KR20150116956A - A method for preparing optically active 3-amino-1-phenylpropanol derivatives as an intermediate and a method for preparing optically active pharmaceutical products using the same - Google Patents

Abstract

The present invention relates to a method for preparing a 3-amino-1-phenylpropanol derivative having (R) or (S) optical activity with 80% or more of an enantiomeric excess (ee), which includes a step of performing an asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor. The invention also relates to a method for preparing an optically active pharmaceutical product, which includes a step of preparing a (R)- or (S)-3-amino-1-phenylpropanol derivative, that is an intermediate, by using the catalyst.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing an optically active 3-amino-1-phenylpropanol derivative as an intermediate and to an optically active pharmaceutical product using the intermediate, for preparing optically active pharmaceutical products using the same}

The present invention relates to a process for the preparation of an optically active ( R ) or ( S ) enantiomeric excess ( ee ) having an enantiomeric excess ( ee ) of at least 80%, comprising asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor. Amino-1-phenylpropanol derivative having the formula (I); And ( R ) - or ( S ) -3-amino-1-phenylpropanol derivatives which are intermediates using the catalyst.

Many molecules produced and / or used in living organisms including naturally occurring amino acids and sugars have optical asymmetry (chirality). Most of the compounds used in vivo show the same chiral properties. For example, most amino acids are of the L type and the sugars are of the D type. Enzymes also have chiral properties and can distinguish two enantiomers of a substrate with chiral properties. For example, supposing an enzyme that envelops the substrate in the form of a bag, when the pouch has an asymmetric structure, depending on the type of substrate, one isomer fits into the asymmetric pocket structure of the enzyme, while the other isomer Due to the structure, it can not enter.

Generally, D-type amino acids are sweet and L-type is tasteless. Spearmint leaves and caraway seeds have L-Carbone and D-Carbone with different fragrances. The reason why the two isomeric molecules give different fragrances is because the human nose is composed of chiral molecules that react differently to enantiomers.

The chiral nature of these molecules is also important in pharmaceuticals. In pharmaceuticals with chiral properties, one isomer has a specific drug effect, while the other isomer has no effect, thus halving the drug efficacy, or even toxic if severe. For example, as thalidomide is a racemic mixture, one enantiomer is effective for mania, while the other enantiomer provokes a deformity. While ethambutol is effective on one isomer of tuberculosis, other isomers cause blindness. While naproxen has an analgesic effect on one isomer such as arthritis, the other has no analgesic effect and causes liver toxicity. The action of steroid receptors or penicillin also exhibits stereoselectivity. Therefore, it must be provided with high purity to prevent potential side effects due to mixing of the enantiomers. However, since the enantiomers have the same physicochemical properties such as molecular weight and polarity except for their optical properties, separation is very difficult. Therefore, it is most important to find a synthesis method capable of selectively producing one isomer.

The optically active 3-amino-1-phenylpropanol derivative is used as a building block for the synthesis of various pharmaceutical intermediates, fine chemicals, or physiologically active substances. Fluoxetine, Nisoxetine and Tomoxetine, for example, commonly contain 3-amino-1-phenylpropanol as a core intermediate (FIG. 1).

Various synthetic methods for synthesizing the 3-amino-1-phenylpropanol and derivatives thereof are known.

U.S. Patent No. 5,708,035 discloses a method for the synthesis of ( R ) -fluoxetine, which is one of the 3-amino-1-phenylpropanol derivatives. Specifically, i) a method for producing epoxycinnamyl alcohol through Sharpless epoxidation in cinnamyl alcohol (Y. Gao and KB Sharpless, J. Org. Chem. , 1988, 53: 4081-4084) and ii) a method using an intermediate synthesized by reducing 3-chloro-1-phenylpropan-1-one with Ipc ₂ BCl is known.

However, the Sharpless epoxidation reaction or the reduction with Ipc ₂ BCl is not suitable for the mass-production process because it involves a complicated process such as a catalyst production process and an anhydrous reaction condition.

It has also been reported that iii) an asymmetric reduction from 3-chloro-1-phenylpropan-1-one in the presence of an oxazaborolidine catalyst and a hydrogen donor (EJ Corey and GA Reichard, Tetrahedron Lett. 30: 5207-5210). However, the above oxazaborolidine catalyst is difficult to produce. For example, the catalyst is very sensitive to atmospheric or moisture, and the reaction using the catalyst requires performing under subzero conditions. Therefore, it is necessary to find a catalyst which is easy to manufacture, stable in air or moisture, and mild in reaction conditions.

Furthermore, iv) Korean Patent No. 10-0501954 describes a method of preparing an optically active alcohol compound and its ester by an enzymatic method using lipase, but the method using the enzyme has a disadvantage of low conversion rate.

There are known serotonin reuptake inhibitors and norepinephrine reuptake inhibitors which are used as antidepressant drugs for treatment of antidepressants such as cynomolgus catechins, nissexetil, fluoxetine, norfloxetine and duloxetine. These drugs commonly include a 3-aryloxy-3-arylpropylamine structure as a basic skeleton. The dual covariance Cetin is the first drug developed as an antidepressant that inhibits norepinephrine reuptake without a strong affinity for the [alpha] - or [beta] -adrenergic receptor. In particular, the ( R ) -isomer of Civilian Cetin is known as Atochoxetine, which has been found to have a 9-fold or greater potency over the ( S ) -isomer and is marketed in the form of its hydrochloride as Strattera have.

However, even though the (R) -form isomer is known to exert more excellent effects in the case of flocetin or nisangetin, it is still used in the form of racemic form. Therefore, conversion of these drugs into optically active substances is very urgent.

The present inventors have found that by carrying out an asymmetric reduction reaction of a 3-amino-1-phenylpropan-1-one compound represented by the formula (1) in the presence of a spiroborate ester catalyst and a hydrogen donor, Amino-1-phenylpropanol derivatives with high optical activity can be prepared with high yield and high optical purity, for example, with high enantiomeric excess ( ee ). Furthermore, it was confirmed that enantiomerically pure ( R ) - atomoxetine, ( R ) - nisoxetine and ( R ) - fluoxetine could be prepared using this method. The present invention is based on this.

The first aspect is the following step, the excess rate of at least 80% enantiomeric containing for asymmetric reduction reaction of the compound represented by formula (1) in the presence of a catalyst and a hydrogen donor spiro borate ester (spiroborate ester) of the present invention (enanthiomeric excess; ee Amino-1-phenylpropanol derivative having an optically active 3-amino-1-phenylpropanol derivative,

[Chemical Formula 1]

In Formula 1,

X < ₁ > is hydrogen or halogen,

R is an amino group represented by halogen or NR ₁ R ₂ ,

Said halogen being F, Cl, Br or I,

R ₁ and R ₂ are each independently hydrogen, C ₁ to C ₄ alkyl, C ₇ to C ₁₂ aralkyl, aryl, pyrrolidinyl, piperidinyl or morpholinyl.

