KR101691792B1 - Enantiomerically pure binaphtol derivatives and method for preparing the same - Google Patents

Abstract

1 1a 1b
상기 화학식 1의 신규 화합물은 2,2'-바이나프톨-3-알데히드 유도체인 하기 화학식 6의 화합물 6, 6a ((S) 형)와 6b ((R) 형)를 제조함에 있어서 중요한 중간체로 사용된다. 또한, 본 발명은 상기 화학식 1의 화합물을 매우 안전한 방법으로 저렴하게 제조하는 방법을 제공한다.
[화학식 6]

6 6a 6b The present invention relates to compounds 1, 1a ((S) type) and 1b ((R) type) represented by the following general formula (1) and a process for their preparation.
[Chemical Formula 1]

1 1a 1b
The novel compounds of formula 1 are used as important intermediates in the preparation of compounds 6, 6a ((S) type) and 6b ((R) type) which are derivatives of 2,2'-binaphthol-3-aldehyde do. The present invention also provides a method for producing the compound of formula (1) at a low cost in a very safe manner.
[Chemical Formula 6]

6 6a 6b

Description

TECHNICAL FIELD [0001] The present invention relates to an optically pure binaphthol derivative and a method for producing the optically pure binaphthol derivative,

The present invention relates to a novel compound used as an important intermediate in the preparation of a compound of 2,2'-binaphthol-3-aldehyde derivative, and a process for preparing the same.

Compounds in which the hydrogen of the 2'hydroxy group of the 2,2'-binaphthol-3-aldehyde is selectively substituted have been used for various purposes. Among these compounds, it is possible to recognize the chiral properties of chiral amino alcohols or amino acids through imine linkage, to separate them into their respective optical isomers, or to be useful for converting L-amino acids to D-amino acids or D-amino acids to L-amino acids The compound of Chemical Formula 6 was developed by the inventors of the present invention and patented (Korean Patent Registration No. 10-0661280).

[Chemical Formula 6]

    6 6a 6b

However, according to the conventional technique of replacing the hydrogen of the 2'hydroxy group of the 2,2'-binaphthol-3-aldehyde, the selectivity to the 2'hydroxy group is low and the substituent for the hydrogen of the 2hydroxy group and the substituent for the hydrogen of the 2'hydroxy group A product in which a substituent for hydrogen is mixed is obtained, and in particular, a substituent for hydrogen of 2hydroxy groups is generated more. Since such a mixture is not easy to separate, there is a problem that the production efficiency of an object is greatly deteriorated. Therefore, in order to obtain a substituent for hydrogen of 2 'hydroxy group, it has been difficult to carry out an alkylation reaction after protecting 2 hydroxyl groups with a protecting group. Therefore, there has been a demand for a technique for increasing the selectivity of the 2'hydroxy group to hydrogen so as not to produce a by-product.

Meanwhile, a novel compound of the present invention, a binaphthol derivative, is represented by the following formula (1).

[Chemical Formula 1]

    1 1a 1b

(2)

    2 2a 2b

In addition, since optically pure binaphthol, which is a starting material used in the prior art, is relatively expensive, development of a method for producing an optically pure binaphthol derivative using a less expensive material has also been required.

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above-mentioned problems of the prior art, and it is an object of the present invention to provide a process for producing 2,2'-binaphthol-3-carboxylate Which is a novel compound prepared by selectively introducing various substituent groups to the hydrogen position of the 2'hydroxy group using an acid.

It is another object of the present invention to provide a method for economically preparing a binaphthol derivative of formula (1) by a safe method without using dangerous substances.

The present invention provides a compound of formula (1).

[Chemical Formula 1]

    1 1a 1b

Wherein X and Y are each independently selected from the group consisting of hydrogen; halogen; Amino; Nitro; Cyano; Halogen, hydroxy, amino, cyano, nitro and C ₆ ~ C at least one selected from the group consisting of aryl substituted with a substituent of ₁₀ or unsubstituted C ₁ ~ C ₁₀ alkyl; C ₁ -C ₁₀ alkylcarbonyl; Aryl of C ₅ ~ C _10; And C ₁ -C ₁₀ alkoxy; n and m are integers from 0 to 5; R &_lt; ₁ > is hydrogen or oxygen; R ₂ is -NO ₂ , -NH (NHBOCNBOC), -NHCX'R ₃ , -NHS (═O) aR ₃ or -NHPO (OH) R ₃ wherein X 'is oxygen or sulfur and a is 1 or 2, and R < ₃ > is hydrogen; C ₁ -C ₁₀ alkyl substituted or unsubstituted with halogen; -NR ₄ R ₅ ; Or OR < ₆ > and R < ₄ > to R < ₆ > are each independently hydrogen; C ₁ -C ₁₀ alkyl substituted or unsubstituted with halogen; Or halogen, nitro, C ₁ ~ C ₅ alkyl group, C ₁ ~ C ₅ alkoxy and C ₁ ~ C ₅ with one or more substituents selected from the group consisting of a perfluoroalkyl group-substituted or unsubstituted C ₅ ~ C _Lt ; / RTI >

The present invention also provides a process for preparing the compound of formula (1), which comprises reacting the compound of formula (2) and the compound of formula (3) in the presence of a base.

