KR20070076800A - A preparation method of nordihydroguaiaretic acid and its analogues - Google Patents

Abstract

A method for preparing nordihydroguaiaretic acid and derivatives thereof is provided to mass-produce nordihydroguaiaretic acid and derivatives thereof having an antioxidative activity in a simple manner. The novel method for preparing a derivative of nordihydroguaiaretic acid represented by the following chemical formula 1 in a high yield comprises the steps of: reacting a Grignard reagent prepared from the following bromine compound(2) with a ketone material(3) to prepare an alcohol material(4); dehydrating the alcohol material(4) with a dehydrating agent to obtain a (Z) isomer(5Z) and an (E) isomer of a butene material, respectively; hydrogenating the respective (Z) and (E) isomers in the presence of a catalyst to obtain a meso isomer(6-meso) and racemate((±)-6) of a butane material, respectively; and demethylating the meso isomer(6-meso) and racemate((±)-6) of the butane material.

Description

A preparation method of nordihydroguaiaretic acid and its analogues

The present invention relates to a novel process for producing NDGA and its derivative compounds having antioxidant activity by a simple method.

Antioxidant activity refers to an activity that prevents the production of free radicals in vivo and prevents oxidative phenomena that cause irreparable damage to cells. The stable oxygen (triplet oxygen) is a highly reactive reactive oxygen such as superoxide radicals, hydroxy radicals, hydrogen peroxide due to enzymatic system, reducing metabolism, chemicals, pollutants, and photochemical reactions Oxygen Species (ROS), which irreversibly destroy cellular components. The action of these free radicals is antioxidant enzymes such as superoxide dismutase (SOD), catalase, peroxidase, and vitamin C, vitamin E, glutathione ( It can be minimized by the action of antioxidants such as glutathione). However, if the biological defenses are abnormal or exposed to excessive free radicals, the balance is broken and the free radicals irreversibly destroy lipids, proteins, DNA, and the like. As a result, various diseases such as aging, cancer, multiple atherosclerosis, arthritis and Parkinson's disease are caused.

Synthetic antioxidants developed so far include butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), nordihydroguaiaretic acid (NDGA), and natural antioxidants such as superoxide dismutase, peroxidase, catalase, glutathione peroxidase and the like. And antioxidant enzymes such as tocopherol (vitamin E), vitamin C (ascorbic acid), carotenoids and glutathione.

Phenolic compounds, widely distributed in nature and considered to be the most representative antioxidants, are secondary metabolites with one or more hydroxyl (OH) groups in the ring structure. These compounds act as inhibitors and promoters for a variety of mammalian enzyme systems and as scavengers and metal chelators of oxygen radicals. Since this antioxidant activity is related to conjugated rings and hydroxyl groups, it is not surprising that most phenolic compounds have antioxidant activity (Sanchez-Moreno C et al., Food Res. Int . 32 , pp 407-412 , 1999; Decker EA., Nutr . Rev. 53 , pp 49-58 , 1995).

Norddihydrogalleatic acid (NDGA, 1aa) is a non-toxic phenolic lignan isolated from effluents containing resins of North American oak bushes, such as Larrea divaricata Cav. In addition, it is used as an antioxidant in food (Lundberg, WO et al., Oil & Soap , 21 , pp 33-35, 1944), and NDGA is a lipoxygenase (Skaltsa, H. et al., J. Biol . Pharm . Bull. 23 , p 47, 2000), inflammatory induction system (Steele, VE et al., J. Expert Opin . Investig.Drugs, 9 , p 2121, 2000; Whitman, S. et al., J . Med. Chem. 45, p 2659, 2002), HSV (herpes simples) (Chen, H. et al., J. Med. Chem. 41, p 3001, 1998), HIV (Hwu, JR et al. , J. Med . Chem . 41 , p 2994, 1998) and human papillomavirus (Craigo, J. et al., Antivir . Res . 47 , p 19, 2000), as well as hyperglycemic activity ( Reed, MJ et al., Diabetologia, 42 , p 102, 1999) has been of increasing interest as it is a pharmaceutical composition comprising inhibiting the activity of. Tetra-O-methyl-NDGA (1ea), an NDGA derivative, showed tumoricidal activity (US Patent Application No. 6417234; Heller, JD et al., Cancer Res) 54 , p 1991s, 1994; Heller, JD et al., Cancer Res . 61 , p 5499, 2001), compounds (1ca) and (1eb) (machillin A) showed strong inhibitory activity on melanin synthesis (Li, G. et al., Biol. Pharm . Bull . 26 , p 1039, 2003).