또는

를 스피로보레이트 에스테르 촉매로 사용하여 수소공여체와 비대칭 환원반응시키는 단계를 포함하는, 상기 화학식 1로 표시되는 화합물로부터 R형 3-아미노-1-페닐프로판올 유도체를 80% 이상의 거울상 이성질체 잉여율로 제조하는 방법을 제공한다.
A second aspect of the present invention is

or

Spiro borate esters using a catalyst and a hydrogen donor asymmetric reduction reaction steps of, preparing a R-type 3-amino-1-phenyl-propanol derivative from a compound represented by the formula (1) to greater than 80% enantiomeric excess of the rate that includes ≪ / RTI >

를 스피로보레이트 에스테르 촉매로 사용하여 수소공여체와 비대칭 환원반응시키는 단계를 포함하는, 상기 화학식 1로 표시되는 화합물로부터 S형 3-아미노-1-페닐프로판올 유도체를 80% 이상의 거울상 이성질체 잉여율로 제조하는 방법을 제공한다.
In a third aspect of the present invention,

Spiro borate esters using a catalyst and a hydrogen donor from the asymmetric reduction reaction step compounds of the formula (1) containing that for producing the S-type 3-amino-1-phenyl-propanol derivative as at least 80% enantiomeric excess rate ≪ / RTI >

또는

의 스피로보레이트 에스테르 촉매 및 수소공여체의 존재 하에 비대칭 환원반응시켜 중간체인 하기 화학식 2로 표시되는 (R)-3-아미노-1-페닐프로판올 유도체를 생산하는 제1단계; 및In a fourth aspect of the present invention,

or

( R ) -3-amino-1-phenylpropanol derivative represented by the following formula (2) as an intermediate by asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor; And

Provides a method for producing a-type drug-to, (R) a second step to an intermediate compound and reacting the compound represented by the formula (3) represented by the formula (2):

(2)

(3)

In the above formulas,

X < ₁ > is hydrogen or halogen,

X < ₂ > is hydroxy or halogen,

Said halogen being F, Cl, Br or I,

R ₁ and R ₂ are each independently hydrogen, C ₁ to C ₄ alkyl, C ₇ to C ₁₂ aralkyl, aryl, pyrrolidinyl, piperidinyl or morpholinyl,

R ₃ is C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy or C ₁ to C ₄ perfluoroalkyl.

Hereinafter, the present invention will be described.

3-amino-1-phenylpropanol derivatives having optical activity can be used as an intermediate for preparing various chiral drugs such as flocetin, chondroitin and nisuccine, Can be prepared from the material in various ways. However, the conventional process for producing 3-amino-1-phenylpropanol derivatives has a problem in that the production yield of the product and the purity ( ee ) of the enantiomer are low, which requires additional separation and purification.

The present invention relates to a process for asymmetrically reducing a 1-phenylpropanone compound in which a halogen or an amine group is substituted at the? -Position, which is a compound represented by the above formula (1), in the presence of a spiroborate ester catalyst and a hydrogen donor, -1-phenylpropanol derivative can be prepared with high yield and high optical purity of 80% ee or more. Furthermore, since the 3-amino-1-phenylpropanol derivative itself can be synthesized with high yield and optical purity by the method according to the present invention, it is possible to produce optically pure R- type enantiomers such as flocetin, Nisin cetin can be prepared.

The term "enantiomeric excess ( ee )" in the present invention is a variable representing the optical purity of an isomer in an optical isomer mixture, expressed as an absolute value of the difference in mole fraction of each optical isomer. For example, the enantiomeric excess of the R -isomer in a mixture of 80 mol of the R -isomer and 20 mol of the S-isomer is | 80-20 | = 60%. Thus, having an ee value of 80% or greater means that it contains at least 90% of the desired isomer in the isomer mixture.

According to a first aspect of the present invention, there is provided a process for preparing a 3-amino-1-phenylpropanol derivative at an enantiomeric excess of 80% or more, comprising reacting a compound represented by the above formula 1 with asymmetrically reducing .

Specifically, the step of performing the asymmetric reduction reaction comprises reacting a? -Halo ketone compound (R is a halogen) or a? -Amino ketone compound (R is an amino group) with a? -Haloalcohol compound or? -Aminoalcohol (2a) or (2b).

[Reaction Scheme 1]

In the above Reaction Scheme 1, R is the same as described above.

More specifically, the first step corresponding to Scheme 1 is an asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor, and in particular, the reaction is carried out by a catalytic asymmetric transfer hydrogenation method. Therefore, generation of the present invention a compound of the spiro-borate ester catalyst for asymmetric 80% by a reduction reaction ee or more, preferably a high optical purity of at least 90% ee S-type with (formula 2a), or R (formula 2b) of mainly The reaction can be induced. The optical properties of the product depend on the type of catalyst used.

Preferably, the 3-amino-1-phenylpropanol derivative may include a phenyl group at the? -Position and a substituent at the? -Position as shown in the following general formula (1) and the general formula (1). More preferably, the substituent at the? -Position may include a substituted or unsubstituted amino group, and the substituent on the amino group may be substituted with C ₁ to C ₄ alkyl, C ₁ to C ₄ aralkyl, aryl, pyrrolidinyl, Piperidinyl or morpholinyl.

The spiroborate ester catalyst used in the asymmetric reduction reaction of the present invention may be synthesized from 1,2-aminoalcohol or 1,2-diamine. Specifically, 1,2-amino alcohol or 1,2-diamine is reacted with 1,2-diol and triisopropyl borate in toluene under reflux, as shown in Scheme 2, represented by the following general formula, A borate ester catalyst can be obtained.

[Reaction Scheme 2]

R ₃ , R ₄ and R ₅ are each independently hydrogen or a C 1 to C 4 aralkyl, or R ₃ and R ₄ or R ₅ are connected to each other to form an N-hetero atom , R ₆ and R ₇ are each independently hydrogen or an aryl group, and R ₈ to R ₁₁ are each independently hydrogen or C ₁ to C ₄ alkyl.

,

,

,

,

,

,

및

등이 있다.Non-limiting examples of spiroborate ester catalysts prepared via Scheme 2 include,

,

,

,

,

,

,

And

.

In the first step, the spiroborate ester catalyst is preferably used in a proportion of 1 to 20 moles per 100 moles of the compound represented by the formula (1). More preferably 3 to 12 moles.

The first step hydrogen donor is a substance which donates hydrogen according to a thermal action or a catalytic action and is selected from the group consisting of BH ₃ -dimethylsulfide (DMS), BH ₃ -tetrahydrofuran (THF), LiAlH ₄ and NaBH ₄ It can be any one or more selected.

In the first step, the hydrogen donor is preferably used in a ratio of 60 to 90 moles per 100 moles of the compound represented by the general formula (1). And more preferably 65 to 85 mol.

In the present invention, the? -Haloalcohol or? -Aminoalcohol compound as the compound represented by the above formula (2a) or (2b) can be obtained through the first step and purified by conventional extraction, distillation, recrystallization or column chromatography can do. Specifically, the first step may be carried out with stirring at 0 캜 to 50 캜 for 1 hour to 24 hours.

