JP3128580B2 - Method for producing 2-benzyloxyestrogen compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a 2-benzyloxyestrogen compound.

[0002]

2. Description of the Related Art Catechol estrogens are known to be one of metabolites of estrogen hormones, and various studies have been made on the synthesis of catechol estrogens and derivatives thereof due to their interest in biological action. . Among them, regarding the synthesis of glycosides,
There are methods disclosed in the following documents. a) T. Nambara et al., "Chem. Pharm. Bull.", Vol. 18, pa.
ge 474 (1970), b) T. Nambara et al., "Chem. Pharm. Bull.", Vol. 18, pa.
ge 1191 (1970) and c) T. Ohkubo et al. "Chem. Pharm. Bull.", Vol. 36, pag.
e 419 (1988). In particular, it is 2-position glycoside of catechol estrogen 2-
In the synthesis of hydroxyestrogen 3-glycoside, the 2-benzyloxyestrogen compound is an important intermediate.According to the above-mentioned documents a) and b), starting from 3-deoxyestradiol acetate, 11 steps are required.
2-benzyloxyestradiol at an overall yield of 6.0% 17
-Synthesizes acetate.

[0003]

SUMMARY OF THE INVENTION The above-mentioned conventional method is applicable to mass production on a commercial scale because the raw material is expensive, requires many steps in production, and has a low yield. There was a problem in the difficult point. Accordingly, an object of the present invention is to provide an advantageous method for producing a 2-benzyloxyestrogenic compound suitable for production on a commercial scale.

[0004]

According to the present invention, the above object is achieved by a general formula

Embedded image (In the formula, R ₁ represents an acetoxyl group, R ₂ represents a hydrogen atom or an ethynyl group, or R ₂ together with R ₁ represents an oxygen atom, and R ₃ represents a hydrogen atom or an acetoxyl group. 3) of 2-acetyl estrogen
By protecting the hydroxyl group at the 2-position with an acetal-type protecting group, the general formula

Embedded image Wherein R ₁ , R ₂ and R ₃ have the above-mentioned meanings, and R ₄ represents an acetal-based protecting group. The general formula is obtained by oxidizing the buyer

Embedded image (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the above-mentioned meanings), a 2-acetoxyestrogen 3-ether form, and then the acetyl group at the 2-position is eliminated to obtain a compound of the general formula

Embedded image (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the same meaning as above), and the 2-position hydroxyl group is benzylated again to give a general formula

Embedded image (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the above-mentioned meanings), the 2-benzyloxyestrogen 3-ether form shown in FIG. General formula

Embedded image (Wherein R ₁ , R ₂ and R ₃ have the same meaning as described above), and the above-mentioned object is achieved while solving the problem.

[0005] In the method of the present invention, the 2-acetyl estrogen compound used as a starting material converts estrogen into 3-acetate, and the 3-acetate compound is converted to a fleece (Frie
s) It can be easily manufactured by rearrangement. In the present invention, the protecting group for the hydroxyl group at position 3 must be capable of withstanding Bayer-Villiger oxidation, acetyl group elimination and benzylation reaction,
For that purpose, acetal-based protecting groups are used. Specific examples of the acetal-based protecting group include a methoxymethyl group,
Examples thereof include a 2-methoxyethoxymethyl group and a tetrahydropyranyl group. If the method of the present invention is adopted,
The overall yield of estrogen to 2-benzyloxyestrogen can be increased to about 70%.

Next, starting from estradiol, 2-
This will be described in detail in connection with the production of benzyloxyestradiol 17-acetate. First, by reacting estradiol and acetic anhydride in pyridine at room temperature overnight, estradiol diacetate is produced quantitatively. This estradiol diacetate
Reaction with aluminum chloride and acetyl chloride in nitrobenzene at 80 ° C. for 1 hour gives 2-acetylestradiol 17-acetate in 85% yield. The 2-acetyl estradiol 17-acetate is then reacted with chloromethyl methyl ether in tetrahydrofuran in the presence of sodium hydride,
2-Acetylestradiol 17-acetate 3-methoxymethyl ether is produced quantitatively and then subjected to Bayer-Villiger oxidation with m-chloroperbenzoic acid in chloroform in the presence of disodium hydrogen phosphate to give 2-acetoxyestradiol 17-acetate. Acetate 3-methoxymethyl
Ether is obtained in 88% yield.