Efforts to develop effective synthesis for the production of lignans have continued for decades. The first synthesis of 1aa was carried out by the demethylation of dimethyl ether (1ba) of hydrogenated (-)-guaiaretic acid in 1918, decades before it was separated from natural products. Schroter, G. et al., Ber . 51 , p 1587, 1918). Later, the current structure of 1aa isolated from natural products was confirmed by synthesis (Haworth, RD et al., J. Chem . Soc . P 1423, 1934; Haworth, RD et al., J. Chem . Soc . P. 120, 1935; Perry, CW et al., J. Org . Chem . 37 , p 4371, 1972). A more systematic synthesis was published in 1947 as a synthesis method whereby the reaction of 1-piperonyl-1-bromoethane and the Grignard reagent derived therefrom is the key reaction ( Liebermann, SV et al., J. Am. Chem . Soc . 69 , p 1540, 1947; Sakakibara, Y., Nippon Kagaku Zasshi , 73 , p 235, 1952; Blears, JG et al., J. Chem . Soc . , Abstracts 1958, 1985). As such, this method has been improved for many years, but failed to increase the yield or selectivity for the desired stereoisomer (Hearon, WM et al., Chem . Rev. 55 , p 957, 1955). The Ti-derived carbonyl coupling reaction of substituted phenylacetones was performed using 1,4-disubstituted-butane-2,3-diol instead of the expected McMurry type butene. 2,3-diols) (Gezginci, M. et al., Tetrahderon Letters, 42 , p 6083, 2001). Oxidative coupling method of beta-keto esters (Gu, WX et al., Chin. Chem . Letters, 11 , p 15, 2000), after double condensation of diethyl succinate and piperonal (Xia, YM et al., Chin. Chem . Letters, 14 , p 359, 2003), the Grignard coupling reaction of halothiophenes catalyzed by metal-phosphine complexes Catalytic reduction method according to (Minato, A. et al., Tetrahderon Letters , 21 , p 4017, 1980) and the like. These methods have some improvement in selectivity and yield for stereoisomers, but also have disadvantages such as the cost of reagents, low yield of reactions, the need for long reaction steps, and limitations in obtaining only asymmetrically substituted NDGAs.

Therefore, the present inventors have developed a novel manufacturing method that can easily produce NDGA and its derivative compounds having antioxidant activity and can be produced in large quantities, thus making asymmetric NDGA, and thus, the present invention has been completed.

It is an object of the present invention to provide a novel production method which can produce NDGA and its derivative compounds having antioxidant activity simply and in large quantities.

In order to achieve the above object, the present invention has studied NDGA compound (1) , which is a biologically important natural substance, as well as a method for preparing a derivative thereof, thereby providing NDGA and its intermediate 1,4-di (substituted-phenyl) -2. A novel process for preparing lignans associated with, 3-dimethylbutan-2-ol is provided.

Accordingly, the present invention provides the first step of converting the following bromine compound (2) into a Grignard reagent and then reacting with the ketone body (3) to produce an alcohol (4) ; Dehydrating the alcohol (4) in the presence of a dehydrating agent to obtain (Z) isomers (5-Z) and (E) isomers (5-E) of butenes; The (Z) and (E) isomers of each of the two butenes in the above two steps are hydrogenated in the presence of a catalyst to give meso -isomers (6- meso ) and racemic-isomers ((±) of butane . -6) third step of obtaining each; It provides a novel process for obtaining a high yield of the NDGA derivative of the general formula (1) comprising a fourth step of demethylating the meso and racemic isomers of the butane body of the above step.

