Enantiomerically pure binaphthol derivatives and method for preparing the same

Abstract

The present invention relates to compounds 1, 1a (S-enantiomer) and 1b (R-enantiomer) of the following formula 1, and a method for preparing the same. [formula 1] The novel compound of the formula 1 is used as an important intermediate for preparing compounds 6, 6a (S-enantiomer) and 6b (R-enantiomer) of the following formula 6, which are 2,2-binaphthol-3-aldehyde derivatives. Also, the present invention provides a method for preparing the compound of formula 1 with a very safe method at low cost. [formula 6]

Claims

1. A method for preparing the compound represented by the formula 1, comprising the step of reacting the compound represented by the formula 2 with the compound represented by the formula 3 in an organic solvent in the presence of a base; ##STR00013## wherein X and Y are each independently selected from the group consisting, of hydrogen; halogen; amino; nitro; cyano; C.sub.1-C.sub.10 alkyl non-substituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro and C.sub.6-C.sub.10 aryl; C.sub.1-C.sub.10 alkyl carbonyl; C.sub.5-C.sub.10aryl; and C.sub.1-C.sub.10 alkoxy; n and m are each independently an integer from 0 to 5; R.sub.1 is oxygen; R.sub.2 is NO.sub.2, NH(NHBOCNBOC), NHCXR.sub.3, NHS(O).sub.aR.sub.3 orNHPO(OH)R.sub.3, wherein X is oxygen or sulfur; a is 1 or 2; and R.sub.3 is hydrogen; C.sub.1-C.sub.10 alkyl non-substituted or substituted with a halogen; NR.sub.4R.sub.5; or OR.sub.6, wherein R.sub.4 to R.sub.6 are each independently selected from the group consisting of hydrogen; C.sub.1-C.sub.10 alkyl non-substituted or substituted with a halogen; C.sub.5-C.sub.12 aryl non-substituted or substituted with at least one substituent selected from the group consisting of halogen, nitro, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy and C.sub.1-C.sub.5 perfluoroalkyl; and Z is halogen.

2. The method for preparing according to claim 1, wherein the base is an organic base which is triethylamine (TEA) or tetramethylethylenediamine (TMEDA), or an inorganic base selected from the group consisting of NaH, NaOH, KOH and K.sub.2CO.sub.3.

3. The method for preparing according to claim 1, wherein the organic solvent is selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and tetrahydrofuran.

4. The method for preparing according to claim 1, wherein the compound represented by the formula 2 is S-enantiomer which is represented by the formula 2a, and the compound represented by the formula 1 is the S-enantiomer which is represented by the formula 1a: ##STR00014## wherein X, Y, n, m, R.sub.1 and R.sub.2 are each as defined in claim 1.

5. The method for preparing according to claim 1, wherein the compound represented by the formula 2 is the R-enantiomer which is represented by the formula 2b, and the compound represented by the formula 1 is the R-enantiomer which is represented by the formula 1b: ##STR00015##

Description

EXAMPLES

Example 1

Preparation of [(S)-4-(2-(3-(3-p-tolylureido)benzyloxy)naphthalene-1-yl)-3-hydroxy-2-naphthoic acid] (Compound 1a (R1O))

(1) After dissolving (S)-3-hydroxy-4-(2-hydroxynaphthalene-1-yl)-2-naphthoic acid (9.0 g, 27 mmol) obtained by separating compounds 2 of reaction formula 2 prepared by applying and improving the known method of M. Noji, M. Nakajima and K. Koga. Tetrahedron Lett. 35 (1994), p. 7983-7984. by resolution using cinchonidine by applying and improving the technology disclosed by Hovorka, M. et al (Hovorka, M.; Stibor, I; Holakovsky, R.; Smiskova, I.; Struzka, V. Czech Rep. (2001), CZ 287879 B6) in 54 mL of DMF, 2.2 g of NaOH is added, and the mixture is stirred for 1 hour at room temperature. After adding 1-(3-(bromomethyl)phenyl)-3-p-tolylurea (8.7 g, 27 mmol) to the reaction solution, the mixture is stirred for three hours, and the solid generated by adding water is filtered to obtain 15.3 g of the subject compound (yield: 99%, purity: 96.5%).

(2) .sup.1H NMR (DMSO-d.sub.6, 400 MHz), 8.60 (s, 1H, OH), 7.84 (d, 1H, ArH), 7.79 (d, 1H, ArH), 7.73 (d, 1H, ArH), 7.43 (s(br), 1H, OH), 7.337.24 (m, 2H, ArH), 7.227.17 (m, 4H, ArH), 7.13 (s(br), 1H, NH), 7.087.00 (m, 4H, ArH), 6.926.88 (m, 3H, ArH), 6.84 (s(br), 1H, NH), 6.61 (d, 1H, ArH), 4.89 (dd, 2H, CH.sub.2), 2.16 (s, 3H, CH.sub.3).

