DE2228473C3 - Process for the preparation of cyclopenta- [f] [l] -benzopyran derivatives - Google Patents

Description

RjO

R ₃ O

(H)

The subject of patent 21 30 053 is a method for the preparation of cyclopenta- [f] [l] -benzopyran derivatives of the general formula 1

O)

is characterized in that a compound of the general formula II

IO

R ₃ O

wherein the radicals Ri, Rj and R ₃ each represent an alkyl group having 1 to 4 carbon atoms, the result R ₃ O

R ₃ O

15th

wherein Ri and R _{3 are} alkyl groups with 1 to 4 carbon atoms and W is a group - (CH ₂ ) JZR ₂ , where Z is a 1,2-phenylenedioxymethylene group and R _{2 is} an alkyl group with 1 to 4 carbon atoms, characterized in that that a compound of the general formula H in which Ri R ₂ , R _{3 have} the above meaning, heated in the presence of an acidic catalyst and an aprotic solvent while distilling off the alcohol formed

In a further development of the method according to patent 21 30 053 it has now been found that one also Cyclopenta-TJ] [l] -benzopyran derivatives of the general Formula A.

30th

35

wherein Ri, R ₃ and W have the abovementioned meaning, according to patent 2130053, heated in the presence of an acidic catalyst and an aprotic solvent with distillation of the alcohol formed

2. The method according to claim 1, characterized in that one per mole of the starting compound 0.001 mole to 0.1 mole of the acidic catalyst is used

(A)

R ₃ O

wherein Ri and R _{3 are} an alkyl group having 1 to 4 carbon atoms and W is a group - (CH ₂ J ₃ -ZR ₂ , where Z is a 1,2-phenylenedioxymethylene group and R _{2 is} an alkyl group having 1 to 4 carbon atoms is thereby obtained that a compound of the general formula H

50

55

60

R ₃ O

wherein Ri, R ₃ and W have the abovementioned meaning, heated in the presence of an acidic catalyst and an aprotic solvent while distilling off the alcohol formed.

The cyclization of compounds of the general formula H in the presence of acidic catalysts Compounds of the general formula A is surprising since the cyclization reactions known from the literature either lead to other products or from run out of other connections. For example, according to Charles J. Sih and co-workers, (j. Amer. former Soc. 85 [1963], pp. 2135 to 2137) by cyclization

3 4

of the compound III in the presence of acetic anhydride and anhydrous sodium acetate, the eno-lactone IV;

O O

HOOC

(ΠΙ)

Suitable alkyl radicals are, for example: the methyl, Ethyl-propyl or n-butyl radical, particularly preferred The methyl and ethyl radicals are alkyl radicals.

The cyclopenta- [fp] -benzopyran derivatives of the im produced by the process according to the invention Claim 1 given general formula are particularly favorable process products for the preparation of des-A-steroid derivatives, since only 4 process steps (reduction, hydrogenation, mild acidic, enol ether cleavage and basic cyclization) are necessary.

In this way, products of the process produced by the process according to the invention are obtained per se known way by reduction with complex metal hydrides or according to the method of Meerwein-Ponndorf the 7-hydroxy compounds of formula B

OH

OR ₂

On the other hand, by investigation- <i by G. Saucy and R. Borer (HeIv. Chim. Acta. VoI. 54 [1971] pp. 2121 bis 2132) known that in the cyclization of the triketo-al-

kohols V obtained the octahydrobenzopyran derivative VI will:

Furthermore, US Pat. No. 3,499,913 describes the cyclization of α, / J-unsaturated acyclic diketones of the formula VII to the corresponding dieno ether VIII described:

H ₃ C-

fvm

(vm)

wherein the radical Ri and the 7-hydroxy group are in the cis position are and receives the hydrogenation products of the formula C from these compounds by hydrogenation

OH

OIH

10

(C)

ORj

in which the incoming 9a-hydrogen atom is transstandig to the radical Ri onentiert and where in the formulas B and C the radicals Ri, R ₃ and V / have the meaning given above. After cleavage of the enol ether by a catalytic amount of acid in ethanol and subsequent cyclization by the action of sodium ethylate, the compounds de, formula C can be converted into the de-A-17 /? -Hydroxy-13-alkyl-9-gonen-3-ones convert to formula D,

15 where V is the group

- (CH ₂ VC-CH ₃

/ \
OO

20th

means.

