NL8007028A - 1,2,3,4,4A, 9B-HEXAHYDRO-4-HYDROXY DIBENZOFURANS. - Google Patents

Description

* * * Λ ΟΑ / 8175-063 Hermans

Center Europeen de Recherches Mauvernay, Riom l, 2,3,4,4a, 9b-hexahydro-4-hydroxy dibenzofurans

The present invention relates to 1,2,3,4,4a, 9b-hexahydro-4-hydroxy dibenzofuran compounds and to a method of preparing these compounds.

Said compounds are particularly suitable as an intermediate in the synthesis of particularly valuable biologically active compounds, such as, for example, the analgesically active 4-amino, 1,2,3,4,4a, 9b-hexahydro dibenzofuran derivatives.

10

A number of amino-substituted dibenzofuran derivatives are known and tested for biological activity because of their structural relationship with morphine.

For example, Winternitz et al., Bull. Soc. Chim.

France 1817 (1956) described the compound of the formula: x CH - N (CHo) t 2 J 2

Godefroi et al *, J. Organ Chem. 28, 1112, 1963, described compounds of general structure: 25 © do 8007028-2. »'*

More recently, other derivatives of dibenzofuran have been described, for example, the structure: RO _ ^> tsCp N <'in US Pat. No. 3,496,181 and the structure: CH3 10 HN-C- (CH_) -N II 2 n ^ 0 15 in German patent application 2,518,289.

In all these cases, the disclosed compounds are the result of very specific synthesis pathways, which permit only the preparation of those substitutions in the tricyclic molecule described above.

It has now been found that new substitutions in the dibenzofuran base molecule are possible when a compound of the general formula I: 1 8007028 35 is used as starting product.

3 lee OH

wherein the substituents R 1, R 2, R 3 and R 4 may be different or the same and represent hydrogen, halogen, alkyl (1-6C), alkoxy (1-6C) or trifluoro methyl.

* '* + - 3 -

The present invention therefore includes the new compounds of the general formula I and a synthesis for the preparation of these compounds.

The new compounds I can be used to prepare 4-amino derivatives of the general formula II:

R, NC

4 R6 in which R1, R2, R3 and R4 have the meaning already indicated above and Rg and Rg represent either hydrogen, alkyl, cycloalkyl, alkoxyalkyl or aralkyl or Rg + Rg together with the nitrogen atom represents a heterocyclic ring, which optionally yet another hetero atom (oxygen or nitrogen) may contain 20.

The 1,2,3,4,4a, 9b-hexahydro-4-hydroxy dibenzofuran derivatives of formula I can be prepared in one step starting from 2- (cyclohexenyl-2) -phenol substituted with the desired groups R 4 , R 2, R 3 and R 2 according to the reaction scheme: R 1 -in R 2 v organic peracid

III

* 4 8007028 • w s.

- 4 -

In order to carry out the reaction, the organic peracid is added in small amounts to a 2- (cyclohexenyl-2) phenol derivative which has been previously dissolved in a suitable organic solvent such as ethyl acetate, methylene chloride or ethyl ether.

During this addition of the peracid, the reaction temperature is kept at 0 ° C. When the addition is complete, stirring is continued for about 4 hours at room temperature, after which the reaction mixture is brought to pH 7 and the organic layer is separated and dried. After evaporation of the solvent, the product is further purified by distillation under reduced pressure.

Depending on the nature of the substituents Rp R2 »r3 and it may be necessary to use a variant of the above reaction scheme, which involves protecting the hydroxy function of the starting material III before reacting the organic peracid . In this case, the reaction consists of three steps according to the following scheme: 'jfoo 4 M r4 metachloroperoxybenzoic acid / CH-Cl * * * * 3 K4 OH "4 8007028% - 5 -

The first stage consists of a treatment of a 2- (cyclohexenyl-2) phenol, for example, with acetyl chloride in an anhydrous solvent (pyridine, a mixture of triethylamine and chloroform or methylene chloride), or any other suitable method to remove the OH group to protect.

In the second stage, epoxy formation of the previously obtained compound takes place by means of an organic peracid. Metachloroperoxybenzoic acid with methylene chloride as solvent is used for this.

In the third stage, the compound obtained in the previous stage is cycled.

After this compound is dissolved in an alcohol, a sodium alcoholate is allowed to act on it. Sodium methanolate with absolute ethanol as solvent is used for this.

The 2- (cyclohexenyl-2) phenols used as starting materials in the process according to the invention can be prepared starting from substituted phenols according to the known method.

For example, by first allowing 1,2-di-bromocyclohexane to act on these compounds - Gogek et al.

[Con.J.Chem. 29, 938 (1951) - and then perform a Claisen rearrangement (Acta Chem. Scan. 20- (6), 1561, 1966) on the resulting (cyclohexenyl-2) -phenyl ether.

In order to obtain the corresponding 1,2,3,4,4a, 9b-hexahydro-4-amino-dibenzofurans, the following reactions can be carried out in a known manner: 8007028 1-6 -pho. * r4 oh r4 o '<= * 4 <5)

V

10

In the first step, the oxidation of the alcohol of formula I takes place in a weakly acidic environment. This oxidation can be carried out, for example, with pyridine chlorochromate complex in the presence of sodium acetate, or with N, N'-dicyclohexylcarbodiimide (DCC) in the presence of anhydrous ortho-phosphosic acid and DMSO (dimethylsulfoxyd).

In the second step, the ketone obtained above is treated with an amine 20 HN 'in the presence of a reducing agent, such as sodium borohydride or sodium cyanoborohydride.

