KR20090080657A - Method for producing chiral athenol of high optical purity - Google Patents

Abstract

The present invention relates to a process for preparing chiral athenol in high optical purity without compromising optical purity of the starting material. More specifically, 1) ECH (epichlorohydrin) is reacted with alkyl-4-hydroxy phenyl acetate in the presence of a catalyst to produce the optically active compound 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (chloro) propane- A first step of producing a 2-ol; 2) Dehydrochlorination of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (chloro) propan-2-ol with base to yield an optically active 1- [4 [(alkoxycarbonyl) methyl Phenoxy] -2,3-epoxypropane; 3) The epoxide ring of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane was opened with isopropyl amine and 1- [4 [(alkoxycarbonyl) methyl] which is an optically active compound. A third step of producing phenoxy] -3- (isopropyl amino) propan-2-ol; And 4) treating the ester group of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol with aqueous ammonia to produce an optically active chiral athenol It relates to a chiral athenol production method comprising a fourth step.

Description

Process for producing chiral athenol with high optical purity {PROCESS FOR THE PREPARATION OF OPTICALLY PURE CHIRAL ATENOLOL}

The present invention relates to a process for the preparation of chiral athenol with high optical purity without compromising the optical purity of the starting material. More specifically, 1) ECH (epichlorohydrin) is reacted with alkyl-4-hydroxy phenyl acetate in the presence of a catalyst to produce the optically active compound 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (chloro) propane- A first step of producing a 2-ol; 2) Dehydrochlorination of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (chloro) propan-2-ol with base to yield an optically active 1- [4 [(alkoxycarbonyl) methyl Phenoxy] -2,3-epoxypropane; 3) The epoxide ring of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane was opened with isopropyl amine and 1- [4 [(alkoxycarbonyl) methyl] which is an optically active compound. A third step of producing phenoxy] -3- (isopropyl amino) propan-2-ol; And 4) treating the ester group of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol with aqueous ammonia to produce an optically active chiral athenol It relates to a chiral athenol production method comprising a fourth step.

Chirality or hand-symmetric molecules are terms used to describe molecular structures in which mirror images cannot overlap each other. A pair of enantiomers of a chiral molecule have the same chemical and physical properties, but when placed in different chiral environments, they exhibit different activities. Especially in biological tissues, a pair of enantiomers are recognized as different substances. The result is different physiological properties.

Most molecules, including macromolecules, have chiral elements, and these molecules are fundamental to many reactions, including interactions between in vivo materials. This is because it works through mutual recognition.

In other words, hand symmetric molecules exhibit specificity that binds to other hand symmetric receptors in only one way, and if any one has other hand symmetry, natural physiological functions such as enzyme reactions will not function properly. Therefore, only one enantiomer of a pair of enantiomers acts as an effective therapeutic agent, and drugs in racemic conditions sometimes cause side effects or exhibit reduced efficacy.

This effect of hand symmetric molecules on the physiological activity has made the synthesis of pure hand symmetric compounds play an important role in the fields of medicines, foods, additives, natural products, pesticides and pesticides, especially in the field of pharmaceuticals. Research and development is active.

For example, an amino acid called Dopa (2-amino-3- (4,3-dihydroxyphenyl) propanoic acid) has one chiral stereocenter, so two stereoisomers exist. The dextrorotatory enantiomer (D) -Dopa has no physiological effect in vivo, but the leprotic enantiomer (L) -Dopa is excellent for Parkin's disease, a chronic disease of the central nervous system. Has effect. In addition, thalidomide was originally sold as a racemate and used as an analgesic and sedative, but the sale of the racemate was stopped due to a side effect of causing one of the enantiomers to give birth to a malformed child.

Chiral athenol having the structure of [Formula 1] is a kind of beta-blocker that is effective for hypertension and angina, and lowers blood pressure by lowering blood vessel tension, and reduces the pressure on the heart. It is a drug that plays a role in preventing (chest pain).

Conventional chirality known to date The preparation method of athenol is as follows.

First, a method for obtaining athenol using chiral (R) -Epichlorohydrine (ECH) is described by Emcure in US Pat. No. 6,982,349 [Emcure Pharmaceuticals Limited, 2006/01/03 (Filing Date: 2003/11/05). ], And is prepared via the following reaction route.

The method is most widely known as a basic method for synthesizing chiral athenol, and has the advantage of low synthesis steps and good reaction yield (yield; 75 to 91%, 2 steps).

First, (R) -ECH of high optical purity is reacted with 4-hydroxy phenyl acetamide at low temperature, and the obtained product is washed and filtered to react with isopropylamine in the presence of water. The resulting solution is reduced to pH 2 with HCl solution to form acid addition salts (salts), and the filtrate is converted to a free base by adjusting the pH to about 12 with NaOH, followed by washing and filtration to produce athenol in a solid state.

