KR20100046533A - The new intermediate of moracin p and o compounds, the preparation thereof and the preparation of moracin p and moracin o compounds using the same - Google Patents

Abstract

PURPOSE: An intermediate, a manufacturing method thereof, and a manufacturing method of moracin P and moracin O compounds using thereof are provided to produce the compounds with high yield with a stable reaction condition. CONSTITUTION: An intermediate is marked as chemical formula V. A manufacturing method of the intermediate comprises the following steps: forming a compound marked as chemical formula III by iodide reacting 2,4-dihydroxybenzaldehyde; forming a compound marked as chemical formula IV protected with di-Boc by reacting the compound marked as the chemical formula III with Boc_2O; and forming the intermediate marked as the chemical formula V by obtaining a benzyl alcohol intermediate by reacting the compound marked as the chemical formula IV with a hydride derivative of aluminum or a hydride derivative of boron, and reacting the benzyl alcohol intermediate with a 2-methylpropenyl metal compound.

Description

Novel intermediates of the Moracin P compound and the Moracin O compound, preparation method of the intermediate and the preparation method of the Moracin P compound and the Moracin O compound using the intermediate {The new intermediate of Moracin P and O compounds, the preparation and the preparation of Moracin P and Moracin O Compounds using the same}

The present invention relates to a novel intermediate of the Moracin P compound and the Moracin O compound, a method for preparing the intermediate, and a method for producing the Moracin P compound and the Moracin O compound using the intermediate.

Hypoxia in solid cancer is a common phenomenon, and solid cancer cells undergo various genetic changes to adapt to these hypoxic conditions, resulting in cancer cells becoming more malignant and resistant to anticancer agents. It is known as a major inducer of malignancy of more than% cancer ( Nature , 386, 403, 1997; Hockel M. and Vaupel P., Semin. Oncol. , 28, 36-41, 2001; Nature Med. , 6, 1335, 2000; Bos et al. Cancer , 97, 1573-1581, 2003).

HIF-1 is known to be the most important molecule that controls the adaptation of cancer cells to this hypoxic state, and the amount of HIF-1α protein is known to have a close correlation with the prognosis of cancer patients. HIF-1 activated by cancer cells by hypoxic conditions or by stimulation of growth factors or oncogenes as mentioned above, or by inactivation of cancer suppressor genes such as pVHL, is known as hexokinase 2, Induces the expression of genes such as glucose transporter 1, erythropoietin, IGF-2, endoglin, VEGF, MMP-2, uPAR, MDR1 and so on apoptosis. Tolerance, increased angiogenesis, increased cell proliferation, increased invasion (invas ion), and the like to acquire traits such as cancer cells eventually become malignant. Therefore, since HIF-1 plays an important role in the growth, proliferation, and malignancy of cancer, in particular, solid cancer, researches to develop anticancer agents by targeting it are very active ( Cancer Res. , 62, 4316, 2002; Nat. Rev. Drug. Discovery , 2, 1, 2003; Semenza et al. Nature Reviews Cancer , 3, 721-732, 2003).

On the other hand, HIF-1 can be used as a target for the development of therapeutic agents for diseases in which not only cancer but also activation of angiogenesis is associated with worsening of the disease. Angiogenesis factors, such as VEGF, derived from HIF-1 that are activated in hypoxia, are associated with the development of diabetic retinopathy and arthritis as well as cancer. Thus, compounds that inhibit HIF-1, which is activated from hypoxia of diseased tissue, could be used as novel therapeutics for diseases such as diabetic retinopathy or rheumatoid arthritis (Eiji Ikeda, Pathology International , 55, 603-610, 2005).

Accordingly, the present inventors have studied to develop a compound that inhibits HIF-1 activation, and the 2-arylbenzofuran-based Moracin O compound, Moracin P compound, and Mulberofuran H are separated It was found that HIF-1, which is a transcription factor induced in hypoxia, can be inhibited. As a result, the 2-arylbenzofuran derivative of the present invention has various cancer diseases such as liver cancer, gastric cancer and breast cancer through HIF-1 inhibitory activity. By discovering that it can be used as an active ingredient for treating diabetic retinopathy and arthritis, the following invention has been filed (Korean Patent Application No. 10-2007-78888). In particular, Moracin O and Moracin P were evaluated by HRE reporter assay in AGS cells and found that IC ₅₀ values of 0.35 and 1.06 nM, respectively, strongly inhibited HIF-1 activation by hypoxia. The MTT assay performed together showed cell viability of about 100% even at concentrations up to 20 mg / mL, suggesting that anti-HIF-1 activity of these natural products was not due to simple cytotoxicity.

