KR101087500B1 - Method for preparing binaphthol aldehyde derivatives and intermediate thereof - Google Patents

Abstract

The present invention provides a method for preparing a compound of Formula 1 and a method comprising the step of reducing the compound of Formula 3 to obtain a compound of Formula 2 and oxidizing the compound of Formula 2 obtained in the step: A method for preparing a naphthol aldehyde derivative.

Scheme 1

Chiral synthesis, amino acid, amino alcohol, binaphthol

Description

Method for preparing binaphthol aldehyde derivatives and intermediates}

The present invention relates to a process for preparing binaphthol aldehyde derivatives and intermediates thereof which is useful for optical resolution of amino acids or amino alcohols and optical transformation of D and L-forms of amino acids.

 Optically pure amino acids and amino alcohols are of great industrial importance because they are widely used as ligands for asymmetric catalysts or as starting materials or intermediates for the synthesis of various pharmaceuticals and bioactive substances.

As a method of obtaining an optically pure amino acid, a fermentation method is mentioned. However, the amino acids obtainable by fermentation are only some of the natural amino acids. Therefore, efforts are being made to economically mass-produce various types of amino acids.

Accordingly, the present inventors have developed a compound of formula 9, which is very useful for recognizing chiral amino alcohol or amino acid chirality through imine bonds, separating them into their respective optical isomers, or converting L-amino acids to D-amino acids. Korea Patent Registration No. 10-0661280).

 [Formula 9]

The binaphthol derivative is a PLP compound (a) Shaw, JP; Petsko, GA Ringe, D. Biochemistry, 1997, 36, 1329-1342; (b) Walsh, CTJ, which plays a central role in the activity of an enzyme called amino acid lasmaze. Biol. Chem. 1989, 264, 2393-2396).

The binaphthol derivatives can be very useful for separating amino alcohols or amino acids into their respective optical isomers, or for preparing optically pure amino acids that have been difficult to prepare by other methods.

A known method for producing the binaphthol derivative is to introduce a formyl group (-CHO) using (b) an optically pure binaphthol as a starting material, followed by (ii) a R ₃ benzyl group.

In general, the process of introducing a formyl group to binaphthol is performed by protecting the OH group of binaphthol with MOM (methoxymethyl) and then using n-butyllithium and DMF. However, this method is very sensitive to moisture and difficult to use in general processes. Therefore, the development of safe methods to replace these methods was required. In addition, since the value of binaphthol used as a starting material is relatively expensive, there is a great need to synthesize the binaphthol derivative using a cheaper material.

상기 식에서, Z은 할로겐이다.On the other hand, R ₃ is substituted at the hydrogen position of the 2'hydroxy group of 2,2'-binapult-3-aldehyde in which a formyl group is introduced into binaptol. The step of introducing the benzyl group is made by directly reacting 2,2'-binapthol-3-aldehyde with a compound represented by the following formula (10). However, in this case, the selectivity of 2,2'-binafitol-3-aldehyde to 2'hydroxy group is low, resulting in a problem that a product in which a substituent of 2 hydroxy group to hydrogen and a substituent to 2 'hydroxy group is mixed is obtained. . Therefore, there is a need for a technique of increasing the selectivity to hydrogen of the 2 ′ hydroxyl group so that no by-products are generated.
[Formula 10]

Wherein Z is halogen.

The present invention is to solve the above problems of the prior art, to provide a method for producing a binaphthol aldehyde derivative and the intermediate thereof of the formula (8) by a safe method without using a dangerous substance such as n-butyllithium For the purpose of

It is also an object of the present invention to provide a process for economically preparing binaphthol aldehyde derivatives of formula (8) and intermediates thereof using inexpensive raw materials.

In addition, the 2,2'-binaphthol-3-aldehyde (2,2'-binaphthol-3-aldehyde) increases the selectivity to the hydrogen position of the 2 'hydroxy group of the binaphthol aldehyde derivative of formula (8) with high efficiency without generating by-products It is an object to provide a method for producing a.

