KR101071293B1 - Method for preparing optically active 2-sulfonyloxy-1-heteroarylethanol and method for preparing enantiomeric pure heteroaryl-aminoalcohol - Google Patents

Abstract

The present invention relates to a method for preparing an optically active 2-sulfonyloxy-1-heteroarylethanol derivative and a method for producing an enantiomerically pure heteroaryl-amino alcohol using the same, more specifically, α-sulfonyloxyhetero Method for preparing 2-sulfonyloxy-1-heteroarylethanol derivative having optical activity formed by asymmetric reduction reaction of aryl ketone compound in the presence of rhodium compound catalyst containing pentamethylcyclopentadienyl group and hydrogen donor and 2- A method for preparing enantiomerically pure heteroaryl-amino alcohols using sulfonyloxy-1-heteroarylethanol derivatives. According to the method for preparing the optically active 2-sulfonyloxy-1-heteroarylethanol derivative according to the present invention, the optically active 2-sulfonyloxy-1-heteroarylethanol derivative can be obtained with higher ee than any conventional method. By using the 2-sulfonyloxy-1-heteroarylethanol derivative having high optical activity as a starting material, it is possible to prepare enantiomerically pure heteroaryl-amino alcohol and duloxetine, as well as conventional methods. A higher ee can be obtained.

α-sulfonyloxyheteroaryl ethanol derivatives, asymmetric transfer hydrogenation, optically active amino alcohols, duloxetine

Description

Method for preparing optically active 2-sulfonyloxy-1-heteroarylethanol derivatives and a method for preparing enantiomerically pure heteroaryl-amino alcohols using the same {Method for preparing optically active 2-sulfonyloxy-1-heteroarylethanol and method for preparing enantiomeric pure heteroaryl-aminoalcohol}

The present invention relates to a method for preparing a 2-sulfonyloxy-1-heteroarylethanol derivative having high optical activity and a method for producing enantiomerically pure heteroaryl-amino alcohol using the same.

2-amino-1-heteroarylethanol residues having optical activity are used in various agricultural, pharmaceutical intermediates, fine chemicals, or building blocks. Beta3-adrenergic receptor agonists or 5-lipoxygenase inhibitors currently in use or in clinical trials or in development, such as duloxetine or bufuralol (5-lipoxygenase inhibitor) is a key intermediate and contains 2-amino-1-heteroarylethanol residues.

A compound having an aminoalcohol skeleton containing a heterocycle as the core intermediate may be represented by the structure of Formula 10 below.

[Formula 10]

Drugs having the structure of Formula 10 include, for example, duloxetine, bufuralol, and zileton. Representative compounds having an aminoalcohol skeleton containing a heterocycle as the core intermediate are shown in the following formula (11).

[Formula 11]

Duloxetine, which is used to treat depression and general anxiety disorder, is a drug belonging to the class of selective serotonin and noepinephrine reuptake blockers that are also used for pain and numbness caused by diabetic neuropathy. Such duloxetine acts by increasing the concentration of serotonin or noepinephrine in the brain, and these components serve to maintain mental balance and block pain signals (US 7,435,563; Pub. 10-2007-0104942). Bufuralol is a beta-adrenoceptor blocking agent and is used as an antihypertensive agent (Tetrahedron: Asymmetry 16 (2005) 3205). In addition, zileuton (Tetrahedron: Asymmetry 19 (2008) 956) as a beta3-adrenergic receptor agonist in clinical trials or developmental stages, 5-lipoxygenase inhibitors (5 L-770,644 (Bioorganic & Medicinal Chemistry Letters, 9 (9), p. 1251-1254), a lipoxygenase inhibitor, contains 2-amino-1-heteroarylethanol residues as key intermediates.

Derivatives comprising heteroarylethanol residues, such as furan, thiophene, benzofuran, etc., as inhibitors of 5-lipoxygenase, cyclooxygenase-2 and beta amyloid accumulation; It acts as an antagonist of brain cannabinoid receptors, central and peripheral GABAB-receptors, the angiotensin II receptors, and oxytocin hormones (Tetrahedron: Asymmetry, 14 (12), p. 1659-1664). In addition, as a natural product, phytochemicals are known as insect toxins (J. Nat. Prod. 1997, 60, 1214).

The process for preparing the compound of Formula 10 is generally subjected to key intermediates represented by the following Formulas 12, 13, 14 and 15.

[Chemical Formula 12]

(In Formula 12, X and Y are as defined in the present specification.)

[Formula 13]

(In Formula 13, X is as defined in the present specification, and W is chlorine, bromine and iodine.)

[Formula 14]

(In Formula 14, X is as defined in the present specification.)

[Formula 15]

(In Formula 15, X is as defined in the present specification, and Z is azido, cyano, and amino.)

In Formula 12, Y is toluenesulfonyloxy or methanesulfonyloxy; Chlorine, bromine, iodine (Formula 13) through conventional chemical reactions; Epoxides (Formula 14); Azido, cyano, amino (formula 15) and the like. This structure of the formula (12) is a key intermediate, it can be very easily and usefully converted to amino alcohol containing a heterocycle represented by the formula (10) through a conventional chemical reaction.

Optically active intermediates represented by the above formulas (10) to (15) are used for a wide variety of applications, and their synthesis methods are known. For example, a method for preparing a compound of Formula 13 or 14 known in the art includes asymmetric reduction reaction of α-substituted acetophenones using an oxazaborolidine catalyst and borane ( Angew . Chem) . ... Int Ed 37, 1986 (1998)]; [Tetrahedron Lett . 38 , 1125 (1997); And [ Tetrahedron Lett . 42 , 8919 (2001); Asymmetric Reduction of α-Substituted Acetophenones Using Asymmetric Transfer Hydrogenation (Paper [ Org . Lett . 7 , 5489 (2005)]; [ Org . Lett . 4 , 4373 (2002)] And Japanese Patent Laid-Open No. 2002-251994); Asymmetric reduction of aminoketones by hydrogen at high pressure (see J. Am . Chem . Soc . 122 , 6510 (2000)); Synthesis of diols using asymmetric dihydroxylation (see Tetraderon : Asymmetry 15 , 3955 (2004)); Dividing α-azidoalcohol by asymmetric acylation by an enzyme (see Tetraderon : Asymmetry 15 , 3939 (2004)); Reduction of α- azidoketone using microorganisms (see Tetraderon : Asymmetry 12 , 3381 (2001); J. Mol . Cat . B: Enzymatic 39 , 9 (2006)) is known.

Among the above methods, the asymmetric reduction of α-substituted acetophenones using an oxazaborolidine catalyst and borane is most frequently used. However, the reaction is essentially carried out at low concentrations while the loading of expensive catalysts used is as high as 0.1 equivalents to the substrate; The variation in optical activity due to the substitution of the phenyl ring is very large; The reaction is very sensitive to water or moisture; Asymmetric reduction of aminoketones by hydrogen at high pressure is only possible when the amino group is disubstituted, making it difficult to derivatize therefrom; A high pressure reactor is needed; There is a problem of using dangerous hydrogen gas.

