KR20100039114A - Method for preparing binaphthol aldehyde derivatives and intermediate thereof - Google Patents

Abstract

PURPOSE: A method for preparing binaphthol aldehyde derivatives and an intermediate thereof are provided to prepare binaphthol aldehyde derivatives and an intermediate thereof using inexpensive raw materials without dangerous materials such as n-butyl lithium. CONSTITUTION: A method for preparing binaphthol aldehyde derivatives comprises the steps of: obtaining a compound of chemical formula 2 by reducing a compound of chemical formula 3; and oxidizing a compound of chemical formula 2. In chemical formulas 1-3, X each is independently selected from the group consisting of hydrogen, amino, nitro, cyano, formyl, carboxyl, substituted or unsubstituted C1~C10 alkyl, C1~C10 alkylcarbonyl, C6~C10 aryl, and C1~C10 alkoxy; Y is independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, formyl, carboxyl, substituted or unsubstituted C1~C10 alkyl, C1~C10 alkylcarbonyl, C6~C10 aryl, and C1~C10 alkoxy; n and m are an integer of 0~5; and R1 is selected from the group consisting of hydrogen, C1~C5 alkyl, tosyl, CH3SO2-, and CH3CO-.

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 and patented a compound represented by the following Chemical Formula 9 which is very useful for recognizing chiral amino alcohol or amino acid chirality through imine bonds and separating them into their respective optical isomers or converting L-amino acids to D-amino acids. Registered (Korean Patent Registration No. 10-0661280).

 [Compound 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.

(Z: 할로겐)를 직접 반응시키는 것에 의해 이루어진다. 그러나, 이 경우 2,2'-바이나프톨-3-알데히드의 2' 히드록시기에 대한 선택성이 낮아서, 2 히드록시기의 수소에 대한 치환체와 2' 히드록시기수소에 대한 치환체가 혼합된 생성물이 얻어지는 문제가 발생한다. 더구나, 이 혼합물의 분리는 쉽지 않아서 목적물의 제조 효율을 크게 저하시킨다. 따라서, 2' 히드록시기의 수소에 대한 선택성을 높여서 부산물이 생성되지 않게 하는 기술이 요구되고 있다. 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 process of introducing benzyl groups is carried out with 2,2'-binaphthol-3-aldehyde.

By reacting (Z: halogen) directly. 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. . Moreover, the separation of this mixture is not easy, which greatly lowers the production efficiency of the target product. 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.

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 method for preparing the 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]

[Formula 3]

In Chemical Formulas 1 to 3, each X is 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; Each Y is 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;

(R2는 C1~C5의 알킬, C6~C10의 아릴알킬, 및 C2~C10의 알콕시알킬로 이루어진 군으로부터 선택됨)를 염기의 존재 하에 반응시켜 하기 화학식 6의 화합물을 얻는 단계;Compound of Formula 1 obtained in the step and

(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) in the presence of a base to obtain a compound of formula 6;

(상기에서 Z은 할로겐이고, R3는 NHCX'R4 또는 NHCHNH₂ ⁺이며, X'는 산소 또는 황이고, R4는 할로겐으로 치환될 수 있는 직쇄 또는 분지쇄 알킬, NR5R6, 또는 OR7이고, R5 내지 R7은 수소 또는 할로겐으로 치환될 수 있는 직쇄 또는 분지쇄 알킬, 또는 아릴이고, R3가 NHCHNH₂ ⁺일 때 상대이온은 할로겐 이온 또는 R8COO^-이고, R8은 알킬 또는 아릴임)을 염기의 존재하에 반응시켜 하기 화학식 7의 화합물을 얻는 단계; 및Compound of formula 6 obtained in the step and

(Wherein Z is halogen, 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, R 5 to R 7 is hydrogen or which may be substituted by halogen, straight-chain or branched-chain alkyl, or aryl, R3 is a counter ion when NHCHNH ₂ ⁺ is a halogen ion or R8COO ^- by reacting in the presence of an a, R8 is alkyl or aryl), base Obtaining a compound of Formula 7; And

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

 [Formula 3]

[Formula 2]

[Formula 1]

[Formula 6]

[Formula 7]

[Formula 8]

In Chemical Formulas 1 to 3 and 6 to 8, X is 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; Each Y is 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—; 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 halogen ion or R 8 CO 0 ^— and R 8 is alkyl or aryl.

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 process for preparing the 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]

[Formula 3]

In Chemical Formulas 1 to 3, each X is independently hydrogen; halogen; Amino; Nitro; Cyano; Formyl; Carboxyl; C1-C10 alkyl substituted or unsubstituted 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; Each Y is 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 Formulas 1 to 3, n and m are 0; More preferably, R1 is methyl.

If the method for producing a compound represented by Chemical Formula 1 is represented by the reaction scheme as follows.