However, the method has a disadvantage in that it is difficult to apply to commercial mass production because the reaction temperature must be kept low (-5 to -10 ° C) to obtain the final product athenol compound having an optical purity of 99% ee or more. If the reaction temperature is maintained at about 0 ℃ or more at room temperature, the optical purity of the product is greatly reduced, for example, the% ee of athenol obtained at the reaction temperature of 5 ℃ is only about 90%. In addition, in order to maintain high optical purity, the reaction rate must be slowed (low temperature reaction for 2 days or more), thereby increasing the production price, thereby lowering the competitiveness of the price. .

As described above, the manufacturing process using (R) -ECH as a raw material has been known in the US patent by Daiso Corporation of Japan [US 5,223,646; Daiso, 1993/01/29 (Filing Date: 1992/04/21), US 5,130,482; Daiso, 1992/01/14 (Filing Date: 1990/12/07)].

In addition, a method of preparing the target compound using 3-benzyloxy-1-tosyloxy-2-propanol as a starting material and undergoing a four-step reaction as described in US Pat 4,085,136 [Imperial Chem. Indu. Lim., 1978/04/18. However, this process is not only low in yield of athenol as a product due to the complicated process, but also requires the use of expensive starting materials and the step of reducing the hydrogen to hydrogen in the presence of a palladium catalyst in an intermediate process. Falls.

As an alternative, a process for the selective separation of S- athenol using a chiral tartaric acid derivative or a cellulose phenylcarbamate separation agent is first developed after the synthesis of athenol in racemic state. The method of using chiral tartaric acid is described by IPCA Lab as follows [WO2006 / 046252, 2006/05/04], and the method of using cellulose phenylcarbamate derivative is JP 61-161226, 1986. / 07/21 (Filing Date: 1985/01/10), respectively.

 However, the method has a low yield (34%) of the chiral product Athenol product as well as having a high possibility that the optical purity is lowered with the change of temperature while performing the recrystallization at 30 ℃. In addition, in order to improve economics, a process of recycling expensive chiral tartaric acid derivatives remaining after recrystallization is essential.

Recently, Boss and Narsaiah have reported a method for preparing chiral athenol using 4-hydrohy phenyl acetophenone as a starting material [Bioorg. Med. Chem., 13 (2005) 627-630. According to this preparation method, a racemic body 1- [4 [(methoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane is obtained after a complicated process of five or more steps using expensive reagents under severe reaction conditions. The resultant racemic epoxide was synthesized through asymmetric hydrolysis reaction using water as a nucleophile under Jacobson catalyst, to form (S) 1- [4 [(methoxycarbonyl) methyl] phenoxy] -2,3 It is made of epoxy propane and diol compound. Diol in this mixture is separated and removed by column, and the epoxide compound is reacted with isopropyl amine and then treated with ammonia water / methol mixture to obtain chiral athenol.

This method has the advantage of producing relatively high optical purity atenols, but separation of chiral 1- [4 [(methoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane and diol compounds Is very difficult and the epoxide yield (34%) and optical purity (94% ee) in asymmetric hydrolysis in the presence of Jacobson catalysts are also low. In addition, there is a disadvantage in that the method of preparing the reactants used in the reaction is difficult, so it is difficult to apply the manufacturing process to the industrial mass production of chiral athenol.

Accordingly, the present inventors can maintain the optical purity of the starting material almost completely to produce the final product in high optical purity without degrading chirality, and the reaction process is simple and economical, which is suitable for industrial mass production. The manufacturing method of the was developed.

It is an object of the present invention to provide a method for producing optically active compounds of chiral athenol from chiral or racemic ECH (epichlorohydrin) using a dimeric chiral salen catalyst in high optical purity.

It is yet another object of the present invention to provide a method for preparing an optically active substance of chiral athenol which is simple and economical for the industrial mass production.

The object of the present invention is 1) by reacting epichlorohydrin (ECH) with alkyl-4-hydroxy phenyl acetate in the presence of a catalyst, 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (chloro A first step of producing propan-2-ol; 2) Dehydrochlorination of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (chloro) propan-2-ol with base to yield an optically active 1- [4 [(alkoxycarbonyl) methyl Phenoxy] -2,3-epoxypropane; 3) The epoxide ring of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane was opened with isopropyl amine and 1- [4 [(alkoxycarbonyl) methyl] which is an optically active compound. A third step of producing phenoxy] -3- (isopropyl amino) propan-2-ol; And 4) treating the ester group of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol with aqueous ammonia to produce an optically active chiral athenol It can be achieved by providing a method for preparing chiral athenol comprising a fourth step.

In addition, the object of the present invention is 1) reacting ECH (epichlorohydrin) with 4-hydroxy benzyl cyanate in the presence of a catalyst 1- [4 [(cyano) methyl] phenoxy] -3- (chloro A first step of producing propan-2-ol; 2) Dehydrochlorination of the 1- [4 [(cyano) methyl] phenoxy] -3- (chloro) propan-2-ol with a base to yield an optically active 1- [4 [(cyano) methyl] phenoxy C) a second step of producing 2,3-epoxypropane; 3) Opening the epoxide ring of 1- [4 [(cyano) methyl] phenoxy] -2,3-epoxypropane with isopropyl amine, which is an optically active 1- [4 [(cyano) methyl] phenoxy ] -3- (isopropyl amino) propan-2-ol; And 4) treating the cyanate group of 1- [4 [(cyano) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol with water in the presence of a platinum / carbon catalyst to obtain an optically active compound. It can be achieved by providing a method for preparing chiral athenol comprising a fourth step of producing chiral athenol.

