JPH06128186A - Benzoperhydroindane derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a synthetic intermediate for steroid compounds having trifluoromethyl at the 13-position. CONSTITUTION:A compound of formula I (R<1> is hydroxyl group-protecting group; R<2> and R<3> are H or R<1>), e.g. (2S,3S,3aR,9bS)-trans-2,3,3a,4,5,9b-trans-2- hydroxy-3-hydroxymethyl-1',2-0-isoylidene-7-methoxy-3a- trifluoromethylcyclopenta[a]naphthalene. This compound is obtained by thermally reacting a benzocyclobutene derivative of formula II usually in an inert gas atmosphere such as nitrogen, preferably at 150-250 deg.C for 10min to 200hr. Furthermore, the compound of formula II is obtained by subjecting, e.g. 1,1,1- trifluoroacetone to the Wittig reaction, subsequently hydrolyzing the reactional product then condensing the prepared product with oxazolidinone, reacting the produced compound of formula III with an aldehyde of formula IV, subsequently reducing the product and then introducing a protecting group thereinto.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a benzoperhydroindane derivative and a method for producing the same. The benzoperhydroindane derivative provided by the present invention is useful as a synthetic intermediate for a steroid hormone derivative such as a male hormone having a trifluoromethyl group at the 13-position, estrogen, luteinizing hormone, glucocorticoid, and mineralocorticoid.

[0002]

Prior Art and Problems to be Solved by the Invention 13
Formula (III) having a trifluoromethyl group at the position

[0003]

[Chemical 3]

And the following formula (IV)

[0005]

[Chemical 4]

It is known that the steroid compound represented by [3] has a pharmacological activity different from that of the steroid compound having a methyl group at the 13-position [Journal of Chemical Society Perkin Transactions].
1 (Journal of Chemical Society Perkin Transaction
s 1), p. 337 (1986)].

It is extremely difficult to synthesize a steroid compound having a trifluoromethyl group at the 13-position by using a natural steroid having a methyl group at the 13-position as a raw material and substituting the trifluoromethyl group for the methyl group. .

Also known is a method of synthesizing a racemic steroid compound having a trifluoromethyl group at the 13-position using 2-trifluoromethylcyclopentane-1,3-dione as a starting material [Journal. Of the Chemical Society Perkin Trans 1 (Journal of Chemical Society Perkin Trans
actions 1), p. 337 (1986); tetrahedron.
See Letters (Tetrahedron Letters), Vol. 33, page 1269 (1992) and Belgian Patent No. 638,079].

An object of the present invention is to provide a benzoperhydroindane derivative which is a synthetic intermediate for a steroid compound having a trifluoromethyl group at the 13-position and a method for producing the same.

[0010]

According to the present invention, the above-mentioned object is achieved by the following general formula (I):

[0011]

[Chemical 5]

(In the formula, R ↑ 1 represents a protective group for a hydroxyl group,
R ↑ 2 and R ↑ 3 each represent a hydrogen atom or a hydroxyl-protecting group. ), A benzoperhydroindane derivative (hereinafter, abbreviated as benzoperhydroindane derivative (I)).
In addition, the following general formula (II)

[0013]

[Chemical 6]

(In the formula, R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above.) A benzocyclobutene derivative (hereinafter abbreviated as benzocyclobutene derivative (II)). It is achieved by providing a method for producing a benzoperhydroindane derivative (I), which comprises reacting under heating.

The hydroxyl-protecting group represented by R ↑ 1, R ↑ 2 and R ↑ 3 may be any substituent as long as it is a substituent capable of protecting the hydroxyl group. For example, a methyl group,
Tertiary butyl group, benzyl group, allyl group, triphenylmethyl group, methoxymethyl group, 1-ethoxyethyl group,
Benzyloxymethyl group, methoxyethoxymethyl group,
An optionally substituted alkyl group such as a tetrahydrofuranyl group and a tetrahydropyranyl group; a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a triisopropylsilyl group, a tertiary butyldimethylsilyl group, a tertiary butyldiphenylsilyl group Group, trisubstituted silyl group such as triphenylsilyl group; formyl group, acetyl group, propionyl group, isobutyryl group, valeryl group, pivaloyl group, trichloroacetyl group, phenoxyacetyl group, benzoyl group, 2,4,6-trimethylbenzoyl An acyl group such as a group; a methoxycarbonyl group,
Examples thereof include alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl group, allyloxycarbonyl group, p-nitrophenoxycarbonyl group, benzyloxycarbonyl group and p-nitrobenzyloxycarbonyl group.

