KR20130065898A - Novel preparation method for preparing nyasol compound showing various physiological activity - Google Patents

Abstract

PURPOSE: A manufacturing method of nyasol is provided to manufacture nyasol which has strong resistance to a bovine uterine estrogen receptor, hypnotization activity, testosterone 5alpha-reductase, restraining activity, and hypnotization activation. CONSTITUTION: A manufacturing method of nyasol comprises a step of obtaining compound A represented by chemical formula 1; a step of obtaining compound 11 by a reaction of compound B in the compound A solution; a step of obtaining compound 20 from the compound 11; a step of obtaining the compound 21 by reaction of the compound 20 solution; a step of obtaining compound 22 from the compound 21 solution; a step of obtaining compound 23 from alcohol 22 solution; a step of obtaining compound 25 from the compound 23; and a step of removing MOM substituent from the compound 25, extracting a reaction mixture by an organic solvent; and purifying the extract.

Description

Novel preparation method for preparing nyasol compound showing various physiological activity

The present invention relates to a novel process for preparing niazoles having various physiological activities.

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The present invention relates to a novel process for preparing niazole, a norlignans compound having various physiological activities.

Nysol, hirnokiresinol, norlignans compounds, and resinol, sequirin C, and sugiresinol compounds, lignans, It constitutes abundant phenylpropanoid derivatives. These phenolic compounds have been shown to be effective in anti-malarial activity against drung, antifungal activity [ 1-3 ], A549 non-small cell lung cancer cell lines, antimalarial activity, and tropical heat protozoa (human malaria species) [ 4-6] ], Are compounds that have received great attention clinically for various physiological activities such as estrogen receptor binding activity. Dual niazoles are isolated from plant roots such as Asparagus gobicus, Asparagus africanus, Anemarrhena asphodeloides, and Asparagus cochinchinensis.Hinkyrecinols are Chamaecyparis obtuse , Libocedrus yateensis And Agathis australis From plants such as [ 7-10 ].

Isomer relationships of nyasol and hirnokiresinol have been named by the literature (Minami et al. And Oketch-Rabah et al., 11-12 ).

Niazoles and hinokiresinol are geometric isomers, and these isomers have different activities [13-15], for example, (+)-hinokiresinol, (-) and (+)-niazoles are bovine uterine estrogen receptors ( strong affinity to the bovine uterine estrogen receptor, but the other two stereoisomeric forms of (+)-niazole have more than seven times more potent binding than (-)-niazole and (+)-hinokoresinol has a low affinity [16]. In addition, (-)-niazole increases hexobarbital induced sleep duration in mice [17] and niaazole has antifungal activity and testosterone 5α-reductase [18-19] inhibitory activity. This result necessitates a proper and mass production method of these natural derivatives. Recently, some researchers (Hoveyda) [20-21] have reported a niazole synthesis method using three substituted vinyl aluminum reagents and copper catalysts, and several approaches to hinokiresinol have been reported [22]. -27].

None of the literature published so far discloses any teachings on synthetic methods that allow simple and efficient mass production of niazol compounds.

The inventors found that (±) -niazole, (±) -iso-niazole and (±) -dimethoxyhinoki from commercially available 4-iodo phenol and 4-hydroxy benzaldehyde. The present invention was completed by finding a method for synthesizing resinol simply and efficiently.

It is an object of the present invention to provide a novel process for the simple and mass production of niazole compounds having various physiological activities.

In order to achieve the above object, the present invention is the reaction of (4- (methoxymethoxy) phenyl) ethynyl) trimethyl silane by TBAF (Tetra-n-butylammonium fluoride) 1-ethynyl-4- (methoxy methoxy First step of obtaining oxy) benzene (A); To the 1-ethynyl-4- (methoxymethoxy) benzene ( A ) solution, n -butyllithium was added dropwise and BF ₃ .OEt was added, followed by (±) -2- (4-methoxymethoxy) phenyl A second step of reacting oxirane ( B ) to give 2,4-bis (4- (methoxymethoxy) phenyl) but-3-yn-1-ol ( 11 ); The imidazole was added to the alcohol body ( 11 ) obtained above, and TBSCl solution was added and reacted to give 2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethyl A third step of obtaining silane) ( 20 ); The solution of 2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethylsilane ( 20 ) obtained in the above step was hydrogenated with a catalyst and a catalytic amount of quinoline was added and the reaction was carried out. A fourth step of obtaining ( Z )-(2,4-bis (4-methoxymethoxy) phenyl) but-3-enyloxy) (tert-butyl) dimethylsilane ( 21 ); TBAF was added to the solution of Compound ( 21 ), followed by stirring. The reaction mixture was extracted with ethyl acetate, and the organic layer was purified ( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-ene- A fifth step of obtaining 1-ol ( 22 ); Dess-martinperiodiane was added to the alcohol solution ( 22 ) in the presence of N _2, the reaction mixture was reacted, and the organic extract was purified to ( Z ) -2,4-bis (4-methoxymethoxy A sixth step of obtaining methoxy) phenyl) but-3-enal ( 23 ); Methyl triphenyl phosphonium iodide was added dropwise n -BuLi the solution was N ₂ Under the conditions of stirring, the compound ( 23) was added dropwise to the solution, reacted and the organic layer was purified to give ( Z ) -4,4 '-(penta-1,4-diene-1,3-diyl) bis ((methoxy Step 7, obtaining methoxy) benzene ( 25 ); adjusting the solution of compound ( 25 ) to pH 2 or less, removing the MOM substituent, extracting the reaction mixture with an organic solvent, and purifying the extract It provides a manufacturing method for preparing a niasol ( 1 ) comprising:

In the first step ((4- (methoxymethoxy) phenyl) ethynyl) trimethylsilane is used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents; TBAF is preferably used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, and the reaction is preferably performed at 0 to 80 ^° C., preferably 0 to room temperature.

In the second step, 1-ethynyl-4- (methoxymethoxy) benzene ( A ) is used in 1 to 10 equivalents, preferably 1 to 3 equivalents; n -butyllithium is used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents; BF ₃ .OEt is used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents; (±) -2- (4-methoxymethoxy) phenyl) oxirane ( B ) is preferably used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, and the reaction is -100 to 10 ^o C, preferably Is preferably performed in the range of -50 to 0 ^° C.

In the third step, alcohol ( 11 ) is used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents; Imidazole is used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents; TBSCl is used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents; (±) -2- (4-methoxymethoxy) phenyl) oxirane ( B ) is preferably used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, and the reaction is 0 to 80 ^° C., preferably Preference is given to performing in the range 0 to 30 ^° C.

In the fourth step, 2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethylsilane ( 20 ) is 1 to 10 equivalents, preferably 1 to 3 Using equivalents; The catalyst is preferably a Lindler's catalyst (10% Pd-CaCO ₃ ), and the reaction is preferably performed in the range of 0 to 80 ^° C., preferably 0 to 30 ^° C.

( Z )-(2,4-bis (4-methoxymethoxy) phenyl) but-3-enyloxy) (tert-butyl) dimethylsilane ( 21 ) in the fifth step is 1 to 10 equivalents, preferably Preferably using 1 to 3 equivalents; TBAF is preferably used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, and the reaction is preferably performed in the range of 0 to 80 ^° C., preferably 0 to 30 ^° C.

In the sixth step, ( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-en-1-ol ( 22 ) is used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents and; Dess-martinperiodiane is preferably used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, and the reaction is preferably carried out in the range of 0 to 80 ^o C, preferably 0 to 30 ^o C. .

In the seventh step, the methyltriphenylphosphonium iodine solution is used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents; n- BuLi is preferably used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, and ( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-enal ( 23 ) is 1 It is preferable to use from 10 to 10 equivalents, preferably 1 to 3 equivalents, and the reaction is preferably performed in the range of 0 to 80 ^° C., preferably 0 to 30 ^° C.

In the eighth step, ( Z ) -4,4 '-(penta-1,4-diene-1,3-diyl) bis ((methoxymethoxy) benzene ( 25 ) is 1 to 10 equivalents, preferably 1 to 3 equivalents are used; pH is a strong acid such as hydrochloric acid or sulfuric acid, or a weak acid such as acetic acid or malic acid, preferably hydrochloric acid or sulfuric acid, more preferably hydrochloric acid, and the organic solvent is clopolom, hexane, ethyl. Acetate, or dimethylene chloride, preferably ethyl acetate organic solvent is preferably used, the reaction temperature is preferably carried out in the range of 0 to 80 ^° C, preferably 0 to 30 ^° C.

It is an object of the present invention to provide a variety of physiological activities, i.e., niazol compounds, which have been shown to be effective in potent bovine uterine estrogen receptors, such as strong affinity, antifungal activity, testosterone 5α-reductase inhibitory activity, and sleep induction activity. To provide an industrially useful manufacturing method, such as to provide a more simple and mass-produced synthetic method, can be chemically synthesized by the method shown in the following schemes, but is not limited to these examples. .

The following schemes represent the preparation steps of the compounds of the present invention in stages of manufacture. The compounds of the present invention may be prepared with minor changes, such as changing the reagents, solvents, and reaction sequences used in the synthesis of Scheme 1. Compounds of the present invention were synthesized according to procedures not included in the scope of Scheme 1, and detailed synthesis procedures for these compounds are described in their respective examples.