According to the method for preparing chiral (S) -athenol of the present invention, a chiral athenol optical active material is prepared from chiral ECH (epichlorohydrin) with a high optical purity of 99% ee or more using a dimer-type chiral salen catalyst. can do. In addition, the production method of the present invention is suitable for the industrial production of chiral (S)-athenol because the whole process is performed under mild conditions and the difficult purification process is excluded and the reaction process is simple and economical.

On the other hand, when the racemic ECH is used as a starting material instead of the chiral ECH, the final target (S)-athenol can be produced in a high yield of 98% ee or more, and the chiral ECH, which is a high optically active compound in the intermediate stage, can be produced. It is economical because it can be recovered as a by-product.

The method for preparing chiral athenol according to the present invention can be summarized by Scheme 1 below.

As shown in Scheme 1, alkyl-4-hydroxy phenyl acetate of the formula (2) can be prepared by condensation reaction of 4-hydroxy benzoic acid with methanol, ethanol and butanol using a concentrated sulfuric acid as a catalyst. The reaction is refluxed using only alcohol without addition of a separate solvent. After completion of the reaction, residual alcohol is evaporated and the product is washed with water to remove sulfuric acid.

R in the above formula means methyl, ethyl, propyl, isopropyl or butyl group (R = 1-4).

1.0 equivalent of chiral (R) -ECH (epichlorohydrin) (preferably 1-1.2 equivalents) is mixed with respect to 1.0 equivalent of alkyl-4-hydroxy phenyl acetate of Chemical Formula 2, and the following formula of RS tech 0.3 mol% (preferably 0.3-0.5 mol%) of the (R, R) -type dimer type salen catalyst (Korean Patent No. 0368002) of 3 was added and reacted at room temperature for 5-10 hours.

In the above formula, R ₁ , R ₂ , R ' ₁ , R' ₂ and R _{3 form} a ring and represent a carbocycle or heterocycle consisting of 4 to 10 atoms, and X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ , X ₈ each represent a hydrogen atom or a t-butyl group, Y 1 and Y 2 are each a hydrogen atom, and M is a metal atom selected from Co, Cr, Mn, Fe, Mo and Ni L represents B or Al, Q represents a halogen atom, and n is an integer from 0 to 4.

The progress of the reaction is measured by TLC (Thin Layer Chromatography), and the reaction is terminated if the presence of the reactant alkyl-4-hydroxy phenyl acetate of Formula 2 is not observed.

At the end of the reaction, the epoxide ring of ECH is opened in the presence of the salen catalyst by the OH group of alkyl-4-hydroxy phenyl acetate to form a chlorohydrin phenyl ester compound of 1- [4 [(alkoxycarbonyl) ) Methyl] phenoxy] -3- (chloro) propan-2-ol.

The effect of the catalyst is important in the ring opening reaction of ECH, and in order to obtain a fast reaction rate without causing a decrease in optical purity, it is necessary to select a catalyst that is highly active and does not cause a decrease in optical activity for the asymmetric nucleophilic ring opening reaction. do. The addition of solvent is not necessary in the reaction of (R) -ECH with alkyl-4-hydroxy phenyl acetate.

In order to measure the optical purity, the product was converted to an epoxide structure by dehydrochloric acid treatment with NaOH in a dichloromethane solvent, and the optical purity of the product was analyzed by HPLC (OD-H column). The optical purity of the chlorohydrin phenyl ester compound obtained in the above was 99% ee or more, maintaining the optical purity of the starting material (R) -ECH as it is, and racemization occurs due to the ring opening reaction. It can be seen that not.

The reaction mixture obtained after the reaction was added with a dichloromethane solvent and 1.2-1.3 equivalents of a solid base, and reacted for 3-5 hours to cause cyclization, resulting in 1- [4 [(alkoxycarbonyl) methyl] phenoxy having the following formula (5). C] -2,3-epoxypropane. Inorganic bases that can be used include alkali metal hydroxides, alkali metal carbonates or alkaline earth metal salts. Preferred alkali metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal phosphates and alkaline earth metal phosphates. Specifically KOH, NaOH, LiOH, Li ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , MgCO ₃ , CaCO ₃ , LiHCO ₃ , NaHCO ₃ , KHCO ₃ , CsHCO ₃ , Li ₃ PO ₄ , K ₃ PO ₄ , Cs ₃ PO ₄ , Mg ₃ (PO ₄ ) ₂ , Ca ₃ (PO ₄ ) ₂ , and most preferably KOH, NaOH and K ₃ PO ₄ . As the organic base, tertiary amines can be used.