Further, R ↑ 2 and R ↑ 3 may be taken together to form a cyclic protecting group. Such protecting groups include
Methylene group, ethylidene group, 1-phenylethylidene group, isopropylidene group, cyclohexylidene group, cyclopentylidene group, benzylidene group, ethoxymethylene group, dimethoxymethylene group, 2-oxacyclopentylidene group, ditertiary butyl group Silylene group, 1,3- (1,
1,3,3-tetraisopropyldisiloxanylidene group, tetra-tert-butoxydisiloxane-1,3-diylidene group, carbonyl group and the like can be mentioned.

Among the benzoperhydroindane derivatives (I) provided by the present invention, the following general formula (Ia)

[0018]

[Chemical 7]

The optically active trans-benzoperhydroindane derivative represented by the formula (wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above) is particularly useful.

The reaction under heating is usually nitrogen,
It is carried out in an atmosphere of an inert gas such as helium or argon, in the presence or absence of an inert solvent. The solvent used may be one that does not significantly inhibit the reaction, and for example, decane, undecane, decalin, benzene, toluene, xylene, cumene, mesitylene, cymene, tetralin, chlorobenzene, dichlorobenzene,
Examples of the hydrocarbon include optionally substituted hydrocarbons such as bromobenzene and nitrobenzene; ethers such as diglyme, triglyme, and tetraglyme; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These solvents are used alone or in combination of two or more. The amount of the solvent used is sufficient to dissolve the benzocyclobutene derivative (II).

The reaction is usually preferably carried out by heating at a temperature in the range of 50 ° C to 350 ° C, more preferably at a temperature in the range of 150 ° C to 250 ° C. When the boiling point of the solvent used is lower than the reaction temperature, the reaction can be carried out under pressure. The reaction time is usually in the range of 1 minute to 1000 hours, preferably 10 minutes to 200 hours. The optimum reaction temperature and reaction time can be appropriately selected depending on the type of the benzocyclobutene derivative (II) used.

The benzoperhydroindane derivative (I) after the reaction can be isolated and purified by a usual method. For example, the reaction mixture is poured into ice water and extracted with an organic solvent such as diethyl ether or ethyl acetate.The extract is washed successively with cold dilute hydrochloric acid, aqueous sodium hydrogen carbonate, brine, dried and concentrated to obtain a crude product. Recrystallizing the crude product if necessary,
Purification by chromatography or the like gives the benzoperhydroindane derivative (I).

The benzoperhydroindane derivative (I) thus obtained can be protected with a hydroxyl group and eliminated by a conventional method, if necessary.

Among the benzocyclobutene derivatives (II) used as a raw material, the benzocyclobutene derivative (II-a) which is a raw material of the optically active trans-benzoperhydroindane derivative represented by the general formula (Ia). Can be easily produced, for example, by the method shown in the following reaction step A.

[0025]

[Chemical 8]

In the above formula, R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above.

The reaction in each step of the reaction step A will be described. 1,1,1-Trifluoroacetone (IX) is subjected to Wittig reaction to hydrolyze the product to obtain an α, β-unsaturated carboxylic acid (VIII), and then an α, β-unsaturated carboxylic acid ( The imide (VII) is obtained by condensing VIII) with oxazolidinone.
The imide (VII) undergoes an aldol reaction with the aldehyde (VI) to give the aldol (V). After reducing aldol (V), the diol part is protected to give a benzocyclobutene derivative (II-a).