The present invention provides a process for preparing a compound of formula 1, comprising the step of reducing the compound of formula 3 to obtain a compound of formula 2 and oxidizing the compound of formula 2 obtained in the step:

[Formula 1]

[Formula 2]

(3)

In Chemical Formulas 1 to 3, X and Y are each independently hydrogen; halogen; Amino; Nitro; Cyano; Formyl; Carboxyl; C1-C10 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, and C6-C10 aryl; C1-C10 alkylcarbonyl; Aryl of C6 ~ C10; And C 1 -C 10 alkoxy; N and m are integers of 0 to 5; R 1 is selected from the group consisting of hydrogen, C 1 -C 5 alkyl, tosyl, CH ₃ SO ₂ —, and CH ₃ CO—.

In addition, the present invention,

Reducing the compound of Formula 3 to obtain a compound of Formula 2;

Oxidizing the compound of Formula 2 obtained in the step to obtain a compound of Formula 1;

Reacting the compound represented by Chemical Formula 1 and the compound represented by Chemical Formula 11 in the presence of a base to obtain a compound represented by Chemical Formula 6;

Reacting the compound represented by Chemical Formula 6 and the compound represented by Chemical Formula 10 in the presence of a base to obtain a compound represented by Chemical Formula 7; And

It provides a method for preparing a compound of formula 8 comprising the step of hydrolyzing the compound of formula 7 obtained in the above step.

 (3)

[Formula 2]

[Formula 1]

[Formula 6]

[Formula 7]

[Formula 8]

[화학식 10]

[화학식 11]

[Formula 10]

(11)

In the above Chemical Formulas 1 to 3, 6 to 8, and 10 and 11, X, Y, n, m and R 1 are the same as defined above; R 2 is selected from the group consisting of C 1 -C 5 alkyl, C 6 -C 10 arylalkyl, and C 2 -C 10 alkoxyalkyl; R 3 is NHCX′R 4 or NHCHNH ₂ ⁺ , X ′ is oxygen or sulfur, R 4 is straight or branched chain alkyl, NR 5 R 6, or OR 7 which may be substituted with halogen, and R 5 to R 7 may be substituted with hydrogen or halogen Straight or branched chain alkyl, or aryl, and when R 3 is NHCHNH ₂ ⁺ , the counterion is a halogen ion or R 8 CO 0 ^— and R 8 is alkyl or aryl; Z is halogen.
Specific examples of the halogen include Br, Cl, I and the like.

According to the manufacturing method of the present invention, unlike the conventional technology, since it does not use a dangerous substance such as n-butyllithium, it is possible to safely manufacture the binaphthol aldehyde derivative of Formula 8 and its intermediate.

In addition, the use of inexpensive raw materials makes it possible to economically prepare the binaphthol aldehyde derivative of formula (8) and its intermediates.

In addition, since the selectivity to the hydrogen position of the 2 'hydroxy group of 2,2'-binaphthol-3-aldehyde (2,2'-binaphthol-3-aldehyde) is high, no by-product substituted at the hydrogen position of the 2 hydroxy group is produced. The binaphthol aldehyde derivative of Chemical Formula 8 can be prepared with high efficiency.

In addition, by the effects of the present invention as described above, it is possible to provide a very excellent economic efficiency when applying the manufacturing method of the present invention to an industrial scale production line.

The present invention relates to a method for preparing a compound of Formula 1, comprising the step of reducing the compound of Formula 3 to obtain a compound of Formula 2 and oxidizing the compound of Formula 2 obtained in the step.

delete

delete

delete

delete

delete

delete

delete

In Formulas 1 to 3, n and m are 0; More preferably, R1 is methyl.

The preparation method of the compound of Formula 1 is represented by the following scheme.

The reaction a refers to a reaction proceeding by dissolving a reducing agent (eg, LiAlH ₄ , NaBH ₄ ) in a solvent (eg, THF), and then adding the compound of Formula 3 above. As the reducing agent and the solvent in this reaction, those known in the art can be used without limitation. In the above, the reaction is preferably performed for about 3 to 7 hours.