(2)

    2 2a 2b

(3)

     3

Wherein X, Y, n, m and R ₂ are the same as defined above, and Z is halogen.

When the compound of formula (2) of the present invention is used, various substituents can be introduced very efficiently at the hydrogen position of the 2'hydroxy group of 2,2'-binaphthol-3-carboxylic acid.

In addition, the process of the present invention provides a method for producing the binaphthol derivative of Formula 1 very safely and economically. Therefore, this method can provide a very large effect when applied to an industrial scale production line.

The present invention relates to a compound represented by the following general formula (1) and a process for producing the same.

[Chemical Formula 1]

    1 1a 1b

Wherein X, Y, n, m, R ₁ and R ₂ are the same as defined above.

The compound of Formula 1 may be useful as an intermediate in the preparation of the compound of Formula 6, which is a 2,2'-binaphthol-3-aldehyde derivative.

The invention also provides a process for the preparation of a compound 1 of Formula 1 which comprises reacting the compound 3 of the formula (2) compound 2 and the formula 3 in the presence of a base.

The above production method is shown in the following reaction scheme.

[Reaction Scheme 1]

      2 3 1 ( R _One = O)

Examples of the solvent which can be used in the reaction include N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidine (NMP), tetrahydrofuran (THF), dichloromethane, . Examples of the base used in the reaction include organic or inorganic bases such as Et ₃ N, NaH, NaOH, KOH, K ₂ CO ₃ , tetramethylethylenediamine (TMEDA), C ₁ to C ₄ sodium or potassium alkoxide And NaOH is preferred. The amount of the base is 1 to 5 equivalents, preferably 2 equivalents. The reaction is carried out at -40 to 30 ° C., preferably at room temperature.

Compound 2 of the formula (2) is very cheap known methods using the compound 4 and compound 5 of the general formula (V) of general formula 4 [M. Noji, M. Nakajima and K. Koga. Tetrahedron Lett. 35 (1994), p. 7983-7984. ≪ / RTI > That is, the following reaction is characterized in that compound 4 is dissolved in THF, then compound 5 is added, and then CuCl (OH) -TMEDA is added to the mixed solution and the reaction is carried out under oxygen (for details, ). Unlike the expensive binaphthol derivatives used in the prior art, the following compounds 4 and 5 are cheap and can be purchased in large quantities, making it possible to economically produce the compound of the formula (1) of the present invention.

[Chemical Formula 4]

         4

[Chemical Formula 5]

      5

In formulas (4) and (5), X, Y, n and m are as defined above.

The method of preparing the compound 2 of the above formula (2) is shown in the following reaction scheme.

[Reaction Scheme 2]

The reaction a is a reaction using the above-mentioned CuCl (OH) -TMEDA, and the reaction b is a reaction in which an ester is hydrolyzed using a base. As the base and the solvent in this reaction, Can be used without restrictions.

The above reactions a and b proceed almost quantitatively, which is economical and has an advantage that it is very safe since it is not necessary to use a compound having a high risk. Therefore, Compound 2 of Formula 2 can be produced safely and economically by the above process.

When the compound 2 of the formula 2 is synthesized by the above reaction, it is necessary to obtain the optically pure compound 2 of the formula 2 since the compound 2 is obtained as a racemic mixture. Optically method for obtaining Compound (2) of formula (2) pure in the present invention is not limited. As a single example, the compound 2 represented by the above formula 2 Hovorka, M. etc. (Hovorka, M .; Stibor, I .; Holakovsky, R .; Smiskova, I .; Struzka, V. Czech Rep. (2001), CZ 287879 B6) can be applied and improved to produce optically pure form by resolution with cinchonidine.

The above exemplary method is schematically shown in the following reaction formula (3).

[Reaction Scheme 3]

       2 2a 2b

When moving the optically pure compounds 2a ((S) type) and 2b ((R) type) can be separated, and to the use of compound 2a reaction according to scheme 4 as described above, the desired compound 1a (R ₁ = O) Or 1a (R < ₁ > = H, H).