The conversion of the protecting group from here on is basically as described in the claims. However, in the case of estradiol, the acetoxyl group at the 17-position is kept for convenience. , Several synthetic routes can be adopted. That is, the first synthetic route is to treat 2-acetoxyestradiol 17-acetate 3-methoxymethyl ether in a mixed solvent of potassium hydrogen carbonate and acetone, water and methanol,
The acetyl group is eliminated to give 2-hydroxyestradiol 17-acetate 3-methoxymethyl ether.
Next, benzylation of the hydroxyl group at position 2 with benzyl chloride in the presence of potassium carbonate in ethanol yields a mixture of the product retaining the acetyl group at position 17 and the product desorbed. Acetylation at the 17-position with pyridine gives 2-benzyloxyestradiol 17-acetate 3-methoxymethyl ether. In this benzylation reaction, if phenyldiazomethane is used as a benzylating agent, it is possible to benzylate the 2-position while retaining the acetyl group at the 17-position. Next, 2-benzyloxyestradiol 1
If the methoxymethyl group of 7-acetate 3-methoxymethyl ether is eliminated in acetic acid containing hydrochloric acid, the desired product, 2-benzyloxyestradiol 17-acetate, is obtained. A second synthetic route involves treating 2-acetoxyestradiol 17-acetate 3-methoxymethyl ether with sodium hydroxide in methanol,
After 2-hydroxyestradiol 3-methoxymethyl ether, the 2-position hydroxyl group is benzylated with benzyl chloride in ethanol in the presence of potassium carbonate in the same manner as above to give 2-benzyloxyestradiol 3-methoxymethyl ether. And Next, the hydroxyl group at the 17-position is acetylated with acetic anhydride-pyridine, and the methoxymethyl group is eliminated in acetic acid containing hydrochloric acid to obtain the desired product, 2-benzyloxyestradiol 17-acetate. Further, the third synthesis route is to treat 2-benzyloxyestradiol 3-methoxymethyl ether, which is the above intermediate product, in methanol containing hydrochloric acid to remove the methoxymethyl group to give 2-benzyloxyestradiol. Then, the hydroxyl groups at the 3rd and 17th positions are replaced with acetic anhydride-
After acetylation with pyridine, the mixture is treated with potassium hydrogen carbonate in a mixed solvent of acetone, water and methanol to selectively remove the acetyl group at the 3-position to give 2-benzyloxyestradiol 1
7-Acetate.

In the above-mentioned production process, the conversion of the protective group from 2-acetoxyestradiol 17-acetate 3-methoxymethyl ether to 2-benzyloxyestradiol 17-acetate, which is the target product, is almost quantitative in each step. The reaction proceeds in yield. The above-mentioned production process is represented by the following reaction formula.

[0009]

Embedded image

Embedded image

[0010]

Next, the present invention will be described in more detail and specifically with reference to Reference Examples and Examples. Reference Example 1 (Production of estradiol diacetate) To 30 g (110 mmol) of estradiol and 300 ml of pyridine
(3.71 mol) and 105 ml (1.08 mol) of acetic anhydride were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1500 g of ice, and the precipitated solid was collected by filtration and sufficiently washed with water. The obtained white solid was dried to obtain 39.3 g (yield: 100%) of a desired estradiol diacetate. ¹ H-NMR spectrum (DMSO-d ₆ ) δ ppm: 0.78 (3H, s, 18-CH ₃ ), 1.1-2.9 (15H, m, CH and CH ₂ ), 2.01 (3H, s, C ₁₇ -OCOCH ₃ ), 2.23 (3H, s, C ₃ -OCOCH ₃ ), 4.62 (1H, t like, C ₁₇ -H), 6.83 (2H, m, C ₂ -H and C ₄ -H), 7.28 (1H, d, J = 10Hz, C ₁ -H).