The reaction b means dissolving the compound of Formula 2 and an oxidizing agent (for example, pyridinium chlorochromate (PCC), DMSO / Ac ₂ O) in a solvent (for example, methylene chloride), and then reacting for about 1 to 6 hours. do. The reaction can proceed at room temperature. As the oxidizing agent and the solvent in this reaction, those known in the art can be used without limitation.

In the above reactions a and b both proceed almost quantitatively and economically, and as in the prior art, there is no need to use a high risk compound such as n-butyl lithium (n-butyl lithium) has the advantage of being very safe. Therefore, the compound of formula 1 which is the target compound of the present invention can be prepared safely and economically by the above method.
The compound of Formula 3 may be prepared by a method of reacting a compound of Formula 4 with a compound of Formula 5 using CuCl (OH) -TMEDA (Tetramethylethylenediamine).

delete

In Chemical Formulas 4 and 5, X, Y, n, m and R 1 are the same as defined above; However, X or Y is not present at positions 8 of Formulas 4 and 5.

The preparation method of the compound of Formula 3 is represented by the following scheme.

The reaction was carried out using a very inexpensive compound of formulas (4) and (5) for the application and improvement of known methods (M. Noji, M. Nakajima and K. Koga. Tetrahedron Lett. 35 (1994), p. 7983-7984.). Can proceed. Briefly, the reaction is characterized by dissolving the compound of Formula 4 in THF, adding the compound of Formula 5, and then adding CuCl (OH) -TMEDA to the mixed solution and reacting under oxygen. See Example 1). Unlike the expensive binaphtol used in the prior art, the compounds of Formulas 4 and 5 are inexpensive and can be purchased in large quantities, thereby economically preparing the compound of Formula 1, which is the target compound of the present invention.

When the compound of Formula 3 is synthesized by the reaction, it is necessary to obtain an optically pure compound of Formula 3 because it is obtained as a racemic mixture.

Therefore, in the preparation method of the present invention, before the step of reducing the compound of Chemical Formula 3, the compound of Chemical Formula 3 is hydrolyzed to obtain 2,2'-dihydroxy-3-binaphthoic acid, which is obtained by cinchonidine. It may further comprise the step of preparing in an optically pure form by resolution ().

For example, a method of obtaining an optically pure compound of Chemical Formula 3 is shown in Scheme 3 below.

That is, the compound of Chemical Formula 3 is hydrolyzed to make a 2,2'-dihydroxy-3-binaphtholic acid (2,2'-dihydroxy-3-binaphtholic acid) derivative to be resolved. Such separation techniques are described by Hovorka, M. et al. (Hovorka, M .; Stibor, I; Holakovsky, R .; Smiskova, I .; Struzka, Vr Czech Rep. (2001), CZ 287879 B6 20010314 Patent written in Czech.Application: CZ 96-64 19960109). The isolated (S) -2,2'-dihydroxy-3-binaphtholic acid derivatives are simply converted into R1 esters by esterification, so eventually form (S) Pure compound of 4 can be obtained. Of course, it is also possible to use separate (R) type.

In addition, the present invention,

Reducing the compound of Formula 3 to obtain a compound of Formula 2;

Oxidizing the compound of Formula 2 obtained in the step to obtain a compound of Formula 1;

Reacting the compound of Chemical Formula 1 and the compound of Chemical Formula 11 in the presence of a base to obtain a compound of Chemical Formula 6;

Reacting the compound of Formula 6 and the compound of Formula 10 in the presence of a base to obtain a compound of Formula 7; And

It relates to a method for preparing the compound of Formula 8 comprising the step of hydrolyzing the compound of Formula 7 obtained in the step.

delete

delete

delete

delete

delete

delete

delete

delete

delete

delete

delete

delete

delete

delete

In the above method of preparing the compound of Formula 8, the above-described information may be applied to the process up to the preparation of the compound of Formula 1.