The following 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane can be distilled under vacuum at 180-190 ° C. to separate from the catalyst and recover as a high optical purity clear liquid.

Next, 5.0-10.0 equivalents of isopropyl amine and 1.5 equivalents of water were mixed with the chiral epoxide and reacted at room temperature for 12 hours to give high optical purity of 1- [4 [(alkoxycarbonyl) of Chemical Formula 6 Methyl] phenoxy] -3- (isopropyl amino) propan-2-ol is obtained. It is preferable to carry out the reflux heat treatment of these mixtures, and the reaction time takes about 5 hours.

The resulting reaction mixture is heated under vacuum to evaporate the solvent, dissolved in a small amount of dichloromethane, and filtered through a white solid powder to recover n-hexane. The obtained residue is also preferably purified by chromatography through a silica gel column.

The resulting chiral 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol (based on 4 grams) was mixed with 40 ml of methanol and 15 ml of ammonia water. It is dissolved in and then sealed and reacted with stirring for 24 hours. After the solvent is removed in vacuo from the product, the solid product may be purified by recrystallization in ethyl acetate solvent to prepare the final product of the athenol of Formula 1 as high optical purity of 99% ee or more.

The manufacturing method is chiral (R) is a description of the production method for the case of using -ECH, the same reaction conditions as the starting material - in the chiral (dimer-type chiral (RR) using the salen catalyst) (R) - It is also possible to use racemic ECH instead of ECH.

In this case, since the dimer-type chiral (RR) -salen catalyst is also used when synthesizing chiral (R) -ECH from racemic ECH, the alkyl-4-hydroxy phenyl acetate of the formula (2) as a nucleophile The optically selective ring opening reaction of the used racemic ECH can be an economical way of producing 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (chloro) propan-2-ol of formula (4). .

The optical purity of the product obtained by applying this method is very high, 98% ee or more, and ECH remaining in the reaction system without attack is also high in optical purity, and thus can be recovered by vacuum distillation. That is, the production of chiral athenol with high optical purity and the production of chiral ECH can be simultaneously performed, resulting in a simplification of the reaction process, reduction of the use of catalyst, and improvement of the yield of the product.

That is, according to the chiral athenol preparation method according to the present invention, the final target compound can be prepared in high optical purity without degrading chirality by maintaining the optical purity of the starting material almost completely. In addition, when the racemic epoxide is used as a starting material, it is possible to obtain chiral athenol having a very high optical purity and to recover the chiral ECH incidentally and to reduce the amount of catalyst used.

On the other hand, as can be seen in Scheme 2, (S)-athenol can be prepared by using 4-hydroxy benzyl cyanate as a reactant instead of methyl-4-hydroxy phenyl acetate of the formula (2).

As in Scheme 2, 4-hydroxy benzyl cyanate of formula 7 is reacted with chiral or racemic ECH at room temperature for 12 hours under RS tech's (R, R) -type dimer type salen catalyst (Formula 3). Let's do it. The progress of the reaction was confirmed by thin layer chromatography (TLC, E.A: HEX, 1: 9), and the reaction was terminated if 4-hydroxy benzyl cyanate did not remain.

At the end of the reaction, the epoxide ring of ECH is opened by the OH group of 4-hydroxy benzyl cyanate in the presence of a salen catalyst to form chlorohydrin phenyl cyanate, 1- [4 [(cyano) methyl] phenoxy C] -3- (chloro) propan-2-ol compound is produced.

CH ₂ Cl ₂ and 1.2-1.3 equivalents of a solid base were added to the obtained residue, followed by a cyclization reaction with stirring for 3-5 hours to obtain an epoxide structure. Inorganic bases that can be used include alkali metal hydroxides, alkali metal carbonates or alkaline earth metal salts. Preferred alkali metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal phosphates and alkaline earth metal phosphates. Specifically KOH, NaOH, LiOH, Li ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , MgCO ₃ , CaCO ₃ , LiHCO ₃ , NaHCO ₃ , KHCO ₃ , CsHCO ₃ , Li ₃ PO ₄ , K ₃ PO ₄ , Cs ₃ PO ₄ , Mg ₃ (PO ₄ ) ₂ , Ca ₃ (PO ₄ ) ₂ , and most preferably KOH, NaOH and K ₃ PO ₄ . Tertiary amine is mentioned as an organic base.

The reaction degree was confirmed by thin layer chromatography (TLC, E.A: HEX, 1: 9), and NaOH was removed by filtration after completion of the reaction. Subsequently, the solvent was removed by vacuum evaporation, and the residue thus obtained was vacuum distilled to obtain pure 1- [4 [(cyano) methyl] phenoxy] -2,3-epoxypropane having the following formula (9) in a yield of 60%.

1- [4 [(cyano) methyl] phenoxy] -2,3-epoxypropane was reacted under reflux for 5 hours by mixing isopropyl amine and water, and the high optical purity of 1- [4 [( Cyano) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol. This residue can be stirred with water in the presence of a platinum / carbon catalyst for 24 hours to afford a white solid (S)-athenol in a yield of 70%.

