KR20090023828A - The method for preparation of 2-sulfonyloxy-1-(4-hydroxyphenyl)ethanol derivatives - Google Patents

Abstract

A method for preparing a 2-sulfonyloxy-1-(4-hydroxyphenyl)ethanol derivative is provided to secure high yield of 2-sulfonyloxy-1-(4-hydroxyphenyl)ethanol derivative having high optical activity. A method for preparing a 2-sulfonyloxy-1-(4-hydroxyphenyl)ethanol derivative represented by the formula 3 comprises asymmetric transfer hydrogenation of an alpha-sulfonyloxy acetophenone derivative in the presence of a hydrogen donor and a rhodium compound catalyst having a pentamethylcyclopentadienyl group. In the formula 3, X is a tosyloxy or mesyloxy group; and R^1 is hydrogen, a methyl group, a benzyl group, an acetyl group, a trimethylsilyl group, or a t- butyldimethylsilyl group.

Description

The manufacturing method of 2-sulfonyloxy-1- (4-hydroxyphenyl) ethanol derivative {THE METHOD FOR PREPARATION OF 2-SULFONYLOXY-1- (4-HYDROXYPHENYL) ETHANOL DERIVATIVES}

The present invention provides a method for preparing an optically active 2-sulfonyloxy-1- (4-hydroxyphenyl) ethanol derivative, and a method for producing a 2-amino-1- (4-hydroxyphenyl) ethanol derivative using the same. It is about.

2-amino-1- (4-hydroxyphenyl) ethanol derivatives having the optical activity of the formula (1) may be prepared by various β-adrenoceptor agonists such as denophamine, tembamide, ageline and octopamine. R ) -optical isomers, which are used as intermediates, fine chemicals, or building blocks for various pesticides or pharmaceuticals.

Where

R ¹ is hydrogen, methyl group, benzyl group, acetyl group, benzoyl group, trimethylsilyl group or t-butyldimethylsilyl group;

R ² is hydrogen, acetyl group, benzoyl group, trans-cinamoyl group, phenylacetyl group, 3,4- (dimethoxyphenyl) acetyl group, methyl group, benzyl group, phenethyl group, 3,4-dimethoxyphen Ethyl group or phenylpropyl group.

Tembamide or azeline, in particular, is a natural product with hypoglycemic acitivity, extracted from the Rutaceae family, and is a traditional medicine used by Indians. In addition, β-adrenoceptor agonists having a skeleton of 2-amino-1-phenylethanol have been used for asthma, bronchitis and congestive heart failure.

Existing methods for synthesizing denophamine are described in US Pat. Nos. 4,032,575 and 4,072,759, and methods for synthesizing octopamine are described in US Pat. No. 2,585,988 and the like. However, these methods are limited to the synthesis of racemic compounds or the resolution of diastereoisomers from racemic compound intermediates. So far, racemic compounds have been marketed as pharmaceuticals, but recent studies have shown that β-adrenoreceptor agonists such as denofamin, tembamide, azeline, and octopamine are known to be active in their ( R ) -optical isomers. have. Therefore, methods for stereoselectively preparing various optically active alcohol compounds using asymmetric catalysts or biocatalysts have been reported.

As an asymmetric synthesis method for ( R ) -denophamine, a method of preparing by asymmetric reduction from α-chloroacetophenone using a 10 mol% oxazaborrolidine catalyst is known as in the following scheme (Corey et al., J. Org. Chem. 1991, 56, 442).

Similar method for making optically active alcohols from α-tosyloxy acetophenone (Cho et al., Tetrahedron: Asymmetry 2002, 13, 1209) and α-bromo acetophenone (Xing et al., Tetrahedron 2003, 59, 9961) Methods are also known. However, the method of using the oxazaborolidin catalyst as described above, the use of the catalyst corresponding to 10 mol% in the process, there is a disadvantage that requires anhydrous reaction conditions.

In addition, to using the enzymatic method using a lipase, such as schemes, β- Oh method for dividing a map alcohol and (R) therethrough - temba imide, (R) - to the old woman Min - Ke jelrin, (R) Methods for preparing are known, but this method has a disadvantage in that the conversion to β-azido alcohol does not exceed 50%, and the mixed product must be separated and purified (Kamal et al., Tetrahedron: Asymmetry 2004, 15, 3939).