In contrast, the process known from Helvetica Chimica Acta 54 [1971Ϊ pp 2121-2132 required for production of des-A-steroid derivatives from comparable precursors 2 process steps more, like the comparison of the following equations shows:

Production of des-a-steroid derivatives:

From the compounds prepared according to the invention

After Helvetica Chimica Acta 54 (1971), pp. 2121-2132

OH

H ₃ C

R ₃ O

reduction

Hydrogenation

OH

OH

Hydrogenation

\ Esterification

Forlsel / ung

From the compounds according to the invention according to Helvetica Chimica AcIa (1971). Pp. 2121-2132

Hydrogenation OH

R ₁

Enol ether cleavage OH

basic cyclization OH

H (D)

Esterification

OCOCH ₃ H ₃ C

Ether splitting

OCOCH ₃ H ₃ C

OCOCH ₃

Cyclization

OCOCH ₃ H ₃ C

H ₃ C

H ₃ C

In this equation, R ₁ , R, and W have the abovementioned meaning, V represents the group

- (CH ₂ ) JC-CHj

/ \
OO

Another advantage of the cyclopentane [f [l] -benzopyran derivatives prepared according to the invention is that that the carbon atoms of the later ring A of the steroid structure are contained in the substituent W (this corresponds to the substituent V of the Des-A steroid compounds D), whereby the synthesis of Steroid compounds from the Des-A-Sieruiucii facilitated (Velluz and colleagues, Angew. Chemie 72 [1960], p. 725).

Thus, the compounds of the formula D can be used in a particularly advantageous manner to be pharmacologically active Steroids such as estrone, estradiol, 18-methylestradiol. Equilenin, testosterone, 18-methyltestosterone, 17Ä-ethyl-19-nortestosterone or 17 "-äthinyI-18-methy-19-nortestosterone produce.

Carboxylic acids and phenols are particularly suitable as Taure catalysts for the cyclization Example: formic acid, acetic acid. Propionic acid, Monvji'Iuoroacetic acid, Trichloroacetic acid, methoxyacetic acid. Trimethyl acetic acid, cyclopentyl propionic acid, Benzoic acid, p-hydroxybenzoic acid, p-nitrobenzoic acid, phenoxyacetic acid, phenylacetic acid, oxalic acid, Malonic acid, succinic acid, phenol, ο-, m- or p-cresol, o-, m- or p-chlorophenol, resorcinol, p-nitrophenol, 2,4-dinitrophenol or 2,4,6-trinitrophenol.

On the other hand, mineral acids and sulfonic acids can also be used as acid catalysts for the cyclization or Lewis acids, such as hydrogen chloride, sulfuric acid, phosphoric acid, perchloric acid, methanesulfonic acid, Use benzenesulfonic acid, p-toluobulfonic acid, or boron trifluoride.

The acids or phenols to be used are preferably used in catalytic amounts, for example in amounts of 0.1 mol to 0.001 mol of the acidic catalyst per mole of starting compound.

As aprotic solvents for the cyclization, for example, ethers, such as diethyl ether and diisopropyl ether. Di-n-butyl ether, tetrahydrofuran, anisole, dimethoxy-ethane or hydrocarbons such as hexane, cyclohexane, benzo !, Tuiuo! or Xyiui udci ohioi ieiie Hydrocarbons such as carbon tetrachloride, chloroform, tetrachloroethane. 1,2-dichloroethane or chlorobenzene suitable.

The alcohol released during the cyclization is removed from the by distillation or vacuum distillation Reaction mixture removed.

The cyclization can be carried out either at a low temperature or at an elevated temperature will. A reaction temperature of 0.degree. C. to 150.degree. C. is preferably used.

The starting compounds of the formula H to be used can be synthesized in the following way will:

W-COCH = CH ₂
+ or

W-COCH ₂ CH ₂ Cl

R ₃ O

R ₃ O

(G)

(H)

(In this formula scheme, Ri, R3 and W have the above meaning.)