In addition, asymmetric reduction of a-substituted acetophenones using asymmetric transfer hydrogenation has also been applied very effectively. However, the reaction is because the α-substituent is mainly -chlorine, -azido, -cyano, etc., the substrate α-haloacetophenone is very irritating to the skin and eyes, and also very unstable to light, there is a problem in mass production , α-azido-, or α-cyano-acetophenone has a problem that it is obtained with a lower ee value than α-haloacetophenone.

Duloxetine, N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine, is a dual serotonin and norepinephrine reuptake inhibitor. (+) Duloxetine has particular therapeutic utility as an antidepressant. Duloxetine and its preparation are described in US Pat. Nos. 5023269 and 4956388, and Tetrahedron Letters, 31, (49), 7101-04, 1990. Synthesis of seven different pathways is also reported in Drugs of the Future 2000, 25 (9) 907-916. The synthesis involved resolution of key intermediates or stereospecific reduction of keto groups to alcohols. The background art can be described as follows.

Known compounds dimethylamino ketones are obtained by conventional Mannich reactions starting from acetylthiophene, formaldehyde and dimethylamine, as shown in Scheme iii) above. In addition, when the chiral modified lithium aluminum hydride (LiAlH ₄ ) was used, the yield of the dimethylaminoalcohol compound was 74%, and the enantiomeric purity was 72% ee, which was relatively low. In addition, as shown in Scheme ii), after the synthesis of racemic dimethylaminoalcohol using sodium borohydride (NaBH ₄ ), it has been reported that the classical splitting, but the method is basically a conversion rate It does not exceed 50% and has the disadvantage of separating and purifying the mixed product.

In general, after the reaction of dimethylaminoalcohol and 1-fluoronaphthalene (EP 0457559 A2) is similarly performed, a method of synthesizing methylaminoalcohol by demethylation once again to obtain duloxetine is known. It is shown in the following scheme iii).

In addition, as shown in the following Scheme iii), a method of dividing β-azido alcohol or γ-chloro alcohol using an enzymatic method using a lipase and the like and a method of preparing the same are known (US 7,435,56). Chirality 12: 26-29 (2000); Tetrahedron Lett. 44 (2003) 4783), which inherently does not exceed 50% conversion and has the disadvantage of separating and purifying the mixed product.

As the asymmetric synthesis method, a method of producing by asymmetric reduction from chloroketone using 10 to 30 mol% of oxazaborrolidine catalyst is known, as shown in the following scheme (iii). However, the asymmetric synthesis method shows the best optical activity when chloroketone is a substrate, so in order to introduce methylamine, conversion to iodine, which is a good leaving group, is essential.

The inventors of the present invention, while studying a method for producing enantiomerically pure heteroaryl-aminoalcohols, are asymmetric in the presence of a rhodium catalyst and a hydrogen donor containing an α-sulfonyloxyheteroarylketone compound containing pentamethylcyclopentadienyl groups. Using a 2-sulfonyloxy-1-heteroethanol derivative having an optical activity by reduction reaction, a method for producing enantiomerically pure heteroaryl-aminoalcohol can be obtained in higher yield and ee than any conventional method. The present invention was completed.

An object of the present invention is to provide a method for preparing a 2-sulfonyloxy-1-heteroarylethanol derivative having high optical activity.

Another object of the present invention is to provide a method for preparing enantiomerically pure heteroaryl-amino alcohol using 2-sulfonyloxy-1-heteroarylethanol derivative having high optical activity.

Furthermore, another object of the present invention is to provide a method for producing enantiomerically pure duloxetine using 2-sulfonyloxy-1-heteroarylethanol derivative having high efficiency optical activity.

In order to achieve the above object, the present invention provides a 2-sulfur having an optical activity formed by asymmetric reduction of an α-sulfonyloxyheteroaryl ketone compound in the presence of a rhodium compound catalyst containing a pentamethylcyclopentadienyl group and a hydrogen donor. Provided is a method for preparing a ponyloxy-1-heteroarylethanol derivative.

In addition, the present invention is to react the 2-sulfonyloxy-1-heteroarylethanol derivative having an optical activity prepared by the above production method with a nitrile compound, and then cyclize the reduced amine compound to introduce an alkyl group A method for producing enantiomerically pure heteroaryl-amino alcohol, which is then carried out by decyclicization reaction, is provided.

Furthermore, in the present invention, the 2-sulfonyloxy-1-heteroarylethanol derivative having the optical activity prepared by the above method is reacted with a nitrile compound, followed by cyclization of the reduced amine compound to introduce an alkyl group. A method for producing enantiomerically pure duloxetine, which is then carried out by a decyclicization reaction and introducing a naphthyl group, is provided.

2-sulfonyloxy-1-hetero having optical activity formed by asymmetric reduction of the α-sulfonyloxyheteroaryl ketone compound according to the present invention in the presence of a rhodium compound catalyst containing a pentamethylcyclopentadienyl group and a hydrogen donor According to the method for preparing an arylethanol derivative, an optically active 2-sulfonyloxy-1-heteroarylethanol derivative can be obtained with a higher ee than any conventional method, and 2-sulfonyloxy having the high optical activity as a starting material. By using the -1-heteroarylethanol derivative, not only enantiomerically pure heteroaryl-amino alcohol and duloxetine can be produced, but also higher ee than the conventional method can be obtained.

Hereinafter, the present invention will be described in detail.

As the present invention is shown in Scheme 1,

2-sulfonyl having the optical activity formed by asymmetrically reducing the α-sulfonyloxyheteroaryl ketone compound of formula 4 in the presence of a hydrogen donor and a rhodium compound catalyst containing a pentamethylcyclopentadienyl group of formula 5 Provided are methods for preparing oxy-1-heteroarylethanol derivatives:

(In Scheme 1, X is oxygen or sulfur and Y is toluenesulfonyloxy or methanesulfonyloxy).

The reaction is characterized by using a process by catalytic asymmetric transfer hydrogenation. Y is a very good leaving group and can be easily reacted with nucleophiles such as N ₃ ^- or amines to be converted into 2-aminoethanol derivatives having optical activity. It can also be easily reacted with nucleophiles such as CN ^- to be converted into precursors of 3-aminoethanol derivatives having optical activity.

The α-sulfonyloxyketone compound of formula 4 used as starting material in the present invention may be prepared as shown in Scheme 4:

(X and Y in Scheme 4 are as defined in Scheme 1 above).