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

(Scheme 1)

For example, in the above scheme, the first step of first reacting TBAF with (4- (methoxymethoxy) phenyl) ethynyl) trimethylsilane to obtain 1-ethynyl-4- (methoxymethoxy) benzene ; To the 1-ethynyl-4- (methoxymethoxy) benzene ( A ) solution, n -butyllithium was added dropwise and BF ₃ .OEt was added, followed by (±) -2- (4-methoxymethoxy) phenyl A second step of reacting oxirane ( B ) to give 2,4-bis (4- (methoxymethoxy) phenyl) but-3-yn-1-ol (11); The imidazole was added to the alcohol body ( 11 ) obtained above, and TBSCl solution was added and reacted to give 2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethyl A third step of obtaining silane) (20); The solution of 2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethylsilane ( 20 ) obtained in the above step was prepared by catalyst (Lindlar's catalyst, 10% Pd-CaCO _3). Hydrogenated) and a catalytic amount of quinoline was added and reacted to react ( Z )-(2,4-bis (4-methoxymethoxy) phenyl) but-3-enyloxy) (tert-butyl) dimethylsilane (21) A fourth step of obtaining; TBAF was added to the solution of Compound ( 21 ), followed by stirring. The reaction mixture was extracted with ethyl acetate, and the organic layer was purified ( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-ene- A fifth step of obtaining 1-ol (22); Dess-martinperiodiane N _{2 in} the alcohol solution ( 22 ) The sixth step of addition in the presence and reaction of the reaction mixture and purification of the organic extract to give ( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-enal (23); To the methyltriphenylphosphonium iodine solution was added dropwise n- BuLi, stirred under N ₂ condition, the compound 23 was added dropwise to the solution and reacted, and the organic layer was purified ( Z ) -4,4 ′-(penta-1,4 Step 7 to obtain diene-1,3-diyl) bis ((methoxymethoxy) benzene (25); adjust compound 25 solution to pH 2 or below, remove MOM substituent and extract reaction mixture with EtOAc In addition, the extract may be purified to obtain a desired niasol (Nyasol, 1).

The manufacturing method of the present invention is a commercially available commercially available 4-iodo phenol and 4, which is relatively inexpensive as a starting material to solve the problems of the prior art, which is limited in application to high cost and industrial mass production. It is a new manufacturing process that reacts from hydroxy benzaldehyde and solves the problems of the existing manufacturing process.

The preparation method of the present invention has been proven to be effective in various physiological activities, ie, strong affinity, antifungal activity, testosterone 5α-reductase inhibitory activity, and sleep induction activity to the potent bovine uterine estrogen receptor. By chemically synthesizing the compound, it provides an industrially useful manufacturing method, such as providing a synthetic method that is simpler and capable of mass production.

Therefore, the present invention also provides an estrogen receptor agonist (agonist) comprising the niazol compound prepared by the above production method as an active ingredient.

Therefore, the present invention also provides an antifungal agent comprising the niazole compound prepared by the above method as an active ingredient.

Therefore, the present invention also provides a testosterone 5α-reductase inhibitor comprising as an active ingredient a niazole compound prepared by the above method.

Therefore, the present invention also provides a sleep inducing agent comprising the niasol compound prepared by the above production method as an active ingredient.

Niacazole compounds of the present invention obtained by the above production method has a variety of physiological activities, that is, strong affinity to the bovine uterine estrogen receptor (antifungal activity), testosterone 5α-reductase inhibitory activity and sleep induction activity and the like Since it shows efficacy, it can be used for pharmaceuticals, health foods and cosmetic compositions.

The novel manufacturing method for preparing the niazol compound exhibiting various physiological activities of the present invention is a manufacturing method to enable mass production of the target substance in high yield and low cost by improving disadvantages such as high cost and small amount production, which are problems in the prior art.

Hereinafter, the present invention will be described in detail by the following Reference Examples and Experimental Examples.

However, the following Reference Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Reference Examples and Experimental Examples.

Reference Example  1. Device used

1-1. Analytical instrument

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

Nuclear magnetic resonance spectra ( ¹ H NMR) ¹³ C NMR) are Varian (500 MHz), nuclear magnetic resonance spectra ( ¹³ C NMR) are 100 MHz (Bruker NMR spectrometer), internal standard (TMS), tetramethylsilane (TMS), CDCl ₃ , DMSO-d ₆ was used as a solvent. Coupling constants ( J ) are expressed in Hz.

1-2. Reagents and Tube chromatography

All used compounds used reagent grade without further purification. The solvent was dried according to standard procedures. All reactions were performed under dry argon gas recovery in flame-dried glassware. Thin layer chromatography (TLC) used 0.25 mm silica plates (E. Merck, silica gel 60 F254) and silica 60 (230-400 mesh Kieselgel 60) for flash column chromatography. In addition, to identify the material separated on the TLC using a UV lamp (wavelength 254 nm) or iodine vapour (iodine vapour), Hanessian's solution or PMA and confirmed under ultraviolet fluorescence.