The preparation of compounds of formula H can be carried out as follows, for example:

A compound of formula F is dissolved in absolute tetrahydrofuran, treated with 0.2 equivalents of sodium hydride and as long heated under reflux until the formation of hydrogen ended is then cooled the mixture to 10 ° C to 30 ⁰ C, it was added with a Vmylketon the Formula WCOCH = CH ₂ , stir the mixture for 24 to 48 hours and add 50 ml of a saturated, aqueous sodium dihydrogen phosphate solution. The organic solvent is then distilled off in vacuo, the aqueous residue is extracted with ethyl acetate and the organic phase is washed neutral with water. After drying over sodium sulfate and distilling off the solvent, the compound of formula G is obtained as a crude product

Another manufacturing method is, for example, the following:

A compound of formula F is dissolved in absolute dimethoxyethane, treated with 1.2 equivalents of sodium hydride and as long heated under reflux until the evolution of hydrogen stopped, the mixture is then cooled to -20 "C to - 50 ⁰ C., it was added with a corresponding jJ-chloroketone of the formula WCOCH ₂ CH ₂ Cl, the mixture is stirred 1 to 5 hours at low temperature (-20 ⁰ C to -50 ⁰ C) and works the reaction mixture as described above.

The resulting compound of formula G is then with an appropriate alcohol in the presence of a acidic catalyst ketaiisiert to the corresponding compound of the formula H This ketalisierung is in usually carried out, for example, as follows:

1 mol of the compound G is with 2.5 mol of a corresponding orthoformic acid ester and about 8 to

10 moles of a corresponding alcohol are added. Then 3 ml of a 0.5% strength are added to the mixture alcoholic p-toluenesulfonic acid solution and leaves that Stand reaction mixture at room temperature.

The reaction mixture, which the compound H ί can be used as such for the process according to the invention without further purification. The alcohol used as the solvent is expediently removed by vacuum distillation and replaced by an aprotic solvent such as benzene ι ο or toluene. In such a mixture is the still contain p-toluenesulfonic acid from ketalization, c)

The compounds of formula H can be isolated as a pure product by ι the reaction Mongrel '-> poured after completion ketalization into ice-cold bicarbonate solution, the mixture extracted with ether, concentrating the ether phase under vacuum and the residue rei by chromatography and / or crystallization nicfl

• "β * '

The systematic designation of the compounds described in the exemplary embodiment was in Checked with regard to the IUPAC nomenclature and changed if necessary, thereby agreeing Connections result in deviations from the German Offenlegungsschrift.

example

3n

31.2 g of rac.-7a-methyl-4- (3 ', 3'-dimethoxy-7', 7'-o-phenylene-dioxy-octyl) -5,6,7, a-tetrahydroindane-1,5-dione is dissolved in 600 ml of absolute benzene, treated with 200 mg of malonic acid and heated to the boil for 90 minutes, 300 ml of distillate are removed. The cooled solution is then mixed with 100 ml of sodium hydrogen carbonate solution added, the organic phase d) separated, the water phase three times with 150 ml Extracted toluene and washed the combined organic phases with water until neutral. After drying - »n 30.6 g of crude product are obtained over sodium sulfate, filtering and distilling off the solvent in vacuo obtain. For cleaning, dissolve the crude product in 2 1 Ethyl acetate and the solution filtered through 250 g of silica gel. e) After the solvent has been distilled off, one obtains 293 g rac. 3-methoxy-6a-methyl-3- (4 ', 4'-o-phenylenedi-

50

55

60

65

p ^ p
benzopyran-7 [1H] -one. IR: bands at 5.75 µ, 6.01 µ, 6.75 µ and 8.1 µ.

The rac used as the starting material above. 7a-methyl-4- (3'3'-dimethoxy-7 ', 7'-o-phenylenedioxy-octyl) -5,6,7,7a-tetrahydroindane-1 , 5-dione is made as follows:

a)

b)

162 g of 5-oxo-hexanonitrile are dissolved in 1 liter of toluene, 243 g of pyrocatechol and 3 g of p-toluenesulfonic acid are added and the mixture is heated on a water separator for 24 hours. The reaction mixture is allowed to cool, it is diluted with 1 liter of benzene and the organic phase is washed with 1 η sodium hydroxide solution and dilute sodium chloride solution, dry it over sodium sulfate and concentrate it in a vacuum. The crude product obtained is distilled under high vacuum to yield 246.5 g of 5,5-o-Phenylendioxyhexanonitril from Kp - 0.13mi »106 ° -110 ⁰ C is