However, in the case of extracts from the natural products, the Moraine O compound and the Moraine P compound are very low in yield when extracted from the epidermis, and thus it is difficult to secure a sufficient amount. .

Accordingly, the present invention is to provide an intermediate useful for synthesizing the Moracin O compound and the Moracin P compound, a method for preparing the intermediate, and a method for preparing the Moracin O compound and the Moracin P compound using the same.

The present invention relates to t-butyl 5-hydroxy-2-iodo-4- (3-methylbut-2-enyl) phenyl carbo, of the general formula (V) which is a useful intermediate for the synthesis of the Moracin O compound and the Moracin P compound. Provide Nate:

[Formula V]

The present invention also provides a method for preparing a compound of Formula V, comprising the following steps:

a) iodide 2,4-dihydroxybenzaldehyde to prepare a compound of formula III; b) reacting the compound of formula III prepared in step a) with Boc ₂ O (Di- tert- butyl pyrocarbonate) in the presence of a base to prepare a compound of formula IV protected with di-Boc; And

c) Reducing the compound of formula IV prepared in step b) in the presence of hydride derivatives of aluminum or hydride derivatives of boron to obtain a benzyl alcohol intermediate, Reacting with a penyl metal compound to produce a compound of formula (V).

[Formula III]

[Formula IV]

[Formula V]

In the method for preparing the compound of Formula V of the present invention, 2,4-dihydroxybenzaldehyde, which is the starting material of step a), may be purchased commercially or directly prepared by a known method. The purchased 2,4-dihydroxybenzaldehyde may be reacted under ordinary iodide reaction conditions to prepare 2,4-dihydroxy-5-iodobenzaldehyde of formula III. The reagent used in the iodide reaction conditions is preferably ICl (iodine monochloride) or iodine and various oxidizing or metal salt mixtures, bis (pyridine) iodine salt, more preferably iodine monochloride. It is also more preferred that the iodine monochloride is reacted in the presence of acetic acid.

On the other hand, in the iodide reaction, not only 2,4-dihydroxy-5-iodobenzaldehyde of the general formula (III) but also regioisomers such as 2,4-dihydroxy-3-iodobenzaldehyde as a by-product are produced by proton NMR. About 2: 1 phase is produced.

In addition, 2,4-dihydroxy-5-iodobenzaldehyde of formula III prepared in step a) may be used as a starting material of step b) in mixture with its regioisomer.

In the method of preparing the following Formula V compound of the present invention, the base of step b) is an inorganic base such as K ₂ CO _3, NaOH, or KOH; And organic bases such as DIPEA (N, N-Diisopropylethylamine), Et ₃ N or DMAP (4-Dimethylamino pyridine) are possible, but K ₂ CO ₃ is preferred. The organic solvent used in step b) may be an organic solvent known to those skilled in the art, for example, diethyl ether, THF and the like.

In the method of preparing the following Formula V compound of the present invention, in step c), the compound of Formula IV is an aluminum hydride derivative or a boron hydride derivative [for example, LiAlH ₄ (Lithium aluminum hydride, LAH), NaBH ₄ and the like] Reduction in the presence of the benzyl alcohol intermediate. For example, benzyl intermediate is obtained by reaction with NaBH _{4 in a} THF and water mixed solvent. At this time, the benzyl alcohol intermediate is reacted with 2-methylpropenyl metal compound in THF solvent to prepare the compound of formula (V). The 2-methylpropenyl metal compound is preferably 2-methylpropenyl magnesium bromide or 2-methylpropenyl lithium.