Example  One. Niazol ( Nyasol , Cis - hinokiresinol ) Produce

1-1. One- Ethynyl -4-( Methoxymethoxy ) Benzene (A): Manufacture

To an ice cold-suspension of ((4- (methoxymethoxy) phenyl) ethynyl) trimethylsilane (1.03 g, 4.39 mmol, 1 equiv) in dry THF (20 ml) TBAF (6.5 ml, 6.5 mmol, 1.0 in THF) .M solution, 1.2 equiv) was added dropwise at 0 ^° C. The resulting solution was stirred at room temperature for 30 minutes. The reaction was stopped with saturated aqueous NH ₄ Cl and the reaction mixture was extracted with EtOAc (3 × 15 ml). The organic layer was washed with brine (1x20ml). After drying with MgSO 4 and solvent evaporation, the crude product is purified by column chromatography (developing solvent: EtOAc / Hexane 94: 6) to give 1 -ethynyl -4- ( methoxymethoxy ) as a brown oil having the following physical properties . Benzene ( 1-ethynyl-4- (methoxymethoxy) benzene, (A), 700 mg, 98.3%) was obtained.

¹ H-NMR (CDCl ₃ , 500 MHz): δ 7.45 (2H, d, J = 8.8 Hz, Ar- H ), 7.00 (2H, d, J = 8.8 Hz, Ar- H ), 5.18 (2H, s , -OC H ₂ OCH ₃ ), 3.48 (3H, s, -OCH ₂ OC H ₃ ), 3.02 (1H, s, -CH).

¹³ C-NMR (CDCl ₃ , 75 MHz): 157.49, 133.49, 116.04, 115.30, 94.15, 83.45, 76.00, 56.03.

1-2. 2,4- Vis  (4-( Methoxymethoxy ) Phenyl ) Boot -3-yn-1-ol (11) Preparation

N -butyllithium (1.6 in hexane) in a stirred solution of 1-ethynyl-4- (methoxymethoxy) benzene ( A ) (134 mg, 0.83 mmol, 1.5 equiv) in anhydrous tetrahydrofuran (5 ml) at 0 ^° C. M, 0.32 ml, 0.83 mmol, 1.5 equiv) was added dropwise. After stirring for 30 min at the same temperature, after 1 h BF ₃ .OEt (0.73 ml, 0.83 mmol, 1.5 eq) was added and then cooled to −50 ^° C. A solution of (±) -2- (4-methoxymethoxy) phenyl) oxirane ( B ) (100 mg, 0.55 mmol, 1 equiv) in anhydrous tetrahydrofuran (3 ml) was injected by syringe. The reaction mixture was stirred at 20 ^° C. for 30 minutes. After stopping the reaction with saturated NH ₄ Cl solution, the obtained reaction mixture was partitioned with ethyl acetate (3 × 15 ml), the mixed solution was washed with water and brine, dried over anhydrous MgSO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography (18% ethyl acetate in hexane) to give 2,4-bis (4- (methoxymethoxy) phenyl) but-3-yn-1-ol (2,4- bis (4- (methoxymethoxy) phenyl) but-3-yn-1-ol (11), 89 mg, 60%) was recovered and 1-ethynyl-4- (methoxymethoxy) benzene (64 mg) was recovered.

¹ H-NMR (CDCl ₃ , 500 MHz): δ 7.40 (2H, d, J = 8.8 Hz, Ar- H ), 7.37 (2H, d, J = 8.3 Hz, Ar- H ), 7.05 (2H, d , J = 8.8 Hz, Ar- H ), 6.98 (2H, d, J = 8.8 Hz, Ar- H ), 5.18 (4H, s, 2x-OC H ₂ OCH ₃ ), 4.04 (1H, t, J = 6.8 Hz, Ar-CH (O H )-), 3.81 (2H, d, -C H ₂ OH), 3.49 (3H, s, -OCH ₂ OC H ₃ ), 3.48 (3H, s, -OCH ₂ OC H ₃ ), 1.96 (1H, brs, -O H ).

¹³ C-NMR (CDCl ₃ , 75 MHz): 157.05, 156.50, 133.51, 133.06, 131.41, 129.00, 116.43, 116.34, 116.06, 94.39, 94.22, 87.06, 84.34, 67.72, 56.03, 55.95, 41.22.

1-3. 2,4- Bis (4- (methoxymethoxy) phenyl) but -3- Enyloxy Tert-butyl) Dimethylsil Column (20) manufacture

Anhydrous CH ₂ Cl ₂ at 0 ^o C To immobilized alcohol 11 (1.30 g, 3.80 mmol, 1 equiv) in (25 ml) was added imidazole (310 mg, 4.56 mmol, 1.2 equiv). After stirring for 10 minutes at the same temperature, a solution of TBSCl (688 mg, 4.56 mmol, 1.2 eq) in DCM (10 ml) was added. The reaction mixture was stirred for 1 hour and the reaction was stopped by addition of H ₂ O. The reaction mixture was extracted with CH ₂ Cl ₂ (3 × 20 ml) and the mixed solution was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (5% ethyl acetate in hexane) to give 2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethylsilane having the following utterance: (2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert -butyl) dimethylsilane (20), 1.67 g, 96.5%) was obtained.