In the above formula, R ₁ to R ₄ groups are each independently a hydrogen atom or a lower alkyl group such as a methyl group or an ethyl group and may be the same as or different from each other.

In the above formula, X is a methylene group or a lower alkyl group such as a hydrogen atom or a methyl group or an ethyl group at the time of ring opening.

In the first step of the manufacturing process, in order to promote the reaction, iodine crystals may be additionally added in addition to the magnesium turning, and the dehydrating agent usable in the second dehydration reaction may be sulfuric acid, phosphoryl chloride (POCl ₃ ). Although it may be used, it is preferable to use sulfuric acid, and the hydrogenation reaction step of the three steps is not limited to the type and the amount used as a catalyst, but it is preferable to use PtO ₂ , used in the demethylation reaction in the fourth step As the demethylation reagent, boron trifluoride and the like are preferable.

An object of the present invention is to provide a method for preparing NDGA and its derivatives, which are active as antioxidants, which can be chemically synthesized by the methods shown in the following schemes, but is not limited thereto.

The following schemes represent the preparation steps of the compounds of the present invention in stages of preparation. The compounds of the present invention may be prepared with minor modifications, such as changing the reagents, solvents, and reaction sequences used in the synthesis of the schemes.

First, the reaction step of the present invention is illustrated by the scheme described in the following scheme.

First, in the first step, the brominated compound (2) may be treated with magnesium to form Grignard reagents, and the ketone body (3) may be reacted to obtain an alcohol (4) . Alcohol product (4) obtained in the above step are present as a mixture of erythro (erythro-) and Treo (threo-) isomer in two stereoisomeric forms. In the present invention, however, the separation of the isomers is not attempted and instead the mixture is carried out immediately to the next step.

The alcohol (4) was dehydrated under a dehydrating agent such as concentrated sulfuric acid to yield about 70% of the bipositional regioisomer (Z) isomer (5-Z) and (E) isomer (5-E) of the butene body. Can be obtained. At this time , the ratio of (5a-Z) and (5a-E) was 3.8: 6.2, and in the case of 5b , the ratio was 3.5: 6.5. The two positional isomers are easily separated because the Z-isomer is oil at room temperature, whereas the E-isomer is a crystal, and the structure of the (Z) isomers (5-Z) and (E) isomers (5-E) is ¹ Confirmation was carried out by comparing the H NMR results with the values of the literature values of the hydrogenation reaction product.

The two-position regioisomer (Z) isomer (5-Z) and (E) isomer (5-E) of the butenes obtained in the above step are subjected to hydrogenation reaction under a reaction catalyst such as PtO ₂ to give (E) isomer (5 ). -E) obtained 1db and 1 eb of the butane meso isomer (6- meso ) , whereas 1da and 1 ea of the racemic isomer ((±) -6) were obtained from the (Z) isomer (5-Z) , respectively. A high yield of more than 85% can be obtained.

As a next step, demethylation of the meso and racemic isomers of the butane in the above step with a reagent such as boron trifluoride (BBr ₃ ) can be carried out to obtain the desired NDGA (1aa) in yield (75%). have.

In addition, the present invention can be prepared NDGA and its derivatives by the same process as in Scheme 4.

The starting compounds (2a) and (3b) in the present invention can be synthesized from 3,4-substituted-1-arylbenzenes which can be prepared using commercially known methods or commercially available.

Carbinol 4c can be obtained in a yield of 82% by reacting 2a and 3b as in the above scheme. Three-step transformation of 4c yields new NDGA derivatives 1fa and 1 fb with yields of 54% and 45%, respectively.

Parafacrecresol was reacted with 1fa obtained in the above step to synthesize 7a , and 1ca , an NDGA derivative, may be prepared through two-step conversion.