In addition, the present invention, starting with t-butyl 5-hydroxy-2-iodo-4- (3-methylbut-2-enyl) phenyl carbonate of the compound of formula V as a starting material Moracin comprising the following steps: Provided are methods for preparing the P compound.

a) preparing a Boc-protected compound of formula VI by reacting the compound of formula V with [6-endo-trig] -closure in the presence of an epoxidation and an acid. ;

b) preparing a compound of formula VII by removing the Boc protecting group in the presence of an acid or a base of compound of formula a);

c) reacting the compound of formula VII of step b) with 1,3-bis- (t-butyl-dimethyl-silanyloxy) -5-ethynyl-benzene under Sonogashira cross coupling conditions and subsequently in situ cyclization Preparing a compound; And

d) preparing the Moracin P compound of formula I in the presence of the compound of formula VIII prepared in step c) in the presence of HF / pyridine, Tetra-n-butylammonium fluoride (TBAF), acid or base.

[Formula VI]

[Formula VII]

(VIII)

[Formula I]

In the method for preparing the Moracin P compound of the present invention, the epoxidation of step a) is preferably peroxycarboxylic acids, peroxyhydrogen, hydrogen peroxide or dioxiranes, m-chloroperbenzoic acid is more preferred.

The acid in step a) is preferably hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or BF ₃ -Et ₂ O, more preferably p-toluenesulfonic acid.

In the method for preparing the molasin P compound of the present invention, the acid of step b) may be ZnBr ₂ HCl, trifluoroacetic acid (TFA), and the like, and the base may be NaOH or pyreridine. ZnBr ₂ is more preferred.

In the method for preparing the Moracin P compound of the present invention, Sonogashira cross coupling conditions of step c) are tripled by coupling aryl or vinyl halides and terminal alkynes in the presence of copper-palladium catalysts and bases. It refers to the process of forming a compound (enynes) with a bond. Pd (Ph ₃ P) ₂ Cl ₂ or Pd (Ph ₃ ) ₄ and CuI or CuBr are preferred, and Pd (Ph ₃ P) ₂ Cl ₂ and CuI are more preferred. Examples of the base is preferably Et2NH, Et ₃ N or DIPEA and, Et ₃ N is more preferable. The solvent may be a variety of organic solvents, dioxane is preferred, the reaction temperature is preferably about 70 to 100 ℃, even more preferably about 85 ℃.

In the method for preparing the Moracin P compound of the present invention, the acid of step d) means an acid such as acetic acid and HCl known to those skilled in the art, and the base means a base such as K ₂ CO ₃ , NaOH known to those skilled in the art. HF / pyridine mixtures are more preferred. The reaction temperature of step d) can be a variety of temperatures, but is preferably about 0 ° C.

The present invention also provides a compound of formula VI, which is an intermediate in the method for preparing the Moracin P compound of the present invention:

[Formula VI]

The present invention also provides a compound of formula (VII), which is an intermediate in the process for preparing the molasin P compound of the present invention:

[Formula VII]

The present invention also provides a compound of formula VIII, which is an intermediate in the process for preparing the Moracin P compound of the present invention:

(VIII)

In addition, the present invention includes the following steps using, as a starting material, t-butyl 5-hydroxy-2-iodo-4- (3-methylbut-2-enyl) phenyl carbonate as a compound of the present invention. Provided are methods for preparing the Moracin O compound:

a) Compound (V) is reacted under epoxidation to prepare an epoxide intermediate, and a base is added to the [5-exo-tet] -cyclization reaction to give a [5-exo-tet] -cyclisation reaction. Preparing an IX compound;

b) Sonogashira cross coupling and subsequently in situ cyclization of the compound of formula IX and 1,3-bis- (t-butyl-dimethyl-silanyloxy) -5-ethynyl-benzene in step a) to produce the compound of formula Making; And

c) preparing a Moracin O compound of formula (II) in the presence of HF / pyridine, Tetra-n-butylammonium fluoride (TBAF), acid or base in step b) Manufacturing Method:

[Formula IX]

[Formula X]

[Formula II]

In the method for preparing the molasin O compound of the present invention, the epoxy condition of step a) is using peroxycarboxylic acids, peroxyhydrogen, hydrogen peroxide or dioxiranes, and m-clone. Loperbenzoic acid is preferred.

In the method for preparing the molasin O compound of the present invention, the base of step a) may be any conventional base such as, for example, LiOH, KOH, LiOH, NaHCO ₃ , Na ₂ CO _3, and more preferably LiOH. . The reaction solvent at this time is preferably a polar organic solvent, for example, methanol, ethanol and the like.

