JP3468211B2 - (+)-Estrone derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intermediate used in a process for producing a (+)-estrone derivative useful as an oral contraceptive, starting from a dicyclopentadiene derivative.

[0002]

2. Description of the Related Art (+)-Estrone is a compound useful as an oral contraceptive, and its production method is obtained from natural sources (US Patent Nos. 1967350 (1934) and 13059).
No. 92 (1962) has been known for the longest time, but its efficiency and yield are so low that it cannot be compared with the synthetic method.

In recent years, several synthetic methods of (+)-estrone, which has a natural configuration, have been developed. Posner et al. (J. Am. Chem. Soc., 108 , 1239 (1986)), after asymmetric Michael addition reaction of a compound having an AB ring skeleton with a compound having an asymmetrically induced D ring skeleton, Furthermore, by intramolecular Diels-Alder reaction, a C ring skeleton is formed, and an estrone skeleton is constructed with a diastereoselectivity of 91 to 94%. However, the total yield was as low as 6.3%,
The reaction process has also gone through 9 steps, which is not efficient.

Also, Taber et al. (J. Org. Chem., 52, 28
(1987) constructed a β-ketoester having a D ring skeleton using a camphor derivative as an asymmetric source, combined it with a benzocyclobutene derivative, and finally constructed a BC ring skeleton by an intramolecular cyclization reaction. Then, (+)-estron having an optical purity of 91% ee is synthesized. However,
This method also has multiple reaction steps. It also takes 5 steps to construct the β-ketoester and 3 steps to synthesize the benzocyclobutene derivative. Furthermore, the desired skeleton is obtained in three steps including the bonding of both. The cyclization yield is low (41%) and the total yield from the β-ketoester precursor is
It is 9.8%, and although the stereoselectivity is relatively good, it is still not an efficient production method.

That is, prior to the present invention, the supply method of (+)-estron, which is in high demand, was in a situation where it cannot be said to be sufficient.

[0006]

From the above points, the inventors of the present invention have diligently studied to achieve the purpose of efficiently obtaining (+)-oestrone derivative and also having good optical purity, and as a result, A method has been found whereby a (+)-estrone derivative can be efficiently obtained using dicyclopentadiene as a starting material. Then, they have found a new intermediate used in the production method.

[0007]

The present invention provides the following formula:

[0008]

[Chemical 5]

(-)-Tricyclo [5.2.
1.0 ^2.6 ] Using deca-4,8-dien-3-one (1) as a starting material, the following formula

[0010]

[Chemical 6]

(In the formula, R represents an alkyl group having 1 to 20 carbon atoms) 4-vinyl-7-alkoxy-1,2
-Asymmetric Diels-Alder reaction with dihydronaphthalene (2)

[0012]

[Chemical 7]

## STR1 ## (wherein R is the same as above), the compound of formula (3)

[0014]

[Chemical 8]

(In the formula, R is the same as above) A (+)-estrone derivative (4) represented by the formula (4) is an intermediate used in a method for producing a (+)-estrone derivative. . In the step of obtaining the (+)-oestrone derivative (4) from the compound (3), the following formula

[0016]

[Chemical 9]

[0017]

[Chemical 10]

[0018]

[Chemical 11]

(In the formula, R represents an alkyl group having 1 to 20 carbon atoms). The reaction route of this production method is shown by the following formula.

[0020]

[Chemical 12]

(-)-Trisic which is the starting material of the present invention
B [5.2.1.0^2.6 ] Deca-4,8-diene-3-
On (1) is dicyclopentadiene to selenium oxai
The resulting racemic-tricyclo [5.
2.1.0^2.6 ] Deca-3-hydroxy-4,6-die
Transesterification with an acylating agent using lipase
Whether or not (Japanese Patent Application No. 1-237546) or acetylated
After hydrolysis (J. Chem. Soc. Chem. Commun.,198
9, 271) It can be obtained by optical resolution.

The obtained (-)-tricyclo [5.2.
1.02.6] Deca-4,8-dien-3-one (1)
And Schmidt's method (Liebigs Ann.Chem ,. 536 , 19
6 (1938); ibid . 537 , 246 (1939)) 4-vinyl-
Compound (3) can be obtained by subjecting 7-alkoxy-1,2-dihydronaphthalene (2) to an asymmetric Diels-Alder reaction in the presence of a Lewis acid. As the Lewis acid used here, diethylaluminum chloride is most preferable, but titanium tetrachloride, aluminum chloride or the like can be used as long as it can catalyze the reaction and control the configuration. The reaction temperature at this time is -78 ° C.
It is -10 ° C, preferably -30 ° C.