In addition, a method of preparing optically active β-azido alcohol from β-azidoketone by a bioreduction method using microorganisms as shown in the following scheme, and through this, ( R ) -tembamide and ( R ) -azeline Methods for preparing these are known (Fardelone et al., J. Mol. Catal. B: Enzymatic 2006, 39, 9).

In addition, a method for preparing optically active β- azido alcohol from β- azidoketone using an enzyme obtained from Daucus Carota , and ( R ) -tembamide and ( R ) -ae Methods for preparing jelly are known (Yadav et al., Tetrahedron: Asymmetry 2001, 12, 3381).

In addition, a method of obtaining cyanohydrin by adding HCN to benzaldehyde (Brown et al., Tetrahedron: Asymmetry 1993, 4, 2149; Baeza et al., Chem. Eur. J. 2005, 11, 3849) and benzaldehyde A method for obtaining nitroaldol by adding nitromethane (Trost et al., Org. Lett. 2002, 4, 2621) has been reported. have.

Accordingly, an object of the present invention is to provide a method for easily preparing a 2-sulfonyloxy-1- (4-hydroxyphenyl) ethanol derivative having high optical activity in order to solve the above problems.

It is also an object of the present invention to provide a method for efficiently preparing a 2-amino-1- (4-hydroxyphenyl) ethanol derivative which is an agonist of β-adrenoceptor using the above method.

According to the present invention, the process by catalytic asymmetric transfer hydrogenation can be used to obtain a product with a higher ee than any existing method.

In one embodiment, the present invention provides 2-sulfonyloxy-1- (4-hydroxyphenyl) of the formula (3) by a catalytic method from the α-sulfonyloxy acetophenone derivative of formula (2) as shown in Scheme 1 below. Provided is a method for preparing ethanol derivative. The 2-sulfonyloxy-1- (4-hydroxyphenyl) ethanol derivatives prepared according to the present invention have a high level of optical activity.

Where

R ¹ is hydrogen, methyl group, benzyl group, acetyl group, benzoyl group, trimethylsilyl group, t-butyldimethylsilyl group;

X is a sulfonyloxy group commonly known as leaving group such as tosyloxy (ie, toluene sulfonyloxy), mesyloxy (ie, methanesulfonyloxy).

The reaction is characterized by using a process by catalytic asymmetric transfer hydrogenation.

The α-sulfonyloxy group is a very good leaving group and may be easily reacted with a nucleophile such as N ₃ ⁻ , or an amine to be converted into a 2-amino-1-phenylethanol derivative having optical activity.

The α-sulfonyloxy acetophenone compound is a precursor for making various heterocyclic compounds such as thiazole, oxazole, imidazole, pyrazole and benzofuran, and the synthesis method thereof is well known.

For example, α-tosyloxy acetophenone compounds are generally i) reactions of acetophenone with (hydroxy (tosyloxy) iodo) benzene (Kose et al., J. Org. Chem. 1982, 47, 2487) ; Or ii) converting acetophenone to silyl enol ether followed by reaction with (hydroxy (tosyloxy) iodo) benzene (Moriarty et al., J. Org. Chem. 1989, 54, 1101). .

In addition, α-mesyloxy acetophenone compounds can be prepared by reaction with (hydroxy (mesyloxy) iodo) benzene from acetophenone in a similar manner as described above (Lodaya, et al., J. Org. Chem. 1988, 53, 210).

The preparation method of the above-mentioned α-tosyloxy acetophenone and α-mesyloxy acetophenone compound is shown in Scheme 2:

Where

R ¹ and X are as defined in Scheme 1.

In the present invention, a rhodium compound having a pentamethylcyclopentadienyl group (generally expressed as C ₅ Me ₅ , Cp *) and an optically active 1,2-diphenylethylene-N- ( p -toluenesulfonyl) diamine A 2-sulfonyloxy-1- (4-hydroxyphenyl) ethanol derivative of Formula 3 was prepared from the α-sulfonyloxyacetophenone derivative at a higher ee from the α-sulfonyloxyacetophenone derivative using the combined catalyst of the following structural formula. can do.

In general, the catalyst of the formula (pentamethylcyclopentadienyl) rhodium (III) chloride dimer ([Rh (C ₅ Me ₅₎ Cl ₂ ] ₂ ) and about 2 equivalents of optically active 1S, 2S-diphenyl A catalyst obtained by reacting ethylene-N- ( p -toluenesulfonyl) diamine ([S, S] -TsDPEN) ([S, S] -TsDPEN-RhCl-Cp *), which has already been described in the literature ( Mashima et al., Chem. Lett. 1998, 1199; Chem. Lett. 1998, 1201).