In the method for preparing the molasin O compound of the present invention, Sonogashira cross coupling of step b) and subsequent in situ cyclization conditions are as mentioned in the method for preparing the molasin P compound of the present invention, and the acid and base of step c) are As mentioned in the preparation method of the Moracin P compound.

The present invention also provides a compound of formula (IX), which is an intermediate in the method for preparing the molasin O compound of the present invention.

[Formula IX]

The present invention also provides a compound of formula (X), which is an intermediate in the method for preparing the Moracin O compound of the present invention.

[Formula X]

The method of preparing the Moracin O compound and the P compound of the present invention is useful for mass production because it has an effect that can be produced in high yield, unlike the conventional method for extracting baekryepi.

Hereinafter, the present invention will be described in more detail with reference to Examples. The following examples merely illustrate the invention and do not limit the invention.

The reagents and solvents used in the examples below were purchased from Aldrich, TCI, Sigma-aldrich, unless otherwise noted.

<Example 1> t Preparation of -Butyl-5-hydroxy-2-iodo-4- (3-methylbut-2-enyl) phenyl carbonate (5)

1-1) t-butyl-4-formyl-6-iodo-1,3-phenylene dicarbonate (4) (tert-butyl 4-formyl-6-iodo-1,3-phenylene dicarbonate) ( 4)

(4)

(4)

Iodine monochloride (14.1) dissolved in 2,4-hydroxybenzaldehyde (10 g, 72.4 mmol) in acetic acid (48 mL) and then dissolved in acetic acid (20 mL) in this solution. g, 86.88 mmol) solution was added. After stirring for 6 hours at room temperature, about 150 ml of saturated NaHSO ₃ aqueous solution was added until the color of the reaction mixture was not changed _, and after diluting with EtoAC (300 ml X 4), the organic layer was separated and washed with water. Thereafter, the mixture was dried over anhydrous Na ₂ SO ₄ and concentrated to prepare (3) a compound. To this mixture was added Boc ₂ O [di-tert-butyl pyrocarbonate] (55.2 g, 0.25 mol), anhydrous K ₂ CO ₃ (17.5 g, 0.127 mol), diethyl ether, and stirred at room temperature overnight. It was confirmed by TLC (thin layer chromatography) whether the reaction was completed, and then concentrated after filtration. Purification by flash silica gel column chromatography (silica gel, 19: 1 hexane / EtOAc) afforded the desired compound as a white solid (16.7 g, 49.7% yield).

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.08 (1H, s, CHO), 8.31 (1H, s, Ar-H), 7.24 (1H, s, Ar-H), 1.58 (9H, s, C ( CH ₃ ) ₃ ), 1.57 (9H, s, C (CH ₃ ) ₃ ).

1-2) t Preparation of -Butyl 5-hydroxy-2-iodo-4- (3-methylbut-2-enyl) phenyl carbonate (5)

(5)

(5)

T -butyl 4-formyl-6-iodo-1,3-phenylene dicarbonate (15 g, 32.32 mmol) prepared in Example 1-1) was prepared by THF / H ₂ O (4: 1, 85.5 mL), followed by addition of NaBH ₄ (1.28 g, 34 mmol) dissolved in water (22.5 mL) at 0 ^° C. with stirring. Thereafter, the mixture was stirred at 0 ^° C. for 5 minutes, and crushed ice and acetic acid were added to about l50 ml, and extracted with diethyl ether (100 ml X2). The organic layer was washed with water, dried over anhydrous Na ₂ SO ₄ , and concentrated to give an oil. The resulting oil was dissolved in THF (180 mL), then cooled to -78 ^o C and 2-methylpropenyl magnesium bromide (0.05 M in THF, 194 mL, 97 mmol) was added. Stirred at −78 ^° C. for 1 h and further stirred at room temperature for 10 h. About 300 ml of 10% HCl aqueous solution was added to the reaction mixture to terminate the reaction, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, dried over anhydrous MgSO ₄ , and concentrated. Separation by flash silica gel column chromatography (5:95 EtOAc / hexane) gave the desired compound as a yellow oil (5 g, 38.24% yield).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.47 (1H, s, Ar-H), 6.67 (1H, s, Ar-H), 5.27 (1H, m, vinylic CH), 5.23 (1H, bs, OH ), 3.29 (2H, d, CH ₂ , J = 6.9 Hz), 1.77 (3H, s, CH ₃ ), 1.75 (3H, s, CH ₃ ), 1.57 (9H, s, C (CH ₃ ) ₃ ) .