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 represented by Chemical Formula 3 may be prepared by a method of reacting a compound represented by Chemical Formula 4 with a compound represented by Chemical Formula 5 using CuCl (OH) -TMEDA (Tetramethylethylenediamine).

In Chemical Formulas 4 and 5, each X is 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; Each Y is 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-, provided that X or Y is in position 8 of Formulas 4 and 5 does not exist.

When the method for preparing the compound represented by Chemical Formula 3 is represented by the scheme, it is as follows.

The reaction is carried out using known methods (Hovorka, M .; Sci gel, R .; gunterova, J .; Tichy, M .; Zavada, J. Tetrahedron 1992, 48, 9503) using very inexpensive compounds of formulas (4) and (5). -9516). Briefly, the reaction is characterized in that the compound of formula 4 is dissolved in THF, and then the compound of formula 5 is added, followed by addition of CuCl (OH) -TMED to the mixed solution and reacted under oxygen. See Example 1). Compounds represented by Formulas 4 and 5 are inexpensive and can be purchased in large quantities, unlike expensive binapitol used in the prior art, 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;

(R2는 C1~C5의 알킬, C6~C10의 아릴알킬, 및 C2~C10의 알콕시알킬로 이루어진 군으로부터 선택됨)를 염기의 존재 하에 반응시켜 하기 화학식 6의 화합물을 얻는 단계;Compound of Formula 1 obtained in the step and

(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) in the presence of a base to obtain a compound of formula 6;

(상기에서 Z은 할로겐이고, R3는 NHCX'R4 또는 NHCHNH₂ ⁺이며, X'는 산소 또는 황이고, R4는 할로겐으로 치환될 수 있는 직쇄 또는 분지쇄 알킬, NR5R6, 또는 OR7이고, R5 내지 R7은 수소 또는 할로겐으로 치환될 수 있는 직쇄 또는 분지쇄 알킬, 또는 아릴이고, R3가 NHCHNH₂ ⁺일 때 상대이온은 할로겐 이온 또는 R8COO^-이고, R8은 알킬 또는 아릴임)을 염기의 존재하에 반응시켜 하기 화학식 7의 화합물을 얻는 단계; 및Compound of formula 6 obtained in the step and

(Wherein Z is halogen, 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, R 5 to R 7 is hydrogen or which may be substituted by halogen, straight-chain or branched-chain alkyl, or aryl, R3 is a counter ion when NHCHNH ₂ ⁺ is a halogen ion or R8COO ^- by reacting in the presence of an a, R8 is alkyl or aryl), base Obtaining 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 above step.

[Formula 3]

[Formula 2]

[Formula 1]

 [Formula 6]

[Formula 7]

[Formula 8]

In Chemical Formulas 1 to 3 and 6 to 8, X is 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; Each Y is 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—; 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 halogen ion or R 8 CO 0 ^— and R 8 is alkyl or aryl.

의 화합물에서 Z은 할로겐이며, 상기 할로겐의 구체예로는 Br, Cl, I 등을 들 수 있다.Described above

In the compound of Z is halogen, specific examples of the halogen include Br, Cl, I and the like.

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 NEt ₃ or NaH. In addition, the reaction a is made at 0 ~ 30 ℃, preferably carried out at room temperature.

은 주로 2 히드록시의 수소 위치에 치환되며,

가 2 히드록시기 및 2' 히드록시기의 수소 위치에 모두 치환된 화합물이 일부 생성된다. 그러나, 이러한 반응 부산물은 가수분해하여 다시 화학식 1의 화합물로 만들면 재활용이 가능하다. 상기 화학식 6의 화합물은 재결정을 통해 98% 이상의 순도 및 90% 이상의 수율로 수득될 수 있다.In the reaction a

Is mainly substituted at the hydrogen position of 2 hydroxy,

Some compounds are produced in which both are substituted at the hydrogen positions of the 2 hydroxy group and the 2 'hydroxy group. 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.

(Z: 할로겐)과 반응시켜서 화학식 7의 화합물을 얻는다. 상기 반응 b에서 반응을 위한 용매로는 N,N-디메틸포름아마이드(N,N-dimethylformamide, DMF), 테트라하이드로퓨란(tetrahydrofuran, THF), CH₂Cl₂ 등을 사용할 수 있으며, DMF가 바람직하다. 상기 반응 b에 사용되는 염기로는 Et₃N, NaH, NaOH 등의 유기 또는 무기염기를 들 수 있으며, NEt₃ 또는 NaH가 바람직하다.In the reaction b, the compound of Formula 1 in the presence of a base

Reaction with (Z: halogen) gives a compound of the 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 NEt ₃ 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 according to the synthesis method of known papers (Hovorka, M .; Sci gel, R .; gunterova, J .; Tichy, M .; Zavada, J. Tetrahedron 1992, 48, 9503-9516). 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 (2.9 g, yield: 90%).