In the case where? -Haloketone (R = X = halogen) is used as a reactant in the asymmetric substitution reaction, a step of introducing an amine group by a substitution reaction with an amine compound may be further performed. This is shown in Reaction Scheme 3 below. To a substitution reaction of the halogen amine group is 3-amino-1-phenyl-propanol derivative was converted to a substituent of γ- position while maintaining the optical properties of a hydroxy group that is, S-type or R-type with an amino group from a halogen having an optically active ( (3a) or (3b).

[Reaction Scheme 3]

Wherein X is Cl, Br or I and R ₁ and R ₂ of NR ₁ R ₂ are as defined for formula (1).

Further, the optically active 3-amino-1-phenylpropanol derivative synthesized by the production method according to the present invention can be purified by further performing ordinary extraction, distillation, recrystallization, column chromatography, and the like.

The thus obtained optically active 3-amino-1-phenylpropanol derivatives can be used as intermediates for the production of flocetin, cynomolgus catechin and nisin cetin.

According to the production method of the first aspect of the present invention, the optically active 3-amino-1-phenylpropanol derivative can be obtained at a higher yield and optical purity ( ee ) than the conventional method.

또는

를 스피로보레이트 에스테르 촉매로 사용하여 수소공여체와 비대칭 환원반응시키는 단계를 포함한다.According to a second aspect of the present invention, there is provided a method for producing an R- type 3-amino-1-phenylpropanol derivative from a compound represented by the above formula (1) at an enantiomeric excess of 80%

or

As a spiroborate ester catalyst to an asymmetric reduction reaction with a hydrogen donor.

를 스피로보레이트 에스테르 촉매로 사용하여 수소공여체와 비대칭 환원반응시키는 단계를 포함한다.According to a third aspect of the present invention, there is provided a method for producing an S- type 3-amino-1-phenylpropanol derivative from a compound represented by the above formula (1) at an enantiomeric excess of 80%

As a spiroborate ester catalyst to an asymmetric reduction reaction with a hydrogen donor.

또는

를 촉매로 사용하는 경우 R형 3-아미노-1-페닐프로판올 유도체를 80% ee 이상의 순도로 생산할 수 있는 반면,

를 촉매로 사용하는 경우 S형 3-아미노-1-페닐프로판올 유도체를 80% ee 이상의 순도로 생산할 수 있음을 확인하였다.In the present invention, it has been confirmed that the kind of the optical isomer mainly generated and the optical purity of the product are determined according to the kind of the spiroborate ester catalyst to be used. In a specific embodiment of the present invention

or

Amino-1-phenylpropanol derivative can be produced with a purity of 80% ee or more when the R- type 3-amino-1-phenylpropanol derivative is used as a catalyst,

Amino-1-phenylpropanol derivative can be produced with a purity of 80% ee or more when S -3-amino-1-phenylpropanol derivative is used as a catalyst.

As described above, the R- or S- type 3-amino-1-phenylpropanol derivative produced according to the second or third aspect of the present invention can be purified by conventional extraction, distillation, recrystallization, column chromatography, and the like .

또는

의 스피로보레이트 에스테르 촉매 및 수소공여체의 존재 하에 비대칭 환원반응시켜 중간체인 하기 화학식 2로 표시되는 (R)-3-아미노-1-페닐프로판올 유도체를 생산하는 제1단계; 및 하기 화학식 2로 표시되는 중간체 화합물을 하기 화학식 3으로 표시되는 화합물과 반응시키는 제2단계를 포함한다.According to a fourth aspect of the present invention, there is provided a process for preparing an ( R ) -type drug, comprising reacting a compound represented by the above formula

or

( R ) -3-amino-1-phenylpropanol derivative represented by the following formula (2) as an intermediate by asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor; And a second step of reacting an intermediate compound represented by the following formula (2) with a compound represented by the following formula (3).

(2)

(3)

In the above formulas,

X < ₁ > is hydrogen or halogen,

X < ₂ > is hydroxy or halogen,

Said halogen being F, Cl, Br or I,

R ₁ and R ₂ are each independently hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ aralkyl, aryl, pyrrolidinyl, piperidinyl or morpholinyl,

R ₃ is C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy or C ₁ to C ₄ perfluoroalkyl.

Preferably, R ₁ and R ₂ are hydrogen and methyl, and R ₃ can be methyl, methoxy or trifluoromethyl.

Preferably, the ( R ) -type drug may be ( R ) -floxetin, ( R ) -cindustine or ( R ) -nline cetin, but is not limited thereto.

The first step according to the fourth aspect of the present invention is specifically the same as the step of asymmetric reduction reaction in the first to third aspects. That is, (R) according to the fourth aspect of the invention is a method of manufacturing a drug-type (R) made from a first aspect - by using a type of 3-amino-1-phenyl-propanol derivative as an intermediate in the second step The reaction can be further carried out to obtain the ( R ) -form drug.

Specifically, through the first aspect, the inventors of the present invention have confirmed that a specific optical isomer can be synthesized with high optical purity by carrying out an asymmetric reduction reaction using a spiroborate ester catalyst. Through the second and third aspects, The type and optical purity of the isomer mainly formed depending on the kind of the spiroborate ester catalyst of the catalyst, and in particular, the catalyst capable of producing the R or S isomer with high optical purity was determined.

( R ) -type drug, particularly ( R ) -floxetin ((( R )) - type drug, by performing the substitution reaction using the ( R ) -3-amino- R) -N-methyl-3- phenyl-3- (4- (trifluoromethyl) phenoxy) propan-1-amine), (R) - Public paroxetine ((R) -N-methyl- 3-phenyl-3- ( o-tolyloxy) propan-1- amine) or (R) - Nisoxetine ((R) -3- (2- methoxyphenoxy) a step of generating a -N-methyl-3-phenylpropan- 1-amine).

[Reaction Scheme 4]

The reaction according to the second step can be carried out according to a conventional method for producing flocetin, cocetin or niacin cetin from 3-amino-1-phenylpropanol derivatives. Specifically, a 3-amino-1-phenylpropanol derivative represented by the general formula (3a) or (3b) is dissolved in a solvent, and then phenol or chlorobenzene (for example, 1-chloro-4- Benzene, o-cresol or methoxyphenol), and reacting them. As the solvent, dimethylsulfoxide (DMSO) or tetrahydrofuran (THF) may be used. Further, when the amino group of the intermediate 3-amino-1-phenylpropanol derivative compound is not a methylamino group, additional functional group elimination may be performed before or after the second step reaction. This can be done according to conventional methods known in the art. For example, in the case of dimethylamino (NMe ₂ ), demethylation is carried out in the presence of Zn and ClCO ₂ CH ₂ CCl ₃ to produce flocetin, cocetin, nisin cetin or intermediates for making them, comprising a monomethylamine group .

In the second step, the compound represented by Formula 3 may be used in an amount of 100 to 300 moles per 100 moles of 3-amino-1-phenylpropanol derivative compound represented by Formula 2.

Further, the second step may be carried out with stirring at 0 ° C to 50 ° C for 1 hour to 48 hours. Or the second step may be carried out while heating at 70 to 110 ° C for 2 to 10 hours.