The α-toluenesulfonyloxyheteroaryl ketone compound of Chemical Formula 4 is generally a heteroaryl ketone of Chemical Formula 6 using [hydroxy (toluenesulfonyloxy) iodo] benzene (coser reagent ( Known as Koser's reagent) (J. Org. Chem. 1982, 47 , 2487), and the α-methanesulfonyloxyheteroaryl ketone compound of Formula 4 may be a heteroaryl ketone of Formula 6 It can be synthesized by reacting with [hydroxy (methanesulfonyloxy) iodo] benzene (Lodaya, et al., J. Org. Chem. 1988, 53, 210). Alternatively, the α-toluenesulfonyloxyheteroaryl ketone compound of Chemical Formula 4 is synthesized by converting the heteroaryl ketone of Chemical Formula 6 to silyl enol ether (hydroxy (toluenesulfonyloxy) iodo) benzene (Moriarty et al., J. Org. Chem. 1989, 54, 1101).

The rhodium compound catalyst having a pentamethylcyclopentadienyl group represented by the formula (5) used in the present invention is a (pentamethylcyclopentadienyl) rhodium (III) chloride dimer ([Rh (C ₅ Me ₅ ) Cl ₂ ]) in methylene chloride. ₂ ) a rhodium compound catalyst having a pentamethylcyclopentadienyl group represented by the following Chemical Formula 5 by reacting an optically active 1,2-diphenylethylene-N- ( p -toluenesulfonyl) diamine (TsDPEN) and then removing methylene chloride. Can be prepared. At this time, triethylamine may be further added to react.

The rhodium compound catalyst of the formula (5) is a known material, a rhodium compound having a pentamethylcyclopentadienyl group (generally represented by C ₅ Me ₅ , Cp *), for example (pentamethylcyclopentadienyl) rhodium ( III) Obtained by the reaction of chloride dimer [Rh (C ₅ Me ₅ ) Cl ₂ ] ₂ with optically active 1,2-diphenylethylene-N- ( p -toluenesulfonyl) diamine (TsDPEN), TsDPEN-RhCl It can be represented by -Cp *.

For example, the rhodium catalyst is described in Mashima et al., Chem . Letters , 1199 (1998); Chem . Letters , 1201 (1998)] , which discloses one equivalent of (pentamethylcyclopentadienyl) rhodium (III) chloride dimer [Rh (C ₅ Me ₅ ) in methylene chloride solvent. ) Cl ₂ ] ₂ , 2 equivalents of optically active 1,2-diphenylethylene-N- ( p -toluenesulfonyl) diamine (TsDPEN) and 4 equivalents of triethylamine were added to the reaction product, followed by washing with water and recrystallization. The rhodium catalyst is obtained in a yield of 70%.

According to the present invention, in addition to the known method, the compound of Chemical Formula 5 may be obtained by the following steps.

Method (i): 1 equivalent of (pentamethylcyclopentadienyl) rhodium (III) chloride dimer [Rh (C ₅ Me ₅ ) Cl ₂ ] ₂ , 2 equivalents of optically active 1,2-di in methylene chloride solvent Phenylethylene-N- ( p -toluenesulfonyl) diamine (TsDPEN) and 4 equivalents of triethylamine are added to remove the solvent from the reaction to obtain the above catalyst in quantitative yield immediately; And

Method (ii): 1 equivalent of (pentamethylcyclopentadienyl) rhodium (III) chloride dimer [Rh (C ₅ Me ₅ ) Cl ₂ ] ₂ and 2 equivalents of optically active 1,2-di in methylene chloride solvent A process for obtaining the above catalyst in quantitative yield after removal of the solvent from the resulting reaction in the absence of triethylamine by addition of phenylethylene-N- ( p -toluenesulfonyl) diamine (TsDPEN).

The methods (i) and (ii) not only can provide a catalyst much more easily than the methods known in the above papers, but also have excellent synthesis yields of catalysts, and are known in terms of efficiency as well as α-chloroacetophenones. It shows the catalytic performance equivalent to the asymmetric reduction of, allowing the production of the desired product with a higher ee (enantiomeric excess) than any conventional method.

The amount of the substrate, i.e., the α-sulfonyloxyheteroarylketone compound of Formula 4, which is a starting material for the catalyst, is typically used in the range of 100 to 100,000 as the molar ratio (S / C) of the substrate to the metal compound. More preferably, 1,000 to 10,000.

The preparation method according to the invention can be carried out using a hydrogen donor. For example, the hydrogen donor may use formic acid, a metal salt or an ammonium salt thereof, or an azeotrope of formic acid with an amine (for example, Et ₃ N). The hydrogen donor can be used without the use of a solvent or dissolved in a solvent. Ethyl acetate, toluene, methylene chloride, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, isopropanol, etc. may be used as the solvent.

The 2-sulfonyloxy-1-heteroaryl ethanol derivative compound of Formula 1 obtained in the present invention can be purified by conventional extraction, distillation, recrystallization, column chromatography, and the like. The ee of the synthesized optically active 2-sulfonyloxy-1-heteroarylethanol can be determined by HPLC using a column equipped with Chiralcel OD-H, DB-H, OJ-H from Daicel.

According to the production method according to the present invention, an optically active 2-sulfonyloxy-1-heteroarylethanol derivative can be obtained with a higher ee than any conventional method.

The present invention also provides a process for preparing enantiomerically pure heteroaryl-amino alcohols.

More specifically, the enantiomerically pure heteroaryl-amino alcohol is represented by Scheme 2 below,

Reacting a 2-sulfonyloxy-1-heteroarylethanol derivative of Formula 1 with a nitrile compound to prepare a nitrile compound of Formula 7 (step 1);

Preparing an amine compound of formula 8 by reducing the nitrile compound of formula 7 prepared in step 1 (step 2);

Preparing a compound of formula 9 by cyclizing the amine compound of formula 8 prepared in step 2 (step 3);

Preparing a compound of Formula 10 by introducing an alkyl group to nitrogen of the compound of Formula 9 prepared in step 3 (step 4); And

It may be prepared by a method comprising the step (step 5) to prepare an alkylamine-alcohol compound of formula 2 by the de-ring reaction of the compound of formula 10 prepared in step 4.

(Wherein X is oxygen or sulfur, Y is toluenesulfonyloxy or methanesulfonyloxy and R is C ₁ to C ₄ straight or branched alkyl).

Hereinafter, the manufacturing method according to the present invention will be described in more detail step by step.

First, step 1 according to the present invention is a step of preparing a nitrile compound of formula 7 by reacting 2-sulfonyloxy-1-heteroaryl ethanol derivative of formula 1 with a nitrile compound.

Step 1 may be carried out by dissolving the 2-sulfonyloxy-1-heteroarylethanol derivative of Chemical Formula 1 in a solvent and then adding a nitrile compound to react for 40 to 70 hours at room temperature under a nitrogen atmosphere. It is preferable to use sodium cyanide, potassium cyanide, or the like as the nitrile compound. Dimethyl sulfoxide (DMSO), methanol, tetrahydrofuran (THF) may be used as the solvent.