Hydrogen donors are used in the process of the present invention, wherein the hydrogen donors donate hydrogen according to thermal or catalysis, preferably formic acid and its metal salts, ammonium formate, formic acid (HCOOH) and amines (e.g. Et of ₃ N) and the like can be given azeotrope compound.

Formic acid and azeotrope of formic acid and amine may not be used as a hydrogen donor, and in the case of using a solvent, the solvent may be ethyl acetate, toluene, dichloromethane, DMF, DMSO, THF, acetonitrile, Isopropanol and the like can be used, but are not limited thereto.

The amount of substrate, ie, α-tosyloxy or mesyloxy acetophenone derivative, to the catalyst is usually 100 to 100,000, preferably 1,000 to 10,000, as the molar ratio (S / C) of the substrate to the metal compound.

The α-tosyloxy or mesyloxy acetophenone derivatives used as substrates in the process of the present invention have much higher yields than in the case of conventional acetophenones where the α position is substituted with Cl, N ₃ , CN, NO _2, etc., respectively. Optical activity is shown.

In another aspect of the present invention, the present invention provides a method for preparing an optically active 2-amino-1- (4-hydroxyphenyl) ethanol derivative of the formula:

[Formula 1]

Where

R ¹ is hydrogen, methyl group, benzyl group, acetyl group, benzoyl group, trimethylsilyl group or t-butyldimethylsilyl group;

R ² is hydrogen, an acetyl group, benzoyl group, trans-cinamoyl group, phenylacetyl group, 3,4-dimethoxyphenyl) acetyl group; Or a methyl group, benzyl group, phenethyl group, 3,4-dimethoxyphenethyl group or phenylpropyl group.

Specific examples of the optically active compound of Chemical Formula 1 include agents of various β-adrenoceptors, for example, ( R ) -optical isomers such as tembamide, azeline, octopamine and denophamine do.

According to the present invention, it is possible to prepare denopamine, tembamid, azeline and octopamine from conventional optically active alcohols of formula 3 synthesized as in Scheme 1, which is illustrated in Scheme 3 below. It was.

In Scheme 3, methods for preparing Formulas 6, 7, 9, and 11 according to the present invention from compounds of Formula 3a or 3b are known (Corey et al., J. Org. Chem. 1991, 56 442; Cho et al., Tetrahedron: Asymmetry 2002, 13, 1209; Kamal et al., Tetrahedron: Asymmetry 2004, 15, 3939; Fardelone et al., J. Mol. Catal. B: Enzymatic 2006, 39, 9 Yadav et al., Tetrahedron: Asymmetry 2001, 12, 3381).

As shown in Scheme 3, the compound of Formula 3a and 3b is reacted with an azide compound such as NaN ₃ , KN _3, TMSN _3, etc. to prepare an azide compound of Formula 4 or 8 (azidation ), The azide compound of formula 4 or 8 An amine compound of Formula 5 or 9 [( R ) -octopamine] is prepared by hydrogenation using Pd / C, Pt / C, Pd (OH) ₂ / C in the presence, or reduction using LiAlH ₄ . (Amination).

In this case, the obtained amine compound 5 is reacted with benzoyl chloride, trans-cinamoyl chloride in the presence of inorganic bases such as NaOH, KOH, NaHCO ₃ , K ₂ CO ₃ or the above ( R ) -Tembamide of Formula 6 or 7 or ( R ) -Azeline can be prepared separately (amidation).

In the case of denophamine, the compound 3b is directly substituted with an amine compound such as 3,4-dimethoxyphenethylamine or Et ₃ N to synthesize the compound of Formula 10 (direct substitution reaction), and then hydrogen When the benzyl protecting group is removed (hydrogenation) by reacting with Pd / C, Pt / C, Pd (OH) ₂ / C in the presence, ( R ) -denopamine of Chemical Formula 11 may be prepared.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Ee of 2-sulfonyloxy-1- (4-hydroxyphenyl) ethanol derivative synthesized according to the present invention is equipped with Chiralcel OD-H, DB-H, OJ-H of Daicel Determined by HPLC.