Example 2 Preparation of t-Butyl 3-hydroxy-6-iodo-2,2, -dimethylchroman-7-yl carbonate (6)

(6)

(6)

T -Butyl 5-hydroxy-2-iodo-4- (3-methylbut-2-enyl) phenyl carbonate (1.2 g, 2.97 mmol) obtained in Example 1-2) was replaced with CHCl ₃ (26 chloroperbenzoic acid (chloroperbenzoic acid) (615 mg, 3.56 mmol) and p - - toluenesulfonic acid (p-toluenesulphonic acid) (28.3 mL) in which m dissolved in CHCl ₃ (14.5 mL) in dissolving, 0 ° C to mg, 0.15 mmol) solution was added. After stirring for 1 hour at 0 ° C., the mixture was further stirred overnight at room temperature. About 100 ml of saturated NaHCO ₃ aqueous solution was added to the reaction mixture to terminate the reaction. After extraction with about 100 ml of ethyl acetate, the organic layer was washed with aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , and concentrated. Flash silica gel column chromatography (85:15 hexanes / EtO Ac) gave the desired compound (764 mg, 61% yield).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.47 (1H, s, Ar-H), 6.69 (1H, s, Ar-H), 3.80 (1H, t, J = 5.1 Hz, CH), 3.05 (1H , dd, J = 5.1 & 16.8 Hz, CH ₂ ), 2.77 (1H, dd,, J = 5.1 & 16.8 Hz, CH ₂ ), 1.57 (9H, s, C (CH ₃ ) ₃ ), 1.34 (3H, s, CH ₃ ), 1.30 (3H, s, CH ₃ ).

Example 3 Preparation of 6-iodo-2,2-dimethylchroman-3,7-diol (7)

(7)

(7)

T-butyl 3-hydroxy-6-iodo-2,2-dimethylchroman-7-yl carbonate prepared in Example 2

ZnBr ₂ (2.67 g, 11.9 mmol) was added to a solution of (550 mg, 1.19 mmol) in CH ₂ Cl ₂ (110 mL), and the reaction mixture was stirred at room temperature overnight. About 30 ml of 1 M HCl was added to the reaction mixture to terminate the reaction, and extracted with ethyl acetate. The organic layer was then washed with aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Separation by flash silica gel column chromatography (80:20 hexane / EtO Ac) gave the desired compound (305 mg, 80% yield).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.32 (1H, s, aromatic-H), 6.50 (1H, s, aromatic-H), 5.07 (1H, bs, OH), 3.77 (1H, m, CH) , 3.02 (1H, dd, J = 5.1 & 17.1 Hz, CH ₂ ), 2.73 (1H, dd, J = 5.1 & 17.1 Hz, CH ₂ ), 1.35 (3H, s, CH ₃ ), 1.30 (3H, s , CH ₃ ).

Example 4 (5- (6-hydroxy-7,7-dimethyl-6,7-dihydro-5H-furo [3,2-g] chromen-2-yl) -1,3-phenyl Len) bis (oxy) bis (t-butyldimethylsilane) [(5- (6-hydroxy-7,7-dimethyl-6,7-dihydro-5H-furo [3,2-g] chromen-2-yl ) -1,3-phenylene) bis (oxy) bis (tert-butyldimethylsilane)] (8)

(8)

(8)