Next, step 2 is a step of preparing an amine compound of formula 8 by reducing the nitrile compound of formula 7 prepared in step 1. The reduction reaction may be carried out in the presence of borane dimethyl sulfide complex after dissolving the nitrile compound of formula 7 in tetrahydrofuran (THF) solvent.

Next, step 3 is a step of preparing a compound of formula 9 by cyclization reaction of the amine compound of formula 8 prepared in step 2.

The cyclization reaction is performed by dissolving the amine compound represented by Chemical Formula 8 in a solvent, and then adding 4-dimethylaminopyridine (DAMP) and stirring with diethyl carbonate, phosgene, and diphosgene. ), Triphosgene (diphosgene), carbonyl diimidazole (carbonyl diimidazole) may be added to the reaction for 7 to 10 hours at room temperature. Methylene chloride, tetrahydrofuran (THF) and the like may be used as the solvent.

Next, step 4 is a step of preparing a compound of formula 10 by introducing an alkyl group to the nitrogen of the compound of formula 9 prepared in step 3.

The introduction of the alkyl group may be performed by dissolving the compound of Formula 9 in a solvent, cooling, adding a base, stirring at room temperature, and reacting with a compound capable of introducing an alkyl group. In this case, as the compound capable of introducing the alkyl group, C ₁ to C ₄ alkyl halides, benzyl halides, allyl halides, and the like may be used. Tetrahydrofuran (THF) may be used as the solvent, and sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium hydride, or the like may be used as the base.

Next, step 5 is a step for preparing an alkylamine-alcohol compound of formula (2) by decyclization of the compound of formula (10) prepared in step 4.

The decyclization reaction may be carried out by dissolving the compound of Formula 10 in a solvent and then refluxing at 90 to 110 ° C. for 5 to 10 hours by adding lithium hydroxy monohydrate dissolved in distilled water. Methanol, ethanol, 2-propanol (i-PrOH) and the like may be used as the solvent.

According to the preparation method according to the present invention, the enantiomerically pure heteroaryl-amino alcohol is enantiomerically pure hetero by using a 2-sulfonyloxy-1-heteroarylethanol derivative having high optical activity as a starting material. Not only can aryl-amino alcohol be produced, but also heteroaryl-amino alcohol can be obtained with a higher ee than the conventional method.

The present invention also provides a method for producing enantiomerically pure duloxetine.

More specifically, the enantiomerically pure duloxetine is shown in Scheme 3 below,

Reacting a 2-sulfonyloxy-1-heteroarylethanol derivative of Formula 1c with a nitrile compound to prepare a nitrile compound of Formula 7c (step A);

Preparing a amine compound of formula 8c by reducing the nitrile compound of formula 7c prepared in step A (step B);

Preparing a compound of formula 9c by cyclizing the amine compound of formula 8c prepared in step B (step C);

Preparing a compound of Formula 10c by introducing a methyl group into nitrogen of the compound of Formula 9c prepared in Step C (step D);

Decyclizing the compound of Chemical Formula 10c prepared in Step D to prepare a methylamine-alcohol compound of Chemical Formula 2c (step E); And

It can be prepared by a method comprising the step (step F) of preparing a duloxetine of formula 3 by introducing a naphthyl group to the methylamine-alcohol compound of formula 2c prepared in step E:

(Y in scheme 3 is toluenesulfonyloxy or methanesulfonyloxy).

Hereinafter, the manufacturing method according to the present invention will be described in more detail step by step.

First, step A according to the present invention is a step of preparing a nitrile compound of Formula 7c by reacting a 2-sulfonyloxy-1-heteroarylethanol derivative of Formula 1c with a nitrile compound.

Step A may be performed by dissolving the 2-sulfonyloxy-1-heteroarylethanol derivative of Formula 1c in a solvent and then adding a nitrile compound to react for 40 to 70 hours at room temperature under a nitrogen atmosphere. It is preferable to use sodium cyanide, potassium cyanide, or the like as the nitrile compound. Dimethyl sulfoxide (DMSO), methanol, tetrahydrofuran (THF) may be used as the solvent.

Next, step B is a step of preparing an amine compound of formula 8c by reducing the nitrile compound of formula 7c prepared in step A. The reduction reaction may be carried out in the presence of borane dimethyl sulfide complex after dissolving the nitrile compound of Formula 7c in a tetrahydrofuran (THF) solvent.

Next, step C is a step of preparing a compound of formula 9c by cyclizing the amine compound of formula 8c prepared in step B.

The cyclization reaction dissolves the amine compound of Formula 8c in a solvent, and then adds 4-dimethylaminopyridine (DAMP) and stirs them with diethyl carbonate, phosgene, and diphosgene. ), Triphosgene (diphosgene), carbonyl diimidazole (carbonyl diimidazole) may be added to the reaction for 7 to 10 hours at room temperature. Methylene chloride, tetrahydrofuran (THF) and the like may be used as the solvent.

Next, step D is a step of preparing a compound of formula 10c by introducing a methyl group to the nitrogen of the compound of formula 9c prepared in step C.

The methyl group may be introduced by dissolving the compound of Formula 9c in a solvent, cooling, adding a base, stirring at room temperature, and then reacting with a compound capable of introducing a methyl group. In this case, the compound capable of introducing methyl may be used methyl iodide, benzyl bromide, allyl bromide and the like. Tetrahydrofuran (THF) may be used as the solvent, and sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium hydride, or the like may be used as the base.

Next, step E is a step for preparing a methylamine-alcohol compound of formula (2c) by decyclization of the compound of formula (10c) prepared in step D.

The decyclization reaction may be performed by dissolving the compound of Formula 10c in a solvent and refluxing at 90 to 110 ° C. for 5 to 10 hours by adding lithium hydroxy monohydrate dissolved in distilled water. Methanol, ethanol, 2-propanol (i-PrOH) and the like may be used as the solvent.

Next, step F is a step of preparing duloxetine of formula 3 by introducing a naphthyl group to the methylamine-alcohol compound of formula 2c prepared in step E.

The naphthyl group may be introduced by dissolving the methylamine-alcohol compound represented by Chemical Formula 2c in a solvent, followed by addition of a base and stirring, followed by reaction with a halogenated naphthalene at room temperature. Dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) may be used as the solvent, and sodium hydride, potassium hydride (KH) may be used as a base, and the halogenated naphthalene may be halogenated fluoro. Preference is given to using naphthalene which is chlorine, bromine or iodine.