Example 1: ( R ) -1- (4-methoxyphenyl) -2- ( p -Tolylsulfonyloxy) ethanol ( 3a )

1- (4-methoxyphenyl) -2- ( p- tolylsulfonyloxy) ethanone (1.602 g, 5 mmol) and [S, S] -TsDPEN-RhCl-Cp * catalyst in a 100 mL round bottom flask ( 3.98 mg, 0.005 mmol) was added thereto and then sealed, and then charged with argon ( g ) for 10 minutes. Thereafter, 35 mL of ethyl acetate was added, and then 1 mL of a mixture of formic acid and triethylamine (5: 2) was added when the starting material was completely dissolved. After 2-3 minutes, the reaction began to change from pale yellow to dark red. Thereafter, after stirring at room temperature for 18 hours, the product was purified by column chromatography.

Yield 92%;

mp 71-72 ° C .;

¹ H NMR (300 MHz; CDCl ₃ ) δ 7.77 (2H, d, J = 8.3 Hz), 7.33 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 6.9 Hz), 6.86 (2H , d, J = 6.8 Hz), 4.92 (1H, dd, J = 8.4 and 3.5 Hz), 4.11 (1H, dd, J = 10.3 and 3.5 Hz), 4.03 (1H, dd, J = 10.4 and 8.5 Hz) , 3.79 (3H, s), 2.45 (3H, s);

¹³ C NMR (CDCl ₃ ) δ 159.72, 145.02, 132.65, 130.30, 129.90, 127.93, 127.46, 114.02, 74.29, 71.48, 55.27, 21.64;

EIMS (70 eV) m / z (relative strength) 322 (M ⁺ , 44), 304 (69), 172 (89), 155 (83), 108 (100), 90 (99), 79 (88)

[α] _D ²⁷ -50.7 ( c 0.79, CHC1 ₃ );

Chiral HPLC analysis (chiralcel OD-H, 250 × 4.6 mm, 2% ethanol / hexane; 1.2 mL / min), 94% ee.

Example 2: ( R ) -1- (4-benzyloxyphenyl) -2- ( p -Tolylsulfonyloxy) ethanol ( 3b )

1- (4-benzyloxyphenyl) -2- ( p- tolylsulfonyloxy) ethanone (4.36 g, 11 mmol) and [S, S] -TsDPEN-RhCl-Cp * catalyst in a 100 mL round bottom flask ( 9 mg, 0.011 mmol) was added and sealed, and charged with argon ( g ) for 10 minutes. Then 22 mL of ethyl acetate was added, and 2.2 mL of a mixture of formic acid and triethylamine (5: 2) was added when the starting material was completely dissolved. Then it was stirred for 6 hours at room temperature and then washed with water. The organic layer was filtered by removing water with anhydrous sodium sulfate, and then the product was purified by column chromatography.

Yield 82%;

mp 91-92 ° C .;

¹ H NMR (300 MHz; CDCl ₃ ) δ 7.77 (2H, d, J = 8.4 Hz), 7.43-7.32 (6H, m), 7.26- 7.20 (3H, m), 6.93 (2H, d, J = 8.8 Hz), 5.05 (2H, s), 4.95 (1H, dt, J = 8.3 and 3.0 Hz), 4.13-3.99 (2H, m), 2.44 (3H, s);

¹³ C NMR (DMSO-d ₆ ) δ 158.90, 145.04, 136.71, 132.62, 130.51, 129.91, 128.59, 128.02, 127.93, 127.49, 127.40, 114.98, 74.28, 71.49, 69.98, 21.65;

EIMS (70 eV) m / z (relative strength) 398 (M ⁺ , 1), 213 (56), 91 (100);

[α] _D ²⁸ -42.5 ( c 0.79, CHCl ₃ );

Chiral HPLC analysis (chiralcel OD-H, 250 × 4.6 mm, 2% ethanol / hexane; 1.2 mL / min), 95% ee.

Example 3: 1- (4-acetoxyphenyl) -2- ( p -Tolylsulfonyloxy) ethanol ( 3c )

1- (4-acetoxyphenyl) -2- ( p- tolylsulfonyloxy) ethanone (0.174 g, 0.5 mmol) and a catalyst (0.4 mg, 0.0005 mmol) were added and sealed in a 25 mL round bottom flask. Filled with argon ( g ) for 10 minutes. After adding 2 mL of ethyl acetate, 0.1 mL of a mixture of formic acid and triethylamine (5: 2) was added when the starting material was completely dissolved. Then stirred for 2 hours at room temperature and washed with water. The organic layer was filtered by removing water with anhydrous sodium sulfate, and then the product was purified by column chromatography.