In conclusion, as a simple and efficient reaction process for the preparation of the NDGA and its derivatives of the present invention, a process for reacting a Grignard reagent prepared from a bromine compound with a ketone which can be easily prepared from a starting material, a dehydration process, and a hydrogenation process The process of the present invention is not only superior to the conventional method for preparing the symmetric NDGA, but also useful as a method for preparing the asymmetrically substituted NDGA derivative.

The production method of the present invention provides an industrially useful production method, such as providing a synthetic method that is simpler and mass-produced by chemically synthesizing NDGA and its derivative compounds, which have been proven effective as antioxidants.

Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Reference Example  One. Device used

The instrument used to confirm the structure of the product obtained in this experiment is as follows.

Melting point (mp) was a Fischer-Jones melting point apparatus and was not calibrated. Nuclear magnetic resonance spectra ( ¹ H NMR) were 250 MHz or 400 MHz (Bruker NMR spectrometer), nuclear magnetic The resonance spectrum ( ¹³ C NMR) was 100 MHz (Bruker NMR spectrometer) and TMS (tetermethylsilane) was used as an internal standard. IR was measured using a Perkin-Elmer 1330 spectrophotometer. Starting materials 2a, 2b, 3a and 3b were prepared and used according to a known method. Reagents and solvents used industrial reagent grades without prior purification. Elemental analysis was performed with a Hewlett-Packard model 185B elemental analyzer.

Example  1.1,4- Vis (3,4- Methylenedioxyphenyl ) -2,3-dimethyl-2- Butene  Preparation of Isomers ((E) -5aa, (Z) -5ab)

Magnesium turning (0.50 g, 20.5 mmol) was added to 20 ml of dry ether and bromo-compound 2a (5.00 g, 20.5 mmol) dissolved in 50 ml of dry ether was slowly poured into the septum using a syringe. Was added. To initiate the reaction, iodine (I ₂ ) crystals (20 mg) were added and the resulting mixture was refluxed for 1.5 hours. After the reaction mixture was cooled to room temperature, 3a (3.00 g, 20.5 mmol) dissolved in 20 ml of dry ether was added dropwise at a rate such that reflux was maintained. At the end of the 10 minute drop, it was further warmed for about 30 minutes and then kept at room temperature for 8 hours. The reaction mixture was cooled in an ice bath and then 10 g of crushed ice was added. Then, 50 ml of 2,5 M sulfuric acid (H ₂ SO ₄ ) was added, and the obtained reaction mixture was extracted three times with 50 ml of ether. The obtained organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ). The solvent was evaporated to give 5.96 g (85%) of the product of the oily material, which was pure enough to go to the next step upon ¹ H NMR confirmation. The obtained oily product 4a (3.42 g, 0.01 mol) was dissolved in 20 ml of concentrated sulfuric acid, and the mixture was heated at 100 ° C. for 2 hours. The reaction result was transferred to a mixture of ether and ice (1: 1, 100 ml). The obtained aqueous layer was extracted twice with 30 ml of ether. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate (MgSO ₄ ). The solvent was evaporated to give 2.36 g (73%) of an oily product which was crystallized in a refrigerator and recrystallized in ethanol to give 1.43 g (44%) of white needles of 1,4-bis (3,4-methylenedioxyphenyl). -2,3-dimethyl-2-butene isomer ((E) -5aa) was obtained (1.43 g, 44%), and then the mother liquor was eluted with methylene chloride (CH ₂ Cl ₂ ) to give silica gel chromatography. The method was carried out to obtain butenes (Z) -5ab (0.89 g, 27% yield ) in the form of an oil having the following physical properties, respectively.

1-1. 1,4- Vis (3,4- Methylenedioxyphenyl ) -2,3-dimethyl-2- Butene  (E) Isomers: (E) -5aa

1.43g (Yield; 44%)

Melting Point (mp): 118-119 ℃

¹ H NMR (250 MHz, CDCl ₃ ) δ 1.69 (s, 6H, 2 x C H ₃ ), 3.34 (s, 4H, 2 x C H ₂ ), 5.92 (s, 4H, OC H ₂ O), 6.63 (d, J = 7.8 Hz, 2H), 6.64 (d, J = 1.8 Hz, 2H), 6.72 (d, J = 7.8 Hz, 2H).