In the case of preparing duloxetine using a conventional method, ethyl chloroformate is added to the amine compound of Formula 8c to modify the amine group, and then reacted with a reducing agent such as lithium aluminum hydride to react the methylamine-alcohol compound of Formula 2c. After the preparation, 1-fluoronaphthalene may be added to prepare the final compound duloxetine. However, when duloxetine is produced by the above method, various by-products may be generated, and the yield may be very low.

According to the preparation method according to the present invention, duloxetine formed by introducing a naphthyl group into an enantiomerically pure heteroaryl-amino alcohol is obtained by enantiomerically pure duloxetine by using the enantiomerically pure heteroaryl-amino alcohol. Not only can it be produced, but also duloxetine can be obtained with a higher ee than the conventional method.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

< Manufacturing example  1> [S, S]- TsDPEN - RhCl - Cp * / HCl · Et ₃ N  Preparation of the catalyst

In a 5 ml two-necked round bottom flask, 0.10 g (0.16 mmol) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and 0.12 g (0.32 mmol) of ( 1S, 2S ) under an argon balloon. After addition of-(-)-N- p -tosyl 1,2-diphenylethylenediamine, 5 ml of anhydrous methylene chloride and 90 µl of anhydrous triethyleneamine (0.65 mmol) were added thereto. The reaction mixture was stirred at room temperature for 2 hours and then the reaction mixture was evaporated under reduced pressure to remove the solvent and dried under high vacuum for 2 hours to give 190 mg of the title compound as an orange powder. The catalyst was used several times in small amounts while kept under argon atmosphere.

< Manufacturing example  2> [R, R]- TsDPEN - RhCl - Cp * / HCl · Et ₃ N  Preparation of the catalyst

12.5 mg (0.02 mmol) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and 14.6 mg (0.04 mmol) of ( 1R, 2R ) in an argon balloon in a 5 ml two-necked round bottom flask. After addition of-(-)-N- p -tosyl 1,2-diphenylethylenediamine, 2 ml of anhydrous methylene chloride and 11.5 µl of anhydrous triethyleneamine (0.08 mmol) were added thereto. The reaction mixture was stirred at room temperature for 2 hours, and then the reaction mixture was evaporated under reduced pressure to remove the solvent and dried under high vacuum for 2 hours to obtain 35 mg of the title compound as an orange powder. The catalyst was used several times in small amounts while kept under argon atmosphere.

< Manufacturing example  3> [R, R]- TsDPEN - RhCl - Cp * Synthesis of Catalyst

6.3 mg (0.01 mmol) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and 7.3 mg (0.02 mmol) of ( 1R, 2R ) in an argon balloon in a 25 ml two-necked round bottom flask. After adding-(-)-N- p -tosyl 1,2-diphenylethylenediamine, 1 ml of anhydrous methylene chloride was added. The reaction mixture was stirred at room temperature for 2 hours, and then the reaction mixture was evaporated under reduced pressure to remove the solvent and dried under high vacuum for 4 hours to obtain 12 mg of the title compound as an orange powder. The catalyst was used several times in small amounts while kept under argon atmosphere.

< Manufacturing example  4> [S, S]- TsDPEN - RhCl - Cp * Synthesis of Catalyst

In a 25 ml two-necked round bottom flask, 12.3 mg (0.02 mmol) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and 14.6 mg (0.04 mmol) of ( 1S, 2S ) under an argon balloon. After adding-(-)-N- p -tosyl 1,2-diphenylethylenediamine, 1 ml of anhydrous methylene chloride was added. The reaction mixture was stirred at room temperature for 2 hours, and then the reaction mixture was evaporated under reduced pressure to remove the solvent and dried under high vacuum for 4 hours to obtain 12 mg of the title compound as an orange powder. The catalyst was used several times in small amounts while kept under argon atmosphere.

< Example  1> (S) -1- (2- Furyl )-2-( Methanesulfonyloxy Production of Ethanol

1- (2-furyl) -2- (methanesulfonyloxy) ethanone (204 mg, 1 mmol) and [S, S] -TsDPEN-RhCl-Cp * / HCl.Et ₃ prepared in Preparation Example 1 After N catalyst (0.8 mg, 0.001 equiv) was completely dissolved in ethyl acetate, 0.2 ml of a mixed solution of HCO ₂ H and Et ₃ N (5: 2) was added. They were reacted in a nitrogen atmosphere at room temperature, and confirmed by thin layer chromatography (TLC), and about 1 hour until all the spots of 1- (2-furyl) -2- (methanesulfonyloxy) ethanone disappeared. After the reaction, the reaction was terminated. The reaction solution was extracted with distilled water and ethyl acetate, washed with brine, and the obtained organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to remove 189 mg of the target substance by column chromatography.

Yield: 92%

[a] _D ²⁷ =-30.70 ( c 1.01, CHC1 ₃ ); 98% ee

¹ H NMR (300 MHz, CDCl ₃ ) 7.40 (s, 1H), 6.38-6.37 (m, 2H), 5.03 (t, 1H, J = 5.5 Hz), 4.47-4.45 (m, 2H), 3.04 (s , 3H)

< Example  2> (R) -1- (2- Furyl )-2-( Methanesulfonyloxy Production of Ethanol

[R, R] -TsDPEN- prepared in Preparation Example 2, instead of the [S, S] -TsDPEN-RhCl-Cp * / HCl Et ₃ N catalyst (0.8 mg, 0.001 equivalent) prepared in Preparation Example 1. The target product was separated in the same manner as in Example 1 using RhCl-Cp * / HCl.Et ₃ N catalyst.

Yield: 94%

[a] _D ²⁷ = + 30.82 ( c 1.07, CHC1 ₃ ); 99% ee

< Example  3> (S) -1- (2- Furyl ) -2- (p- Toluenesulfonyloxy Production of Ethanol

1- (2-furyl) -2- ( p -toluenesulfonyloxy) ethanone (280 mg, 1 mmol) and [S, S] -TsDPEN-RhCl-Cp * / HCl. Et ₃ N (0.8 mg, 0.001 equiv) was completely dissolved in ethyl acetate, and 0.2 ml of a mixed solution of HCO ₂ H and Et ₃ N (5: 2) was added. They were reacted in a nitrogen atmosphere at room temperature, and confirmed by thin layer chromatography (TLC) until the spots of 1- (2-furyl) -2- ( p -toluenesulfonyloxy) ethanone disappeared. After the reaction for 1 hour, the reaction was terminated. The reaction solution was extracted with distilled water and ethyl acetate, washed with brine, and the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to remove 276 mg of the target substance by column chromatography.