¹ H-NMR (CDCl ₃ , 500 MHz): δ 7.39 (2H, d, J = 8.8 Hz, Ar- H ), 7.36 (2H, d, J = 8.8 Hz, Ar- H ), 7.02 (2H, d , J = 8.8 Hz, Ar- H ), 6.97 (2H, d, J = 8.8 Hz, Ar- H ), 5.18 (4H, s, 2x-OC H ₂ -OCH ₃ ), 3.95 (1H, t, J = 6.8 Hz, Ar-C H ), 3.75 (1H, dd, J = 6.8,2.4 Hz, Ar-CH (OH) C H _α H _β OTBS), 3.74 (1H, dd, J = 6.8, 2.4 Hz, Ar-CH (OH) CH _α H _β OTBS), 3.48 (6H, s, 2x-CH ₂ OC H ₃ ), 0.88 (9H, s, -SiC (C H ₃ ) ₃ ), 0.01 (6H, s, -Si (C H ₃ ) ₂ ).

¹³ C-NMR (CDCl ₃ , 75 MHz): 156.82, 156.27, 132.95, 132.63, 129.28, 117.06, 116.03, 94.51, 94.29, 88.41, 83.21, 68.54, 55.87, 41.15, 25.87, 18.32, -5.46.

1-4. ( Z )-(2,4- Bis (4-methoxymethoxy) phenyl ) Boot -3- Enyloxy ) (Tert-butyl) Dimethylsilane ( 21) Manufacturing

Stirred 2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethylsilane ( 20 ) in ethyl acetate (60 ml) (1.67 mg, 3.65 mmol, 1 Equivalent) The solution was hydrogenated with a catalyst (Lindlar's catalyst, 10% Pd-CaCO ₃ ) and a catalytic amount of quinoline was added. The reaction mixture was stirred for 2 hours. After confirming the completion of the reaction by TLC, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (8% ethyl acetate in hexane) to give ( Z )-(2,4-bis (4-methoxymethoxy) phenyl) but-3-enyloxy) (tertiary) having the following physical properties. -Butyl) dimethylsilane (( Z )-(2,4-bis (4-methoxymethoxy) phenyl) but-3-enyloxy) ( tert -butyl) dimethylsilane (21), 1.83 mg, 100%) was obtained.

¹ H-NMR (CDCl ₃ , 500 MHz): δ7.22 (2H, d, J = 8.8 Hz, Ar- H ), 7.19 (2H, d, J = 8.8 Hz, Ar- H ), 6.99 (2H, d , J = 8.8 Hz, Ar- H ), 6.96 (2H, d, J = 8.8 Hz, Ar- H ), 6.56 (1H, d, J = 11.7 Hz, ArC H = CHCH (CH _α H _β OTBS) Ar ), 5.85 ((1H, dd, J = 11.7, 11.2 Hz, ArCH = C H CH (CH _α H _β OTBS) Ar), 5.17 (2H, s, -OC H ₂ OCH ₃ ), 5.15 (2H, s , -OC H ₂ OCH ₃ ), 3.99 (1H, m, ArCH = CHC H (CH _α H _β OTBS) Ar), 3.77 (1H, d, J = 9.7, 3.9 Hz, ArCH = CHCH (C H _α H _β OTBS) Ar), 3.75 (1H, d, 1H, dd, J = 9.7, 3.9 Hz, ArCH = CHCH (CH _α H _β OTBS) Ar), 3.48 (3H, s, —OCH ₂ OC H ₃ ), 3.47 (3H, s, -OCH ₂ OC H ₃ ), 0.83 (9H, s, -SiC (C H ₃ ) ₃ ),-0.05 (6H, s, -Si (C H ₃ ) ₂ ).

¹³ C-NMR (CDCl ₃ , 75 MHz): 156.00, 155.75, 135.96, 131.59, 131.11, 129.94, 129.67, 128.85, 116.24, 115.80, 94.53, 94.40, 68.33, 55.94, 55.87, 45.76, 25.85, 18.28, -5.47, -5.49.

1-5. ( Z ) -2,4- Bis (4-methoxymethoxy) phenyl ) Boot -3-en-1-ol (22)

To a stirred solution of Compound ( 21 ) (1.83 g, 3.99 mmol, 1 equiv) in anhydrous tetrahydrofuran (30 mL) was added TBAF (1.0 M solution in 5.19 mL THF, 1.6 mmol, 1.3 equiv) at 0 ^° C. . The reaction mixture was stirred at 2-3 hours. TLC confirmed the reaction was complete, the reaction mixture was stopped with H ₂ O and extracted with ethyl acetate (3 × 30 ml) and washed with brine (50 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The product was purified by column chromatography (28% ethyl acetate in hexane) to give ( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-en-1-ol in oily phase having the following physical properties. (( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-en-1-ol (22), 1.38 g, 98%) was obtained.

