JPH0625087B2 - Novel benzocyclopten derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel benzocyclobutene derivative, and more particularly to a benzocyclobutene derivative suitable as a raw material for synthesizing a steroid skeleton.

(Prior Art) Steroids, which are physiologically active substances, show various pharmacological actions and are useful as raw materials for pharmaceuticals and the like. Various methods have been developed so far for the synthesis of the steroid skeleton, but recently, as a new method, a synthesis method utilizing the intramolecular Diels-Alder reaction of -quinodimethane has attracted attention (Tetrahedron VoL. 3-1
6 pages 1981 etc.).

In this method, a raw material having a methyl group at the 2-position and a vinyl group at the 3-position of the cyclopentanone moiety corresponding to the D ring of the steroid skeleton is previously synthesized, and then the benzocyclobutene moiety is introduced, and then the intramolecular Diels -The desired steroid skeleton is synthesized by carrying out the Alder reaction.

However, in the case of this method, it is difficult to selectively introduce benzocyclobutene into the 2-position, and there is a problem in stereocontrol of the cyclopentanone moiety.

(Problems to be Solved by the Invention) Therefore, as a result of intensive studies to solve the above-mentioned drawbacks, the present inventors have introduced a benzocyclobutene moiety into the 2-position of cyclopentanone in advance, which is a key in steroid skeleton synthesis. The present invention has been completed by finding a benzocyclobutene derivative capable of efficiently synthesizing an intermediate (see compound 5 in Reference Example 2 below).

(Means for Solving Problems) Thus, according to the present invention, a novel benzocyclobutene derivative represented by the following general formula (I) is provided.

(In the formula, R represents a lower alkyl group.) The benzocyclobutene derivative of the present invention is easily synthesized, for example, by the following method. First, an enol salt of a 2-oxocyclopentanecarboxylic acid ester represented by the following general formula (II) and a benzocyclobutene compound represented by the following general formula (III) are brought into contact with each other to carry out an alkylation reaction. A 2-oxocyclopentanecarboxylic acid derivative represented by IV) is synthesized.

(In the above formulas, A represents an allyl type residue, R represents a lower alkyl group, and X represents a halogen atom.) Here, the carbon number of the allyl type residue is the value of 2-substituted-2-cyclopentenone in the next step. It may be within the range that does not have an adverse effect on the synthesis, and specific examples thereof include an allyl group, a crotyl group, a methallyl group, a geranyl group, a cinnamyl group, a p-chlorocinnamyl group and the like.

R is a lower alkyl group, and examples thereof include a methyl group, an ethyl group and a propyl group. Of these, a methyl group is preferred.

Further, specific examples of X include halogens such as chlorine, bromine and iodine, and sulfoxy groups such as p-toluenesulfoxy group, methanesulfoxy group and phenylsulfoxy group.

The 2-oxocyclopentanecarboxylic acid ester derivative is synthesized, for example, by alkylating the enol salt of the 2-oxocyclopentanecarboxylic acid ester with the benzocyclobutene compound.

The enol salt used in the reaction may be any as long as it can be alkylated with the benzocyclobutene compound, and specific examples thereof include alkali metal salts such as sodium salt and potassium salt, magnesium salt, calcium salt and the like. Examples thereof include alkaline earth metal salts and ammonium salts, but among them, alkali metal salts are preferred.

The enol salt may be synthesized according to a conventional method, and specific examples thereof include, for example, 2-in the general formula (II).
A method of reacting oxocyclopentanecarboxylic acid ester with a base such as sodium hydride, sodium alkoxide, potassium carbonate, etc., a method of reacting cyclopentanone and a carbonic acid ester of an applicable allyl alcohol in the presence of a base, an applicable allyl Examples include a method in which an adipic acid ester of a type alcohol is subjected to Diekemann condensation in the presence of a base.

The reaction between the enol salt and the benzocyclobutene compound is carried out in the presence of an inert solvent. The solvent used may be any solvent so long as it is inert to the reaction, but is usually polar or non-polar such as acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, hexane, cyclohexane and the like. A solvent is used.