Yield: 98%

[a] _D ²⁷ =-25.46 ( c 1.63, CHCl ₃ ); 99% ee

¹ H NMR (300 MHz, CDCl ₃ ) 7.79 (d, 2H, J = 8.4 Hz), 7.36-7.34 (m, 3H), 6.33 (s, 2H), 5.00-4.53 (m, 1H), 4.30 (dd , 1H, J = 10.4 and 4.3 Hz), 4.24 (dd, 1H, 10.4 and 7.1 Hz), 2.45 (s, 3H), 2.41 (d, 1H, J = 5.1 Hz)

< Example  4> (R) -1- (2- Furyl ) -2- (p- Toluenesulfonyloxy Production of Ethanol

[R, R] -TsDPEN-RhCl prepared in Preparation Example 2, instead of [S, S] -TsDPEN-RhCl-Cp * / HClEt ₃ N (0.8 mg, 0.001 equivalent) prepared in Preparation Example 1 The desired product was separated in the same manner as in Example 3 using a -Cp * / HCl.Et ₃ N catalyst.

Yield: 96%

[a] _D ²⁷ = + 25.37 ( c 1.01, CHC1 ₃ ); 99% ee

< Example  5> (S) -1- (2- Sienil )-2-( Methanesulfonyloxy Production of Ethanol

1- (2-cyenyl) -2- (methanesulfonyloxy) ethanone (220 mg, 1 mmol) and [S, S] -TsDPEN-RhCl-Cp * / HCl. Et ₃ N (0.8 mg, 0.001 equiv) was completely dissolved in ethyl acetate, and then 0.2 mL of a mixed solution of HCO ₂ H and Et ₃ N (5: 2) was added. They were reacted in a nitrogen atmosphere at room temperature, and confirmed by thin layer chromatography (TLC) until the spots of 1- (2-cyenyl) -2- (methanesulfonyloxy) ethanone disappeared. After the reaction for 3 hours, the reaction was terminated. The reaction solution was extracted with distilled water and ethyl acetate, washed with brine, and the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to remove the target product.

Yield: 95%

[a] _D ²⁷ =-33.2 ( c 0.56 CHCl ₃ ); 95% ee

¹ H NMR (300 MHz, CDCl ₃ ) 7.32 (d, 1H, J = 5.0 Hz), 7.07 (d, 1H, J = 3.3 Hz), 7.02 (dd, 1H, J = 5.0 and 3.5 Hz), 5.32- 5.27 (m, 1H), 4.42 (dd, 1H, J = 10.9 and 4.0 Hz), 4.36 (dd, 1H, J = 10.9 and 7.4 Hz), 3.06 (s, 3H), 2.89 (d, 1H, J = 4.0 Hz)

< Example  6> (R) -1- (2- Sienil )-2-( Methanesulfonyloxy Production of Ethanol

[R, R] -TsDPEN-RhCl prepared in Preparation Example 4 instead of [S, S] -TsDPEN-RhCl-Cp * / HClEt ₃ N (0.8 mg, 0.001 equivalent) prepared in Preparation Example 1 The desired product was separated in the same manner as in Example 5 using a -Cp * catalyst.

Yield: 91%

[a] _D ²⁷ =-32.72 ( c 0.23 CHCl ₃ ); 93% ee

< Example  7> (S) -1- ( Thiophene -2- days) -2- Toluenesulfonyloxy  Preparation of Ethanol

1- (2-cyenyl) -2- ( p -toluenesulfonyloxy) ethanone (296 mg, 1 mmol) and [S, S] -TsDPEN-RhCl-Cp * / prepared in Preparation Example 1 HCl.Et ₃ N (0.8 mg, 0.001 equiv) was completely dissolved in ethyl acetate, and then 0.2 mL of a mixed solution of HCO ₂ H and Et ₃ N (5: 2) was added. When these were reacted under a nitrogen atmosphere at room temperature, the result was confirmed by thin layer chromatography (TLC), and when all the spots of 1- (2-cyenyl) -2- ( p -toluenesulfonyloxy) ethanone disappeared. After the reaction for about 1 hour, the reaction was terminated. The reaction solution was extracted with distilled water and ethyl acetate, washed with brine, and the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to remove 289 mg of the target substance by column chromatography.

Yield: 97%

[a] _D ²⁷ =-31.3 ( c 1.12, CHC1 ₃ ); 96% ee

¹ H NMR (300 MHz, CDCl ₃ ) 7.80 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.1 Hz), 7.28-7.26 (m, 1H), 6.98-6.95 (m, 2H ), 5.25-5.20 (m, 1H), 4.23 (dd, 1H, J = 10.2 and 3.6 Hz), 4.17-4.08 (m, 1H), 2.67 (s, 1H, J = 3.9 Hz), 2.45 (s, 3H)

< Example  8> (R) -1- ( Thiophene -2- days) -2- Toluenesulfonyloxy  Preparation of Ethanol

Preparation of the [R, R] -TsDPEN-RhCl-Cp * catalyst prepared in Preparation Example 4 instead of the [S, S] -TsDPEN-RhCl-Cp * / HClEt ₃ N catalyst prepared in Preparation Example 1 Except for using to separate the target in the same manner as in Example 7.

Yield: 95%

[a] _D ²⁷ =-30.73 ( c 1.10, CHCl ₃ ); 95% ee

< Example  9> (R) -1- (3- Sienil )-2-( p - Toluenesulfonyloxy Production of Ethanol

1- (3-cyenyl) -2- ( p -toluenesulfonyloxy) ethanone (296 mg, 1 mmol) and [S, S] -TsDPEN-RhCl-Cp * / prepared in Preparation Example 1 HCl.Et ₃ N (0.8 mg, 0.001 equiv) was completely dissolved in ethyl acetate, and then 0.2 mL of a mixed solution of HCO ₂ H and Et ₃ N (5: 2) was added. The reaction was carried out at room temperature in a nitrogen atmosphere, and confirmed by thin layer chromatography (TLC), until the spots of 1- (3-cyenyl) -2- ( p -toluenesulfonyloxy) ethanone disappeared. After the reaction, the reaction was terminated. The reaction solution was extracted with distilled water and ethyl acetate, washed with brine, and the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to remove. Then, 253 mg of the target product was obtained by column chromatography.

 Yield: 85%

[a] ^D ₂₇ =-33.7 ( c 1.28, CHC1 ₃ ); 96% ee

¹ H NMR (300 MHz, CDCl ₃ ) 7.78 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 9.1 Hz), 7.31-7.25 (m, 2H), 7.01 (dd, 1H, J = 5.0 and 1.4 Hz), 5.08-5.06 (m, 1H), 4.20 (dd, 1H, J = 10.3 and 3.4 Hz), 4.08 (dd, 1H, J = 10.3 and 8.1 Hz), 2.52 (d, 1H, J = 3.8 Hz), 2.45 (s, 3H)

< Example  10> (S) -3- ( Methylamino ) -1- (2- Cyenyl )-One- Propanol  Produce

Step 1: (S) -3- Hydroxy -3- Of thiophenepropanenitrile  Produce

(S) -1- (Ciophen-2-yl) -2-toluenesulfonyloxy ethanol (1.2 g 4.02 mmol) prepared in Example 7 was placed in a round bottom flask and 26 ml of dimethyl sulfoxide (DMSO). Was added to dissolve. Sodium cyanide (591.31 mg, 12.06 mmol) was added to the resulting solution, and the reaction was carried out under nitrogen atmosphere at room temperature, and confirmed by TLC to confirm that (S) -1- (thiophen-2-yl) -2-toluenesulfonyloxy spot was all present. The reaction was terminated after reacting for about 60 hours until disappeared. The reaction mixture was extracted with distilled water, ethyl acetate and brine. The obtained organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated to remove. Then, 544 mg of the target substance was separated by flash silica column chromatography (n-hexane: EA = 2: 1).