Hereinafter, an embodiment of the present invention will be described in detail.

[ Example  One]

5.0 g (0.030 mol) of methyl-4-hydroxy phenyl acetate of Chemical Formula 2 is mixed with 3.3 g (0.036 mol) of chiral (R) -ECH, and (R, R) -type dimer type salen catalyst of RS tech Co., Ltd. (N, N'-Bis (3,5-tert-butylsalicylidene) -1,2-cyclohexane diaminato] cobailt] boron trifluoride dimer) (0.23 g, 0.0018 mmol) was added thereto and reacted at room temperature for 3 hours. To produce 1- [4 [(methoxycarbonyl) methyl] phenoxy] -3- (chloro) propan-2-ol of formula (4). The progress of the reaction was confirmed by thin layer chromatography (TLC, E.A: HEX, 1: 9) and the reaction was terminated if the presence of the reactant methyl-4-hydroxy phenyl acetate was not observed.

20 ml of CH ₂ Cl ₂ and 1.43 g of NaOH were added thereto and stirred for 2 hours. The degree of cyclization by NaOH to the epoxide structure (Chemical Formula 5) was confirmed by thin layer chromatography (TLC, EA: HEX, 1: 9), and 1- [4 [(methoxycarbo) of the chemical formula 4 as a reactant. Yl) methyl] phenoxy] -3- (chloro) propan-2-ol if no presence is observed and the reaction is terminated. After the reaction is completed, NaOH is removed through filtration. The solvent was then removed by vacuum evaporation and the residue obtained was evaporated in vacuo to give 1- [4 [(methoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane (E-1) of pure formula 5 4.4. g (yield 66%, optical purity 99.5% ee) was obtained.

The optical purity (% ee) of this compound was calculated from its area ratio using high performance liquid chromatography (HPLC). As a column, an OD-H column (0.46 cm X 25 cm) manufactured by Daicel Chemical Industries Co., Ltd. was flowed with a mixed solvent of 97: 3 (v / v) of n-hexane and isopropanol at a flow rate of 1 ml / min. Spectra were obtained at 254 nm, and (R) was detected at 25.1 minutes and (S) at 28.6 minutes.

2 g (0,009 mol) of 1- [4 [(methoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane having the structure of formula 5 was mixed with 7.5 ml (0.09 mol) of isopropyl amine and 0.25 ml of water The mixture was refluxed for 6 hours to obtain 1- [4 [(methoxycarbonyl) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol having the formula (6). The progress of the reaction was confirmed by thin layer chromatography (TLC, EA: HEX, 1: 9) and the presence of the reactant 1- [4 [(methoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane If no is observed, terminate the reaction.

After completion of the reaction, the resulting residue was heated under vacuum to evaporate the solvent. A small amount of dichloromethane was added thereto to dissolve it, and again n-hexane was added and filtered to obtain 1.85 g (yield 73%) of white solid powder (A-1).

35 ml of methanol cold with 3.6 g (0.012 mol) of chiral 1- [4 [(methoxycarbonyl) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol having a structure of Formula 6 It was dissolved in a mixed solution of 15ml ammonia and then sealed and reacted with stirring for 24 hours. After the solvent in the product was removed in vacuo, the solid product was purified by recrystallization in ethyl acetate solvent. 2.4 g of (S) -Athenol, a white solid having the structure of Formula 1, in a yield of 70% (optical purity 99.5% ee.). Got.

Optical purity (% ee) of (S) -Athenol was calculated from the area ratio using high performance liquid chromatography (HPLC). The column was a OD-H column (0.46 cm x 25 cm) manufactured by Daicel Chemical Industries, Ltd. and a mixed solvent of EtOH: Hex: Diethylether = 20: 80: 0.6 (v / v) was flowed at a flow rate of 1 ml / min. Spectra were obtained at 254 nm, and (R) was detected at 8.5 minutes and (S) at 10.3 minutes.

[ Example  2]

6.2 g (0.030 mol) of butyl-4-hydroxy phenyl acetate having the structure of Chemical Formula 2 was mixed with 3.3 g (0.036 mol) of chiral (R) -ECH, and (R, R) -type dimer type salen of RS tech Co., Ltd. (N, N'-Bis (3,5-tert-butylsalicylidene) -1,2-cyclohexanediaminato] cobailt] boron trifluoride dimer) (0.23 g, 0.0018 mmol) was added to the reaction for 3 hours at room temperature. To produce 1- [4 [(butoxycarbonyl) methyl] phenoxy] -3- (chloro) propan-2-ol of formula (4). The progress of the reaction was confirmed by thin layer chromatography (TLC, E.A: HEX, 1: 9) to terminate the reaction if the presence of the butyl-4-hydroxy phenyl acetate of the formula (II) structure as a reactant was not observed.