Among the benzoperhydroindane derivatives (I), benzoperhydroindane derivative (Ia ')
Is, for example, by the method shown in the following reaction step B:
13 represented by formula (III-a) or formula (IV-a)
It can lead to a steroid hormone derivative having a trifluoromethyl group at the position.

[0029]

[Chemical 9]

In the above formula, R ↑ 3 represents a hydrogen atom or a hydroxyl-protecting group, and Me represents a methyl group.

That is, the benzoperhydroindane derivative represented by the formula (Ia ') is oxidized, deprotected, dehydrated, hydrogenated, and then oxidized in the presence of a copper catalyst to give the ketone (X). obtain. This is a known method [Angewandte Chemie, Vol. 72, No. 725].
Page (1960)], a steroid hormone derivative having a trifluoromethyl group at the 13-position represented by formula (III-a) or formula (IV-a) is derived.

[0032]

EXAMPLES The present invention will be specifically described below with reference to examples and reference examples, but the present invention is not limited to these examples.

Reference Example 1 [Synthesis of (E) -3-methyl-4-trifluoro-2-butenoic acid] To 150 ml of a benzene suspension of 3.9 g of sodium hydride, 33 ml of ethyl diethylphosphonoacetate was added, Stirred at room temperature for 1 hour. After cooling to 0 ℃, 1,1,
A solution of 1-trifluoroacetone in 10 ml of benzene was added, and the mixture was stirred under ice cooling for 1 hour and then at room temperature for 2 hours.
The reaction solution was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. To the residue obtained by distilling off the solvent, 100 ml of tetrahydrofuran, 100 ml of water and 8.46 g of lithium hydroxide were added, and the mixture was stirred at room temperature for 7 hours. Diethyl ether was added to the reaction mixture, and the mixture was extracted with saturated aqueous sodium hydrogen carbonate.
The aqueous layer was acidified with diluted hydrochloric acid and then extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was distilled under reduced pressure (80 ° C /
21 mmHg), 3.15 g of (E) -3-methyl-4-trifluoro-2-butenoic acid having the following physical property values was obtained as a colorless oil (yield 12%). IR spectrum (ν ↓ max, cm ↑ -1): 1710 Proton NMR spectrum (60 MHz, deuterated chloroform, δ, ppm): 2.28 (3H, s), 6.37
(1H, broads), 12.06 (1H, broads)
ad s)

Reference Example 2 [(2'E, 4R, 5S) -4-Methyl-1- (3'-
Synthesis of Methyl-4 ', 4', 4'-trifluoro-2-butenoyl) -5-phenyl-2-oxazolidinone]
A solution of 703 mg of (E) -3-methyl-4-trifluoro-2-butenoic acid in anhydrous tetrahydrofuran was added at -78 ° C.
At 0.83 ml of triethylamine and 0.62 ml of pivaloyl chloride were added, and the mixture was stirred for 15 minutes at the same temperature and then for 45 minutes at 0 ° C. In this solution, (4S, 5S) -4-
Methyl-5-phenyl-2-oxazolidinone 1.48
g and n-hexane solution of n-butyllithium (1.
56M) -78 ml lithium reagent prepared from 5.4 ml
The mixture was stirred at the same temperature for 15 minutes and then at room temperature for 100 minutes. A saturated aqueous sodium hydrogensulfate solution was added to the reaction solution, the organic solvent was evaporated, and the obtained water-containing residue was extracted with diethyl ether. Diethyl ether layer is saturated sodium bicarbonate water,
After successively washing with brine, drying over anhydrous sodium sulfate, distilling off the solvent and subjecting the obtained residue to silica gel column chromatography, the following physical properties are obtained (2'E, 4R, 5S). -4-methyl-1-
(3'-methyl-4 ', 4', 4'-trifluoro-2
1.15 g of -butenoyl) -5-phenyl-2-oxazolidinone was obtained as a colorless solid (yield 81%). Melting point: 57-58 ° C IR spectrum (chloroform, ν ↓ max, cm ↑-
1): 1780,1690 Proton NMR spectrum (90 MHz, deuterated chloroform, δ, ppm): 0.95 (3H, d, J = 6.6H)
z), 2.22 (3H, d, J = 1.5 Hz), 4.8
2 (1H, dq, J = 6.6 Hz and 7.3 Hz),
5.71 (1H, d, J = 7.3 Hz), 7.30-
7.53 (5H, m) Mass spectrum (m / z): 313 (M ↑ +) Elemental analysis (C ↓ 15H ↓ 14O ↓ 3NF ↓ 3): Calculated values: C 57.51%, H 4.50% , N 4.
47% Found: C 57.60%, H 4.50%, N 4.
59%