Yield: 88.31%

[a] _D ² ° =-39.7 (c 0.45, CHCl ₃ )

¹ H NMR (300 MHz, CDCl ₃ ) 7.36 (dd, 1H, J = 5.1 and 1 Hz), 7.13 (d, 1H, J = 3.5 Hz), 7.05-7.03 (m, 1H), 5.34 (q, 1H , J = 4.3 Hz), 2.93-2.90 (m, 2H), 2.56 (d, 1H, J = 4.2 Hz)

Step 2: (S) -3-amino-1- (2- Sienil )-One- Propanol  Produce

(S) -3-hydroxy-3-thiophenepropanenitrile (550 mg, 3.59 mmol) prepared in step 1 was added to a round bottom flask, and 10 ml of tetrahydrofuran (THF) was added thereto to dissolve. Borane dimethyl sulfide complex (0.57 mL, 5.38 mmol) was slowly added dropwise to the resulting solution using a syringe, and dimethyl sulfide was evaporated in an oil bath, and the reaction mixture was refluxed to confirm by TLC (S). The reaction was carried out for about 2 hours until all of the 3-hydroxy-3-thiophenepropanenitrile spots disappeared. After injecting 30 ml of methanol into the reaction solution, the solvent was evaporated under reduced pressure, and used directly in the next reaction without separation and purification.

[a] _D ² ° =-10.7 (c 0.45, CHCl ₃ )

¹ H NMR (300 MHz, CDCl ₃ ) 7.22 (dd, 1H, J = 4.9 and 1.3 Hz), 6.98-6.92 (m, 2H), 5.22 (ddd, 1H, J = 8.8 and 3.3 and 0.4 Hz), 3.19 -3.12 (m, 1H), 3.02-2.94 (m, 1H), 2.71 (bs, 3H), 2.04-1.81 (m, 2H)

Step 3: (S) -6- ( Thiophene -2 days) -1,3- Oxa Jinan Preparation of 2-one

(S) -3-amino-1- (2-cyenyl) -1-propanol (185 mg, 1.17 mmol) prepared in step 2 was added to a round bottom flask and dissolved with 7 ml of methylene chloride. 4-dimethyl aminopyridine (DMAP) (8.57 mg, 0.7 mmol) was added to the resulting solution, and the mixture was stirred for 10 minutes. While stirring, N, N'-carbonyl diimidazole (CDI) (317 mg, 1.76 mmol) was added thereto, and reacted at room temperature to confirm by TLC (S) -3-amino-1- (2-cyenyl) The reaction was carried out for about 8 hours until all of the -1-propanol spots disappeared. After removing the solvent by evaporation under reduced pressure, the reaction solution was extracted with ethyl acetate, distilled water and brine. The obtained organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated to remove. Then, 151 mg of the target substance was separated by flash silica column chromatography (n-hexane: EA: MC = 1: 9: 1).

Yield: 70.5%

[a] _D ² ° = + 23.2 (c 0.46, CHCl ₃ )

¹ H NMR (300 MHz, CDCl ₃ ) 7.34-7.32 (dd, 1H, J = 5.0 and 1.2 Hz), 7.10-7.08 (m, 1H), 7.02-6.99 (m, 1H), 5.77 (bs, 1H) , 5.59 (ddd, 1H, J = 9.2 and 3.1 and 0.6 Hz), 3.50-3.43 (m, 2H), 2.37-2.16 (m, 2H)

Step 4: (S) -3- methyl -6- ( Thiophene -2-yl) -1,3- Oxa Jinan Preparation of 2-one

(S) -6- (Ciophen-2yl) -1,3-oxazinan-2-one (110 mg, 0.6 mmol) prepared in step 3 above was placed in a round bottom flask and tetrahydrofuran (THF) 6 Add ㎖ and dissolve. The resulting solution was cooled to 0 ° C., followed by sodium hydride (NaH) (36 mg, 1.5 mmol), stirred at room temperature for 30 minutes, and then methyl iodide (MeI). It was confirmed by TLC and reacted for about 6 hours until all of the (S) -6- (thiophen-2yl) -1,3-oxazinan-2-one spots disappeared. The reaction solution is extracted with ethyl acetate, brine and distilled water. The obtained organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated to remove. Then, 105 mg was separated by flash silica column chromatography (n-hexane: EA: MC = 1: 5: 1).

Yield 88.7%

[a] _D ² ° = + 31.8 (c 0.5, CHCl ₃ )

¹ H NMR (300 MHz, CDCl ₃ ) 7.33-7.30 (m, 1H), 7.08-7.06 (m, 1H), 7.01-6.98 (m, 1H), 5.54 (ddd, 1H, J = 9.0 and 3.54 and 0.7 Hz), 3.52-3.43 (m, 1H), 3.36-3.28 (m, 1H), 3.01 (s, 3H), 2.41-2.23 (m, 2H)

Step 5: (S) -3- ( Methylamino ) -1- (2- Cyenyl )-One- Propanol  Produce

(S) -3-methyl-6- (thiophen-2-yl) -1,3-oxazinan-2-one (81 mg, 0.41 mmol) prepared in step 4 was added to a round bottom flask, and methanol 5 ML was added and dissolved. Lithium hydroxy monohydrate (120.42 mg, 2.87 mmol) was dissolved in distilled water (2.5 mL) and then added to the resulting solution. It was confirmed by TLC while refluxing at 100 ° C. and reacted for about 8 hours until all of the (S) -3-methyl-6- (thiophen-2-yl) -1,3-oxazinan-2-one spots disappeared. The reaction solution was evaporated under reduced pressure and extracted with distilled water, saline and diethyl ether. The obtained organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated to remove. 58.9 mg of the target substance was separated by flash silica column chromatography (MC: MeOH: NH ₄ OH = 40: 10: 1).