[Reaction Scheme 4]

     2a 1a ( R _One = O) 1a ( R _One = H, H)

The reaction c is performed in the presence of N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO) Tetrahydrofuran (THF), dichloromethane and the like can be used, and DMF is preferable. Examples of the base used in the above reaction c include organic or inorganic bases such as Et ₃ N, NaH, NaOH, and C ₁ -C ₄ sodium or potassium alkoxide, and NaOH is preferable. The amount of the base is 1 to 5 equivalents, preferably 2 equivalents. Also, the reaction c is carried out at -40 to 30 캜, preferably at room temperature.

As the solvent for the reaction in the reaction d, tetrahydrofuran, dioxane, dichloromethane, toluene and the like can be used, and tetrahydrofuran is preferable. Examples of the reducing agent used in the reaction d may be used, without limitation, those that are known in the art, it is preferred to use a mixture of hydrides in beam _{3 ·} Et ₂ O and sodium BF.

It can also be prepared the desired compound 1b (R ₁ = O) or _{1b (R 1 = H, H} ) Compound 2b ((R) type) obtained in Reaction Scheme 3 by the method of Scheme 4 as a starting material.

Compound 1 , 1a or 1b of the present invention recognizes the chiral property of a chiral amino alcohol or an amino acid through imine bonding and separates the chiral amino alcohol or the amino acid into an optical isomer, separates the L-amino acid into a D-amino acid or a D- Is used as an important intermediate in the preparation of a compound of formula (6) which is very useful for conversion to an amino acid.

[Chemical Formula 6]

    6 6a 6b

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

[ Example ]

Example 1: Preparation of [(S) -4- (2- (3- (3-p- tolylido ) benzyloxy ) naphthalen-1-yl) -3- hydroxy-2-naphthoic acid 1a (R < ₁ > = O)

The known method [M. Noji, M. Nakajima and K. Koga. Tetrahedron Lett. 35 (1994), p. . 7983-7984] for the application and the compound 2 produced by improving Hovorka, M. etc. (Hovorka, M .; Stibor, I ; Holakovsky, R .; Smiskova, I .; Struzka, V. Czech Rep (2001). , CZ 287879 B6), to obtain (S) -3-hydroxy-4- (2-hydroxynaphthalen-1-yl) -2-naphthoic acid g, 27 mmol) was dissolved in 54 mL of DMF, then 2.2 g of NaOH was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, 1- (3- (bromomethyl) phenyl) -3-p-tolyl urea (8.7 g, 27 mmol) was added and stirred for 3 hours. Water was poured out, 15.3 g (yield: 99%, purity: 96.5%) of a compound was obtained.

_{^{1 H NMR (DMSO-d 6}} , 400MHz), δ 8.60 (s, 1H, OH), 7.84 (d, 1H, ArH), 7.79 (d, 1H, ArH), 7.73 (d, 1H, ArH), 7.43 (br), 1H, OH), 7.33-7.24 (m, 2H, ArH), 7.22-7.17 (m, 4H, ArH), 7.13 (D, 2H, CH ₂ ), 2.16 (d, 2H, ArH), 6.92-6.88 (m, 3H, ArH), 6.84 s, 3H, CH _3).

HPLC analysis conditions; Analytical instrument-HPLC (Agilent 1200 series), column - CAPCELL PAK UG120 C ₁₈ (3.0 x 150 mm, Shisheido), temperature (30 캜); Solvent - 60% acetonitrile _{/ H 2 O (0.1% H} 3 PO 4) (6/4, v / v), flow rate: 0.5 mL / min, detection wavelength: 230nm

Example 2: Synthesis of [(S) -1- (3 - ((1- (2-hydroxy-3- ( hydoxylmethyl ) naphthalen- 3-p-tolyl urea] (Compound 1a (R ₁ = H, H))

Naphthalen-1-yl) -3-hydroxy-2-naphthoic acid (15.3 g, 27.0 mmol) obtained in Example 1 mmol) was dissolved in THF (150 mL), BF ₃揃 Et ₂ O (3.1 g) and sodium borohydride (15 g) were added successively. The reaction mixture was stirred at 60 < 0 > C for 8 hours, then diluted hydrochloric acid was added to terminate the reaction, and ethyl acetate (150 mL) and water (150 mL) were added. The organic layer was dried over anhydrous MgSO ₄ , filtered, and concentrated to obtain the title compound (14.9 g, yield: 100%, purity 95.5%).

_{^{1 H NMR (CDCl 3, 400}} MHz), δ 7.91 (d, 1H, ArH), 7.81 (d, 1H, ArH), 7.71 (d, 1H, ArH), 7.68 (s, 1H, ArH), 7.63 ( 2H, ArH), 7.25-7.12 (m, 5H, ArH), 7.03 ~ 6.87 (s, 1H, ArH) (m, 4H, ArH), 6.61 ~ 6.57 (m, 2H, ArH), 6.00 (s, 1H, NH), 5.08 (d, 1H, 1 / 2CH 2 OH), 4.91 (d, 1H, 1 / 2CH _{2 OH), 4.73 (dd,} 2H, CH 2), 2.25 (s, 3H, CH 3).