20 ml of CH ₂ Cl ₂ and 1.43 g of NaOH were added thereto and stirred for 2 hours. The degree of cyclization by NaOH to the epoxide structure (Chemical Formula 5) was confirmed by thin layer chromatography (TLC, EA: HEX, 1: 9) and 1- [4 [(butoxycarbo) Yl) methyl] phenoxy] -3- (chloro) propan-2-ol if no presence is observed and the reaction is terminated.

After the reaction is completed, NaOH is removed by filtration. The solvent was then removed by vacuum evaporation, and the residue thus obtained was vacuum distilled to give 1- [4 [(butoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane (E-3) of pure formula 5 4.4. g (yield 66%, optical purity 99.5% ee) was obtained.

The optical purity (% ee) of this compound was calculated from the area ratio using high performance liquid chromatography (HPLC). The column was an OD-H column (0.46 cm X 25 cm) manufactured by Daicel Chemical Industries Co., Ltd. and a mixed solvent of 97: 3 (v / v) of n-hexane and isopropanol was flowed at a flow rate of 1 ml / min. Spectra were obtained at 254 nm, and (R) was detected at 17.7 min and (S) was at 20.0 min.

2.4 g (0,009 mol) of 1- [4 [(butoxy carbonyl) methyl] phenoxy] -2,3-epoxypropane of formula 5 in 7.5 ml (0.09 mol) of isopropyl amine and 0.25 ml of water The mixture was refluxed for 6 hours to obtain 1- [4 [(butoxycarbonyl) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol having the formula (6).

The degree of reaction was confirmed by thin layer chromatography (TLC, EA: HEX, 1: 9), and 1- [4 [(butoxy carbonyl) methyl] phenoxy] -2,3-epoxy having the structure of Chemical Formula 5 as a reactant. If no presence of propane is observed, the reaction is terminated. After completion of the reaction, the resulting residue was heated under vacuum to evaporate the solvent. A small amount of dichlormethane was added thereto to dissolve it, and n-hexane was added thereto, followed by filtration to obtain 2.2 g (yield 73%) of white solid powder (A-3).

35 ml of methanol with 3.9 g (0.012 mol) of chiral 1- [4 [(butoxycarbonyl) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol as a white solid having the structure of Formula 6 It was dissolved in a mixed solution of 15ml ammonia and then sealed and reacted with stirring for 24 hours. After the solvent in the product was removed in vacuo, the solid product was purified by recrystallization in ethyl acetate solvent. 2.6 g of (S) -Athenol, a white solid of Formula 1, was obtained in 70% yield (optical purity; 99.5% ee). Got it.

[ Example  3]

On the other hand, by using the ethyl-4-hydroxy phenyl acetate of the formula (2) as a reaction in the same manner as in Examples 1 and 2 it was possible to obtain a high optical purity of (S)-athenol in 72% yield. (Optical purity; 99.5% ee).

[ Example  4]

5.0 g (0.030 mol) of methyl-4-hydroxy phenyl acetate having the structure of Formula 2 is mixed with 6.1 g (0.066 mol) of racemic ECH, and RS Tech's (R, R) -type dimer type salen catalyst (Formula 3) (N, N'-Bis (3,5-tert-butylsalicylidene) -1,2-cyclohexanediaminato] cobailt] boron trifluoride dimer) (0.2 g, 0.0015 mmol) was added and reacted at room temperature for 10 hours to form a compound of formula (4). Produced 1- [4 [(methoxycarbonyl) methyl] phenoxy] -3- (chloro) propan-2-ol. The progress of the reaction was confirmed by thin layer chromatography (TLC, EA: HEX, 1: 9), and the reaction was terminated if the presence of the methyl-4-hydroxy phenyl acetate of the structure of the formula (2) as a reactant was not observed.

20 ml of CH ₂ Cl ₂ and 1.43 g of NaOH were added thereto and stirred for 2 hours. The degree of cyclization by NaOH to the epoxide structure (Formula 5) was confirmed by thin layer chromatography (TLC, EA: HEX, 1: 9), and 1- [4 [(methoxycarbo) Yl) methyl] phenoxy] -3- (chloro) propan-2-ol if no presence is observed and the reaction is terminated.

After completion of the reaction, NaOH was removed by filtration. Subsequently, the solvent was removed by vacuum evaporation, and the residue thus obtained was vacuum distilled to obtain pure 1- [4 [(methoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane (E-1) having a structure of 4.3. g (yield 64%, optical purity 98.5% ee) was obtained.

1- [4 [(methoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane having the structure of Formula 5 was mixed with isopropyl amine and water for reflux reaction for 6 hours and 1- [4 of the Structure of Formula 6 [(Methoxy carbonyl) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol was obtained. This residue was purified by n-hexane to give a white solid powder (A-1).

This white solid, chiral 1- [4 [(methoxycarbonyl) methyl] phenoxy] -3- (isopropylamino) propan-2-ol, was dissolved in cold methanol and ammonia water solution and sealed for 24 hours. After the reaction was carried out at room temperature with stirring, the (S) -Athenol as a white solid having the structure of Formula 1 was obtained in a yield of 70% (optical purity 99.0% ee).