¹ H-NMR (CDCl ₃ , 500 MHz): δ7.23 (2H, d, J = 8.3 Hz, Ar-H), 7.19 (2H, d, J = 8.3 Hz, Ar- H ), 7.03 (2H, d , J = 8.3 Hz, Ar- H ), 6.98 (2H, d, J = 8.3 Hz, Ar- H ), 6.65 (1H, d, J = 11.7 Hz, ArC H = CHCH (CH ₂ OH) Ar), 5.83 ((1H, dd, J = 11.7, 10.7 Hz, ArCH = C H CH (CH ₂ OH) Ar), 5.18 (2H, s, -OC H ₂ OCH ₃ ), 5.17 (2H, s, -OC H ₂ OCH ₃ ), 4.05 (1H, m, ArCH = CHC H (CH ₂ OH) Ar), 3.77 (1H, d, J = 9.7 Hz, ArCH = CHCH (C H ₂ OH) Ar), 3.47 (6H, s, 2x-OCH ₂ OC H ₃ ), 1.60 (1H, brs, -OH).

¹³ C-NMR (CDCl ₃ , 75 MHz): δ 156.01, 134.69, 131.01, 130.30, 129.84, 128.69, 116.61, 115.92, 94.40, 94.29, 77.24, 76.99, 76.73, 67.54, 55.89, 45.90.

1-6. ( Z ) -2,4- Bis (4-methoxymethoxy) phenyl ) Boot -3- Enal  Manufacture (23)

CH ₂ Cl ₂ (3ml) of the alcohol material (22) (100mg, 0.290mmol, 1 equiv) was added Dess-Martin periodate Dian (Dess-martinperiodiane, 185mg, 0.435 , 1.5 eq) of N ₂ The reaction mixture was added in the presence and the reaction mixture was stirred at 0 ^° C. for 5 minutes and further stirred at room temperature for 1 hour. The reaction was saturated with NaHCO ₃ Stopped by addition and the organic layer was removed from CH ₂ Cl ₂ (3 × 10 ml) and the combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The product was purified by column chromatography (14% ethyl acetate in hexane) to give ( Z ) -2, 4-bis (4-methoxymethoxy) phenyl) but-3-enal ( ( Z ) in the oily phase having the following physical properties. -2, 4-bis (4-methoxymethoxy) phenyl) but-3-enal, 23, 56 mg, 56%) was obtained.

¹ H-NMR (CDCl ₃ , 500 MHz): δ9.63 (1H, d, J = 1.9 Hz, -C H O), 7.21 (2H, d, J = 8.8 Hz, Ar- H ), 7.17 (2H, d, J = 8.8 Hz, Ar- H ), 7.07 (2H, d, J = 8.8 Hz, Ar- H ), 7.05 (2H, d, J = 8.8 Hz, Ar- H ), 6.79 (1H, d, J = 11.2 Hz, Ar-C H = CHCH (CHO) -Ar), 5.99 (1H, dd, J = 11.2,10.2 Hz, Ar-CH = C H CH (CHO) -Ar), 5.18 (4H, s , 2x-OC H ₂ OCH ₃ ), 4.68 (1H, dd, J = 1.9,5.6 Hz, Ar-CH = CHC H (CHO) -Ar), 3.50 (6H, s, 2x-OCH ₂ OC H ₃ ) .

¹³ C-NMR (CDCl ₃ , 75 MHz): 198.19, 156.59, 132.84, 129.97, 129.82, 129.53, 129.40, 129.25, 124.10, 117.06, 116.10, 94.35, 56.91, 56.02.

1-7. ( Z ) -4,4 ’-(Penta-1,4- Dien -1,3- Dill ) Vis (( Methoxymethoxy Benzene) Manufacture (25)

At 0 ^o C was added dropwise anhydrous THF (10 ml) methyl triphenyl phosphonium iodide solution n -BuLi (in hexane 1.6M, 0.838ml, 1.341, 1.5 equiv.) In (723 mg, 1.788 mmol, 2.0 eq) of N, and ₂ Stir for 5 minutes under conditions. Compound 23 (306 mg, 0.894 mmol, 1 equiv) in dry THF (5 ml) was added dropwise to the solution at 0 ^° C. and stirred for 5-10 minutes. The reaction was stopped with NH ₄ Cl solution, the mixture was extracted with ethyl acetate, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (6% ethyl acetate in hexane) to give a colorless oily ( Z ) -4,4 '-(penta-1,4-diene-1,3-diyl) bis (( Methoxymethoxy) benzene, (( Z ) -4, 4 '-(penta-1,4-diene-1, 3-diyl) bis ((methoxymethoxy) benzene, 25, 204 mg, 67%) was obtained.

