7.0-7.6 (8H, m) ppm.

(3-4) Preparation of (-) - 1- (2-benzyl-0'-oxy-3-methoxyphenyl) ethylamine

Reactions and purifications were performed as described in Reference Examples (3-3) except that 8.56 g (0.03 mol) of 2-benzyloxy-3-methoxyacetophenone-O-methyloxime was used. as an ether (this compound was prepared in Reference Example 2 and Compound 4 of Table 2). 5.0 g of (-) - 1- (2-benzyloxy-3-methoxyphenyl) ethylamine were obtained with an optical purity of 73.6%. [α] 25 D - 28.1 ° (c 1.0, water) (hydrochloride).

The hydrochloride of the above amine is dissolved in 20 water and added to a solution of 3.36 g of N-acetyl-L-leucine in 19.1 ml of IN aqueous sodium hydroxide.

The precipitated crystals are filtered off, the amine is liberated with aqueous sodium hydroxide solution and extracted with methylene chloride. 3.17 g of (-) - 1- (2-benzyloxy-3-methoxyphenyl) ethylamine are obtained with an optical purity of 95.0%.

[α] 25 D -35.66 ° (c 0.99, water) (hydrochloride).

1 H NMR (CDCl ₃ ): δ = 1.29 (3H, d), 2.63 (2H, s), 3.88 (3H, s), 4.83 (1H, q), δ 04 (2H, s),

6.8-7.17 (3H, m); 7.2-7.55 (5H, m) ppm.

(3-5) Preparation of (+) - 1- (2-benzyloxy-5-methoxyphenyl) ethylamine

Using the procedure described in Reference Example 3-3, using 7.42 g (0.026 mol) of 2-benzyloxy-5-methoxyacetophenone-O-methyloxime as the oxime ether compound in Reference Example 2. Compound No. 5 of Table 2) (3.76 g) of (+) - 1- (2-benzyloxy-5-methoxyphenyl) ethylamine can be prepared. Optical rotation of the hydrochloride of the compound (?) +2.45 (c 0.94, water).

Recrystallization from isopropanol gave 2.68 g of purified product having an optical purity of 95.2%.

[.alpha.] D @ 20 + 3.41 DEG (c 1.0, water) (hydrochloride).

1 H-NMR Spectrum: (CDCl ₃ ): δ = 1.39 (3H, d), 1.69 (2H, s), 3.77 (3H, s), 4.42 (2H, q), δ , 04 (2H, s),

6.6-7.0 (3H, m); 7.2-7.5 (5H, m) ppm.

Preparation of (3-6) (-) - 1- (3-benzyloxyphenyl) ethylamine

The reaction and purification were carried out as described in Reference Example 3-3 except that 6.64 g of 3-benzyloxyacetophenone-O-methyloxime prepared in Reference Example (2-6) were used as the oximeter compound. (-) - (3-Benzyloxyphenyl) ethylamine having an optical purity of 87.4% was obtained.

[α] 25 D -2.56 ° (c 1.05, water) (hydrochloride).

Preparation of (3-7) (-) and (+) - 1- (2-benzyloxyphenyl) ethylamine

To a solution of 2-benzyloxyacetophenone O-oxime (56.26 g, 0.22 mol) in Reference Example 2 (see Compound 1 of Table 2) in tetrahydrofuran (250 ml) was added 26.74 g (0.352 mol). ) borane dimethyl sulfide complex at room temperature. The resulting mixture was stirred for 5 hours and then allowed to stand overnight. At this time, 10% hydrochloric acid was added to the reaction mixture to decompose the reducing agent. The mixture was basified with aqueous sodium hydroxide solution, extracted with methylene chloride, washed with water, dried, concentrated and then distilled to give (±) -1- (2-benzyloxyphenyl) ethylamine (48.6 g). m.p. 152-153 ° C / 24.0 mbar.

This amine is converted to its hydrochloride with hydrochloric acid. To a solution of 1.319 g (5 mmol) of this hydrochloride in 14 mL of water was added 0.761 g (5 mmol) of (-) - mandelic acid, 1 mL of water and 5 mL of IN aqueous sodium hydroxide at room temperature. Crystals precipitated: 5 ml of water were added and recrystallized to give 0.93 g of crude (-) - 1- (2-benzyloxyphenyl) ethylamine - (+) - mandelic acid salt.

[α] D + 36.3 ° (c 0.97, water).

This was recrystallized from water to give 0.53 g of purified salt.

[a] ^{2 4} D -32.04 (c = 0.82, water).

The salt was quenched with aqueous sodium hydroxide solution and extracted with chloroform to give (-) - 1- (2-benzyloxyphenyl) ethylamine (0.31 g).