(3) HPLC analysis condition: analysis instrument: HPLC (Agilent 1200 series); column: CAPCELL PAK UG120 C.sub.18 (3.0150 mm, Shisheido), temperature: 30 C.; solvent: 60% acetonitrile/H.sub.2O (0.1% H.sub.3PO.sub.4) (6/4, v/v), flow rate: 0.5 mL/min, detection wavelength: 230 nm

Example 2

Preparation of [(S)-1-(3-((1-(2-hydroxy-3-(hydroxymethyl)naphthalene-1-yl) naphthalene-2-yloxy)methyl)phenyl)-3-p-tolylurea] (Compound 1a (R1H,H))

(4) After dissolving the (S)-4-(2-(3-(3-p-tolylureido)benzyloxy)naphthalene-1-yl)-3-hydroxy-2-naphthoic acid (15.3 g, 27.0 mmol) obtained in example 1 in THF (150 mL), BF.sub.3.Et.sub.2O (3.1 g) and sodium borohydride (15 g) are added sequentially. After stirring the reaction mixture at 60 C. for 8 hours, dilute hydrochloric acid is added to complete the reaction, and ethyl acetate (150 mL) and water (150 mL) are added. The subject compound is obtained by drying the organic layer with anhydrous MgSO.sub.4 and filtering and condensing it (14.9 g, yield: 100%, purity: 95.5%).

(5) .sup.1H NMR (CDCl.sub.3, 400 MHz), 7.91 (d, 1H, ArH), 7.81 (d, 1H, ArH), 7.71 (d, 1H, ArH), 7.68 (s, 1H, ArH), 7.63 (s, 1H, ArH), 7.48 (s, 1H, OH), 7.37 (d, 1H, ArH), 7.347.29 (m, 2H, ArH), 7.257.12 (m, 5H, ArH), 7.036.87 (m, 4H, ArH), 6.616.57 (m, 2H, ArH), 6.00 (s, 1H, NH), 5.08 (d, 1H, 1/2CH.sub.2OH), 4.91 (d, 1H, 1/2CH.sub.2OH), 4.73 (dd, 2H, CH.sub.2), 2.25 (s, 3H, CH.sub.3).

(6) HPLC analysis condition: analysis instrument: HPLC (Agilent 1200 series); column: CAPCELL PAK UG120 C.sub.18 (3.0150 mm, Shisheido), temperature: 30 C.; solvent: 60% acetonitrile/H.sub.2O (0.1% H.sub.3PO.sub.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-tolylureido)benzyloxy)naphthalene-1-yl)-3-hydroxy-2-naphthoic acid] (Compound 1b (R1O))

(7) The subject compound is obtained by the same method as example 1 using (R)-3-hydroxy-4-(2-hydroxynaphthalene-1-yl)-2-naphthoic acid.

(8) .sup.1H NMR (DMSO-d.sub.6, 400 MHz), 8.61 (s, 1H, OH), 7.87 (d, 1H, ArH), 7.81 (d, 1H, ArH), 7.73 (d, 1H, ArH), 7.377.17 (m, 8H, ArH+NH), 7.076.89 (m, 9H, ArH+NH), 6.69 (d, 1H, ArH), 4.94 (dd, 2H, CH.sub.2), 2.19 (s, 3H, CH.sub.3)

Example 4

Preparation of [(R)-1-(3-((1-(2-hydroxy-3-(hydroxymethyl)naphthalene-1-yl)naphthalene-2-yloxy)methyl)phenyl)-3-p-tolylurea] (Compound 1b (R1H,H))

(9) The subject compound is obtained by the same method as example 1 using (R)-4-(2-(3-(3-p-tolylureido)benzyloxy)naphthalene-1-yl)-3-hydroxy-2-naphthoic acid.

(10) .sup.1H NMR (CDCl.sub.3, 400 MHz), 7.96 (d, 1H, ArH), 7.85 (d, 1H, ArH), 7.76 (d, 1H, ArH), 7.74 (s, 1H, ArH), 7.59 (s, 1H, ArH), 7.51 (d, 1H, ArH), 7.49 (d, 1H, ArH), 7.447.15 (m, 8H, ArH), 7.056.96 (m, 4H, ArH), 6.65 (d, 1H, ArH), 6.58 (s, 1H, NH), 5.19 (d, 1H, 1/2CH.sub.2OH), 5.01 (d, 1H, 1/2CH.sub.2OH), 4.78 (dd, 2H, CH.sub.2), 2.26 (s, 3H, CH.sub.3).