¹³ C NMR (62.5 MHz, CDCl ₃ ) δ 18.86, 40.32, 101.16, 108.49, 109.21, 121.62, 129.32, 134.97, 146.03, 148.03.

Anal Cald. for C ₂₀ H ₂₀ O ₄ : C, 74.06; H, 6.21. Found: C, 74.08; H, 6.23.

1-2. 1,4- Vis (3,4- Methylenedioxyphenyl ) -2,3-dimethyl-2- Butene  (E) Isomers: (Z) -5ab

¹ H NMR (250 MHz, CDCl ₃ ) δ 1.63 (s, 6H, 2 x C H ₃ ), 3.40 (s, 4H, 2 x C H ₂ ), 5.90 (s, 4H, OC H ₂ O), 6.62 -6.75 (m, 6 H).

¹³ C NMR (62.5 MHz, CDCl ₃ ) δ 18.42, 39.65, 100.70, 107.99, 108.80, 121.22, 128.63, 134.37, 145.57, 147.55.

Anal Cald. for C ₂₀ H ₂₀ O ₄ : C, 74.06; H, 6.21. Found: C, 74.06; H, 6.24.

Example  2. 1,4- Vis (3,4- Dimethoxyphenyl ) -2,3-dimethyl-2- Butene  Preparation of Isomers ((E) -5ba, (Z) -5bb)

A white needle-like butene (E) isomer (E) -5 ba (two-step process yield; 53%) and an oily phase having the following physical properties were carried out except for starting materials, and were subjected to the same process as described in Example 1. Butene (Z) isomer (Z) -5bb (two step process yield; 32%) was obtained respectively.

 2-1. 1,4- Vis (3,4- Dimethoxyphenyl ) -2,3-dimethyl-2- Butene  (E) Isomers: (E) -5 ba

Melting point (mp): 104-105 ° C.

¹ H NMR (250 MHz, CDCl ₃ ) δ 1.73 (s, 6H, 2 × C H ₃ ), 3.38 (s, 4H, 2 × C H ₂ ), 3.80 (s, 6H, 2 × OC H ₃ ), 3.84 (s, 6H, 2 x OC H ₃ ), 6.68-6.78 (m, 6H)

2-2. 1,4- Vis (3,4- Dimethoxyphenyl ) -2,3-dimethyl-2- Butene  (Z) Isomers: (Z) -5bb

¹ H NMR (250 MHz, CDCl ₃ ) δ 1.66 (s, 6H, 2 x C H ₃ ), 3.46 (s, 4H, 2 x C H ₂ ), 3.83 (s, 6H, OC H ₃ ), 3.89 ( s, 6H, OC H ₃ ), 6.65-6.88 (m, 6H).

Anal Cald. for C ₂₂ H ₂₈ O ₄ : C, 74.13; H, 7.92. Found: C, 74.16; H, 7.94.

Example  3. 1-4- Vis (3,4- Methylenedioxyphenyl Preparation of 1,4-Bis (3,4-methylenedioxyphenyl) -2,3-dimethylbutane) compounds and isomers

20 ml of ethyl acetate was passed through hydrogen gas while stirring the suspension prepared by adding butene (E) -5aa (100 mg, 0.31 mmol) and PtO ₂ (10 mg) in the Parr hydrogenation bottle. And a pressure of approximately 40 psi was maintained. The resulting mixture was shaken for 1.5 hours and filtered to remove insoluble matter. The organic layer was washed with water and dried over magnesium sulfate. To obtain white crystals, recrystallized in a refrigerator with methanol (CH ₃ OH) solvent and the solvent was evaporated to obtain butane compounds having the following physical properties.

3-1. Meso-1,4- Vis (3,4- Methylenedioxyphenyl ) -2,3-dimethylbutane (1da)

90 mg (yield; 90%)

Pale yellow oil

Melting point (mp): 48-49 ° C (literature; 48-50 ° C)

¹ H NMR and ¹³ C NMR results are the same as the data for the natural sample.