Yield 94%;

Oil phase;

¹ H NMR (300 MHz; CDCl ₃ ) δ 7.77 (2H, d, J = 8.4 Hz), 7.36-7.32 (4H, m), 7.06 (2H, d, J = 8.6 Hz), 4.99 (1H, dd, J = 8.5 and 3.2 Hz), 4.12 (1H, dd, J = 10.4 and 3.4 Hz), 4.01 (1H, dd, J = 10.4 and 8.7 Hz), 2.61 (1H, d, J = 3.2 Hz), 2.45 ( 3H, s) 2.30 (3H, s);

¹³ C NMR (CDCl ₃ ) δ 169.41, 150.63, 145.14, 135.79, 132.44, 129.96, 127.94, 127.32, 121.82, 74.18, 71.37, 21.64, 21.08;

EIMS (70 eV) m / z (relative strength) 165 (M ⁺ -CH ₂ OTs, 39), 123 (100), 91 (17); [α] _D ²⁹ -41.20 ( c 1.085 g, CHCl ₃ );

Chiral HPLC analysis (chiralcel OD-H, 250x4.6 mm, 5% ethanol / hexane; 0.5 mL / min), 96% ee

Example 4: 1- (4-t - Butyldimethylsilyloxyphenyl) -2- ( p -Tolylsulfonyloxy) ethanol ( 3d )

25 mL round bottom flask 1- (4-t - butyl-dimethyl-silyloxy-phenyl) -2- (p- tolyl rilseol sulfonyl oxy) ethanone (0.420 g, 0.1 mmol) and catalyst (0.7 mg, 0.001 mmol) to It was sealed and filled with argon ( g ) for 10 minutes. Then, 2 mL of ethyl acetate was added, and then 0.2 mL of a mixture of formic acid and triethylamine (5: 2) was added when the starting material was completely dissolved. Then stirred for 2 hours at room temperature and washed with water. The organic layer was filtered by removing water with anhydrous sodium sulfate, and then the product was purified by column chromatography.

Yield 60%;

Oil phase;

¹ H NMR (300 MHz; CDCl ₃ ) δ 7.78 (2H, d, J = 8.3 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 8.3 Hz), 6.79 (2H , d, J = 8.6 Hz), 4.92-4.90 (1H, m), 4.11 (1H, dd, J = 10.4 and 3.4 Hz), 4.02 (1H, dd, J = 10.4 and 8.6 Hz), 2.45 (3H, s) 0.97 (9H, s), 0.18 (6H, s);

¹³ C NMR (CDCl ₃ ) δ 155.92, 145.03, 132.67, 130.82, 129.92, 127.93, 127.40, 120.23, 74.32, 71.57, 25.62, 21.65, 18.16, -4.46;

EIMS (70 eV) m / z (relative strength) 422 (M ⁺ , 1) 237 (100), 193 (19), 149 (12), 91 (14);

[α] _D ²⁹ -37.35 ( c 1.02 g, CHCl ₃ );

Chiral HPLC analysis (chiralcel OD-H, 250x4.6 mm, 1% ethanol / hexane; 0.4 mL / min), 96% ee

Example 5: ( R )-(-)-2-azido-1- (4-methoxyphenyl) ethanol ( 4 )

In a 100 mL round bottom flask, ( R ) -1- (4-methoxyphenyl) -2- ( p -tolylsulfonyloxy) ethanol ( 3a ) (1.73 g, 5.38 mmol) and sodium azide (0.70 g, 10.75 mmol), dissolved in dimethylsulfoxide (12 mL) and stirred at 80 ° C. for 2 hours. After cooling at room temperature, 15 mL of water was added thereto, followed by extraction with ethyl acetate. The organic layer was filtered by removing water with anhydrous sodium sulfate, and then the product was purified by column chromatography.