Reference Example 2 (2-acetylestradiol
Production of 17-acetate) 25.0 g of estradiol diacetate obtained in Reference Example 1
(70.1 mmol) was dissolved by adding 250 ml of nitrobenzene. 18.6 g (139 mmol) of aluminum chloride was added to this solution.
And 2.0 ml (28 mmol) of acetyl chloride at 80 ° C.
Stir for 1 hour. After the reaction mixture was ice-cooled, the cold solution was poured into 1000 g of ice, then 100 ml of concentrated hydrochloric acid was added, and the mixture was extracted four times with chloroform. Merge organic layers, 1
Washed with N-hydrochloric acid. Next, the residue was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, and concentrated by a vacuum evaporator to obtain 25.3 g of a crude product. To this was added 150 ml of methanol to obtain 17.7 g (yield: 70.6%) of desired 2-acetylestradiol 17-acetate as a methanol-insoluble portion. The methanol wash was concentrated and subjected to silica gel column chromatography (eluent, chloroform: hexane = 2: 1) to give 3.48 g of the desired compound. Total yield was 85%. ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.84 (3H, s, 18-CH ₃ ), 1.2-3.0 (15H, m, CH and CH ₂ ), 2.07 (3H, s, C ₁₇ -OCOCH ₃ ) , 2.59 (3H, s, C ₂ -COCH ₃ ), 4.70 (1H, t like, C ₁₇ -H), 6.67 (1H, s, C ₄ -H), 7.59 (1H, s, C ₁ -H) , 12.03 (1H, s, C ₃ -OH).

Example 1 a) Preparation of 2-acetylestradiol 17-acetate 3-methoxymethyl ether Sodium hydride (oily, content 60%) 1.01 g (net weight 606 mg, 25.3 mmol) was washed three times with hexane. Later, T
HF 40 ml, chloromethyl methyl ether 3.83 ml (50.4
mmol) and 6.00 g (16.8 mmol) of 2-acetylestradiol 17-acetate obtained in Reference Example 2 in THF
70 ml of the solution was added and stirred at 50 ° C. for 20 minutes. After pouring the reaction mixture into 100 g of ice, 600 ml of water was added. The precipitated solid is collected by filtration, washed sufficiently with water, and dried to obtain the desired 2-acetylestradiol 17-.
6.76 g of acetate 3-methoxymethyl ether (Yield:
100%). ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.82 (3H, s, 18-CH ₃ ), 1.2-3.0 (15H, m, estrogen CH and CH ₂ ), 2.05 (3H, s, C ₁₇ -OCOCH ₃ ), 2.62 (3H, s, C ₂ -COCH ₃ ), 3.50 (3H, s, O-CH ₃ ), 4.68 (1H, t like, 17α-H), 5.24 (2H, s, O-CH _2- O), 6.88 (1H, s, Ar C ₄ -H), 7.66 (1H, s, Ar C ₁ -H). Silica gel TLC: Rf = 0.32 (Hexane: Ethyl acetate = 4: 1).

B) Preparation of 2-acetoxyestradiol 17-acetate 3-methoxymethyl ether 2.50 g (6.24 mmo) of 2-acetylestradiol 17-acetate 3-methoxymethyl ether obtained in a) above.
l), m-chloroperbenzoic acid 2.15 g (12.5 mmol), disodium hydrogen phosphate 1.77 g (12.5 mmol) and chloroform 5
0 ml was added and the mixture was stirred at room temperature for 16 hours. After filtering off insolubles in the reaction mixture, the chloroform layer was poured into ice-cooled ether, and washed successively with a 5% aqueous sodium carbonate solution, water, and then saturated brine. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using an evaporator to obtain 2.90 g of a crude product. Crude product 2.
1.80 g of 90 g was purified by silica gel column chromatography (elution solvent, hexane: ethyl acetate = 4: 1) to obtain 1.41 g of desired 2-acetoxyestradiol 17-acetate 3-methoxymethyl ether (yield: 8
7.6%). ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.81 (3H, s, 18-CH ₃ ), 1.2-3.0 (15H, m, estrogen CH and CH ₂ ), 2.05 (3H, s, C ₁₇ -OCOCH ₃ ), 2.30 (3H, s, C ₂ -OCOCH ₃ ), 3.46 (3H, s, O-CH ₃ ), 4.69 (1H, t like, 17α-H), 5.12 (2H, s, O-CH _2- O), 6.90 (1H, s, Ar C ₄ -H), 6.93 (1H, s, Ar C ₁ -H). Silica gel TLC: Rf = 0.36 (Hexane: Ethyl acetate = 4: 1).