In the manufacturing method of Chemical Formula 8, the process of preparing the compound of Chemical Formula 8 from the compound of Chemical Formula 1 is represented as follows.

As the solvent for the reaction in the reaction a, N, N-dimethylformamide (N, N-dimethylformamide, DMF), tetrahydrofuran (THF), CH ₂ Cl ₂ and the like can be used, DMF is preferred. . Examples of the base used in the reaction a include organic or inorganic bases such as Et ₃ N, NaH, NaOH, and Et ₃ N or NaH. In addition, the reaction a is made at 0 ~ 30 ℃, preferably carried out at room temperature.

In the reaction a, the compound of Formula 11 is mainly substituted at the hydrogen position of 2 hydroxy, and a compound in which the compound of Formula 11 is substituted at both the hydrogen position of the 2 hydroxy group and the 2 ′ hydroxy group is partially produced. However, these reaction by-products can be recycled by hydrolysis to form the compound of Formula 1 again. The compound of Chemical Formula 6 may be obtained by recrystallization with a purity of 98% or more and a yield of 90% or more.

In reaction b, the compound of formula 1 is reacted with the compound of formula 10 in the presence of a base to obtain a compound of formula 7. N, N-dimethylformamide (N, N-dimethylformamide, DMF), tetrahydrofuran (THF), CH ₂ Cl _2, etc. may be used as a solvent for the reaction in the reaction b, and DMF is preferable. . Examples of the base used in the reaction b include organic or inorganic bases such as Et ₃ N, NaH, NaOH, and Et ₃ N or NaH.

In the reaction c, the obtained compound of formula 7 is hydrolyzed in a conventional manner to obtain a compound of formula 8. The yield is at least 90%.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are provided to illustrate the present invention, and the present invention is not limited to the following examples and may be variously modified and changed.

Example 1 Preparation of a Compound of Formula 3 (2,2'-dihydroxy-1,1'-binaphthyl-3-carboxylic acid methyl ester)

Compound 3 was synthesized by applying and improving the synthesis method of known papers (M. Noji, M. Nakajima and K. Koga.Tetrahedron Lett. 35 (1994), p. 7983-7984.). That is, 3-hydroxy-2-naphthalate methyl ester (2.0 g, 9.89 mmol) was dissolved in THF (20 ml), followed by 2-naphthol (1.42 g, 9.89 mmol). Added. CuCl (OH) -TMEDA (1.15 g, 4.94 mmol) was added to this mixed solution at room temperature and stirred for 3 days under oxygen. After the reaction was finished, and then remove the THF, and extracted with 10 ml chloroform and 1 N hydrochloric acid solution (2 x 5 ml), the solid compound obtained was recrystallized and dried by evaporating the organic layer with CHCl ₃ / n- hexane 2,2 Dihydroxy-1,1'-binaphthyl-3-carboxylic acid methyl ester compound was obtained (3.1 g, yield: 90%).

mp 167 ° C .; ¹ H NMR (CDCl ₃ , 250 MHz): δ 10.80 (s, 1H), 8.74 (s, 1H), 7.8-8.0 (m, 3H), 7.0-7.5 (m, 8H), 4.06 (s, 3H) .

Example 2 Preparation of Compound of Formula 2 (2,2'-dihydroxy-3-hydroxymethyl-1,1'-binaphthalene)

Lithium aluminum hydride (LiAlH ₄ , 0.51 g, 13.3 mmol) was dissolved in THF (30 ml), and then 2,2'-dihydroxy-1,1'-binafphyl-3 prepared in Example 1 was used. -Carboxylic acid methyl ester (3.07 g, 8.89 mmol) was added in an ice bath. After stirring for 5 hours at room temperature, the reaction was terminated by adding dilute hydrochloric acid, extracted with ethyl acetate (EA), treated with anhydrous MgSO ₄ and concentrated to give 2,2 ',-dihydroxy-3-hydroxymethyl- A 1,1'-binaphthalene compound was obtained (2.53 g, yield: 90%).

mp 194 ° C .; ¹ H NMR (DMSO-d ₆ , 250 MHz): δ 7.8-8.0 (m, 4H), 6.7-7.4 (m, 7H), 4.74 (s, 2H).