Reference Example 3 [(1 "S, 2'R, 4R, 5S) -1- (2'-
(2 "-(1,2-dihydro-4-methoxybenzocyclobuten-1-yl) -1" -hydroxyethyl)-
3'-trifluoromethyl-3'-butenoyl) -4-
Synthesis of Methyl-5-phenyl-2-oxazolidinone]
(2'E, 4R, 5S) -4-Methyl-1- (3'-methyl-4 ', 4', 4'-trifluoro-2-butenoyl) -5-phenyl-2-oxazolidinone 280 mg
1.3 ml of a methylene chloride solution (1.0 M) of dibutylborane trifluoromethanesulfonate was added dropwise to a solution of 5 ml of anhydrous methylene chloride in -78 ° C. 5 at -78 ° C
After stirring for 1 minute, 0.23 ml of triethylamine was added and stirred for 1 hour. The reaction solution was heated to 0 ° C., stirred for 15 minutes, and then, at −78 ° C., 265 mg of 3- (1,2-dihydro-4-methoxybenzocyclobuten-1-yl) propan-1-al in anhydrous chloride was added. A methylene solution was added and the mixture was stirred for 1 hour and then at 0 ° C for 1 hour. 1M
50 ml of an aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with a mixed liquid (1: 1) of n-hexane and ethyl acetate. The extract was washed with saturated brine, the solvent was evaporated, the residue was dissolved in diethyl ether, and 2 ml of a phosphate buffer solution and 2 ml of 30% hydrogen peroxide solution were added to the resulting solution at 0 ° C. to give 1
Stir for hours. 50 ml of 1M potassium hydrogensulfate aqueous solution was added, and the mixture was extracted with a mixed liquid of n-hexane and ethyl acetate (1: 1). The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the resulting residue was subjected to silica gel column chromatography (1 "S, 2 'R, 4R, 5
S) -1- (2 ′-(2 ″-(1,2-dihydro-4-
Methoxybenzocyclobuten-1-yl) -1 ″ -hydroxyethyl) -3′-trifluoromethyl-3′-butenoyl) -4-methyl-5-phenyl-2-oxazolidinone (206 mg) was obtained as a colorless oil ( Yield 47
%).