¹ H-NMR (CDCl ₃ , 500 MHz): δ7.23 (2H, d, J = 8.31 Hz, Ar- H ), 7.16 (2H, d, J = 8.31 Hz, Ar- H ), 7.01 (2H, d , J = 8.8 Hz, Ar- H ), 6.99 (2H, d, J = 8.80 Hz, Ar- H ), 6.54 (1H, d, J = 11.24 Hz, Ar-C H = CHCH (CH = CH ₂ ) -Ar), 6.06-5.99 (1H, m, Ar-CH = CHCH (C H = CH ₂ ) -Ar), 5.71 (1H, dd, J = 11.7,9.7 Hz, Ar-CH = C H CH (CH = CH ₂ ) -Ar), 5.18 (2H, m, Ar-CH = CHCH (CH = C H ₂ ) -Ar), 5.16 (4H, s, 2x-OC H ₂ OCH ₃ ), 4.52 (1H, dd , J = 9.78, 6.35 Hz, Ar-CH = CHC H (CH = CH ₂ ) -Ar), 3.50 (3H, s, -OCH ₂ OC H ₃ ), 3.48 (3H, s, -OCH ₂ OC H ₃ ).

¹³ C-NMR (CDCl ₃ , 75 MHz): 156.16, 155.81, 140.62, 136.72, 131.92, 130.87, 129.81, 128.68, 116.38, 115.98, 115.09, 94.53, 94.42, 56.00, 55.94, 46.89.

1-8. Niazol ( Nyasol , Cis - hinokiresinol Manufacturing (1)

Concentrated hydrochloric acid was added to 25 (150 mg, 0.44 mmol) of the Compound 25 solution in methanol: water (4ml: 1ml) until pH 2 or lower (8 drops) and the mixture was stirred at room temperature for 12 hours. The MOM substituent was removed after 12 hours and the reaction mixture was concentrated in vacuo and methanol was removed. The residue was extracted with EtOAc (3x20ml) and the extract was washed with brine, dried over MgSO ₄ and concentrated in vacuo. The product was subjected to column chromatography (ethyl acetate in 30% hexane) to obtain niasol (Nyasol, 1) having the following physical properties (89 mg, 80%).

¹ H-NMR (CD ₃ OD, 500 MHz): δ7.13 (2H, d, J = 8.3 Hz, Ar- H ), 7.11 (2H, d, J = 8.3 Hz, Ar- H ), 6.74 (2H, d, J = 8.8 Hz, Ar- H ), 6.72 (2H, d, J = 8.3 Hz, Ar- H ), 6.47 (1H, d, J = 11.2 Hz, Ar-C H = CHCH (CH = CH ₂ ) -Ar), 6.00 (1H, m, Ar-CH = CHCH (C H = CH ₂ ) -Ar), 5.63 (1H, dd, J = 11.7, 9.7 Hz, Ar-CH = C H CH (CH = CH ₂ ) -Ar), 5.11 (2H, m, Ar-CH = CHCH (CH = C H ₂ ) -Ar), 4.45 (1H, t, J = 8.8 Hz, Ar-CH = CHC H (CH = CH ₂ ) -Ar).

¹³ C-NMR (CD ₃ OD, 75 MHz): 157.64, 156.93, 142.76, 135.75, 132.49, 130.96, 129.97, 129.69, 116.32, 116.00, 114.79, 48.47.

Claims (29)

A first step of reacting (4- (methoxymethoxy) phenyl) ethynyl) trimethylsilane with TBAF to give 1-ethynyl-4- (methoxymethoxy) benzene (A); To the 1-ethynyl-4- (methoxymethoxy) benzene ( A ) solution, n -butyllithium was added dropwise and BF ₃ .OEt was added, followed by (±) -2- (4-methoxymethoxy) phenyl A second step of reacting oxirane ( B ) to give 2,4-bis (4- (methoxymethoxy) phenyl) but-3-yn-1-ol ( 11 ); To the 2,4-bis (4- (methoxymethoxy) phenyl) but-3-yn-1-ol ( 11 ) obtained above, imidazole is added, TBSCl solution is added and reacted to give 2,4-bis ( 4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethylsilane) ( 20 ); The solution of 2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethylsilane ( 20 ) obtained in the above step was hydrogenated with a catalyst and a catalytic amount of quinoline was added and the reaction was carried out. A fourth step of obtaining ( Z )-(2,4-bis (4-methoxymethoxy) phenyl) but-3-enyloxy) (tert-butyl) dimethylsilane ( 21 ); TBAF was added to the solution of Compound ( 21 ), followed by stirring. The reaction mixture was extracted with ethyl acetate, and the organic layer was purified ( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-ene- A fifth step of obtaining 1-ol ( 22 ); Dess-martinperiodiane was added to the alcohol solution ( 22 ) in the presence of N _2, the reaction mixture was reacted, and the organic extract was purified to ( Z ) -2,4-bis (4-methoxymethoxy A sixth step of obtaining methoxy) phenyl) but-3-enal ( 23 ); To the methyltriphenylphosphonium iodine solution was added dropwise n- BuLi, stirred under N ₂ conditions, the compound ( 23) was added dropwise to the solution and reacted, and the organic layer was purified ( Z ) -4,4 '-(penta-1). Step 7, obtaining 4-4-diene-1,3-diyl) bis ((methoxymethoxy) benzene ( 25 ); adjusting the solution of compound ( 25 ) to pH 2 or below, removing the MOM substituent and removing the reaction mixture To prepare a niazole ( 1 ) comprising an eighth step of extracting with an organic solvent and purifying the extract:
(Formula 1)