C) Preparation of 2-hydroxyestradiol 17-acetate 3-methoxymethyl ether 2-acetoxyestradiol 17- obtained in b) above.
Acetate 3-methoxymethyl ether 1.35g (3.24mm
ol) was dissolved in 32.3 ml of acetone, and 647 mg (6.46 mmol) of potassium hydrogen carbonate was added to 16.1 ml of water and 8 ml of methanol.
Add a solution dissolved in 0.7 ml of the mixed solvent, and add
The mixture was then stirred at 50 ° C. for 3 hours. 20 ml of water was added to the reaction mixture, and acetone and methanol were removed by an evaporator. The precipitated solid was filtered, washed with water and dried to give the desired 2-hydroxyestradiol 17-acetate 3-methoxymethyl ether
1.20 g (yield: 99.2%) was obtained. ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.82 (3H, s, 18-CH ₃ ), 1.2-2.9 (15H, m, estrogen CH and CH ₂ ), 2.05 (3H, s, C ₁₇ -OCOCH ₃ ), 3.51 (3H, s, O-CH ₃ ), 4.68 (1H, t like, 17α-H), 5.16 (2H, s, O-CH ₂ -O), 5.74 (1H, s, C ₂ -OH) ), 6.79 (1H, s, Ar C ₄ -H), 6.89 (1H, s, Ar C ₁ -H). Silica gel TLC: Rf = 0.49 (Hexane: Ethyl acetate = 2: 1).

D) 2-benzyloxyestradiol 17
Preparation of 3-acetate 3-methoxymethyl ether 2-hydroxyestradiol obtained in c) above 17-
Acetate 3-methoxymethyl ether 1.13g (3.02mm
ol), ethanol 25 ml, potassium carbonate 626 mg (4.54 mm
ol) and 0.452 ml (3.93 mmol) of benzyl chloride, refluxed for 4 hours, and further 0.174 ml of benzyl chloride.
(1.51 mmol) was added and refluxed for 2 hours. After cooling to room temperature, insolubles in the reaction mixture were filtered off, and the filtrate was concentrated with an evaporator. Add water to the concentrate to solidify,
This is filtered, washed with water and dried to give 2-
1.44 g of a mixture of benzyloxyestradiol 3-methoxymethyl ether and 2-benzyloxyestradiol 17-acetate 3-methoxymethylether was obtained. To 1.41 g (equivalent to 2.96 mmol) of this mixture, 4.0 ml (49.5 mmol) of pyridine and 3.0 ml (31.7 m
mol) was added and the mixture was stirred at room temperature for 23 hours. The reaction mixture was poured into 150 g of ice, added with 40 ml of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed sequentially with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, water, and then with a saturated saline solution. Next, the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure using an evaporator to obtain a crude product.
1.51 g was obtained. The crude product was subjected to silica gel column chromatography (elution solvent, hexane: ethyl acetate = 6:
Purify in 1) to give the desired 2-benzyloxyestradiol 17-acetate 3-methoxymethyl ether 1.35g
(Yield: 98.5%). ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.81 (3H, s, 18-CH ₃ ), 1.1-2.9 (15H, m, estrogen CH and CH ₂ ), 2.05 (3H, s, C ₁₇ -OCOCH ₃ ), 3.51 (3H, s, O-CH ₃ ), 4.68 (1H, t like, 17α-H), 5.10 (2H, s, C ₆ H ₅ -C H ₂ ), 5.18 (2H, s, O- CH ₂ -O), 6.85 (2H, s, Ar C ₄ -H and C ₁ -H), 7.2-7.5 (5H, m, C ₆ H ₅ ). Silica gel TLC: Rf = 0.50 (Hexane: Ethyl acetate = 4: 1).

E) 2-benzyloxyestradiol 17
Preparation of 2-acetate 2-benzyloxyestradiol obtained in d) above
3.70 g of 17-acetate 3-methoxymethyl ether (7.9
7 mmol), add 20 ml of acetic acid and 2.0 ml of 2N hydrochloric acid,
The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 500 ml of water, and the precipitated solid was filtered, washed with water and dried to obtain 3.41 g of a crude product. The crude product was purified by silica gel column chromatography (elution solvent, hexane: ethyl acetate = 6: 1) to obtain 3.02 g (yield: 90.1%) of desired 2-benzyloxyestradiol 17-acetate. ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.83 (3H, s, 18-CH ₃ ), 1.1-2.9 (15H, m, estrogen CH and CH ₂ ), 2.05 (3H, s, C ₁₇ -OCOCH ₃ ), 4.69 (1H, t like, 17α-H), 5.06 (2H, s, C ₆ H ₅ -C H ₂ ), 6.65 (1H, s, Ar C ₄ -H), 6.85 (1H, s, Ar C ₁ -H), 7.39 (5H, s, C ₆ H ₅ ). Silica gel TLC: Rf = 0.37 (Hexane: Ethyl acetate = 5: 1).