6-Iodo-2,2-dimethylchroman-3,7-diol (7) (300 mg, 0.94 mmol), Pd (Ph ₃ P) ₂ Cl ₂ (65.7 mg, 0.094 mmol) prepared in Example 3. ), 1,3-bis- (t-butyl-dimethyl-silanyloxy) in a solution of CuI (35.7 mg, 0.19 mmol) and Et ₃ N (1 mL, 7.5 mmol) dissolved in dioxane (5 mL). -5-ethynyl-benzene {1,3-Bis- (tert-butyl-dimethyl-silanyloxy) -5 -ethynyl-benzene} (680 mg, 1.9 mmol) was added. The reaction mixture was stirred at 85 ^° C. for 20 hours. The reaction mixture was concentrated, diluted with EtoAC and washed with dilute HCl solution, NaHCO ₃ aqueous solution and water. The organic layer was washed with aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Flash silica gel column chromatography (50:50 CH ₂ Cl ₂ / hexanes) afforded the title compound (192 mg, 36.9% yield).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.21 (1H, s, aromatic-H), 6.98 (1H, s, aromatic-H), 6.91 (2H, d, J = 2.4 Hz, aromatic-H), 6.81 (1H, s, aromatic-H), 6.31 (1H, t, J = 2.4 Hz, aromatic-H), 3.84 (1H, m, CH), 3.22 (1H, dd, J = 4.2 & 16.8 Hz, CH ₂ ), 2.73 (1H, dd, J = 5.1 & 16.8 Hz, CH ₂ ), 1.39 (3H, s, CH ₃ ), 1.35 (3H, s, CH ₃ ), 1.00 (18H, s, (CH ₃ ) ₃ ), 0.24 (12H, s, (CH ₃ ) ₂ ).

Example 5 Preparation of (+/-)-Moracin P

(5- (6-hydroxy-7,7-dimethyl-6,7-dihydro-5H-furo [3,2-g] chromen-2-yl) -1,3- obtained in Example 4 phenylene) bis (oxy) bis (t- bukil dimethylsilane) (17 mg, 0.031 mmol) to THF / pyridine (4: 1, 1.2 mL) 70% in the dissolving, the solution to 0 ^o C HF / Pyridine solution (0.08 mL) was added. After stirring for 2 hours at room temperature, the reaction was terminated with saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated. Purification by prep TLC (60:40 EtOAc / hexane) gave the desired compound as a white solid (7.5 mg, 75% yield).

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.21 (1H, s, aromatic-H), 6.87 (1H, s, aromatic-H), 6.85 (1H, s, aromatic-H), 6.75 (2H, d , J = 2.1 Hz, aromatic), 6.24 (1H, t, J = 2.1 Hz, aromatic), 3.84 (1H, dd, J = 5.4 & 7.5 Hz, CH), 3.14 3.22 (1H, dd, J = 5.7 & 16.8 Hz, CH ₂ ), 2.73 (1H, dd, J = 7.5 & 16.5 Hz, CH ₂ ), 1.35 (3H, s, CH ₃ ), 1.27 (3H, s, CH ₃ ).

Example 6 2- (2-hydroxypropan-2-yl) -5-iodo-2,3-dihydrobenzofuran-6-ol

Preparation of 2- (2-hydroxypropan-2-yl) -5-iodo-2,3-dihydrobenzofuran-6-ol} (11)

(11)

(11)

T -butyl 5-hydroxy-2-iodo-4- (3-methylbut-2-enyl) phenyl carbonate (200 mg, 0.49 mmol) obtained in Example 1-2) was diluted with EtOAc (5 mL). ), Then m -chlorobenzoic acid (171 mg, 0.99 mmol) dissolved in EtOAc (10 mL) at 0 ° C was added. After stirring for 4 hours at 0 ° C., aqueous NaHSO ₃ solution (1 g in 10 ml of water) was added slowly and stirred for 20 minutes to terminate the reaction, and the organic layer was washed with saturated aqueous NaHCO ₃ solution. The organic layer was then washed with aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The concentrate was dissolved in MeOH (9.5 mL), and LiOH (73 mg, 1.73 mmol) was added to this solution, followed by stirring at room temperature overnight. Thereafter, 10% HCl was added to the reaction mixture to terminate the reaction, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Flash silica gel column chromatography (40:60 Et ₂ O / hexane) afforded the desired compound (90 mg, 56.7% yield).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.35 (1H, s, aromatic-H), 6.50 (1H, s, aromatic-H), 5.17 (1H, bs, OH), 4.66 (1H, t, J = 9 Hz, CH), 3.10 (2H, d, J = 9 Hz, CH ₂ ), 1.32 (3H, s, CH ₃ ), 1.20 (3H, s, CH ₃ ).