According to the method for producing an ( R ) -type drug according to the third aspect of the present invention, by using the 3-amino-1-phenylpropanol derivative having high optical activity obtained through the first step and the second step as an intermediate, as well as the type drug (e.g., a flock paroxetine, Public paroxetine, Nisoxetine, etc.) can be produced, the (R) with high optical purity (ee) than the conventional method - enantiomerically pure (R) to form the drug .

In the first step according to the fourth aspect of the present invention, as described in the first embodiment, when a halogen-substituted? -Haloketone compound is used as a reactant, a step of introducing an amine group by a substitution reaction with an amine compound . ≪ / RTI >

When the amino group contains at least one methyl group or a substituent other than the methyl group, a reaction such as demethylation may be further carried out to convert the amino group to a methylamino group. The conversion of the amino group to the methylamino group may be performed at any time before or after the second step.

More specifically, as shown in Reaction Scheme 5 below, when 3-methylamino-1-phenylpropanone is used as a starting material, firstly, ( R ) -3-methylamino- - it may generate a type drug - generating a phenyl propanol, followed by the (R) through a two-phase reaction - (R) such as Nisoxetine-floc paroxetine, (R) - Public paroxetine or (R).

[Reaction Scheme 5]

When 3-dimethylamino-1-phenylpropanone is used as a starting material as shown in the following reaction scheme 6, the reaction is demethylated in the second step to obtain a target ( R ) -type from an intermediate containing a monomethylamine group The drug ( R ) -type drug can be prepared by preparing a drug or by demethylating it after the second step reaction.

[Reaction Scheme 6]

According to the process for producing duloxetine according to the fourth aspect of the present invention, by using the ( R ) -3-amino-1-phenylpropanol derivative having high optical activity obtained through the first step, enantiomerically pure R) - type drugs for example, (R) - floc paroxetine, (R) - Public paroxetine or (R) - nisok above, the high purity (ee than that of the conventional method) as well can be produced, such as paroxetine (R) - Can be obtained.

Amino-1-phenylpropanol derivatives according to the present invention and an enantiomerically pure enantiomerically enriched cetethine, nisuccine and flocetin using the same, - a phenyl propanol derivative as compared to the conventional in any way more can be obtained in high yield and optical purity (ee), by using it as an intermediate enantiomerically pure and high optical purity (ee) (R) - type Public paroxetine , Nisse citrate and flocetine can be prepared.

1 is a schematic diagram showing an optically active 3-amino-1-phenylpropanol residue as a core intermediate of duloxetine, fluoxetine, nisoxetine and tomoxetine.

Hereinafter, the constitution and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Manufacturing example  1. Preparation of reactants

1.1. 3-dimethylamino-1- Phenylpropane One (3- dimethylamino -One- phenylpropane -1-one < / RTI >

(1.43 g, 1 equiv.), Dimethylamine hydrochloride (11.64 g, 3 eq.) And acetophenone (13 ml, 2.3 eq.) Were dissolved in ethanol (10 ml ). 35% hydrochloric acid (0.2 mL) was added and the mixture was refluxed for 5 hours. The yellowish solution was diluted with cold acetone (50 mL) and cooled at 0 < 0 > C for several hours. The crystals were filtered, washed with acetone (20 ml × 2), dissolved in water (20 ml), and extracted with ethyl acetate (35 ml × 2). The aqueous layer was treated with potassium carbonate (pH 10) and extracted with ethyl acetate (35 ml × 5). The organic phases were dried over magnesium sulphate magnesium and concentrated under reduced pressure to give an oil-like Mannich base (77%).

^{1 H NMR d 2.19 (s,} 6H), 2.66 (t, 2H, J = 7.3 Hz), 3.05 (t, 2H, J = 7.3 Hz), 7.35 (t, 2H, J = 7.4 Hz), 7.44 (t , ≪ / RTI > 1H, J = 7.4 Hz), 7.86 (d, 2H, J = 7.1 Hz);

¹³ C NMR d 36.9, 45.5, 54.4, 128.1, 128.6, 133.0, 137.0, 199.0;

MS (ESI): 178 [M + H] < ⁺ >.

1.2. 3- ( Benzylmethylamino) -One- Phenylpropane -1-one hydrochloride (3- ( benzylmethylamino ) -1-phenylpropan-1-one hydrochloride )

Acetophenone (12.5 g, 100 mmol, 1.0 eq.) Dissolved in isopropyl alcohol (IPA, 65 mL) and n-methyl-1-phenylmethanamine hydrochloride , 266.3 mmol, 2.5 eq.), Paraformaldehyde (7.0 g, 233 mmol, 2.4 eq.) And 37% hydrochloric acid (5.1 mL, 51.7 mmol, 0.5 eq. After cooling the reaction mixture to room temperature, the white solid was filtered and washed with IPA (50 mL). The white solid was dried in vacuo to give the product (22.4 g, 74% yield).

White solid;

^{1 H NMR (300 MHz, DMSO-} d 6) δ H 10.86 (bs, 1H, H Cl) 8.03-7.99 (m, 2H, Ar- H), 7.63-7.41 (m, 8H, Ar- H), 4.49 -4.27 (m, 2H, -NC H 2 C 6 H 5), 3.72 (t, 2H J = 7.5 Hz, -COCH 2), 3.49-3.28 (m, 2H, C H 2 N-), 2.70 (d , 3H, J = 4.6, -NC H 3);

EI-MS: m / z (%) 253 (M ⁺ , 10), 162 (45), 120 (25), 105 (40), 91 (100).

1.3. 3- ( Methyl amino )-One- Phenylpropane -1-one hydrochloride (3- ( methylamino ) -1-phenylpropan-1-one hydrochloride )

To a flame dried 100 mL sealed tube was added acetophenone (3.1 g, 25 mmol), paraformaldehyde (1.05 g, 35 mmol) and N-methyl amine hydrochloride , 1.86 g, 27.5 mmol) was added and dissolved in 12.5 ml of anhydrous EtOH. To the stirred reaction mixture was added concentrated hydrochloric acid (conc. HCl, 0.125 mL) and the vessel screw was tightly fitted, followed by heating at 110 DEG C for 20 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude residue was dissolved in 50 mL of ethyl acetate and stirred vigorously until precipitation occurred. The precipitate was filtered and crude precipitate (4.33 g, 87%) was recrystallized three times with hot IPA.

The light yellow solid (1.98 g, 39.8%, 95% purity - determined from ¹ H NMR spectra);

^{1 H NMR (300 MHz, CDCl} 3) 8.09-8.03 (m, 2H), 7.66-7.63 (q, J = 1.9 Hz, 1H), 7.57-7.51 (m, 2H), 3.56 (t, J = 6.2 Hz , 2H), 3.40 (q, J = 6.8 Hz, 2H), 2.98 (s, 3H);

EI-MS (70 eV) (rel. Intensity): m / z 163 (58%) [M] ⁺ .