Yield 91%;

Oil phase;

¹ H NMR (300 MHz; CDCl ₃ ) δ 7.30 (2H, d, J = 8.5 Hz), 6.91 (2H, d, J = 8.8 Hz), 4.86-4.81 (1H, m), 3.48 (1H, dd, J = 12.5 and 8.0 Hz), 3.81 (3H, s), 3.40 (1H, doublet of doublets, J = 12.5 and 4.1 Hz), 2.29 (1H, d, J = 3.1 Hz);

¹³ C NMR (CDCl ₃ ) δ 159.62, 132.66, 127.19, 114.07, 73.03, 58.05, 55.29; EIMS (70 eV) m / z (relative strength) 193 (M ⁺ , 5), 137 (39), 109 (70), 94 (97), 77 (100);

[α] _D ²⁵ -86.1 ( c 1.39, CHCl ₃ )

Example 6: ( R )-(-)-2-amino-1- (4-methoxyphenyl) ethanol ( 5 )

5% Pd / C (0.02 g) and ( R )-(-)-2-azido-1- (4-methoxyphenyl) ethanol ( 4 ) (0.71 g, 3.68 mmol) were added to the reaction vessel. Dissolved in 6 mL and reacted for 2 hours at room temperature under hydrogen gas charge (30 psi). The product was passed through diatomaceous earth, filtered, distilled under reduced pressure, concentrated and vacuum dried.

Yield 95%;

mp 100-102 ° C .;

¹ H NMR (300 MHz; CDCl ₃ ) δ 7.27 (2H, d, J = 6.70 Hz), 6.89 (2H, d, J = 6.67 Hz), 4.57 (1H, dd, J = 7.8 and 4.0 Hz), 3.80 (3H, s), 2.96 (1H, doublet of doublets, J = 12.7 and 4.1 Hz), 2.79 (1H, doubled, J = 12.7 and 7.8 Hz);

¹³ C NMR (CDCl ₃ ) δ 158.10, 134.61, 127.01, 113.30, 74.13, 55.02, 50.29;

EIMS (70 eV) m / z (relative strength) 167 (M ⁺ , 8), 136 (91), 109 (100), 94 (86); [α] _D ²⁵ -38.3 ( c 0.49, EtOH)

Example 7: ( R )-(-) Tembamide ( 6 )

50% aqueous sodium hydroxide solution (0.24 g, 3 mmol) was added to a 50 mL round bottom flask, and the mixture was diluted with 3 mL of water. ( R )-(-)-2-amino-1- (4-methoxyphenyl) ethanol ( 5 ) (0.167 g, 1 mmol) was dissolved in dichloromethane (3 mL) and added at 0-5 ° C. Then stirred for 10 minutes. Benzoylchloride (1.2 mmol) was dissolved in toluene, added, and then stirred for 1 hour. Then diluted by the addition of water, followed by extraction with dichloromethane. The organic layer was concentrated by distillation under reduced pressure, and the product was recrystallized (ethanol / water = 80:20).

Yield 92%;

mp 145-147 ° C .;

¹ H NMR (300 MHz; CDCl ₃ ) δ 7.76 (2H, d, J = 6.9 Hz), 7.51 (1H, t, J = 7.3 Hz), 7.43 (2H, t, J = 7.5 Hz), 7.33 (2H , d, J = 8.7 Hz), 6.90 (2H, d, J = 8.7 Hz), 6.58 (1H, bs), 4.94-4.89 (1H, m), 3.93-3.85 (1H, m), 3.81 (3H, s), 3.56-3.48 (1H, m), 3.09 (1H, d, J = 3.5 Hz);

¹³ C NMR (CDCl ₃ ) δ 168.52, 159.34, 134.12, 133.87, 131.66, 128.60, 127.09, 126.97, 113.98, 73.34, 55.29, 47.75;

EIMS (70 eV) m / z (relative strength) 254 (M ⁺ -OH, 17), 150 (7), 134 (29), 105 (60), 77 (100);

[α] _D ²⁵ -59.4 ( c 0.57, CHCl ₃ )

Example 8: ( R )-(-) Azeline ( 7 )

50% aqueous sodium hydroxide solution (0.24 g, 3 mmol) was added to a 50 mL round bottom flask, and the mixture was diluted with 3 mL of water. ( R )-(-)-2-amino-1- (4-methoxyphenyl) ethanol ( 5 ) (0.167 g, 1 mmol) was dissolved in dichloromethane (3 mL) and added at 0-5 ° C. Then stirred for 10 minutes. ( E ) -cinnamoyl chloride (1.2 mmol) was dissolved in toluene and added, followed by stirring for 1 hour. Then diluted by the addition of water, followed by extraction with dichloromethane. The organic layer was concentrated by distillation under reduced pressure, and the product was recrystallized (ethanol / water = 80:20).