Example 3: Preparation of Compound of Formula 1 (2,2'-dihydroxy-1,1'-binaphthyl-3-carboxaldehyde)

2,2'-dihydroxy-3-hydroxymethyl-1,1'-binaphthalene (2.53 g, 7.98 mmol) and pyridinium chlorochromate (PCC, 3.44 g, obtained in Example 2, 15.9 mmol) was added to methylene chloride (50 mL) and stirred at room temperature for 3 hours. After the reaction was completed, the precipitate was filtered off and the resulting solution was concentrated to give a 2,2'-dihydroxy-1,1'-binafphyl-3-aldehyde compound in solid form (2.14 g, yield: 85%).

¹ H NMR (CDCl ₃ , 250 MHz): δ 10.24 (s, 1H), 8.38 (s, 1H), 7.8-8.1 (m, 3H), 7.0-7.6 (m, 7H), 4.95 (s, 1H ).

Example 4 Preparation of Compound of Chemical Formula 6 (2-methoxymethoxy-2'-hydroxy-1,1'-binaphthyl-3-carboxaldehyde)

(S) -2,2'-dihydroxy-1 obtained by esterifying (S) -2,2'-dihydroxy-3-binaphthoic acid, which has been resolved by Hovorka, M. et al. (S) -2,2'-dihydroxy-1,1'-binafphyl-3-aldehyde was prepared via, l'-binaphthoic acid methyl ester through Examples 1 to 3. The (S) -2,2'-dihydroxy-1,1'-binafphyl-3-aldehyde (3.9 g, 12.4 mmol) thus obtained was dissolved in DMF (40 ml), followed by stirring with NaH (0.45 g). , 11 mmol) was added. To this solution was added methoxymethyl chloride (MOMCl, 1.08 ml, 12.4 mmol) dissolved in DMF (40 ml), followed by reaction for 15 hours. The reaction solution was extracted with water and ethyl acetate (EA), and the organic layer was dried. The obtained product was subjected to column chromatography (eluent: EA / hexane 1/5) to give a compound of formula (S) -2-meth. The methoxymethoxy-2'-hydroxy-1,1'-binafphyl-3-aldehyde compound was obtained (2.9 g, yield: 65%).

mp 164 ° C .; [a] _D = -108.2 (c = 0.42 in EtOH); ¹ H NMR (CDCl ₃ , 250 MHz): δ 10.59 (s, 1H), 8.62 (s, 1H), 8.09 (d, 1H), 7.99-7.88 (m, 2H), 7.54-7.27 (m, 6H) ), 7.07 (d, 1 H), 5.08 (s, 1 H), 4.74 (dd, 2 H), 3.03 ppm (s, 3H); ¹³ C NMR (CDCl ₃ , 62.5 MHz): δ 154.4, 151.0, 136.6, 133.3, 132.7, 130.0, 130.7, 130.3, 129.7, 128.2, 128.5, 127.3, 126.1, 125.4, 124.3, 124.7, 123.4, 118.5, 114.2 , 100.8, 57.3 ppm. HRMS (EI) calcd for C ₂₃ H ₁₈ O ₄ : 358.1205; found: 358.1198

Example 5 Preparation of Compound of Formula 7 (2-methoxymethoxy-2 '-(3-phenyluryl-benzyl) oxy-1,1'-binaphthyl-3-carboxaldehyde)