The amounts of both components charged may be appropriately selected, but usually 0.5 to 3 mol, preferably 0.7 to 1.5 mol of the benzocyclobutene compound per mol of the enol salt, and the reaction temperature is usually 0 to 2 mol.
It is in the range of 00 ° C, preferably 50 to 150 ° C. The yield can be improved by the presence of a quaternary ammonium salt or a quaternary phosphonium salt such as trimethylbenzylammonium halide, tetrabutylammonium halide, tetrabutylphosphonium halide, etc., if necessary.

The 2-oxocyclopentanecarboxylic acid derivative of the general formula (IV) thus obtained is subjected to decarboxylation and dehydrogenation at the same time as shown in the following reaction formula to give a benzocyclobutene derivative of the present invention (general formula ( I)] is obtained.

A catalyst consisting essentially of a platinum group metal compound, preferably a platinum group metal compound, and a ligand is used in the above reaction. The platinum group metal compound is a salt or complex of palladium, ruthenium, platinum, rhodium and the like, and specific examples thereof include tris (dibenzylideneacetone) dipalladium (0) and tris (tribenzylideneacetylacetone) tripalladium (0 ), Palladium acetate, palladium propionate, palladium butyrate, palladium benzoate,
Palladium acetylacetonate, palladium nitrate, palladium sulfate, palladium chloride, dihydrotetrakis (triphenylphosphine) ruthenium, ruthenium acetylacetonate, platinous acetate, platinum acetylacetonate and the like can be mentioned.

Of the platinum group metals, palladium is preferable in terms of reactivity, and it is preferable to use a 0-valent olefin complex or a divalent organic compound.

Also, the ligand used is a V atom of the periodic table as a coordinating atom.
It is an electron-donating compound having a group element, that is, nitrogen, phosphorus, arsenic or antimony, and specific examples thereof include pyridine, quinoline, trimethylamine, triethylamine, tributylamine, α, α′-dipyridyl, 1,1.
Nitrogen-containing compounds such as 0-phenanthroline; triethylphosphine, tri-n-butylphosphine, triphenylphosphine, tri-o-tolylphosphine, tri-p-biphenylphosphine, tri-o- Methoxyphenylphosphine, phenyldiphenoxyphosphine,
Triethylphosphite, tri-n-butylphosphite, tri-n-hexylphosphite, triphenylphosphite, tri-o-tolylphosphite, triphenylthiophosphite, α, β-ethylenedi (diphenyl) phosphine, α , Β-ethylenedi (diethyl) phosphine, α, β-ethylenedi (dibutyl) phosphine, and other phosphorus-containing compounds; triethylarsenic, tributylarsenic, triphenylarsenic, and other arsenic-containing compounds; such as tripropylantimony and triphenylantimony Examples thereof include antimony compounds. Of these, phosphorus-containing compounds are preferable in terms of reaction activity, selectivity, economy and the like.

The amount of such a ligand to be used is usually 0.1 mol or more per 1 mol of the platinum group metal compound, and it is preferably 1 mol or more, particularly 2 to 20 mol from the viewpoint of reaction activity.

The amount of the catalyst used in the present invention is appropriately selected, but the platinum group metal compound is usually 0.01 to 10 per 100 mol of the raw material.
It is used in such a proportion that the molar amount is preferably 0.1 to 5 mol. Although the platinum group metal compound and the ligand may be reacted in advance, the catalyst is usually prepared by bringing the respective components into contact with each other in the reaction system.

A diluent may be present during the reaction, and specific examples thereof include amides such as methylformamide, diethylformamide, dimethylacetamide, dimethylpropioamide, N-methylpyrrolidone; methanol, ethanol, propanol, ter- Examples thereof include alcohols such as butanol, ethylene glycol, and diethylene glycol monoethyl ether, and alcohols are especially preferred.

These diluents are usually used in a ratio such that the concentration of the 2-oxocyclopentanecarboxylic acid derivative is 1 to 50% by weight, and the use thereof improves the activity of the reaction and the stability of the catalyst. You can

The reaction is carried out by mixing the 2-oxocyclopentanecarboxylic acid derivative and the catalyst at 50 to 150 ° C. for 5 minutes to 3 in the presence of a suitable solvent.
It can easily proceed by contacting them for a while.

After the completion of the reaction, a highly pure benzocyclobutene derivative can be obtained by separating the desired product from the reaction solution by a conventional method such as solvent extraction, distillation and recrystallization.