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

After dissolving lithium aluminum hydride (LiAlH 4, 0.34 g, 9.02 mmol) in THF (30 ml), 2,2′-dihydroxy-1,1′-binafphyl-3- prepared in Example 1, above Carboxylic acid methyl ester (2.60 g, 7.52 mmol) was added in an ice bath. After stirring for 5 hours at room temperature, the precipitate was filtered off and the resulting solution was evaporated to give a 2,2'-dihydroxy-3-hydroxymethyl-1,1'-binaphthalene compound (2.15 g, yield: 90% ).

mp 164 ^o 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 3: Preparation of Compound of Formula 1 (2,2'-dihydroxy-1,1'-binaphthyl-3-carboxaldehyde)

2,2'-dihydroxy-3-hydroxymethyl-1,1'-binaphthalene (2.0 g, 6.31 mmol) and pyridinium chlorochromate obtained in Example 2 were added to methylene chloride at room temperature for 3 hours. Stirred. After the reaction was completed, the precipitate was filtered off and the resulting solution was dried using a rotavapor to obtain a 2,2'-dihydroxy-1,1'-binafphyl-3-aldehyde compound in solid form. 2.9 g, yield: 65%).

mp 164 ^o 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 4 Preparation of Compound of Chemical Formula 6 (2-methoxymethoxy-2'-hydroxy-1,1'-binaphthyl-3-carboxaldehyde)

The 2,2'-dihydroxy-1,1'-binafthyl-3-aldehyde (3.9 g, 12.4 mmmol) obtained in Example 3 was dissolved in DMF (40 ml) and stirred well, followed by 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 obtain 2-methoxymethoxy- (Compound 1). 2'-hydroxy-1,1'-binafphyl-3-aldehyde compound was obtained (2.9 g, yield: 65%).

mp 164 ^o 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)

The 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), and NaH (0.30) was dissolved. g, 7.43 mmol) was added under ice bath conditions to 50 mL of DMF. 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 2-methoxymethoxy-2 '-(3-phenylureyl-benzyl) oxy-1,1'-binafryl- 3-aldehyde compound was obtained (3.3 g, yield: 84%).

mp 140 ^o 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)

2-methoxymethoxy-2 '-(3-phenylureyl-benzyl) oxy-l, l'-binapthyl-3-aldehyde (2.00 g, 3.43 mmol) obtained in Example 5 was added to ethanol (200 ml), concentrated hydrochloric acid (37%, 0.28 ml, 3.43 mmol) was added thereto, and the mixture was stirred while heating at 70 ^° C. for 1 hour. The product obtained after evaporation of the whole solution was subjected to column chromatography (eluate: EA / hexane 1/1) to 2-hydroxy-2 '-(3-phenylureyl-benzyl) oxy-1,1'-binafryl. A 3-aldehyde compound was obtained (1.76 g, yield: 95%).

mp 217 ^o 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 (7)

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]

[Formula 3]

In Chemical Formulas 1 to 3, each X is 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; Each Y is 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—. 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 separated by cinchonidine. A method for preparing a compound of formula 1, further comprising the step of preparing in an optically pure form by resolution. 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. [Formula 4]

[Chemical Formula 5]

In Chemical Formulas 4 and 5, each X is 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; Each Y is 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-, provided that X or Y is in position 8 of Formulas 4 and 5 does not exist. 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; Compound of Formula 1 obtained in the step and

(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) in the presence of a base to obtain a compound of formula 6; Compound of formula 6 obtained in the step and

(Wherein Z is halogen, 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, R 5 to R 7 is hydrogen or which may be substituted by halogen, straight-chain or branched-chain alkyl, or aryl, R3 is a counter ion when NHCHNH ₂ ⁺ is a halogen ion or R8COO ^- by reacting in the presence of an a, R8 is alkyl or aryl), base Obtaining a compound of 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: [Formula 3]

[Formula 2]

[Formula 1]

 [Formula 6]

[Formula 7]

[Formula 8]

In Chemical Formulas 1 to 3 and 6 to 8, X is 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; Each Y is 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—; 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 halogen ion or R 8 CO 0 ^— and R 8 is alkyl or aryl. The method of claim 5, wherein before the step of reducing the compound of Formula 3, the compound of Formula 3 is hydrolyzed to obtain 2,2'-dihydroxy-3-binaphthoic acid, which is separated by cinchonidine. A method for preparing a compound of Formula 8, further comprising the step of preparing in an optically pure form by resolution. The method of claim 5, 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. [Formula 4]

[Chemical Formula 5]

In Chemical Formulas 4 and 5, each X is 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; Each Y is 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-, provided that X or Y is in position 8 of Formulas 4 and 5 does not exist.