3-2. ( Racemic ) -1,4- Vis (3,4- Methylenedioxyphenyl ) -2,3-dimethylbutane (1db)

White couch; Melting Point: 48-49 ° C (literature; 48-50 ° C)

¹ H NMR and ¹³ C NMR results are the same as the data for the natural sample.

3-3. (Metho) -1,4- Vis (3,4- Dimethoxyphenyl ) -2,3-dimethylbutane (1 ea )

White couch; Melting Point: 101-102 ° C (Literature Value; 100-101 ° C)

¹ H NMR and ¹³ C NMR results are the same as in the previous data.

3-4. ( Racemic ) -1,4- Vis (3,4- Dimethoxyphenyl ) -2,3-dimethylbutane (1 eb )

White couch; Melting Point: 70-71 ° C (Literature Value; 70.4-71.2 ° C)

¹ H NMR and ¹³ C NMR results are the same as in the previous recording (colorless prism).

3-5. ( Treo ) -1- (3,4- Methylenedioxyphenyl ) -4- (3,4- Dimethoxyphenyl ) -2,3-dimethylbutane (1fa)

White couch; Melting point 62-63 ℃

¹ H NMR (250 MHz, CDCl ₃ ) δ .79 (d, J = 6.0 Hz, 3H, CHC H ₃ ), 0.81 (d, J = 7.0 Hz, 3H, CHC H ₃ ), 1.75 (m, 2H) , 2.51 (AB quartet, 4H, benzylic H), 3.83 (s, 3H, OC H ₃ ), 3.85 (s, 3H, OC H ₃ ), 5.90 (s, 2H, OC H ₂ -O), 6.54-6.82 (m, 6 H).

Anal Cald. for C ₂₁ H ₂₆ O ₄ : C, 73.66; H, 7.65. Found: C, 73.72; H, 7.64.

3-6. ( Erislow ) -1- (3,4- Methylenedioxyphenyl ) -4- (3,4- Dimethoxyphenyl ) -2,3-dimethylbutane (1) fb )

Semisolid.

¹ H NMR (250 MHz, CDCl ₃ ) δ 0.79 (d, J = 6.0 Hz, 3H, CH CH ₃ ), 0.81 (d, J = 7.0 Hz, 3H, CHC H ₃ ), 1.75 (m, 2H), 2.49 (AB quartet, 4H, benzylic H), 3.82 (s, 3H, OC H ₃ ), 3.83 (s, 3H, OC H ₃ ), 5.90 (s, 2H, OC H ₂ -O), 6.54-6.82 ( m, 6H).

Anal Cald. for C ₂₁ H ₂₆ O ₄ : C, 73.66; H, 7.65. Found: C, 73.76; H, 7.66.

Example  4. 1- (3,4- Dimethoxyphenyl ) -4- (3- Methoxy -4- Hydroxyphenyl ) -2,3-dimethylbutane (1- (3,4-Dimethoxyphenyl) -4- (3-methoxy-4-hydroxyphenyl) -2,3-dimethylbutane, aka Meso - monomethyldihydroguaiaretic  acid) Preparation of Compound (1ca) and Isomers

Compound 1fa (1.0 g, 0.32 mmol), parathiocresol (2.0 g) and NaH (1.0 g) obtained in the above step were added to DMF (30 mL), and the resulting suspension was refluxed for 1 hour. The reaction solution was cooled to room temperature, diluted with addition of water (100 ml), neutralized with hydrochloric acid and extracted with benzene (100 ml x 3 times). The combined organic layers were washed with water, dried over sodium sulfate (Na ₂ SO ₄ ) and concentrated to give an oil (1.1 g, 94%). The resulting oil (1.1 g, 0.30 mmol), methyl sulfate (2 mL) and anhydrous potassium carbonate (K ₂ CO ₃ , 1.0 g) were added to acetone (50 mL) and the resulting suspension was refluxed for 6 hours. The reaction solution was filtered, and then the crude product obtained by concentration was added with 1 N methanolic hydrochloric acid (25 mL) and refluxed for 0.5 hour. Water (30 ml) was added to the reaction mixture, diluted with water, and extracted with benzene (30 ml x 3 times). The benzene layers were combined, washed with water, dried and concentrated. The oily product was purified by column chromatography (eluent hexane: benzene = 1: 3) with silica gel (25 g ) to give 0.62 g (65% ) of the desired product (1ca) as oil. )