Yield: 84%

[a] _D ² ° =-10.8 (c 0.52, MeOH)

¹ H NMR (300 MHz, CDCl ₃ ) 7.22-7.20 (m, 1H), 6.98-6.91 (m, 2H), 5.21 (ddd, 1H, J = 8.2 and 3.2 and 0.7 Hz), 3.56 (bs, 2H) , 3.01-2.83 (m, 2H), 2.45 (s, 3H), 2.04-1.83 (m, 2H)

< Example  11> (S)- Duloxetine  Produce

(S) -3- (methylamino) -1- (2-thienyl) -1-propanol (41 mg, 0.24 mmol) prepared in step 5 of Example 10 was placed in a round bottom flask and dimethyl sulfoxide 1.5 ml (DMSO) was added and dissolved. Sodium hydride (NaH) (14.36 mg, 0.36 mmol) was added to the resulting solution, stirred for 30 minutes, and then reacted with 1-fluoronaphthalene. It was confirmed by TLC and reacted for about 24 hours until all of the (S) -3- (methylamino) -1- (2-cyenyl) -1-propanol spots disappeared. The reaction solution was extracted with ethyl acetate, distilled water and brine. The obtained organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated to remove the residue, and the target product was separated by flash silica column chromatography (MC: MeOH: NH ₄ OH = 100: 10: 1).

Yield: 78%

[a] _D ² ° = + 110.5 (c 1.1, MeOH)

¹ H NMR (300 MHz, CDCl ₃ ) 8.37-8.33 (m, 1H), 7.79-7.74 (m, 1H), 7.50-7.44 (m, 2H), 7.39-7.37 (m, 1H), 7.28-7.18 ( m, 2H), 7.05-7.04 (m, 1H), 6.93-6.90 (m, 1H), 6.86-6.84 (m, 1H), 5.78 (dd, 1H, J = 7.6 and 5.3 Hz), 2.86-2.78 ( m, 2H), 2.50-2.39 (m, 4H), 2.27-2.16 (m, 1H)

Claims (14)

As shown in Scheme 1 below, 2-sulfonyl having the optical activity formed by asymmetrically reducing the α-sulfonyloxyheteroaryl ketone compound of formula 4 in the presence of a hydrogen donor and a rhodium compound catalyst containing a pentamethylcyclopentadienyl group of formula 5 Process for preparing oxy-1-heteroarylethanol derivative: Scheme 1

(In Scheme 1, X is oxygen or sulfur and Y is toluenesulfonyloxy or methanesulfonyloxy). The method of claim 1, wherein the rhodium compound catalyst is a compound represented by the following Formula (5). [Chemical Formula 5]

(R, R) -TsDPEN-RhCl-Cp *

(S, S) -TsDPEN-RhCl-Cp * According to claim 1, wherein the α-sulfonyloxyheteroaryl ketone compound of Formula 4 is a 2-sulfonyloxy- characterized in that using a range of 100 to 100,000 as the molar ratio (S / C) of the substrate to the rhodium compound. Process for the preparation of 1-heteroarylethanol derivatives. According to claim 1, wherein the α-sulfonyloxyheteroaryl ketone compound of Formula 4 is a 2-sulfonyloxy-characterized in that using a range of 1,000 to 10,000 as the molar ratio (S / C) of the substrate to the rhodium compound. Process for the preparation of 1-heteroarylethanol derivatives. [Claim 2] The 2-sulfonyloxy-1-heteroarylethanol derivative according to claim 1, wherein the hydrogen donor is any one selected from the group consisting of formic acid or a metal salt or ammonium salt thereof, or an azeotrope of formic acid and amine. Manufacturing method. The method of claim 5, wherein the hydrogen donor is used without or using a solvent, the solvent is ethyl acetate, toluene, methylene chloride, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran ( THF), acetonitrile and isopropanol any one solvent selected from the group consisting of The manufacturing method of the 2-sulfonyloxy-1-heteroarylethanol derivative characterized by the above-mentioned. As shown in Scheme 2 below, A step of preparing a nitrile compound of formula 7 by reacting a 2-sulfonyloxy-1-heteroarylethanol derivative of formula 1 prepared by the method according to any one of claims 1 to 6 with a nitrile compound (step 1 ); Preparing an amine compound of formula 8 by reducing the nitrile compound of formula 7 prepared in step 1 (step 2); Preparing a compound of formula 9 by cyclizing the amine compound of formula 8 prepared in step 2 (step 3); Preparing a compound of Formula 10 by introducing an alkyl group to nitrogen of the compound of Formula 9 prepared in step 3 (step 4); And Method for producing an enantiomerically pure heteroaryl-amino alcohol comprising the step (step 5) of preparing an alkylamine-alcohol compound of formula (2) by the decyclicization reaction of the compound of formula (10) prepared in step 4. Scheme 2

(Wherein X is oxygen or sulfur, Y is toluenesulfonyloxy or methanesulfonyloxy and R is C ₁ to C ₄ straight or branched alkyl). 8. The method of claim 7, wherein the nitrile compound of step 1 is sodium cyanide or potassium cyanide. 9. 8. The method for preparing enantiomerically pure heteroaryl-amino alcohol according to claim 7, wherein the reduction reaction of step 2 is carried out in the presence of borane dimethyl sulfide complex. The method of claim 7, wherein the cyclization reaction of step 3 consists of diethyl carbonate, phosgene, diphosgene, diphosgene, and carbonyl diimidazole. A process for preparing enantiomerically pure heteroaryl-amino alcohol, characterized in that it is carried out using any one selected from the group. As shown in Scheme 3 below, A method of preparing a nitrile compound of formula 7c by reacting a 2-sulfonyloxy-1-heteroarylethanol derivative of formula 1c prepared by the method according to any one of claims 1 to 6 with a nitrile compound (step A ); Preparing a amine compound of formula 8c by reducing the nitrile compound of formula 7c prepared in step A (step B); Preparing a compound of formula 9c by cyclizing the amine compound of formula 8c prepared in step B (step C); Preparing a compound of Formula 10c by introducing a methyl group into nitrogen of the compound of Formula 9c prepared in Step C (step D); Decyclizing the compound of Chemical Formula 10c prepared in Step D to prepare a methylamine-alcohol compound of Chemical Formula 2c (step E); And A method for preparing enantiomerically pure duloxetine of formula (3) comprising the step (step F) of preparing duloxetine of formula (3) by introducing a naphthyl group to the methylamine-alcohol compound of formula (2c) prepared in step E : Scheme 3

(Y in scheme 3 is toluenesulfonyloxy or methanesulfonyloxy). 12. The method for preparing enantiomerically pure duloxetine according to claim 11, wherein the nitrile compound of step A is sodium cyanide or potassium cyanide. 12. The method for preparing enantiomerically pure duloxetine according to claim 11, wherein the reduction reaction of step B is carried out in the presence of borane dimethyl sulfide complex. The method of claim 11, wherein the cyclization reaction of step C consists of diethyl carbonate, phosgene, diphosgene, diphosgene, and carbonyl diimidazole. Method for producing enantiomerically pure duloxetine, characterized in that it is carried out using any one selected from the group.