Manufacturing example  2. Preparation of Catalyst

2.1. cat -1 production

A; (2.5 mmol, 140 ㎕ ethylene glycol) was added anhydrous ethylene glycol in a round bottom flask equipped with a septum and N ₂ flow. Triisopropylborate (2.55 mmol, 0.58 mL) was then added followed by dry toluene (7 mL). The reaction mixture was gently heated to reflux until a homogeneous, colorless solution was formed. Of dry toluene was dissolved in (5 ㎖) (S) - (-) - 2- amino -1,1,3- triphenyl-1-propanol ((S) - (-) - 2-amino-1,1,3 -triphenyl-1-propanol; 2.5 mmol, 759 mg) was added to the reaction mixture. A white precipitate was observed during the addition process. The reaction mixture was allowed to stand at 80 < 0 > C for 1 hour and then all volatiles were evaporated in vacuo. The white crystalline solid was dried under high vacuum to yield the title compound as a quantitative yield.

2.2. cat -2 production

Of anhydrous ethylene glycol (2.5 mmol, 140 ㎕) was added to a round bottom flask equipped with a septum and N ₂ flow. Triisopropylborate (2.55 mmol, 0.58 mL) was then added followed by dry toluene (7 mL). The reaction mixture was carefully heated to reflux until a homogeneous, colorless solution formed. It was dissolved in dry toluene (5 ㎖) (S) - (-) - α, α- diphenyl-2-pyrrolidine methanol ((S) - (-) - α, α-diphenyl-2-pyrrolidinemethanol; 2.49 mmol , 633 mg) was added to the reaction mixture. A white precipitate was observed during the addition process. The reaction mixture was allowed to stand at 80 < 0 > C for 1 hour and then all volatiles were evaporated in vacuo. The white crystalline solid was dried under high vacuum to yield the title compound in quantitative yield.

2.3. cat -3 production

Of anhydrous ethylene glycol (2.5 mmol, 140 ㎕) was added to a round bottom flask equipped with a septum and N ₂ flow. Triisopropylborate (2.55 mmol, 0.58 mL) was then added followed by dry toluene (7 mL). The reaction mixture was carefully heated to reflux until a homogeneous, colorless solution formed. Of dry toluene was dissolved in (5 ㎖) (S) - (-) - α, α- di- (2-naphthyl) -2-pyrrolidine methanol ((S) - (-) - α, α-di- (2-naphthyl) -2-pyrrolidinemethanol; 2.5 mmol, 880 mg) was added to the reaction mixture. A white precipitate was observed during the addition process. The reaction mixture was allowed to stand at 80 < 0 > C for 1 hour and then all volatiles were evaporated in vacuo. The white crystalline solid was dried under high vacuum to yield the title compound in quantitative yield.

2.4. cat -4 production

Anhydrous pinacol (2.5 mmol, 296 mg) was added to a round-bottomed flask equipped with a septum and N ₂ flow. Triisopropylborate (2.55 mmol, 0.58 mL) was then added followed by dry toluene (7 mL). The reaction mixture was carefully heated to reflux until a homogeneous, colorless solution formed. It was dissolved in dry toluene (5 ㎖) (S) - (-) - α, α- diphenyl-2-pyrrolidine methanol ((S) - (-) - α, α-diphenyl-2-pyrrolidinemethanol; 2.49 mmol , 633 mg) was added to the reaction mixture. A white precipitate was observed during the addition process. The reaction mixture was allowed to stand at 80 < 0 > C for 1 hour and then all volatiles were evaporated in vacuo. The white crystalline solid was dried under high vacuum to yield the title compound in quantitative yield.

2.5. cat Production of -5

Anhydrous catechol (2.5 mmol, 275 mg) was added to a round-bottomed flask equipped with a septum and N ₂ flow. Triisopropylborate (2.55 mmol, 0.58 mL) was then added followed by dry toluene (7 mL). The reaction mixture was carefully heated to reflux until a homogeneous, colorless solution formed. It was dissolved in dry toluene (5 ㎖) (S) - (-) - α, α- diphenyl-2-pyrrolidine methanol ((S) - (-) - α, α-diphenyl-2-pyrrolidinemethanol; 2.49 mmol , 633 mg) was added to the reaction mixture. A white precipitate was observed during the addition process. The reaction mixture was allowed to stand at 80 < 0 > C for 1 hour and then all volatiles were evaporated in vacuo. The white crystalline solid was dried under high vacuum to yield the title compound in quantitative yield.

2.6. cat -6 production

Of anhydrous ethylene glycol (2.5 mmol, 140 ㎕) was added to a round bottom flask equipped with a septum and N ₂ flow. Triisopropylborate (2.55 mmol, 0.58 mL) was then added followed by dry toluene (7 mL). The reaction mixture was carefully heated to reflux until a homogeneous, colorless solution formed. To a solution of ( R ) - (+) -, alpha -diphenyl-2-pyrrolidine methanol (( R ) - (+) - alpha, alpha-diphenyl-2-pyrrolidineemethanol dissolved in dry toluene , 633 mg) was added to the reaction mixture. A white precipitate was observed during the addition process. The reaction mixture was allowed to stand at 80 < 0 > C for 1 hour and then all volatiles were evaporated in vacuo. The white crystalline solid was dried under high vacuum to yield the title compound in quantitative yield.

Example  One: ( R ) -3- Chloro -1-phenylpropanol (( R ) -3- chloro -One- phenylpropanol )

1.1. cat -1 R ) -3- Chloro -One- Of phenylpropanol  Produce

Cat-1 (0.05 mmol, 20 mg) prepared in Preparation Example 2.1 was dissolved in 1 ml of THF, BH _3. DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. To the reaction mixture was added dropwise a solution of 3-chloropropiophenone (0.59 mmol, 100 mg) in 0.45 mL of THF dropwise over 5 minutes. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. After removal of the solvent, ethyl acetate and water were added to separate the organic layer. Ethyl acetate was added to the separated aqueous layer to further extract it. The organic layers were combined, dried over Na ₂ SO ₄ and filtered. The obtained filtrate was concentrated and purified by column chromatography (hexane: EtOAc = 3: 1) to obtain solid ( R ) -3-chloro-1-phenylpropanol (yield: 71%).

¹ H-NMR (300 MHz, CDCl ₃ )? 7.36-7.25 (m, 5H), 4.93 (dd, J = 8.25 Hz, 1H), 3.77-2.68 , 2.28-2.17 (m, 1 H), 2.13-2.02 (m, 2 H);

HPLC (Chiralcel OB-H column, i- PrOH / Hexane 20/80, 0.8 ml / min): t ₁ = 7.0 min (S), t ₂ = 8.2 min (R); ee = 47%.

1.2. cat -2 using ( R ) -3- Chloro -One- Of phenylpropanol  Produce

Cat-2 (0.06 mmol, 20 mg) prepared in Preparation Example 2.2 was dissolved in 1 ml of THF, BH _3. DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. To the reaction mixture was added dropwise a solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF dropwise. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. ( R ) -3-chloro-1-phenylpropanol (yield: 83%, 93% ee ) was obtained in the same manner as in Example 1.1.

1.3. cat -3 ( R ) -3- Chloro -One- Of phenylpropanol  Produce

Cat-3 (0.05 mmol, 20 mg) prepared in Preparation Example 2.3 was dissolved in 1 mL of THF, BH _3. DMS (0.42 mmol, 0.04 mL) was added, and the mixture was stirred for about 7 minutes. To the reaction mixture was added dropwise a solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF dropwise. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. ( R ) -3-chloro-1-phenylpropanol (yield: 76%, 87% ee ) was obtained in the same manner as in Example 1.1.