Yield: 65%

¹ H NMR δ 0.80 (d, J = 6 Hz, 6H), 1.75 (m, 4H), 2.50 (m, 4H), 3.80 (s, 3H, OCH ₃ ), 3.83 (s, 3H, OCH ₃ ), 3.85 (s, 3H, OCH ₃ ), 5.55 (s, D 2 O-exchangeable, OH), 5.88 (s, 2H), 6.45-6.90 (m, 6H).

Example  5. (Meso) Of nordihydrogalliatic acid (NDGA, 1aa)  Produce

A mixed solution of the compound (1 ea ) (358 mg, 1.0 mmol) obtained in the above step and boron bromide (BBr ₃ , 10 ml, 1.0 M solution) using methylene chloride as a solvent was dissolved in 10 ml of dry methylene chloride and under Ar stream. After stirring at 78 ° C. for 1.5 hours, the reaction mixture reached room temperature and then operated in a conventional manner to obtain a pale yellow solid. Methanol was subjected to silica gel chromatography using a developing solvent, and recrystallized from an eluent to obtain the desired (meth) -nordihydrogalaliaretic acid (NDGA, 1aa) (227 mg) of a cream acicular crystal.

Melting Point: 185-186 ° C (Literature Value; 184-185 ° C)

¹ H NMR (250 MHz, CD ₃ OD) δ 0.79 (d, J = 6.0 Hz, 6H, CHC H ₃ ), 1.66 (q, J = 7.0 Hz, 2H, C H CH ₃ ), 2.12 (dd, J = 13.0, 9.0 Hz, 2H, benzylic H), 2.61 (dd, J = 13.0, 6.0 Hz, 2H, benzylic H), 4.98 (br. S, 4H, OH), 6.37 (dd, J = 7.8, 1.2 Hz , 2H), 6.62 (d, J = 1.2 Hz, 2H), 6.73 (d, J = 7.8 Hz, 2H).

The novel production method for preparing NDGA and its derivative compounds useful as the antioxidant of the present invention improves the disadvantages of high cost and small amount production, which are problems of the prior art, so that mass production of the target material is possible at high yield and low cost. In addition, it was possible to prepare asymmetric NDGA by synthesizing asymmetric NDGA, which was not possible with the previous method.

Claims (4)

A first step of reacting a Grignard reagent prepared from a bromine compound (2) with a ketone body (3) to produce an alcohol body (4) ; A second step of dehydrating the alcohol (4) with a dehydrating agent to obtain (Z) isomers (5 Z) and (E) isomers (5 E) of the butenes, respectively; A third step in which the (Z) and (E) isomers of the respective butenes of the second step are hydrogenated in the presence of a catalyst to obtain meso isomers (6- meso ) and racemic isomers ((±) -6) of the butanes, respectively; step; Novel preparation method for obtaining NDGA derivative of general formula (1) comprising a fourth step of demethylating the meso and racemic isomers of butane in the above step:

In the above formula, X is a lower alkyl group such as a methylene group or a ring-opened hydrogen atom or a methyl group or an ethyl group.

In the above formula, R ₁ to R ₄ groups are each independently a hydrogen atom or a lower alkyl group such as a methyl group or an ethyl group and may be the same as or different from each other. The method of claim 1, wherein the dehydrating agent of the second step uses sulfuric acid (H ₂ SO ₄ ). The method according to claim 1, wherein the third hydrogenation reaction step uses PtO ₂ as a catalyst. The method according to claim 1, wherein boron trifluoride is used as the demethylation reagent used in the demethylation reaction in the fourth step.