The results in Table 1 below show that chlorohydrin phenyl ester is obtained by reacting racemic ECH with an alkyl-4-hydroxy phenyl acetate derivative of formula (II) structure in the presence of a (R, R) -type dimer type salen catalyst of RS tech. The reaction activity for the case is shown in comparison. As can be seen from the table, in all reactions, it can be seen that the optical purity of 98% ee or more and the yield of 60% or more.

When racemic ECH is used in place of the chiral (R) -ECH used in Examples 1 and 2, alkyl-4-hydroxy phenyl acetate (Formula 2) is used to directly 1- [4 [(methoxycarbonyl) methyl], an open compound for the synthesis of chiral 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -2,3-epoxy propane (Formula 5) Phenoxy] -3- (chloro) propan-2-ol can be prepared with high optical purity (98% ee or more).

Entry R ¹ R ² Mole ^a % Time (h) Yield ^b (%) Optical purity ^c (%) One CH ₂ COOBu CH ₂ Cl 0.5 10 64 > 98 2 CH ₂ COOBu CH ₂ Cl 1.0 8 62 > 98 3 CH ₂ COOEt CH ₂ Cl 0.5 12 60 > 98 4 CH ₂ COOMe CH ₂ Cl 0.5 12 62 > 98 5 CH ₂ COOMe CH ₂ Cl 1.0 8 61 > 98

The catalyst addition amount is mole% relative to the phenol reactant based on the cobalt units in the salen structure.

b Yield is based on reactant phenol and is taken by distillation after epoxidation.

c% ee value was determined by chiral OD-H column for the epoxide compound.

[ Example  5]

4.0 g (0.030 mol) of 4-hydroxy benzyl cyanate of formula 7 is mixed with 6.1 g (0.066 mol) of racemic ECH and RS technic (R, R) -type dimer type salen catalyst (Formula 3) (N , N'-Bis (3,5-tert-butylsalicylidene) -1,2-cyclohexanediaminato] cobailt] boron trifluoride dimer (0.2 g, 0.0015 mmol) was added and reacted at room temperature for 12 hours to give 1- [ To yield 4 [(cyano) methyl] phenoxy] -3- (chloro) propan-2-ol. The progress of the reaction was confirmed by thin layer chromatography (TLC, E.A: HEX, 1: 9) to terminate the reaction if no reactant 4-hydroxy benzyl cyanate remained.

20 ml of CH ₂ Cl ₂ and 1.43 g of NaOH were added to the obtained residue, followed by cyclization with stirring for 4 hours to obtain an epoxide structure. The degree of reaction was confirmed by thin layer chromatography (TLC, EA: HEX, 1: 9), and 1- [4 [(cyano) methyl] phenoxy] -3- (chloro) propane-2 having the structure of formula 8 as a reactant. Terminate the reaction if no presence of -ol is observed.

After completion of the reaction, NaOH is removed by filtration. Subsequently, the solvent was removed by vacuum evaporation, and the residue thus obtained was vacuum distilled to give 60% pure 1- [4 [(cyano) methyl] phenoxy] -2,3-epoxypropane having a chemical formula 9 structure (optical purity 98.3). %).

The optical purity (% ee) of this compound was calculated from the area ratio using high performance liquid chromatography (HPLC). The column was an OD-H column (0.46 cm X 25 cm) manufactured by Daicel Chemical Industries, Ltd. and a 90: 10 (v / v) mixed solvent of n-hexane and isopropanol was flowed at a flow rate of 1 ml / min. Spectra were obtained at 254 nm, and (R) sieves were detected at 36.1 minutes and (S) sieves at 38.8 minutes.

1- [4 [(cyano) methyl] phenoxy] -2,3-epoxypropane was mixed with isopropyl amine and water to reflux for 5 hours to produce 1- [4 [(cyano) methyl] Phenoxy] -3- (isopropyl amino) propan-2-ol. The residue was stirred for 24 hours with water in the presence of platinum / carbon catalyst to give (S) -Athenol of formula (1) as a white solid in 70% yield and at least 99.5% ee optical purity.

The results of Table 2 below are (R, R) -type dimer type salen catalyst (Formula 3) (N, N'-Bis (3,5-tert-butylsalicylidene) -1,2-cyclohexanediaminato] cobailt] boron of RS tech In the presence of trifluoride dimer) racemic ECH is reacted with 4-hydroxy benzyl cyanate of Scheme 2 to obtain the chlorohydrin phenyl cyanate.

As can be seen from the table, in all reactions, it can be seen that the optical purity of 98% ee or more. That is, 4-hydroxy benzyl cyanate directly opens the epoxide ring of the racemic ECH by chiral 1- [4 [(cyano) methyl] phenoxy] -3- (chloro) propan-2-ol It can be produced in high optical purity (98% ee or more).

On the other hand, it is also possible to obtain (S) -athenol by reacting chiral (R) -ECH in place of 4-hydroxy benzyl cyanate and racemic ECH in this reaction.