25

Another known method of preparing the 4-amino derivatives is shown in the following scheme: "$ 3?" · -:% ¾.

4 / R1 «^ LiAlH.

R * y ° no

80 0 7 0 28 h'S ^ '0 · "Y

R4 nh2 - 7 -

The resulting 4-amino compound can then be alkylated in a known manner to the nitrogen atom.

Example 1 8-fluoro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy dibenzofuran To 368 g (1.92 M) 4-fluoro-2- (cyclohexenyl-2) phenol in 6 liters of methylene chloride 513 g (2.97 M) of metachloroperoxy-10 benzoic acid was added slowly and with continuous stirring. After stirring at room temperature for 1 hour, the metachlorobenzoic acid formed was filtered off. The filtrate was washed with CO2-containing water and then with water, after which the organic layer was dried and evaporated to dryness in vacuo. The oily residue was then distilled under reduced pressure; resulting in 218 g of product with a boiling point of 135 ° C.

Example 2 20 1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran 87.12 g (0.5 M) 2- (cyclohexenyl-2) phenol was dissolved in 250 g of anhydrous pyridine, followed by dropwise 47 1 g of acetyl chloride was added at a temperature of about 60 ° C. After the reaction was completed, 750 ml of ice water was added, the reaction mixture was acidified with HCl, and then extracted with methylene chloride. After washing with water and drying over sodium sulfate, the extract was filtered and the solvent was evaporated, and the resulting product (ester) was distilled under reduced pressure.

In this way 99.4 g of 1- (cyclohexenyl-2) -2- (acetyloxy) benzene with a boiling point at 0.5 atm was obtained. of 125 ° C.

.35 8007028 *. - - 8 -

The resulting ester (90.8 grams) was then dissolved in a liter of chloroform at room temperature after which 86.8 g of metachloroperoxybenzoic acid was added portionwise and the reaction mixture was stirred for 8 hours.

After filtering off the formed metachlorobenzoic acid, the filtrate was washed and dried over Na 2 SO 4, after which the solvent was evaporated.

In this way, 97.5 g of 2- (2-acetyloxy-phenyl) -7-oxabicyclo [4,1,6] -heptane were obtained.

Then, under a nitrogen atmosphere, the resulting epoxide (97.5 g), dissolved in 100 ml of absolute ethanol, was slowly added to a solution of 34 g (0.63 M) sodium methanolate in 500 ml of absolute ethanol at a temperature of 60 ° C .

After 4 hours, the reaction was stopped and the solvent was evaporated. The residue was taken up in water, treated with HCl and then made slightly alkaline. *

The title product was then extracted from this alkaline mixture using chloroform, after which the extract was dried and the solvent was evaporated.

The residue was then distilled under reduced pressure to give 80 g of 1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran, b.p. 133 ° C.

30 8007028 - 9 -

Example 3

In a similar manner as described in Example 2, the following compounds were obtained: 8-chloro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran; boiling point (0.5 atm.) 165 ° C; 6-chloro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran; 8-methyl-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzo-10 furan; 8-methoxy-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran, boiling point (0.1 atm) = 180 ° C; 8-isopropyl-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran; 7-trifluoromethyl-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran; 7,9-dichloro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran; 6,8-dichloro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-20 dibenzofuran, mp 69 ° C; β-methoxy-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran; 8-fluoro-1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran, mp 65 ° C.

25

Example 4 1.2,3.4.4a.9b-Hexahydro-4-methylamino-dibenzofuran.HCl To 1.3 liters of methylene chloride were added successively with stirring: 100 g (0.53 Μ) 1,2,3,4,4a, 9b-hexahydro-4-hydroxy-dibenzofuran, 13.12 g (0.16 M) sodium acetate and 170 g (0.79 M) pyridine chlorochromate complex.

After stirring for 6 hours, the solvent was partially evaporated and the concentrate extracted with ether.

After evaporation of the ether and distillation of the residue, 45 g of the ketone 1,2,3,4,4a, 9b-hexahydro-4-oxo 8007028 • ψ - 10 - dibenzofuran were obtained with a boiling point (0.5 atm.) 150 ° C.

4 g of the resulting ketone were then dissolved in 40 ml of methanol. To this solution, 4 ml of a 33% methylamine solution in absolute ethanol was added, after which - after standing for 5 minutes - 1.6 g of sodium borohydride were added in small portions.

After stirring for 1H hour, the solvents were evaporated and the resulting residue was taken up in water, the chloroform extracted and the extract dried over Na2SO4.

The extract was then filtered and the solvent evaporated. The residue was taken up in anhydrous ethyl acetate and crystallized as HCl salt after passing through HCl gas.

Yield: 3.1 g; mp 235 ° C.

20 x 8007028

Claims (3)

1. Dibenzofuran derivatives with the general formula: Xe? 3 r 4 1 where R 1, R 1, R 4 and R 4 may be the same or different and represent hydrogen, halogen, a lower alkyl or alkoxy group or a trifluoromethyl group. Process for the preparation of the compounds according to claim 1, characterized in that the compound 2- (cyclohexenyl-2) -phenol, substituted by the groups R 1, R 1, R 1 and R 4, is cycled using an organic peracid . 3. Process according to claim 2, characterized in that first the hydroxy function of the 2- (cyclohexenyl-2 -) - phenol is protected, then the resulting compound is treated with the organic peracid and finally the cyclization is effected with the aid of a sodium- alcoholate. 8007028 Process according to claim 2 or 3, characterized in that the peracid used is metachloroperoxybenzoic acid.