(2)

(Formula 3)

(Formula 4)

(Formula 5)

(Formula 6)

(Formula 7)

(Formula 8)

The method of claim 1,
Wherein ((4- (methoxymethoxy) phenyl) ethynyl) trimethylsilane in the first step uses 1 to 10 equivalents. The method of claim 1,
TBAF in the first step is characterized in that 1 to 10 equivalents. The method of claim 1,
The reaction in the first step is characterized in that carried out at 0 to 80 ^o C. The method of claim 1,
1-ethynyl-4- (methoxymethoxy) benzene ( A ) in the second step is characterized in that it uses 1 to 10 equivalents. The method of claim 1,
N -butyllithium in the second step is characterized in that 1 to 10 equivalents. The method of claim 1,
In the second step, the BF ₃ .OEt is characterized in that 1 to 10 equivalents. The method of claim 1,
In the second step, the (±) -2- (4-methoxymethoxy) phenyl) oxirane ( B ) is characterized in that it uses 1 to 10 equivalents. The method of claim 1,
In the second step, the reaction is carried out at -100 to 10 ^oC . The method of claim 1,
2,4-bis (4- (methoxymethoxy) phenyl) but-3-yn-1-ol ( 11 ) in the third step is characterized in that 1 to 10 equivalents. The method of claim 1,
In the third step, the imidazole is characterized in that it uses 1 to 10 equivalents. The method of claim 1,
In the third step, the TBSCl is characterized in that it uses 1 to 10 equivalents. The method of claim 1,
In the third step, the (±) -2- (4-methoxymethoxy) phenyl) oxirane ( B ) is characterized in that it uses 1 to 10 equivalents. The method of claim 1,
In the fourth step, the 2,4-bis (4- (methoxymethoxy) phenyl) but-3-ynyloxy) tert-butyl) dimethylsilane ( 20 ) is characterized by using 1 to 10 equivalents Way. The method of claim 1,
In the fourth step, the catalyst is characterized in that the Lindler's catalyst (Lindlar's catalyst, 10% Pd-CaCO ₃ ). The method of claim 1,
In the fifth step, ( Z )-(2,4-bis (4-methoxymethoxy) phenyl) but-3-enyloxy) (tert-butyl) dimethylsilane ( 21 ) uses 1 to 10 equivalents Characterized by the above. The method of claim 1,
In the fifth step, the TBAF is characterized in that using 1 to 10 equivalents. The method of claim 1,
( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-en-1-ol ( 22 ) in the sixth step is characterized by using 1 to 10 equivalents. The method of claim 1,
In the sixth step, the Dess-martinperiodiane is characterized in that 1 to 10 equivalents are used. The method of claim 1,
The methyl triphenylphosphonium iodine solution in the seventh step is characterized in that it uses 1 to 10 equivalents. The method of claim 1,
In the seventh step, the n- BuLi is characterized in that 1 to 10 equivalents used. The method of claim 1,
In the seventh step, the ( Z ) -2,4-bis (4-methoxymethoxy) phenyl) but-3-enal ( 23 ) is characterized in that 1 to 10 equivalents are used. The method of claim 1,
In the eighth step, ( Z ) -4,4 '-(penta-1,4-diene-1,3-diyl) bis ((methoxymethoxy) benzene ( 25 ) is used in an amount of 1 to 10 equivalents How to. The method of claim 1,
In the eighth step, the pH is characterized by using a strong acid, such as hydrochloric acid, sulfuric acid, or a weak acid, such as acetic acid, malic acid. The method of claim 1,
In the eighth step, the organic solvent is characterized in that using chloroform, hexane, ethyl acetate, or dimethylene chloride. An estrogen receptor agonist comprising the niazol compound prepared by the method of claim 1 as an active ingredient. An antifungal agent comprising the niazol compound prepared by the method of claim 1 as an active ingredient. A testosterone 5α-reductase inhibitor comprising as an active ingredient a niazole compound prepared by the method of claim 1. Sleep inducing agent comprising the niazol compound prepared by the method of claim 1 as an active ingredient.