[α] D -19.1 ° (c 1.0, water) (hydrochloride).

Optical purity by high performance liquid chromatography has been found to have an optical purity of at least 99%.

After separation of said crude (-) - 1- (2-benzyloxyphenyl) ethylamine (+) - mandelic acid, additional crystals precipitated from the mother liquor. They were filtered and dried, yielding 0.31 g of (+) - (2-benzyloxyphenyl) ethylamine (+) - mandelic acid.

[α] D + 59.35 ° (c, 0.83, water).

This salt was quenched with aqueous sodium hydroxide solution and extracted with chloroform to give 0.18 g of (+) - 1- (2-benzyloxyphenyl) ethylamine.

[α] D + 19.27 ° (c 1.1, water) (hydrochloride).

Optical purity: 98.2%.

154-156 ° C (hydrochloride).

The following 1-6. Example 1 illustrates the preparation of compounds of formula (I).

Example 1 To a solution of methanol (2.64 g) was added (+) - 1- (2-benzyloxyphenyl) ethylamine (2.64 g) and 0.26 g of 5% palladium on charcoal. the mixture is hydrogenated at room temperature under normal pressure while 256 ml of hydrogen are absorbed. After filtration of the catalyst, the filtrate was concentrated in vacuo to give 1.78 g of (+) - 1- (2-hydroxyphenyl) ethylamine hydrochloride.

[.alpha.] D @ 20 + 21.36 DEG (c 1.06, water).

135-136 ° C.

The resulting salt was then neutralized with aqueous ammonia and extracted with methylene chloride to give 1.30 g of (+) - 1- (2-hydroxyphenyl) ethylamine.

[?] D + 12.24 ° (c 1.1, _CHCl3).

M.p. 83-83.5 ° C.

HU 206 505 Β

Nuclear Magnetic Resonance Spectrum (δ ppm, CDCl ₃ -DMF-d ₇ ) (hydrochloride): 1.70 (3H, d), 4.70 (1H, q), 6.6-7.5 (4H, m),

7.4-8.7 (4H, broad).

Example 2

The procedure described in Example 1 was followed except that 1.37 g of (+) - 1- (2-benzyloxyphenyl) propylamine hydrochloride was used as described in Reference Example 3-2. was prepared in place of (+) - 1- (2-benzyloxyphenyl) ethylamine used in Example 1. 0.95 g of (+) - 1- (2-hydroxyphenyl) propylamine hydrochloride is obtained.

[α] D + 28.6 ° (c 1.2, water).

Melting point: 194-196 ° C.

The salt thus obtained was neutralized and worked up as described in Example 1. 0.72 g of the free amine is obtained, which is an oily substance.

[a] ² D ² + 17.21 ° (c 1.32, CHC1 _3).

Nuclear Magnetic Resonance Spectrum (δ ppm, CDCl 3): 0.89 (3H, t), 3.96 (1H, t), 1.75 (2H, m), 6.6-7.25 (4H, m), 3 , 5-5.5 (3H, broad).

Example 3

Reaction and neutralization were carried out as in Example 1 except that (+) - 1- (2-benzyloxyphenyl) ethylamine was used in Example 1 instead of the compound prepared in Reference Example 3-3. (-) - 1- (2-Benzyloxy-3-methyl-phenyl) -ethylamine hydrochloride. In this way, 1.38 g of (+) - 1- (2-hydroxy-3-methylphenyl) ethylamine are obtained, which is crystalline. Recrystallization from cyclohexane gave 1.08 g of purified product having an optical purity of 98.8%.

[.alpha.] D @ 20 + 17.8 DEG (c 1.1, CHCl3).

Melting point: 115-116 ° C.

Nuclear Magnetic Resonance Spectrum (δ ppm, CDCl ₃ -DMF-d ₇ ) (hydrochloride): 1.68 (3H, d), 4.80 (1H, q). 2.29 (3H, s), 6.68-7.40 (3H, in). 7.8-9.0 (4H, broad).

Example 4

Reaction and neutralization were performed as described in Example 1, except that 3.21 g (3-) was used instead of (+) - 1- (2-benzyloxyphenyl) ethylamine used in Example 1. (-) - 1- (2-Benzyloxy-3-methoxyphenyl) ethylamine hydrochloride prepared according to Reference Example 4. In this way, 1.81 g of (+) - 1- (2-hydroxy-3-methoxyphenyl) ethylamine is obtained, which is crystalline.

[α] D +13.14 ° (c 1.04, ethyl acetate).

Melting point: 95-97 ° C.

Nuclear Magnetic Resonance Spectrum (δ ppm, CDCl3): 1.46 (3H, d), 3.86 (3H, s), 4.35 (1H, q), 4.4-5.0 (3H, broad).