1.4. cat -4 using ( R ) -3- Chloro -One- Of phenylpropanol  Produce

Cat-4 (0.06 mmol, 20 mg) prepared in Preparation 2.4 was dissolved in 1 ml of THF, BH _3. DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. To the reaction mixture was added dropwise a solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF dropwise. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. ( R ) -3-chloro-1-phenylpropanol (yield: 63%, 63% ee ) was obtained in the same manner as in Example 1.1.

1.5. cat -5 ( R ) -3- Chloro -One- Of phenylpropanol  Produce

Cat-5 (0.05 mmol, 20 mg) prepared in Preparation Example 2.5 was dissolved in 1 ml of THF, BH _3. DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. To the reaction mixture was added dropwise a solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF dropwise. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. ( R ) -3-chloro-1-phenylpropanol (yield: 75%, 73% ee ) was obtained in the same manner as in Example 1.1.

1.6. cat -2 using ( R ) -3- Chloro -One- Of phenylpropanol  Mass production

Cat-2 (1.78 mmol, 575 mg) prepared in Preparation Example 2.2 was dissolved in 25 mL of THF, and BH ₃ DMS (12.5 mmol, 1.18 mL) was added thereto, followed by stirring for 7 minutes. A solution of 3-chloropropiophenone (17.8 mmol, 3.0 g) in 6 mL of THF was added dropwise to the reaction mixture dropwise over 10 minutes. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. ( R ) -3-chloro-1-phenyl-propanol (yield: 95%, 93% ee ) was obtained in the same manner as in Example 1.1.

The above compound was recrystallized from the nucleic acid to obtain ( R ) -3-chloro-1-phenyl-propanol (86% recovery) with 99% ee .

HPLC (Chiralcel OB-H column, i- PrOH / Hexane 20/80, 0.8 ml / min): t ₁ = 7.01 min (S), t ₂ = 8.22 min (R).

Example  2: ( R ) -3-dimethylamino-1-phenylpropanol (( R ) -3- dimethylamino -1-phenylpropanol)

2.1. Tri (3-dimethylamino-1- Phenylpropyl ) Borate's  Produce

Cat-2 (0.05 mmol, 18 mg) prepared in Preparation Example 2.2 was dissolved in 1 ml of THF, BH _3. DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. To the reaction mixture was added dropwise a solution of 3-dimethylaminopropiophenone (0.56 mmol, 100 mg) in 0.45 mL of THF dropwise. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. After removal of the solvent, ethyl acetate and water were added to separate the organic layer. Ethyl acetate was added to the separated aqueous layer to further extract it. The organic layers were combined, dried over Na ₂ SO ₄ and filtered. The resulting filtrate was concentrated and purified by column chromatography (hexane: ethyl acetate = 3: 1) to obtain tri (3-dimethylamino-1-phenylpropyl) propyl 3-dimethylamino- ) Tri (3-dimethylamino-1-phenylpropyl) borate (90.6 mg, yield 89%) was obtained in the form of an oil.

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.34 (m, 5H), 4.70 (t, J = 6.45 Hz, 1H), 3.02-2.75 (m, 2H), 2.56 (s, 3H), 2.52 (s , ≪ / RTI > 3H), 2.15 (m, 3H);

HPLC (Chiralcel OD-H column, i- PrOH / Hexane = 5/95, 0.5 ml / min): t ₁ = 57.6 min (S), t ₂ = 67.6 min (R); ee = 95%.

2.2. ( R ) -3-dimethylamino-1- Of phenylpropanol  Produce

(3-dimethylamino-1-phenylpropyl) borate (780 mg, 1.43 mmol) prepared in Preparation Example 2.1 was dissolved in 5 ml of methanol and heated at 80 ° C for 20 hours. After removal of the solvent, ethyl acetate and water were added to separate the organic layer, and the aqueous layer was extracted again with ethyl acetate. The extracted organic layer was dried over Na ₂ SO ₄ and filtered. The resulting filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate: methanol: triethylamine = 10: 10: 1) to obtain ( R ) -3-dimethylamino-1-phenylpropanol (692 mg, yield 90% Lt; / RTI > as a solid.

^{1 H-NMR δ 7.31 (5H} , m), 5.87 (1H, br), 4.93 (1H, m), 2.66 (1H, m) 2.48 (1H, m), 2.30 (6H, s, CH3), 1.83 ( 2H, m);

HPLC (Chiralcel OD-H column, i- PrOH / Hexane = 5/95, 1.0 ml / min, wavelength 254 nm): t ₁ = 6.9 min (S), t ₂ = 9.1 min (R); ee = 96%.

Example  3: ( R ) -3- Benzyl (methyl) amino -1-phenylpropanol (( R ) -3-benzyl (methyl) amino-1-phenylpropanol)

Cat-2 (0.08 mmol, 26 mg) prepared in Preparation Example 2.2 was dissolved in 2 mL of THF, and BH ₃ DMS (0.55 mmol, 0.05 mL) was added thereto, followed by stirring for about 7 minutes. A solution of 3-benzyl (methyl) aminopropiophenone (0.79 mmol, 200 mg) in 0.45 mL of THF was added dropwise to the reaction mixture. After 2 hours of reaction at room temperature, 5 ml of methanol was added to terminate the reaction and the reaction was heated at 80 ° C for 20 hours. After removal of the solvent, ethyl acetate and water were added to separate the organic layer. Ethyl acetate was added to the separated aqueous layer to further extract it. The extracted organic layer was dried over Na ₂ SO ₄ and filtered. The obtained filtrate was concentrated and purified by column chromatography (hexane: ethyl acetate = 3: 1) to obtain ( R ) -3-benzyl (methyl) amino-1-phenylpropanol as a solid (yield: 84%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.36-7.22 (m, 5H), 4.75-4.67 (m, 1H), 4.03-3.84 (m, 2H), 2.94-2.58 (m, 2H), 2.42 ( s, 3H), 2.36-2.25 (m, 2H), 2.05 (br, IH);

HPLC (Chiralcel OD-H column, i- PrOH / Hexane = 20/80, 0.8 ml / min): t ₁ = 19.9 min (S), t ₂ = 22.1 min (R); ee = 89%.

Example  4: ( S ) -3- Chloro -1-phenylpropanol (( S ) -3- chloro -One- phenylpropanol )

Cat-6 (1.78 mmol, 575 mg) prepared in Preparation 2.6 was dissolved in 25 mL of THF, and BH ₃ DMS (12.5 mmol, 1.18 mL) was added thereto, followed by stirring for about 7 minutes. A solution of 3-chloropropiophenone (17.8 mmol, 3.0 g) in 6 mL of THF was added dropwise to the reaction mixture dropwise over 10 minutes. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. ( S ) -3-chloro-1-phenyl-propanol (yield: 94%, 91% ee ) was obtained in the same manner as in Example 1.1.