As the reaction solvent, hydrocarbon and halogen type solvents can be used, and n-hexane and dichloromethane are particularly preferable. The reaction time varies depending on the treatment amount and the like, but is 12 to 96 hours, preferably 24 to 36 hours. The resulting compound (3) can be methylated with methyl iodide in the presence of a base to give compound (5). The base is particularly preferably potassium t-butoxide, but any kind of base may be used as long as it promotes methylation. Further, as the methylating agent, methyl bromide or methyl chloride can be used.

O obtained as a by-product at this stage
The compound (8) which is a methyl form is separated by column chromatography or the like, and can be easily returned to the compound (3) by treating with hydrochloric acid at 0 ° C. That is, it can be used again as a synthetic intermediate of (+)-oestrone. Compound (6) was obtained by treating Compound (5) with trifluoroacetic acid and triethylsilane.
To get

By further heating, a retro Diels-Alder reaction is carried out to obtain the compound (7). Finally,
The unsaturated bond of the compound (7) can be reduced by catalytic hydrogenation to obtain the desired (+)-oestrone derivative (4). The reduction catalyst may be a catalytic catalyst such as Raney nickel, but is preferably palladium carbon.

[0026]

EFFECTS OF THE INVENTION By using the above-mentioned intermediate, the starting material dicyclopentadiene derivative (1)
Therefore, the (+)-estrone derivative can be obtained in good yield with a small number of steps. Taking the recovery of the compound (8) into consideration, (+)-oestrone can be obtained in a better yield.

[0027]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples. Example 1 (-) - tricyclo [5.2.1.0 ^2.6] deca -4,
1.72 g (11.8 mmol) of 8-dien-3-one (1) and 2.63 g (14.1 mmol) of 4-vinyl-7-methoxy-1,2-dihydronaphthalene (2) were dissolved in 25 ml of dichloromethane, and -30 Cooled to ° C. Add 15 ml (14.1 mmo) of diethylaluminum chloride (0.94 M, n-hexane solution) to this solution.
l) was added dropwise. After stirring at -30 ° C for 32 hours, 5% hydrochloric acid was added, and the mixture was further extracted with dichloromethane. Next, the dichloromethane layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated saline solution in this order, and dried over magnesium sulfate. After distilling off dichloromethane, the residue was subjected to silica gel column chromatography to obtain 3.1 g (yield 81.5%) of compound (3).

The physical properties of this compound are as follows. [Α] _D ³¹ −168.3 ° (c1.01, CHCl ₃ ) IR (film) νmax 1730, 1605 cm ^{−1 1} H-NMR (500 MHz, CDCl ₃ ) J, 1.35 (1H, d, J = 8.5H
z) 1.51 (1H, d, J = 7.9Hz), 1.84 (1H, ddd, J = 17.1, 12.2,
4.9Hz), 1.95-2.02 (1H, m), 2.16-2.27 (2H, m), 2.36-2.51
(3H, m), 2.58-2.62 (1H, m), 2.72-2.91 (4H, m), 3.09-3.12
(1H, m), 3.80 (3H, s), 6.15-6.22 (3H, m), 6.66 (1H, d, J
= 8.6Hz), 7.47 (1H, d, J = 8.6Hz) MS m / z 332 (M +), 266 (100%) Analysis Calculated _{C 23 H 24 O 2: C} 83.10, H 7.28 Found: C 83.16, H 7.34.

Example 2 Compound (3) 560 mg (1.96 mmol) of dimethoxyethane 8 ml
At room temperature, potassium t-butoxide 37.8 mg (3.37 mm)
ol) was added and stirred for 12 minutes. Methyl iodide under ice cooling 1.
1 ml (17 mmol) was added dropwise, the mixture was further stirred for 12 minutes, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the ether / n-hexane (1/1) fraction, 334 mg of the compound (5) (57% yield) and 123 mg of the compound (8) (21% yield) were obtained. Further, the compound (5) was recrystallized from methanol to give colorless needle crystals.

The physical properties of this compound are as follows. Mp 161~162 ℃ [α] _D ³¹ +130 DEG _{(c0.665, CHCl 3) IR (} film) νmax 1735, 1606 cm -1 1 H-NMR (90MHz, CDCl 3) J, 1.09 (3H, s), 1.48-2.65
(9H, m), 2.80-3.21 (5H, m), 3.78 (3H, s), 5.81-6.06 (2H,
m) 6.10-6.28 (1H, m), 6.57-6.79 (2H, m), 7.39 (1H, d, J = 8.
3 Hz) MS m / z 246 (M ⁺ 100%) Elemental analysis calculated value C ₂₄ H ₂₆ O ₂ : C 83.20, H 7.56 Actual value: C 83.21, H 7.78.