(S) -2-methoxymethoxy-2'-hydroxy-1,1'-binafphyl-3-aldehyde (2.42 g, 6.75 mmol) obtained in Example 4 was dissolved in DMF (20 ml). To DMF (50 ml) containing NaH (0.30 g, 7.43 mmol) was added under ice bath conditions. After 1 hour, 3-phenylureyl-benzylbromide (2.26 g, 7.42 mmol) was added and stirred for 5 hours. After the reaction, the whole solution was extracted with EA and water. The product obtained in the organic layer was subjected to silica column chromatography (eluate: EA / hexane 1: 1) to give (S) -2-methoxymethoxy-2 '-(3-phenylureyl-benzyl) oxy-1,1'- The binaphthyl-3-aldehyde compound was obtained (3.3 g, yield: 84%).

mp 140 ° C .; [a] _D = -43.4 (c = 0.42 in EtOH); ¹ H NMR (CDCl ₃ , 250 MHz): δ 10.48 (s, 1H), 8.51 (s, 1H), 7.98-7.09 (m, 20H), 6.87 (s, 1H), 6.75 (d, 1H), 5.07 (d, 2 H); 4.71 (dd, 2H), 2.66 ppm (s, 3H); ¹³ C NMR (CDCl ₃ , 62.5 MHz): δ 192.9, 153.9, 152.8, 152.0, 138.9, 138.7, 137.7, 137.3, 135.0, 133.4, 130.3, 130.2, 129.8, 129.0, 128.1, 127.0, 126.2, 125.0, 124.0 , 123.1, 120.1, 119.7, 118.5, 118.3, 117.8, 114.5, 100.0, 69.8, 56.8 ppm. HRMS (EI) calcd for C ₃₇ H ₃₀ N ₂ O ₅ : 582.2155; found: 582.2147.

Example 6 Preparation of Compound of Formula 8 (2-hydroxy-2 '-(3-phenyluryl-benzyl) oxy-1,1'-binaphthyl-3-carboxaldehyde)

(S) -2-methoxymethoxy-2 '-(3-phenylureyl-benzyl) oxy-1,1'-binafphyl-3-aldehyde (2.00 g, 3.43 mmol) obtained in Example 5. Was dissolved in ethanol (200 ml), concentrated hydrochloric acid (37%, 0.28 ml, 3.43 mmol) was added thereto, and the mixture was heated and stirred at 70 ° C. for 1 hour. The product obtained after evaporating the whole solution was subjected to column chromatography (eluent: EA / hexane 1/1) to give (S) -2-hydroxy-2 '-(3-phenylureyl-benzyl) oxy-1,1'. -Binaphthyl-3-aldehyde compound was obtained (1.76 g, yield: 95%).

mp 217 ° C .; [a] _D = -215.2 (c = 0.58 in EtOH); ¹ H NMR ([D ₆ ] DMSO, 250 MHz): δ 10.30 (s, 1 H), 10.20 (s, 1 H), 8.68 (s, 2 H), 8.60 (s, 1 H), 8.15-7.03 (m, 16H) 6.67 (s, 1 H), 5.20 ppm (d, 2H); ¹³ C NMR ([D ₆ ] DMSO, 62.5 MHz): δ 196.9, 154.0, 152.9, 152.3, 139.6, 139.5, 137.9, 136.9, 136.7, 133.2, 130.1, 130.0, 129.7, 128.9, 128.7, 128.5, 128.1, 127.1, 126.6, 124.4, 124.3, 124.0, 123.6, 122.6, 121.7, 120.2, 118.1, 117.6, 117.3, 116.8, 115.6, 70.0 ppm. HRMS (EI) calcd for C ₃₅ H ₂₆ N ₂ O ₄ : 538.1893; found: 538.1898

Claims (11)

A method for preparing a compound of Formula 1, comprising the steps of obtaining a compound of Formula 2 by reducing the compound of Formula 3 and oxidizing the compound of Formula 2 obtained in the step: [Formula 1]

[Formula 2]

(3)