The above compound was recrystallized from the nucleic acid to obtain ( S ) -3-chloro-1-phenyl-propanol (84% recovery) at 99% ee .

HPLC (Chiralcel OB-H column, i- PrOH / Hexane 20/80, 0.8 ml / min): t ₁ = 6.95 min (S), t ₂ = 8.36 min (R).

Example  5: ( R ) -3- Chloro -1- (4- Fluorophenyl ) -1-propanol (( R ) -3- chloro -1- (4-fluorophenyl) -1-propanol)

Cat-3 (0.03 mmol, 25 mg) prepared in Preparation Example 2.3 was dissolved in 1 ml of THF, and BH ₃ · DMS (0.38 mmol, 0.04 ml) was added thereto, followed by stirring for about 7 minutes. To the reaction mixture was added dropwise a solution of 3-chloro-4'-fluoropropiophenone (0.54 mmol, 100 mg) in 0.45 mL of THF dropwise over 30 minutes. After 6 hours of reaction at room temperature, methanol was added to terminate the reaction. After removal of the solvent, ethyl acetate and water were added to separate the organic layer. Ethyl acetate was added to the separated aqueous layer to further extract it. The extracted organic layers were combined, dried over Na ₂ SO ₄ and filtered. The obtained filtrate was concentrated and purified by column chromatography (hexane: ethyl acetate = 3: 1) to obtain ( R ) -3-chloro-1- (4-fluorophenyl) .

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.32 (m, 2H), 7.03 (m, 2H), 4.92 (dd, J = 8.45 Hz, J = 4.69 Hz 1H), 3.71 (m, 1H), 3.52 (m, 1 H), 2.19 (m, 2 H), 2.04 (m, 1 H);

^{13 C-NMR (75 MHz,} CDCl 3) 163.9, 160.7, 139.4 (d, J CF = 3.1 Hz), 127.5 (d, J CF = 7.9 Hz), 115.5 (d, J CF = 21.4 Hz), 70.6, 41.5 (d, J _CF = 9.4 Hz);

EI-MS (70 eV): m / z 188 (M ⁺ , 9), 125 (100), 97 (70), 77 (19);

HPLC (Chiralcel OD-H column, i- PrOH / Hexane = 20/80, 0.8 ml / min): t ₁ = 6.2 min (S), t ₂ = 6.8 min (R); ee = 93%.

Example  6: ( R ) - Flocetin (( R ) - fluoxetine )

6.1. ( R ) -3- Iodo -1-phenylpropanol (( R ) -3- iodo -One- phenylpropanol )

NaI (5.5 g, 36 mmol) was added to a solution of ( R ) -3-chloro-l-phenylpropanol (3.2 g, 18.7 mmol) in acetone (250 mL). The reaction mixture was refluxed for 16 hours. The resulting mixture was filtered, concentrated in vacuo and diluted with diethyl ether. This was washed with brine (brine), filtered, dried over magnesium sulfate and concentrated to dryness to an oil form (R) -3- iodo-1-phenyl-propanol ((R) -3-iodo- 1-phenyl-1- propanol) (4.5 g, 91% yield).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.4-7.2 (5H, m), 4.7 (1H, dd, J = 4.8, 8.0 Hz), 3.3-3.2 (1H, m), 3.2-3.1 (1H, m ), 2.3 (1H, s), 2.3-2.1 (2H, m).

6.2. ( R ) -3- Methyl amino -1-phenylpropanol (( R ) -3- methylamino -1-phenylpropanol)

A solution of the obtained ( R ) -3-iodo-1-phenylpropanol (1.5 g, 5.7 mmol) and methylamine (40% aqueous solution, 4.4 ml, 57.2 mmol) in THF (10 ml) And stirred overnight. To the solution was added 2 N NaOH (2 mL), and the solvent was then removed under reduced pressure. The residue was extracted with ether and the organic phase was washed with brine and then dried over anhydrous sodium sulfate to give ( R ) -3-methylamino-1-phenylpropanol (800 mg, yield 85%) as an oil.

_{^{1 H NMR (CDCl 3) δ}} 7.36-7.20 (m, 5H), 4.84 (dd, J = 4.0, 7.8 Hz, 1H), 4.02 (br s, 2H, -NH and -OH), 2.80? 2.73 (m , 2H), 2.36 (s, 3H), 1.84 - 1.72 (m, 2H);

_{^{13 C NMR (CDCl 3):}} 145.2, 128.2, 126.9, 125.6, 74.8, 50.0, 37.0, 35.9;

_{HRMS (ESI) for C 10 H} 15 NNaO [M + Na] +, calcd 188.1051, found: 188.1056.

6.3. ( R ) - Of fluoxetine  Produce

( R ) -3-methylamino-1-phenylpropanol (0.427 g, 2.58 mmol) obtained in Example 6.2 was placed in a round bottom flask and 13 ml of dimethylsulfoxide (DMSO) was added to dissolve. Sodium hydride (NaH, 60%, 0.160 g, 4 mmol) was added to the solution and the mixture was heated at 55 占 폚 for 2 hours. After the solution turned dark orange, 1-chloro-4-trifluoromethylbenzene (0.53 ml, 3.87 mmol) was added and the mixture was heated at 90 占 폚 for 6 hours. After the reaction was completed, water (10 ml) was added and extracted several times with 20 ml of ether. The extracted organic layer was washed with brine, and the obtained organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to remove the solvent. The residue was separated by flash silica column chromatography (MeOH) to obtain the title compound ( R ) -floxetin 0.42 g, yield 84%).

_{^{1 H-NMR (CDCl 3)}} δ 7.32 (d, 2H, J = 8.52 Hz), 7.25-7.16 (m, 5H), 6.81 (d, 2H, J = 8.57 Hz), 5.22 (dd, 1H, J 1 _{= 4.72 Hz, J 2 = 7.87} Hz), 2.79-2.65 (m, 2H), 2.34 (s, 3H), 2.27-1.88 (m, 2H).

Example  7: ( R ) - Civilian Satin (( R ) - tomoxetine ) And ( R ) - Nyxatetin (( R ) - nisoxetine )

7.1. ( S ) -3- Iodo -1-phenylpropanol (( S ) -3- iodo -One- phenylpropanol )

One embodiment (S) produced according to example 4-chloro-3-phenyl-1-propanol (3.2 g, 18.7 mmol) from the Example 6.1, in the same manner as (S) -3-iodo-1-phenyl propanol (Yield: 78%).

7.2. ( S ) -3- Methyl amino -1-phenylpropanol (( S ) -3- methylamino -1-phenylpropanol)

( S ) -3-methylamino-1-phenylpropanol was obtained from ( S ) -3-iodo-1-phenylpropanol (1.5 g, 5.7 mmol) obtained in the above Example 7.1. Phenylpropanol (yield: 88%) was obtained.