Example 7 2- {6- [3,5-bis- (t-butyl-dimethylsilaneyloxy) -phenyl] -2,3,5,6-tetrahydrobenzo [1, 2-b; 5 , 4-b '] difuran-2-yl} -propa-2-ol {2- {6- [3,5-bis- (tert-butyl-dimethylsilanyloxy) -phenyl] -2,3,5, Preparation of 6-tetrahydrobenzo [1, 2-b; 5,4-b '] difuran-2-yl} -propa-2-ol} (12)

(12)

(12)

2- (2-hydroxypropan-2-yl) -5-iodo-2,3-dihydrobenzofuran-6-ol (180 mg, 0.56 mmol) prepared in Example 6, Pd (Ph ₃ P ) 1,3-bis- () in a solution of ₂ Cl ₂ (39.4 mg, 0.056 mmol), CuI (21.4 mg, 0.113 mmol) and Et ₃ N (0.6 mL, 4.5 mmol) dissolved in dioxane (4 mL). t-butyl-dimethyl-silanyloxy) -5-ethynyl-benzene {1,3-Bis- (tert-butyl-dimethyl-silanyloxy) -5-ethynyl-benzene} (408 mg, 1.13 mmol) added The reaction mixture was then stirred at 85 ^° C. for 20 hours. The reaction mixture was then concentrated and diluted with EtoAc, then the organic layer was washed successively with dilute HCl aqueous solution, NaHCO ₃ aqueous solution and water, dried over anhydrous Na ₂ SO ₄ , and concentrated. Flash silica gel column chromatography (50:50 CH ₂ Cl ₂ / hexanes) afforded the desired compound (97 mg, 31.1% yield).

¹ H NMR (DMSO- d ₆ , 300 MHz) δ 7.36 (1H, s, aromatic-H), 7.30 (1H, s, aromatic-H), 6.99 (1H, s, aromatic-H), 6.89 (2H, d, J = 1.5 Hz.aromatic-H), 6.26 (1H, t, J = 2.1 Hz.aromatic-H), 4.64 (1H, t, J = 8.7 Hz, CH), 3.20 (2H, dd, J = 3.6 Hz & 8.1 Hz, CH ₂ ), 1.14 (6H, s, CH ₃ ), 0.96 (18H, s, (CH ₃ ) ₃ ), 0.22 (12H, s, (CH ₃ ) ₂ ).

Example 8 Preparation of (+/-) Moracin O (1B)

2- {6- [3,5-bis- (t-butyl-dimethylsilanyloxy) -phenyl] -2,3,5,6-tetrahydrobenzo [1,2-b prepared in Example 7 ; 5,4-b '] difuran-2-yl} -propa-2-ol (50 mg, 0.09 mmol) in a solution dissolved in THF / pyridine (4: 1, 3.5 mL) at 0 ^° C. 70% HF / pyridine solution (0.24 mL) was added. After stirring for 2 hours at room temperature, saturated sodium bicarbonate solution) was added to terminate the reaction, and extracted with ethyl acetate. The organic layer was then washed with water, dried over anhydrous MgSO ₄ and concentrated. Purification by prep TLC (60:40 EtOAc / hexane) gave the desired compound as a white solid (22 mg, 74.8% yield).

¹ H NMR (CD ₃ OD , 300 MHz) δ 7.29 (1H, s, aromatic-H), 6.89 (1H, s, aromatic-H), 6.84 (1H, s, aromatic-H), 6.73 (2H, d , J = 2.1 Hz, aromatic-H), 6.22 (1H, t, J = 2.1 Hz, aromatic-H), 4.67 (1H, t, J = 8.7 Hz, CH), 3.24 (2H, m, CH ₂ ) , 1.27 (3H, s, CH ₃ ), 1.23 (3H, s, CH ₃ ).

Claims (30)

a) iodide 2,4-dihydroxybenzaldehyde to prepare a compound of formula III; b) reacting the compound of formula III prepared in step a) with Boc ₂ O (Di- tert- butyl pyrocarbonate) in the presence of a base to prepare a compound of formula IV protected with di-Boc; And c) reducing the compound of formula IV prepared in step b) in the presence of aluminum hydride derivatives of aluinum or hydride derivatives of boron to obtain a benzyl alcohol intermediate, Method of preparing a compound of formula V comprising the step of reacting with a penyl metal compound to produce a compound of formula V. [Formula III]

[Formula IV]

[Formula V]