Example 2 a) 2-Hydroxyestradiol 3-methoxymethyl
Preparation of ether 2-acetoxyestradiol obtained in Example 1-b) 17
-Acetate 3-methoxymethyl ether 5.30g (12.7m
mol), 106 ml of methanol and 1N sodium hydroxide
53 ml was added and the mixture was stirred at room temperature for 2.5 hours. After removing the methanol in the reaction mixture with an evaporator,
2.37 ml was added. Then, the mixture was extracted with ethyl acetate, and the organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water, and then with a saturated saline solution. Next, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure by an evaporator to obtain 4.23 g (yield: 100%) of desired 2-hydroxyestradiol 3-methoxymethyl ether. ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.77 (3H, s, 18-CH ₃ ), 1.1-2.9 (15H, m, estrogen CH and CH ₂ ), 3.51 (3H, s, O-CH ₃ ) , 3.73 (1H, t like, 17α-H), 5.16 (2H, s, O-CH ₂ -O), 5.75 (1H, br.s, C ₂ -OH), 6.79 (1H, s, Ar C ₄ -H), 6.89 (1H, s, Ar C ₁ -H). Silica gel TLC: Rf = 0.20 (Hexane: Ethyl acetate = 2: 1).

B) 2-benzyloxyestradiol 3-
Preparation of methoxymethyl ether To 4.20 g (12.6 mmol) of 2-hydroxyestradiol 3-methoxymethyl ether obtained in a) above, 100 ml of ethanol, 2.62 g (19.0 mmol) of potassium carbonate and 1.89 ml (16.4 mmol) of benzyl chloride were added. After adding and refluxing for 4 hours, further 0.73 ml (6.33 mmol) of benzyl chloride was added.
Was added and refluxed for 2 hours. After cooling to room temperature, insolubles in the reaction mixture were separated by filtration, and the filtrate was concentrated with an evaporator. The concentrate was solidified by adding water, which was filtered, washed with water and dried to obtain 5.64 g of a crude product.
I got 1.50 g of 5.64 g of this crude product was subjected to silica gel column chromatography (elution solvent: hexane:
Purify with ethyl acetate = 3: 1) to give the desired 2-benzyloxyestradiol 3-methoxymethyl ether
1.40 g (yield: 98.6%) was obtained. ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.76 (3H, s, 18-CH ₃ ), 1.0-2.9 (15H, m, estrogen CH and CH ₂ ), 3.51 (3H, s, O-CH ₃ ) , 3.72 (1H, t like, 17α-H), 5.10 (2H, s, C ₆ H ₅ -C H ₂ ), 5.19 (2H, s, O-CH ₂ -O), 6.85 (1H, s, Ar C ₄ -H), 6.88 (1H, s, Ar C ₁ -H), 7.2-7.5 (5H, m, C ₆ H ₅ ). Silica gel TLC: Rf = 0.38 (Hexane: Ethyl acetate = 2: 1).

C) 2-benzyloxyestradiol 17
Preparation of 2-acetate 3-methoxymethyl ether 2-benzyloxyestradiol obtained in b) above
4.00g of crude product of 3-methoxymethyl ether
12 ml (148 mmol) of pyridine and 9.0 ml (95.2 mmol) of acetic anhydride were added to (equivalent to 8.94 mmol), and the mixture was stirred at room temperature for 23 hours. The reaction mixture was poured into 200 g of ice, and 2N-hydrochloric acid 10
0 ml was added and extracted with ethyl acetate. Organic layer, 1N
-Washed sequentially with hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water and then a saturated saline solution. Next, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure by an evaporator to obtain 4.36 g of a crude product. The crude product is subjected to silica gel column chromatography (elution solvent, hexane
: Ethyl acetate = 6: 1) to give 3.93 g of desired 2-benzyloxyestradiol 17-acetate 3-methoxymethyl ether (yield: 94.7% from 2-hydroxyestradiol 3-methoxymethyl ether) . The analysis data of the substance obtained here is the same as in Example 1-d)
Was the same as that obtained in Step 1. The compound obtained in this section can be derivatized to 2-benzyloxyestradiol 17-acetate as described in Example 1-e).