Example 3 304 mg (0.878 mmol) of compound (5) in 6 ml of dichloromethane
0.68 ml (8.83 mmol) of trifluoroacetic acid and 0.70 ml (4.38 mmol) of triethylsilane were added dropwise to the solution, and the mixture was stirred at room temperature for 20 hours. Add saturated aqueous sodium hydrogen carbonate solution under ice cooling,
It was extracted with dichloromethane, washed with saturated saline, and then dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and 2.65 mg (yield 87%) of compound (6) was obtained from the fraction of ether / n-hexane (1/15). . Recrystallization from methanol gave colorless needle crystals.

The physical properties of this compound are as follows. Mp 173~174 ℃ [α] _D ³¹ +126 DEG (c0.96, CHCl ₃₎ IR ^{(Nujol) νmax 1728cm -1 1 H-NMR} (500MHz, CDCl 3) J, 1.07 (3H, s) 1.35-1.48 ( 3H, m), 1.52-1.74 (5H, m), 2.07-2.18 (2H, m),
2.25-2.32 (1H, m), 2.77 (1H, tb, J = 10.4, 4.3Hz), 2.87
-2.98 (3H, m) 3.08 (1H, br, s), 3.24 (1H, dd, J = 10.3, 4.2Hz), 3.77 (3
H, s), 6.02 (1H, dd, J = 5.5, 3.0Hz), 6.22 (1H, dd, J =
5.5, 3.0Hz), 6.64 (1H, d, J = 3.0Hz), 6.70 (1H, dd, J = 1
1.0, 2.5Hz), 7.16 (1H, d, J = 9.1Hz) MS m / z 348 (M ⁺ ), 282 (100%) Elemental analysis Calculated value C ₂₄ H ₂₈ O ₂ : C 82.72, H 8.10 Measured value : C 82.55, H 8.10.

Example 4 13 mg (0.037 mmol) of diphenyl ether 1 of compound (6)
The ml solution was heated to reflux for 1.5 hours. Subjected to silica gel column chromatography, 8 mg of the enone form (7) (yield 76
%) Was obtained. To an ethanol solution of 39 mg (0.14 mmol) of enone form, 4 mg of 10% palladium carbon was added, and 50% under hydrogen flow.
Stir for minutes. After filtration through Celite, the filtrate was concentrated under reduced pressure,
The residue was subjected to silica gel column chromatography,
33 mg (yield 84%) of estrone methyl ether (4) was obtained from a stream of ether / n-hexane (1/6).

The physical properties of this compound are as follows. Mp 174~175.5 ℃ [α] _D ³³ +159 DEG (c0.72, CHCl ₃₎ IR ^{(Nujol) νmax 1735cm -1 1 H-NMR} (90MHz, CDCl 3) J, 0.88 (3H, s) 1.20-2.51 ( 13H, m), 2.72-2.98 (2H, m), 3.77 (3H, s), 6.5
4-6.67 (2H, m), 6.55-6.76 (1H, m), 7.20 (1H, d, J = 8.3H
z) MS m / z 284 (M ⁺ 100%).

Example 5 Compound (8) (melting point: 103 to 105 ° C., [α] _D ³³ + 215 ° (c
123 mg of 1.0.1, CHCl ₃ ) was dissolved in 5 ml of 10% HCl-THF (1: 3) mixed solvent at 0 ° C., and the temperature was gradually returned to room temperature from 0 ° C. over 1.5 hours with stirring. The mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate solution under ice cooling, extracted with dichloromethane, washed with saturated brine, and dried over magnesium sulfate. After distilling off dichloromethane, the residue was subjected to silica gel chromatography to obtain 100 mg (quantitative) of compound (3).

Claims (4)

(57) [Claims] 1. A general formula: (In the formula, R represents an alkyl group having 1 to 20 carbon atoms). 2. A general formula: (In the formula, R represents an alkyl group having 1 to 20 carbon atoms). 3. The general formula [Chemical 3] (Wherein R represents an alkyl group having 1 to 20 carbon atoms)
Compound. 4. The general formula [Chemical 4] (Wherein R represents an alkyl group having 1 to 20 carbon atoms)
Compound.