183 g are dissolved in 1830 ml of toluene, the solution cooled to -50 ⁰ C, strength within one hour with 79OmI of a 20% solution of diisobutyl aluminum hydride in toluene after a) 5,5-obtained o-phenylenedioxy-hexa- nonitril added and then stirred ^{at -5O 0 C for one hour.} The reaction mixture is then acidified with 4 η hydrochloric acid to pH = 3, diluted with one liter of ethyl acetate, the organic phase is washed with dilute sodium chloride solution, dried over sodium sulfate and concentrated to dryness in vacuo. The residue is distilled in a high vacuum and 174 g of 5,5-o-phenylenedioxyhexanal with a boiling point of 90 ° -92 ° C. are obtained. 40 g of magnesium chips are reacted in 800 ml of tetrahydrofuran with vinyl chloride, the solution obtained is cooled to -3O ⁰ C, treated dropwise with a solution of 173 g according to b) obtained 5,5-o-phenylenedioxy-hexanal was added in 1800 ml of tetrahydrofuran and the reaction mixture Stored for 3 hours at -30 ° C. 260 ml of saturated ammonium chloride solution are then added dropwise to the mixture, the mixture is filtered and the resulting solution is concentrated in vacuo. The residue is dissolved in 2000 ml of acetone, the solution to - 10 ⁰ C and cooled within 30 minutes with 200 ml of Jones reagent (an aqueous solution containing 267 g of chromium (VI) -oxyd and 230 ml of concentrated sulfuric acid per liter) offset. The mixture is left to stand for one hour, 100 ml of methanol and 7000 ml of methylene chloride are added, the organic phase is separated off, washed with dilute sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product obtained is distilled in a high vacuum and 172 g of 7,7-o-phenylenedioxy-1-octen-3-one vom

Bp. 0.0026 mbar 88 - 92 ° C.

23 g-3-one 7,7-o-phenylenedioxy-l-octene are dissolved in 150 ml of chloroform and cooled to about 0 C to ^r c) obtained. Then passes to 30 minutes dry hydrogen chloride through the solution, the chloroform at 20 ⁰ C. bath temperature is distilled off in vacuo and 23.9 g of l-chloro-7 7-o-phenylene dioxy-octan-3-one as a residue. 33.5 g of rac. ^ A-Methyi-S.öJJa-tetrahydroindane-IS-dione are dissolved in 450 ml of absolute dimethoxyethane, 5.1 g of sodium hydride are added to the solution and the solution is kept in an argon atmosphere for 5 hours at 50 ° -55 ° C stirred. Then cool down to -10 ° C. a solution of 57 g of 7,7-o-phenylenedioxy-lchloro-octan-3-one obtained in d) in 300 ml of absolute dimethoxyethane is added dropwise within 30 minutes and the mixture is stirred for 6 hours at 0 ^° C. The reaction mixture is then added with 100 ml of sodium dihydrogen phosphate solution, the dimethoxyethane is largely distilled off in vacuo, the residue is extracted with methylene chloride, the organic phase is washed several times with semi-saturated NaCl solution, dried with sodium sulfate, filtered and the solvent is distilled off in vacuo.

The crude product obtained (82.6 g) is chromatographed on 1.5 kg of silica gel with a hexane-acetone gradient (0 to 40% by volume of acetone), 100 ml of fractions being removed. Fractions 22-33 contain 34.95 g 7a-methyl-4- (7 ', 7'-o-phe-

nylenedioxy-S'-keto-octyl ^ S.ejJa-tetrahydroindane-1,5-dione as a light yellow oil IR: bands at 5.73 µ, 536 µ, 6.07 µ, 6.73 µ and 8.1 µ.

32.1 g of the above rac.-7a-methyl-4> (7 ', 7'-o-phenylenedioxy-S'-kelo-octylJ-S.öJ ^ a-tetrahydroindane-1,5-hione are in 300 ml methanol and 32.1 ml of trimethyl orthoformate dissolved, the solution was cooled to 0 ° C, with 4 ml of a V offset / o methanolic p-toluenesulfonic acid and kept for 4 hours at ^{0 °} C. Then the reaction mixture is poured into 1 l of ice-cold

Sodium bicarbonate solution. extracted with methylene chloride, the methylene chloride phase is washed with 15% sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. 31.2 g of rac.-7a-methyl-4- (3 ', 3'-dimethoxy-7', 7'-o-phenylenedioxy-octyl) -5.6 7.7a-t £ trahydroindan-1 are obtained, 5-dione as a yellow oil.
IR: bands at 5.74 µ, 6.07 µ, 6.73 µ and 8.09 µ.

Claims (1)

Patent claims: 1. Process for the preparation of cyclopenta- [fjij-benzopyran derivatives of the general formula A. R ₃ O (A)