HPLC analysis conditions; Analytical instrument-HPLC (Agilent 1200 series), column - CAPCELL PAK UG120 C ₁₈ (3.0 x 150 mm, Shisheido), temperature (30 캜); Solvent - 60% acetonitrile _{/ H 2 O (0.1% H} 3 PO 4) (6/4, v / v), flow rate: 0.5 mL / min, detection wavelength: 230 nm

Example 3: Preparation of [(R) -4- (2- (3- (3-p- tolylido ) benzyloxy ) naphthalen-1-yl) -3- hydroxy-2-naphthoic acid 1b (R < ₁ > = O)

(R) -3-hydroxy-4- (2-hydroxynaphthalen-1-yl) -2-naphthoic acid, the title compound was obtained in the same manner as in the above Example 1.

_{^{1 H NMR (DMSO-d 6}} , 400 MHz), δ 8.61 (s, 1H, OH), 7.87 (d, 1H, ArH), 7.81 (d, 1H, ArH), 7.73 (d, 1H, ArH), 7.37 ~ 7.17 (m, 8H, ArH + NH), 7.07 ~ 6.89 (m, 9H, ArH + NH), 6.69 (d, 1H, ArH), 4.94 (dd, 2H, CH 2), 2.19 (s, 3H , CH ₃₎

Example 4: Preparation of [(R) -1- (3 - ((1- (2-hydroxy-3- ( hydroxymethyl ) naphthalen- 3-p-tolyl urea] (Compound 1b (R ₁ = H, H))

Naphthalen-1-yl) -3-hydroxy-2-naphthoic acid was used in place of (R) -4- (2- (3- (3- To give the title compound.

_{^{1 H NMR (CDCl 3, 400MHz}} ), δ 7.96 (d, 1H, ArH), 7.85 (d, 1H, ArH), 7.76 (d, 1H, ArH), 7.74 (s, 1H, ArH), 7.59 (s , 7.45 (d, 1H, ArH), 7.51 (d, 1H, ArH), 7.49 1H, ArH), 6.58 (s , 1H, NH), 5.19 (d, 1H, 1 / 2CH 2 OH), 5.01 (d, 1H, 1 / 2CH 2 OH), 4.78 (dd, 2H, CH 2), _{2.26 (s, 3H, CH 3} )

Claims (5)

Which comprises reacting a compound of the formula (2) and a compound of the formula (3): in the presence of a base, with a 2'-hydroxy group without protection of the 2-hydroxy group in an organic solvent.
[Chemical Formula 1]

(2)

(3)

In this formula,
R &_lt; ₁ > is oxygen;
R ₂ is -NO ₂ , -NHCX'R ₃ , or -NHS (═O) _a R ₃ , wherein X 'is oxygen or sulfur, a is 1 or 2, and R ₃ is hydrogen; C ₁ -C ₁₀ alkyl substituted or unsubstituted with halogen; -NR ₄ R ₅ ; Or OR < ₆ > and R < ₄ > to R < ₆ > are each independently hydrogen; C ₁ -C ₁₀ alkyl substituted or unsubstituted with halogen; Or halogen, nitro, C ₁ ~ C ₅ alkyl group, C ₁ ~ C ₅ alkoxy and C ₁ ~ C ₅ with one or more substituents selected from the group consisting of a perfluoroalkyl group-substituted or unsubstituted C ₅ ~ C _& Lt; / RTI >
Z is halogen;
X and Y are each independently hydrogen; halogen; Nitro; Cyano; C ₁ -C ₁₀ alkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano and nitro; C ₁ -C ₁₀ alkylcarbonyl; Aryl of C ₅ ~ C _10; And C ₁ -C ₁₀ alkoxy; n and m are integers of 0 to 5; The process according to claim 1, wherein the base is an organic base in which the base is triethylamine (TEA) or tetramethylethylenediamine (TMEDA), or an inorganic base selected from the group consisting of NaH, NaOH, KOH and K ₂ CO ₃ . 3. The process according to claim 1 or 2, wherein the organic solvent is selected from the group consisting of N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidine and tetrahydrofuran. 3. The process according to claim 1 or 2, wherein the compound of formula (2) is an (S) -form compound represented by the following formula (2a)
[Formula 1a]

(2a)

Wherein X, Y, n, m, R ₁ and R ₂ are the same as defined in claim 1 . 3. The process for producing a compound according to claim 1 or 2, wherein the compound of formula (2) is an (R) -form compound represented by the following formula (2b)
[Chemical Formula 1b]

(2b)

Wherein X, Y, n, m, R ₁ and R ₂ are the same as defined in claim 1 .