In Chemical Formulas 1 to 3, X and Y are each independently hydrogen; halogen; Nitro; Cyano; Carboxyl; C 1 -C 10 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, and C 6 -C 10 aryl; Aryl of C6 ~ C10; And C 1 -C 10 alkoxy; N and m are integers of 0 to 5; R 1 is hydrogen or C 1 -C 5 alkyl. The compound of claim 1, wherein n and m are 0; R 1 is a method for producing a compound of formula 1, characterized in that methyl. The method of claim 1, wherein before the step of reducing the compound of Formula 3, the compound of Formula 3 is hydrolyzed to obtain 2,2'-dihydroxy-3-binaphtholic acid, which is converted into cinchonidine. A method for preparing a compound of Formula 1, characterized in that it further comprises the step of resolution to prepare in optically pure form. The method of claim 1, wherein the compound of Formula 3 is prepared by a method of reacting a compound of Formula 4 with a compound of Formula 5 using CuCl (OH) -TMEDA Way: [Formula 4]

[Chemical Formula 5]

In Chemical Formulas 4 and 5, X, Y, n, m and R 1 are the same as defined above; However, X or Y is not present at positions 8 of Formulas 4 and 5. The method for producing a compound of formula 1 according to any one of claims 1 to 4, wherein the compound of formula 1 is optically pure and exists in (S) form. The method for producing a compound of formula 1 according to any one of claims 1 to 4, wherein the compound of formula 1 is optically pure and exists in (R) form. Reducing the compound of Formula 3 to obtain a compound of Formula 2; Oxidizing the compound of Formula 2 obtained in the step to obtain a compound of Formula 1; Reacting the compound represented by Chemical Formula 1 and the compound represented by Chemical Formula 11 in the presence of a base to obtain a compound represented by Chemical Formula 6; Reacting the compound represented by Chemical Formula 6 and the compound represented by Chemical Formula 10 in the presence of a base to obtain a compound represented by Chemical Formula 7; And Method for preparing a compound of formula 8 comprising the step of hydrolyzing the compound of formula 7 obtained in the step: (3)

[Formula 2]

[Formula 1]

 [Formula 6]

[Formula 7]

[Formula 8]

[Formula 10]

[Formula 11]

In Chemical Formulas 1 to 3, 6 to 8, and 10 and 11, X and Y are each independently hydrogen; halogen; Nitro; Cyano; Carboxyl; C 1 -C 10 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, and C 6 -C 10 aryl; Aryl of C6 ~ C10; And C 1 -C 10 alkoxy; n and m are integers from 0 to 5; R 1 is hydrogen or C 1 -C 5 alkyl; R 2 is selected from the group consisting of C 1 -C 5 alkyl, C 6 -C 10 arylalkyl, and C 2 -C 10 alkoxyalkyl; R 3 is NHCX′R 4 or NHCHNH ₂ ⁺ , X ′ is oxygen or sulfur, R 4 is straight or branched chain alkyl, NR 5 R 6, or OR 7 which may be substituted with halogen, and R 5 to R 7 may be substituted with hydrogen or halogen Straight or branched chain alkyl, or aryl, and when R 3 is NHCHNH ₂ ⁺ , the counterion is a halogen ion or R 8 CO 0 ^— and R 8 is alkyl or aryl; Z is halogen. 8. The method of claim 7, wherein before the step of reducing the compound of formula 3, the compound of formula 3 is hydrolyzed to obtain 2,2'-dihydroxy-3-binaphtholic acid, which is converted into cinchonidine. Process for preparing a compound of formula 8 characterized in that it further comprises the step of resolution to prepare in optically pure form. The method of claim 7, wherein the compound of Formula 3 is prepared by a method of reacting a compound of Formula 4 with a compound of Formula 5 using CuCl (OH) -TMEDA Way: [Formula 4]

[Chemical Formula 5]

In Chemical Formulas 4 and 5, X, Y, n, m and R 1 are the same as defined above; However, X or Y is not present at positions 8 of Formulas 4 and 5. The method for preparing a compound of formula 8 according to any one of claims 7 to 9, wherein the compound of formula 8 is optically pure and exists in (S) form. 10. The process according to any one of claims 7 to 9, wherein the compound of formula 8 is optically pure and is present in the form (R).