<Comparison of reaction activity between racemic ECH and 4-hydroxy benzyl cyanate derivative (using (R, R) -type dimer type salen catalyst of RS tech)> Entry R ¹ R ² Mole ^a (%) Time (h) Yield ^b (%) Optical purity ^c (%) One CH ₂ CN CH ₂ Cl 0.4 12 60 > 98 2 CH ₂ CN CH ₂ Cl 0.6 10 57 > 98 3 CH ₂ CN CH ₂ Cl 1.0 10 54 > 98

a Catalyst addition is mole% of reactant based on cobalt units in the salen structure.

b Yield is based on reactant phenol and is taken by distillation after epoxidation.

c The% ee value is determined by chiral OD-H column for the epoxide compound.

Claims (12)

1) Reaction of epichlorohydrin (ECH) with alkyl-4-hydroxy phenyl acetate of formula (2) in the presence of a catalyst to yield 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (chloro A first step of producing propan-2-ol; 2) Dehydrochlorination of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (chloro) propan-2-ol with base to yield 1- [4 [(alkoxycarbo) Nil) methyl] phenoxy] -2,3-epoxypropane; 3) The epoxide ring of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -2,3-epoxypropane was opened with isopropyl amine to form 1- [4 [(alkoxycarbonyl) A third step of producing) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol; And 4) Treatment of the ester group of 1- [4 [(alkoxycarbonyl) methyl] phenoxy] -3- (isopropylamino) propan-2-ol with ammonia water to give chiral athenol of formula (I) Generating a fourth step; Chiral athenol production method comprising a. [Formula 1]

[Formula 2]

[Formula 4]

[Formula 5]

[Formula 6]

In the above formula, R means methyl, ethyl, propyl, isopropyl or butyl group (R = 1-4). The method of claim 1, wherein the catalyst of the first step is a chiral athenol production method, characterized in that the dimeric chiral salen catalyst of the formula (3). [Formula 3]

In the above formula, R ₁ , R ₂ , R ' ₁ , R' ₂ and R _{3 form} a ring and represent a carbocycle or heterocycle consisting of 4 to 10 atoms, and X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ and X ₈ each represent a hydrogen atom or a t-butyl group, Y 1 and Y 2 are each a hydrogen atom, and M is a metal atom selected from Co, Cr, Mn, Fe, Mo and Ni L represents B or Al, Q represents a halogen atom, and n is an integer from 0 to 4. The method of claim 1 or 2, wherein the ECH of the first step is chiral (R) -ECH method of producing chiral athenol. 3. The method of claim 1 or 2, wherein the ECH of the first step is racemic ECH. 4. The method of claim 3, wherein the final product is a chiral athenol having an optical purity of 99% ee or higher. 5. The method of claim 4, wherein the final product is chiral athenol having an optical purity of 98% ee or higher. 1) Reaction of epichlorohydrin (ECH) with 4-hydroxy benzyl cyanate of formula (7) in the presence of a catalyst to yield the optically active 1- [4 [(cyano) methyl] phenoxy] -3- (chloro) propane of formula (8) First step to produce -2-ol; 2) Dehydrochlorination of 1- [4 [(cyano) methyl] phenoxy] -3- (chloro) propan-2-ol with base to yield 1- [4 [(cyano) A second step of producing methyl] phenoxy] -2,3-epoxypropane; 3) 1- [4 [(cyano) methyl of Formula 10 which is an optically active compound by opening the epoxide ring of 1- [4 [(cyano) methyl] phenoxy] -2,3-epoxypropane with isopropyl amine Phenoxy] -3- (isopropyl amino) propan-2-ol; And 4) The cyanate group of 1- [4 [(cyano) methyl] phenoxy] -3- (isopropyl amino) propan-2-ol with optical water by treatment with water in the presence of platinum / carbon catalyst Generating a chiral athenol of 1; Chiral athenol production method comprising a. [Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

8. The method of claim 7, wherein the catalyst of the first step is a dimeric chiral salen catalyst of formula (3). [Formula 3]

In the above formula, R ₁ , R ₂ , R ' ₁ , R' ₂ and R _{3 form} a ring and represent a carbocycle or heterocycle consisting of 4 to 10 atoms, and X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ and X ₈ each represent a hydrogen atom or a t-butyl group, Y 1 and Y 2 are each a hydrogen atom, and M is a metal atom selected from Co, Cr, Mn, Fe, Mo and Ni L represents B or Al, Q represents a halogen atom, and n is an integer from 0 to 4. 10. The method of claim 7 or 8, wherein the ECH in the first step is chiral (R) -ECH. The method of claim 7 or 8, wherein the first step ECH is racemic ECH, characterized in that the chiral athenol production method. 10. The method of claim 9, wherein the final product is chiral athenol optical purity of 99% ee or more characterized in that the chiral athenol production method. The method of claim 10, wherein the final product is chiral athenol optical purity of 98% ee or more chiral athenol production method characterized in that.