Yield 84%;

mp 194-195 ° C;

¹ H (300 MHz; DMSO-d ₆ ) δ 8.14 (1H, t, J = 5.6 Hz), 7.54 (2H, d, J = 6.4 Hz), 7.44-7.35 (3H, m), 7.27 (2H, d , J = 8.6 Hz), 6.89 (2H, d, J = 8.7 Hz), 6.72 (1H, d, J = 15.8 Hz), 5.44 (1H, d, J = 4.3 Hz), 4.63-4.58 (1H, m ), 3.44-3.36 (1H, m), 3.26-3.17 (1H, m);

¹³ C (DMSO-d ₆ ) δ 165.06, 158.35, 138.49, 135.73, 134.95, 129.36, 128.91, 127.46, 127.15, 122.35, 113.42, 70.93, 55.00, 47.02;

EIMS (70 eV) m / z (relative strength) 297 (M ⁺ , 3), 285 (21), 103 (15), 71 (56), 57 (100);

[α] _D ²⁵ -49.1 ( c 0.27, MeOH)

Example 9: ( R )-(-)-2-azido-1- (4-benzyloxyphenyl) ethanol ( 8 )

In a 100 mL round bottom flask, ( R ) -1- (4-benzyloxyphenyl) -2- ( p -tolylsulfonyloxy) ethanol ( 3b ) (3.39 g, 8.51 mmol) and sodium azide (1.11 g, 17.01 mmol), dissolved in dimethylsulfoxide (15 mL) and stirred at 80 ° C. for 2 h. After cooling at room temperature, 20 mL of water was added and extracted with ethyl acetate. The organic layer was filtered by removing water with anhydrous sodium sulfate, and then purified by column chromatography.

Yield 91%;

mp 69-70 ° C .;

¹ H (300 MHz; CDCl ₃ ) δ 7.45-7.27 (7H, m), 6.98 (2H, d, J = 8.8 Hz), 5.07 (2H, s), 4.86-4.81 (1H, m), 3.48 (1H , dd, J = 12.6 and 8.0 Hz) 3.40 (1H, dd, J = 12.6 and 4.1 Hz), 2.26 (1H, d, J = 3.2 Hz);

¹³ C (DMSO-d ₆ ) δ 158.77, 136.74, 132.91, 128.58, 128.00, 127.41, 127.20, 114.98, 72.99, 70.00, 57.99;

EIMS (70 eV) m / z (relative strength) 213 (M ⁺ -CH ₂ N ₃ , 37), 91 (100);

[α] _D ²⁸ -66.34 ( c 1.09, CHCl ₃ )

Example 10: ( R )-(-)-Octopamine ( 9 )

20% Pd (OH) ₂ / C (150 mg) and ( R )-(-)-2-azido-1- (4-benzyloxyphenyl) ethanol ( 8 ) (539 mg, 2 mmol) in reaction vessel Was added, dissolved in 10 mL of ethanol and reacted for 9 hours at room temperature under a hydrogen gas charge (60 psi). The product was passed through diatomaceous earth, filtered, distilled under reduced pressure, concentrated, and dried in vacuo.

Yield 99%;

mp 168-170 ° C .;

¹ H (300 MHz; DMSO-d ₆ ) δ 7.16 (2H, d, J = 8.5 Hz), 6.76 (2H, d, J = 8.5 Hz), 4.38 (1H, dd, J = 7.4 and 4.7 Hz), 2.69-2.56 (2H, m);

¹³ C (DMSO-d ₆ ) δ 146.51, 124.94, 117.32, 104.98, 64.58, 40.55;

EIMS (70 eV) m / z (relative strength) 153 (M ⁺ , 4), 136 (11), 123 (100), 95 (30), 77 (23);

[α] _D ²⁵ -31.37 ( c 1.02 g, H ₂ 0)

Example 11: ( R )-(-)-One-( p -Benzyloxyphenyl) -2- (3,4-dimethoxyphenethylamino) ethanol ( 10 )

1- (4-benzyloxyphenyl) -2- ( p -tolylsulfonyloxy) ethanol ( 3b ) (0.398 g, 1 mmol) and 3,4-dimethoxyphenethylamine (0.544) in a 25 mL round bottom flask g, 3 mmol) was added, dissolved in tetrahydrofuran (20 mL), triethylamine (0.202 g, 2 mmol) was added, and the mixture was stirred at 100 ° C. for 5 hours. After cooling at room temperature, 3 mL of water was added thereto, followed by extraction with diethyl ether. The organic layer was filtered by removing water with anhydrous magnesium sulfate, and then the product was purified by column chromatography.