The method of claim 1, wherein the iodide reaction conditions of step a) are reacted in the presence of iodine monochloride (ICl) and acetic acid. The method of claim 1, wherein the base of step b) is K ₂ CO ₃ , NaOH, KOH, DIPEA (N, N-Diisopropylethylamine), Et ₃ N or DMAP (4-Dimethylamino pyridine). The process of claim 3, wherein the base of step b) is K ₂ CO ₃ . The method of claim 1, wherein the 2-methylpropenyl metal compound of step c) is 2-methylpropenylmagnesium bromide or 2-methylpropenyllithium. The method of claim 1, wherein the aluminum hydride derivatives of aluinum or hydride derivatives of boron of step c) are LiAlH ₄ or NaBH ₄ . Formula V compound of claim 1. [Formula V]

a) [6-endo-trig] -closure reaction of the compound of Formula V of claim 7 in the presence of an epoxidation and an acid to Manufacturing step; b) preparing a compound of formula (VII) by removing the Boc protecting group in the presence of an acid or a base of the compound of formula (VI); c) Sonogashira cross coupling reaction and subsequent in situ cyclization of compound VII of step b) with 1,3-bis- (t-butyl-dimethyl-silanyloxy) -5-ethynyl-benzene To prepare a compound of formula VIII; And d) preparing a Moracin P compound of formula (VIII) prepared in step c) in the presence of HF / pyridine, Tetra-n-butylammonium fluoride (TBAT), acid or base Manufacturing method. [Formula VI]

[Formula VII]

(VIII)

[Formula I]

The method of claim 8, wherein the epoxidation of step a) is peroxycarboxylic acids, peroxyhydrogen, hydrogen peroxide or dioxiranes. 10. The method of claim 9, wherein the peroxycarboxylic acid is m-chloroperbenzoic acid. 9. The method of claim 8, wherein the acid of step a) is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or BF ₃ -Et ₂ O. 12. The method of claim 11, wherein the acid of step a) is p-toluenesulfonic acid. The method of claim 8, wherein the acid of step b) is ZnBr _2, HCl or trifluoroacetic acid (TFA), and the base is NaOH or pyreridine Method for preparing Moracin P Compound. The method of claim 13, wherein the acid of step b) is ZnBr ₂ . The method according to claim 8, wherein the Sonogashira cross coupling of step c) and subsequent in situ cyclization conditions are reacted in the presence of Pd (Ph ₃ P) ₂ Cl ₂ , CuI, and Et ₃ N. Method for preparing Sin P compound. The method of claim 8, wherein the acid of step d) is acetic acid or HCl. The method of claim 8, wherein the base of step d) is K ₂ CO ₃ or NaOH. The compound of formula VI of claim 8. [Formula VI]

The compound of formula VII of claim 8. [Formula VII]

The compound of formula VIII of claim 8. (VIII)

a) reacting the compound of claim 7 under epoxidation to prepare an epoxide intermediate, and adding a base to the [5-exo-tet] -cyclization reaction Preparing a compound of Formula IX; b) Sonogashira cross coupling and subsequent in situ cyclization of the compound of Formula IX of step a) with 1,3-bis- (t-butyl-dimethyl-silanyloxy) -5-ethynyl-benzene Preparing a compound of Formula X; And c) preparing a Moracin O compound of formula (II) in the presence of HF / pyridine, Tetra-n-butylammonium fluoride (TBAT), acid or base in step b) Manufacturing method. [Formula IX]

[Formula X]

[Formula II]

The method of claim 21, wherein the epoxy condition of step a) is peroxycarboxylic acids, hydrogen peroxide, or dioxiranes. 23. The method of claim 22, wherein the peroxycarboxylic acid is m-chloroperbenzoic acid. The method of claim 21, wherein the base of step a) is LiOH, KOH, NaHCO ₃ , or Na ₂ CO ₃ . 25. The method of claim 24, wherein the base of step a) is LiOH. The method of claim 21, wherein the Sonogashira cross coupling of step b) and subsequent in situ cyclization conditions are reacted in the presence of Pd (Ph ₃ P) ₂ Cl ₂ , CuI, and Et ₃ N Process for preparing O compound. The method of claim 21, wherein the acid of step c) is acetic acid or HCl. The method of claim 21, wherein the base of step c) is K ₂ CO ₃ or NaOH. The compound of formula IX of claim 21. [Formula IX]

The compound of formula X of claim 21. [Formula X]