7.3. ( R ) - Civil Engineering  Produce

To a solution of ( S ) -3-methylamino-1-phenylpropanol (200 mg, 1.2 mmol) obtained in Example 7.2 and o-cresol (130 mg, 1.2 mmol) in THF , Triphenylphosphine (328 mg, 1.25 mmol) and diethyl azodicarboxylate (218 mg, 1.25 mmol) were added, respectively, and the reaction solution was stirred at room temperature for 12 hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate was added to the residue to extract several times. The extracted organic layer was washed with brine, and the obtained organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to remove the solvent. The residue was purified by flash silica column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH = 1) to obtain the title compound ( R ) -Citomycetin (205 mg, yield 67%).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.36-7.22 (m, 5H), 7.11 (d, J = 7.2 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.60 ( d, J = 8.4 Hz, 1H), 5.25 (dd, J 1 = 4.4 Hz, J 2 = 8.4 Hz, 1H), 2.78-2.74 (m, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 2.20 - 2.17 (m, 1H), 2.05 - 2.02 (m, 1H);

¹³ C NMR (100 MHz, CDCl ₃ ): 142.2, 130.8, 129.0, 128.8, 128.5, 127.6, 126.7, 125.9, 125.8, 120.4, 112.9, 78.1, 48.7, 39.0, 36.7, 16.8;

HRMS (ESI) for C ₁₇ H ₂₁ N NaO [M + Na] ⁺ , calcd 278.1521, found: 278.1526.

7.4. ( R ) - Nissex  Produce

and it is synthesized and separated in the same manner as in Example 7.3 except for using 2-methoxyphenol (150 mg, 1.2 mmol) instead of o- cresol to give the title compound, (R) -. Nisoxetine (212 mg, yield 65%).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.36-7.26 (m, 5H), 6.88-6.87 (m, 2H), 6.70-6.68 (m, 1H), 6.62-6.60 (m, 1H), 5.19 (dd _{, J 1 = 4 Hz, J} 2 = 8.4 Hz), 3.97 (s, 3H), 2.96-2.89 (m, 2H), 2.53 (s, 3H), 2.36-2.29 (m, 1H), 2.10-2.03 ( m, 1 H);

¹³ C NMR (100 MHz, CDCl ₃ ): 149.7, 147.1, 141.2, 128.6, 127.7, 125.8, 121.7, 120.7, 116.1, 81.1, 55.9, 48.2, 36.9, 35.1, 11.7;

_{HRMS (ESI) for C 17 H} 21 NNaO 2 [M + Na] +, calcd 294.1470, found: 294.1474.

Claims (16)

(3) having an optically active enantiomeric excess ( ee ) of 80% or more, comprising subjecting a compound represented by the formula (1) to asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor. ≪ RTI ID = 0.0 > amino-1-phenylpropanol < / RTI &
[Chemical Formula 1]

In Formula 1,
X < ₁ > is hydrogen or halogen,
R is an amino group represented by halogen or NR ₁ R ₂ ,
Said halogen being F, Cl, Br or I,
R ₁ and R ₂ are each independently hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ aralkyl, aryl, pyrrolidinyl, piperidinyl or morpholinyl.
The method according to claim 1,
And when R is halogen, the method further comprises the step of introducing an amine group by a substitution reaction with an amine compound after the asymmetric reduction reaction.
The method according to claim 1,
The spiroborate ester catalyst comprises

,

,

,

,

,

,

,

And

≪ RTI ID = 0.0 > and / or < / RTI >
The method according to claim 1,
Wherein the hydrogen donor is at least one selected from the group consisting of BH ₃ -dimethylsulfide (DMS), BH ₃ -tetrahydrofuran (THF), LiAlH ₄ and NaBH ₄ .

or

Spiro borate ester with a hydrogen donor and a catalyst for asymmetric reduction reaction, which comprises for preparing a R-type 3-amino-1-phenyl-propanol derivative from a compound represented by the general formula (1) to greater than 80% enantiomeric excess rate Way:
[Chemical Formula 1]

In Formula 1,
X < ₁ > is hydrogen or halogen,
R is an amino group represented by halogen or NR ₁ R ₂ ,
Said halogen being F, Cl, Br or I,
R ₁ and R ₂ are each independently hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ aralkyl, aryl, pyrrolidinyl, piperidinyl or morpholinyl.
6. The method of claim 5,
And when R is halogen, the method further comprises the step of introducing an amine group by a substitution reaction with an amine compound after the asymmetric reduction reaction.
6. The method of claim 5,
The hydrogen donor is a method of not less than one selected from the group consisting of _{BH 3 -DMS, BH 3 -THF,} LiAlH 4 and NaBH _4.

Amino-1-phenylpropanol derivative from a compound represented by the following formula (1), wherein the S- type 3-amino-1-phenylpropanol derivative is an asymmetric reduction reaction with a hydrogen donor using a spiroborate ester catalyst Way:
[Chemical Formula 1]

In Formula 1,
X < ₁ > is hydrogen or halogen,
R is an amino group represented by halogen or NR ₁ R ₂ ,
Said halogen being F, Cl, Br or I,
R ₁ and R ₂ are each independently hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ aralkyl, aryl, pyrrolidinyl, piperidinyl or morpholinyl,
R ₃ is C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy or C ₁ to C ₄ perfluoroalkyl.

R is an amino group represented by halogen or NR ₁ R ₂ ,
Said halogen being F, Cl, Br or I,
R ₁ and R ₂ are each independently hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ aralkyl, aryl, pyrrolidinyl, piperidinyl or morpholinyl.
9. The method of claim 8,
And when R is halogen, the method further comprises the step of introducing an amine group by a substitution reaction with an amine compound after the asymmetric reduction reaction.
9. The method of claim 8,
The hydrogen donor is a method of not less than one selected from the group consisting of _{BH 3 -DMS, BH 3 -THF,} LiAlH 4 and NaBH _4.
A compound represented by the following formula (1)

or

( R ) -3-amino-1-phenylpropanol derivative represented by the following formula (2) as an intermediate by asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor; And
To, (R) a second step of reacting the compound represented an intermediate compound represented by the formula (2) by the following formula (3) - process for producing the drug form:
[Chemical Formula 1]

(2)

(3)

In the above formulas,
X < ₁ > is hydrogen or halogen,
X < ₂ > is hydroxy or halogen,
Said halogen being F, Cl, Br or I,
R ₁ and R ₂ are each independently hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ aralkyl, aryl, pyrrolidinyl, piperidinyl or morpholinyl,
R ₃ is C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy or C ₁ to C ₄ perfluoroalkyl.
12. The method of claim 11,
Wherein R ₁ and R ₂ are hydrogen and methyl,
And R < ₃ > is methyl, methoxy or trifluoromethyl.
13. The method of claim 12,
Wherein the ( R ) -type drug is ( R ) -floxetin, ( R ) -cindustine or ( R ) -ninitetine.
14. The method according to any one of claims 11 to 13,
And when R is halogen, the method further comprises the step of introducing an amine group by a substitution reaction with an amine compound after the asymmetric reduction reaction.
15. The method of claim 14,
Lt; RTI ID = 0.0 > amino group < / RTI > to a methylamino group.
14. The method according to any one of claims 11 to 13,
The hydrogen donor is a method of not less than one selected from the group consisting of _{BH 3 -DMS, BH 3 -THF,} LiAlH 4 and NaBH _4.

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