Example 5

Reaction and neutralization were performed as described in Example 1 except that 2.57 g (3-) was replaced with (+) - 1- (2-benzyloxyphenyl) ethylamine as in Example 1. (+) - 1- (2-Benzyloxy-5-methoxyphenyl) ethylamine hydrochloride prepared in Reference Example 5. In this way, 1.42 g of (+) - 1- (2-hydroxy-5-methoxyphenyl) ethylamine was obtained as an oily substance.

[.alpha.] D @ 20 + 21.70 DEG (c 0.96, chloroform).

Example 6

The reaction was carried out in the same manner as in Example 1, except that instead of (+) - 1- (2-benzyloxyphenyl) ethylamine hydrochloride used in Example 1, 3.21 g (3- (-) - 1- (3-Benzyloxyphenyl) ethylamine hydrochloride prepared according to Reference Example 6. The catalyst was removed by filtration, and the reaction mixture was concentrated in vacuo, neutralized with ammonia and extracted with ethyl acetate to give 1.60 g of (-) - 1- (3-hydroxyphenyl) ethylamine.

[.alpha.] D @ 20 -24.52 DEG (c 0.98, ethyl acetate).

Nuclear Magnetic Resonance Spectrum (δ ppm, CDCl ₃ ): 1.40 (3H, d), 3.0-3.4 (3H, s), 4.09 (1H, q), 6.6-6.9 (3H). , m), 7.08-7.2 (1H).

7-10. Examples 1 to 5 illustrate the preparation of the amine borane compounds

Example 7

To a solution of (+) - 1- (2-hydroxyphenyl) ethylamine (0.1372 g, 1 mmol) in deuterochloroform (4 mL) was added borane dimethyl (0.10 mL, 1 mmol) at 0 ° C under nitrogen. sulfide complex and the mixture was stirred at this temperature for 1 hour and then at room temperature for a further half hour. An additional 0.10 mL (1 mmol) of borane dimethyl sulfide complex was added and the mixture was stirred for 0.75 hours at room temperature. Thus, an optically active amine borane compound is prepared. The compound has a BNMR spectrum (δ ppm, reference: BF ₃ x OEt ₂ ) = -37.1.1 -20.2, +1.3, +2.5, +21.0, +26.1.

8-10. example

Optically active aminoborane compounds were prepared as described in Example 7. Instead of (+) - 1- (2-hydroxyphenyl) ethylamine used in Example 7, (+) - 1- (2-hydroxy-3-methoxyphenyl) ethylamine, (+) - 1- ( 2-hydroxy-3-methylphenyl) ethylamine and (+) - 1- (2-hydroxy-5-methoxyphenyl) ethylamine are used. The obtained compounds ^H BNMR spectra are shown in Table 3 below.

Table 3

example Number ^h B-NMR spectrum (δ ppm, reference: BF ₃ x OEt ₂ ) 8th -39.0, -20.3, + 1.0, + 21.0, + 27.2 9th -20.4, -5.0, +0.5, +1.5, +20.8, +26.9 10th -20.4, + 1.3, + 2.3, + 20.8, + 26.7

PATENT CLAIMS

Claims (9)

PATENT CLAIMS A process for the preparation of an amine borate compound of an optically active compound of formula (I), characterized in that an optically active amine of formula (I) wherein HU 206 505 Β R ¹ is hydrogen, C 1-4 alkyl or C 1-4 alkoxy, R ² is C 1 -C 5 alkyl, * is an asymmetric carbon atom, and the hydroxyl group is ortho or meta in the phenyl group at the asymmetric C 5 atom, with a borohydride. The process of claim 1, wherein the optically active amine of formula (I) is reacted wherein the hydroxy group is ortho to the asymmetric carbon atom of the phenyl group. A process according to claim 2, wherein the compound of formula I is reacted wherein R ¹ is C 1-4 alkoxy. A process according to claim 3, wherein the C 1 -C 4 alkoxy group is in a meta-position on the phenyl group with respect to the asymmetric carbon. 5. A process according to claim 2 wherein the compound of formula I is wherein R ¹ is hydrogen or C 1-4 alkyl. 6. A process according to claim 1, wherein the optically active amine derivative of formula (I) is reacted with a hydroxyl group in a meta-position on the phenyl group relative to the asymmetric carbon atom. 7. The process of claim 1 wherein the borohydride is diborane, borane tetrahydrofuran complex or borane dimethyl sulfide complex. 8. A process according to claim 1 wherein 1 mol of the compound of formula (I) is reacted with 2 to 3 mol of borohydride relative to bromine. Process according to claim 1, characterized in that the reaction is carried out at a temperature of -40 to + 50 ° C.