Reference Example 4 [(4S, 5R) -4- (1,2-dihydro-4-methoxybenzocyclobuten-1-yl) methyl-2,2-
Dimethyl-5- (1-trifluoromethyl) vinyl-
Synthesis of 1,3-dioxane] (1 ″ S, 2′R, 4R,
5S) -1- (2 ′-(2 ″-(1,2-dihydro-4
-Methoxybenzocyclobuten-1-yl) -1 "-hydroxyethyl) -3'-trifluoromethyl-3'-
To a solution of 185 mg of butenoyl) -4-methyl-5-phenyl-2-oxazolidinone in 3 ml of tetrahydrofuran was added 0.42 ml of a solution of tributylboron in tetrahydrofuran (1.0 M) and 0.032 ml of acetic acid at room temperature, and the mixture was stirred for 90 minutes. Then, under ice cooling, 16 ml of lithium borohydride and 1 ml of tetrahydrofuran
The solution was added and stirred for 1 hour, and then stirred at room temperature for 1 hour.
After completion of the reaction, 3 ml of methanol and 0.025M under ice cooling
1.5 ml of disodium hydrogen phosphate aqueous solution and 30%
3 ml of a mixed solution of hydrogen peroxide water and methanol (1: 2) was added, and the mixture was stirred at room temperature for 90 minutes. After distilling off the solvent,
10% aqueous sodium hydrogen carbonate was added, and the mixture was extracted with methylene chloride. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off,
The residue is dissolved in methylene chloride and the resulting solution is 2,2-
0.23 ml of dimethoxypropane and a catalytic amount of camphorsulfonic acid were added, and the mixture was stirred for 3 hours at room temperature. Methylene chloride was added to the reaction mixture, and the resulting mixture was saturated aqueous sodium hydrogen carbonate,
After sequentially washing with saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography to give (4S, 5R) -4- (1) having the following physical properties. , 2-Dihydro-4-methoxybenzocyclobuten-1-yl) methyl-2,2-
Dimethyl-5- (1-trifluoromethyl) vinyl-
86 mg of 1,3-dioxane was obtained as a colorless oil (yield 63%). Proton NMR spectrum (500 MHz, deuterated chloroform, δ, ppm): 1.47 (3H, S), 1.49
(3H, s), 3.77 (3H, s), 4.21-4.
27 (2H, m), 5.95 (1H, s), 6.22
(1H, s), 6.67 and 6.69 (1H, s, d
iastereomeric), 6.73 (1H, d,
J = 7.9 Hz), 6.95 and 6.97 (1H,
d, J = 7.9 Hz, diastereomeric) Mass spectrum (m / z): 356 (M ↑ +) High resolution mass spectrum (m / z): Calculated value: 356.1599 Actual value: 356.1591

Example 1 (4S, 5R) -4- (1,2-dihydro-4-methoxybenzocyclobuten-1-yl) methyl-2,2-dimethyl-5- (1-trifluoromethyl) vinyl -1,
3-dioxane 84.8 mg was added to o-dichlorobenzene 5
After dissolving in 0 ml and heating under reflux for 5 hours, the solvent was evaporated, the obtained residue was subjected to silica gel column chromatography, and the following physical property values were obtained from the elution part of n-hexane-ethyl acetate (19: 1). Have (2S, 3S, 3aR, 9
bS) -trans-2,3,3a, 4,5,9b-hexahydro-2-hydroxy-3-hydroxymethyl-
1 ', 2-O-isoylidene-7-methoxy-3a-trifluoromethylcyclopenta [a] naphthalene 51.
5 mg was obtained as a colorless oil (yield 61%). Proton NMR spectrum (500 MHz, deuterated chloroform, δ, ppm): 1.33 (3H, s), 1.42
(3H, s), 3.77 (3H, s), 6.67 (1
H, s), 6.69 (1H, d, J = 8.2 Hz),
6.96 (1H, d, J = 8.2 Hz) In Example 1, as a protective group for the hydroxyl group corresponding to R ↑ 1, a tertiary butyldimethylsilyl group was used instead of the methyl group,
The benzoperhydroindane derivative (I) was similarly obtained when an acetyl group or a methoxycarbonyl group was used.

Examples 2 to 4 A benzoperhydroindane derivative was prepared in the same manner as in Example 1 except that the groups shown in Table 1 were used as the groups corresponding to R ↑ 2 and R ↑ 3. (I) was obtained. The results are shown in Table 1.

[0039]

[Table 1]

[0040]

INDUSTRIAL APPLICABILITY According to the present invention, there are provided synthetic intermediates for various steroid hormones having a trifluoromethyl group at the 13-position, and a method for producing the synthetic intermediates.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07C 69/65 9279-4H 69/78 9279-4H C07D 309/12 7252-4C C07F 7/18 A 8018-4H

Claims (2)

[Claims] 1. The following general formula (I): (In the formula, R ↑ 1 represents a protecting group for a hydroxyl group, and R ↑ 2 and R ↑ 2
↑ 3 represents a hydrogen atom or a hydroxyl-protecting group, respectively. ) A benzoperhydroindane derivative represented by 2. The following general formula (II): The benzocyclobutene derivative represented by the formula (wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above.) Is reacted under heating. Method for producing hydroindane derivative.