Yield 82%;

mp 119-120 ° C .;

¹ H (300 MHz; CDCl ₃ ) δ 7.43-7.28 (5H, m), 7.21 (2H, d, J = 8.7 Hz), 6.92 (2H, d, J = 8.6 Hz), 6.84-6.69 (3H, m ), 5.06 (2H, s), 4.67 (1 h, dd, J = 8.1 and 5.0 Hz), 3.79 (3H, s), 3.77 (3H, s), 2.86-2.68 (6H, m);

¹³ C (DMSO-d ₆ ) δ 158.57, 149.34, 147.87, 137.59, 135.41, 132.46, 128.30, 127.66, 127.37, 127.09, 120.82, 114.67, 112.43, 112.07, 71.73, 69.78, 56.46, 55.36, 55.21, 50.21. ;

EIMS (70 eV) m / z (relative strength) 407 (M ⁺ , 2), 194 (35), 91 (100);

[α] _D ²⁸ -19.27 ( c 1.1 g, MeOH)

Example 12: ( R )-(-)-Denopamine ( 11 )

20% Pd (OH) ₂ / C (50 mg) and ( R )-(-)-1- ( p -benzyloxyphenyl) -2- (3,4-dimethoxyphenethylamino) ethanol in the reaction vessel ( 10 ) (0.203 g, 0.5 mmol) was added, dissolved in 20 mL of ethanol, and reacted for 2 hours at room temperature under hydrogen gas filling (60 psi). The product was passed through diatomaceous earth, filtered, distilled under reduced pressure, concentrated, and dried in vacuo.

Yield 96%;

mp 162-164 ° C .;

¹ H (300 MHz; CDCl ₃ ) δ 7.12 (2H, d, J = 8.5 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.79 (1H, d, J = 1.7 Hz), 6.73-6.69 ( 3H, m), 4.64 (1H, d, J = 8.2 and 4.9 Hz), 3.80 (3H, s), 3.79 (3H, s), 2.86-2.68 (6H, m);

¹³ C (DMSO-d ₆ ) δ 156.99, 149.34, 147.86, 133.82, 132.49, 127.12, 120.82, 114.98, 112.45, 112.07, 71.88, 56.49, 55.36, 55.23, 50.53, 34.92;

EIMS (70 eV) m / z (relative strength) 317 (M ⁺ , 1), 165 (37), 121 (34), 107 (63), 91 (86) 77 (100);

[α] _D ²⁷ -25.90 ( c 0.91 g, MeOH)

Claims (5)

2-sulfonyloxy- of formula 3, comprising asymmetric transfer hydrogenation of an α-sulfonyloxy acetophenone derivative in the presence of a rhodium compound catalyst having a pentamethylcyclopentadienyl group and a hydrogen donor Process for preparing 1- (4-hydroxyphenyl) ethanol derivative: [Formula 3]

Where X is a tosyloxy or mesyloxy group; R ¹ is hydrogen, methyl group, benzyl group, acetyl group, benzoyl group, trimethylsilyl group or t-butyldimethylsilyl group. The method of claim 1, The rhodium compound catalyst is a catalyst having a structure of the following formula.

The method of claim 1, And said hydrogen donor is formic acid or a metal salt or ammonium salt thereof, or an azeotrope of formic acid and amine. The method of claim 1, Wherein the α-sulfonyloxy acetophenone compound is used in an amount ranging from 100 to 100000 as the molar ratio (S / C) of the substrate to the metal compound of the catalyst. Preparing a 2-sulfonyloxy-1- (4-hydroxyphenyl) ethanol derivative of the following Chemical Formula 3 by the method according to any one of claims 1 to 4; 2-sulfonyloxy-1- (4-hydroxyphenyl) ethanol derivative i) amidation, amination and optionally amidation, or ii) direct substitution and hydrogenation with amine compounds Method for producing a 2-amino-1- (4-hydroxyphenyl) ethanol derivative of the formula (1) comprising: [Formula 1]

[Formula 3]

Where X is a tosyloxy or mesyloxy group; R ¹ is hydrogen, methyl group, benzyl group, acetyl group, benzoyl group, trimethylsilyl group or t-butyldimethylsilyl group; R ² is hydrogen, acetyl group, benzoyl group, trans-cinamoyl group, phenylacetyl group, 3,4- (dimethoxyphenyl) acetyl group, methyl group, benzyl group, phenethyl group, 3,4-dimethoxyphen Ethyl group or phenylpropyl group.