Example 3 a) Production of 2-benzyloxyestradiol 1.35 g (3.19 mmo) of the purified 2-benzyloxyestradiol 3-methoxymethyl ether obtained in Example 2-b)
To l), 27 ml of methanol and 2.7 ml of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 2 hours. Next, after removing about half of the methanol with an evaporator, the mixture was poured into 300 ml of water, the precipitated solid was filtered, washed with water, and dried to obtain 1.20 g of the desired 2-benzyloxyestradiol (yield:
99.2%). ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.78 (3H, s, 18-CH ₃ ), 1.0-2.9 (15H, m, estrogen CH and CH ₂ ), 3.73 (1H, t like, 17α-H) , 5.07 (2H, s, C ₆ H ₅ -C H ₂ ), 6.66 (1H, s, Ar C ₄ -H), 6.87 (1H, s, Ar C ₁ -H), 7.40 (5H, s, C ₆ H ₅ ) .Silica gel TLC: Rf = 0.37 (Hexane: Ethyl acetate = 2: 1).

B) Preparation of 2-benzyloxyestradiol diacetate 2-benzyloxyestradiol obtained in the above a)
To 1.18 g (3.12 mmol), 3.0 ml (37.1 mmol) of pyridine and 2.5 ml (26.4 mmol) of acetic anhydride were added, and the mixture was stirred at room temperature for 21 hours. The reaction mixture was poured into ice, and the precipitated solid was filtered, washed with water and dried to obtain 1.40 g of desired 2-benzyloxyestradiol diacetate.
(Yield: 97.2%). ¹ H-NMR spectrum (CDCl ₃ ) δ ppm: 0.82 (3H, s, 18-CH ₃ ), 1.1-2.9 (15H, m, estrogen CH and CH ₂ ), 2.06 (3H, s, C ₁₇ -OCOCH ₃ ), 2.26 (3H, s, C ₃ -OCOCH ₃ ), 4.68 (1H, t like, 17α-H), 5.04 (2H, s, C ₆ H ₅ -C H ₂ ), 6.75 (1H, s, Ar C ₄ -H), 6.93 (1H, s, Ar C ₁ -H), 7.36 (5H, s, C ₆ H ₅ ). Silica gel TLC: Rf = 0.42 (Hexane: Ethyl acetate = 4: 1).

C) 2-benzyloxyestradiol 17
Preparation of 2-acetate 2-benzyloxyestradiol obtained in b) above
Dissolve 1.35 g (2.92 mmol) of diacetate in 29.2 ml of acetone, add a solution of 585 mg of potassium hydrogen carbonate in a mixed solvent of 14.6 ml of water and 73.0 ml of methanol, and add at room temperature for 21 hours and then at 50 ° C. Stirred for 6 hours.
Water was added to the reaction mixture, and acetone and methanol were removed with an evaporator. The precipitated solid was filtered, washed with water and dried to obtain 1.23 g of a crude product. This was purified by silica gel column chromatography (elution solvent, hexane: ethyl acetate = 6: 1) to obtain 1.18 g (yield: 95.9%) of desired 2-benzyloxyestradiol 17-acetate. The analytical data of the substance obtained here were the same as those obtained in Example 1-e).

[0023]

According to the method of the present invention, 2-benzyloxyestrogens, which are important intermediates for synthesizing 3-position glycosides of catechol estrogens, require a smaller number of steps when compared with conventional synthesis methods. It can be produced in good numbers and in good yields. Therefore, the method of the present invention is suitable as a low-cost mass production method of a 2-benzyloxyestrogen compound.

──────────────────────────────────────────────────続 き Continued on the front page (72) Kunio Yagi, Inventor 2-21 Nishisato-cho, Meito-ku, Nagoya-shi, Aichi (58) Field surveyed (Int. Cl. ⁷ , DB name) C07J 1/00 C07J 7/00 CA (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (In the formula, R ₁ represents an acetoxyl group, R ₂ represents a hydrogen atom or an ethynyl group, or R ₂ together with R ₁ represents an oxygen atom, and R ₃ represents a hydrogen atom or an acetoxyl group. 3) of 2-acetyl estrogen
By protecting the hydroxyl group at the 1-position with an acetal-based protecting group, the general formula: Wherein R ₁ , R ₂ and R ₃ have the above-mentioned meanings, and R ₄ represents an acetal-based protecting group. Is converted to a general formula by oxidation of (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the above-mentioned meanings), a 2-acetoxyestrogen 3-ether form, and then the acetyl group at the 2-position is eliminated to obtain a compound of the general formula Embedded image (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the same meaning as described above), and the 2-position hydroxyl group is benzylated again to give the general formula 5] (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the above-mentioned meanings), the 2-benzyloxyestrogen 3-ether form shown in FIG. A general formula characterized by the following: (Wherein R ₁ , R ₂ and R ₃ have the same meanings as described above).