(Effect of the Invention) Thus, according to the present invention, a novel substance useful as a raw material for synthesizing a steroid skeleton is provided. When this substance is used as a starting material, not only estrone, which is a known substance, but also a steroid having a substituent other than a methyl group at the 18-position of the steroid bone nucleus can be easily synthesized.

That is, a vinyl group is introduced into a cyclopentene ring (3-position) of a benzocyclobutene derivative by using a vinylating agent such as vinyllithium, and then a methylating agent such as methyl iodide is reacted to give a methyl group at the 2-position of the cyclopentene ring. By introducing a group, a known steroid intermediate can be synthesized with high stereoselectivity.

Esterone can be obtained by subjecting this intermediate to an intramolecular Diels-Alder reaction according to a conventional method to synthesize a steroid skeleton, and then deprotecting the hydroxyl group at the 3-position according to a conventional method.

(Example) Hereinafter, the present invention will be described more specifically with reference to Examples.

Reference Example 1 Allyl 2-oxocyclopentanecarboxylate (Compound
1 ) 1.3 g, 4-methoxy-1.2-benzocyclobutene derivative (Compound 2 ) 2.0 g and potassium carbonate 15 g were added to acetone 100 ml, and reacted under heating reflux for 20 hours. After the reaction, acetone was distilled off, and an oily product was separated by column chromatography. This product is NM
When analyzed by R and IR, the yield confirmed to be a compound (compound 3 ) in which a benzocyclobutene moiety was introduced at the 1-position of allyl 2-oxocyclopentanecarboxylate was 80%. The physical properties of this substance are as follows. ¹ H NMR (Ccl ₄ ) δ; 1.4-2.9 (m, 10H), 3.0-3.4 (m, 3)
H), 3.67 (s, 3H) 6.40-7.00 (m, 3H), 4.47 (d, 2H, J = 5HZ), 4.92-6.20
(M, 3H) IR (oil) 1720 cm ^-1 (ester), 1745 cm ^{-1 (ketone) 1581cm -1, 1600cm -1, 1470cm} -1 Example 1 0.98 part of palladium acetate, 1.7 of triphenylphosphine
1 part was melt | dissolved in 1200 parts of acetonitrile, and it heated at 80 degreeC. To this, 204 parts of Compound 3 obtained in Reference Example 1 was added dropwise over 1 hour, and then the mixture was stirred as it was at 80 ° C. for 2 hours. After distilling off acetonitrile from the reaction solution, an oily product was separated by column chromatography. When this product was analyzed by NMR and IR, it was confirmed to be a benzocyclobutene derivative having a cyclopentenone ring (Compound 4 ). The yield was 85%. The physical properties of this substance are as follows. _{^{1 H NMR (Cc l4) δ}} ; 1.45-2.82 (m, 8H), 3.13-3.50
(M, 3H), 3.80 ( S, 3H) 6.60-7.10 (m, 3H), 7.30 (m, 1H) IR ( ^{oil) 1695cm -1, 1630cm -1, 1600cm} -1 , 1582
cm ^-1 Elemental analysis Calculated value C: 79.34% H: 7.44% O: 13.22% Measured value C: 79.32% H: 7.45% O: 13.23% Reference Example 2 0.88 mmol of cuprous cyanide was dissolved in 1 ml of ether, and a 1N ether solution containing 1.7 mmol of vinyllithium was added dropwise thereto at -70 ° C. After the temperature was raised to -10 ° C, the mixture was stirred for 10 minutes, cooled to -70 ° C again, and the compound
4 0.21 mmol dissolved in 2 ml of ether and added, -4
Stirred at 0 ° C. for 10 minutes. Then, the temperature was raised to 20 ° C, 1 ml of hexamethylphosphoric triamide was added, and -4 again.
The mixture was cooled to 0 ° C, 8 mmol of methyl iodide was added, and the mixture was stirred at -20 ° C for 10 minutes. After the reaction, the mixture was treated with an aqueous solution of ammonium chloride, the organic layer was extracted with ether and then concentrated to obtain an oily steroid intermediate (Compound 5 ) as a known substance by column chromatography. The yield was 70%, and the ratio of the trans form and the cis form of the cyclopentane part was 6: 1.

Claims (1)

[Claims] 1. A benzocyclobutene derivative represented by the following general formula (I). (In the formula, R represents a lower alkyl group.)