NO140458B - METAL POWDER FOR USE IN THERMAL SPRAYING AND THE PROCEDURE FOR MAKING IT - Google Patents

Abstract

Metal powder for use in thermal spraying and the process for its preparation.

Description

Process for the production of 6-trifluoromethylsteroids.

The present invention relates to a process for the production of 3-keto-A<4>'(<i->6-trifluoromethylsteroids and 3-keto-AM'°-6-trifluoromethylsteroids of the androstane series, the 19-nor-androstane series, the pregnane series and 19- nor pregnancy series.

The method according to the invention

is characterized by the fact that a 3-keto-A<4->6a-trifluoromethylsteroid, where the 3-keto group has been converted into a cyclic ketal group, is reacted with N-bromosuccinimide, after which

the reaction product is dehydrobrominated, e.g. by boiling it with a tertiary amine, such as collidine, and then removing the ketal group by acid hydrolysis, after which, if a 3-keto-Ai,4-o-6-trifluoromethylsteroid is desired, dehydrating the resulting 3-keto-A4'"- 6-trifluoromethylsteroid in known manner.

In addition to the 3-keto group and the 6-trifluoromethyl group, the compounds which can be prepared by the method according to the invention may contain in the other positions of the steroid ring such substances which appear in the steroids in the aforementioned series which have androgenic, progestational, anabolic or adreno-cortical activity.

The compounds produced by

the method according to the invention are hitherto unknown substances. They show therapeutically useful effects of the kind mentioned, but usually more marked than those of the 3-keto-A'-steroids from which they are derived. For example 6-trifluoromethyl-α<4>'°-pregnadien-17α-ol-3,20-dione-17-acetate and 6-trifluoromethyl-α1*t',1-pregnatrien-17α-ol-3,20-dione -17-ace-tat shows extremely strong progestational activity when administered orally.

In the method according to the invention, they

nelsen used as starting material the cycloketals of the 3-keto-A<4->6a-trifluoromethyl steroids are new substances, which can be prepared by adding a 3-enoleter of a corresponding steroid compound, which does not contain a trifluoromethyl group in the 6-position , react with trifluoroiodomethane in the presence of an organic base under irradiation with ultraviolet light, after which the reaction product is treated with a strong acid and the 3-ketoA<4->6a-trifluoromethylsteroid thus formed in a manner known per se is reacted with a 1,3-dioxolane in the presence of an acid catalyst to form a 3-cyclo-ketal compound of the 3-keto-A<4->6a-trifluoromethylsteroid.

The reaction between the 3-cycloketal of the 3-keto-A<4->6«-trifluoromethylsteroid and the N-bromosuccinimide is carried out in an organic solvent such as tetrachloromethane, under irradiation of the reaction mixture with light from a photolamp. The 3-cycloketal group is hydrolysed to the corresponding 3-keto group by acid hydrolysis.

The A<1> double bond can be introduced by treating the 3-keto-A<4>'"-6-trifluoromethyl steroid dissolved in an organic solvent with a dehydrating agent, such as selenium dioxide or 2,3-dichloro-5,6- dicyanobenzoquinone, preferably at an elevated temperature After the reaction has been completed, the excess of the dehydrating agent is removed, after which the reaction product is recovered by conventional methods, such as precipitation, recrystallization or chromatography.

The introduction of the A^ double bond can also be carried out with the help of a micro-organism known to have the ability to form an A^ double bond in steroids, such as species from the genus Colletotrichum and Corynebacterium and Didymella lycopersica.

The invention will now be described in the following examples.

Example 1.

(a) 6α-trifluoromethyl-17α-acetoxy-progesterone-3-cyclo-ethylene ketal.

A mixture of 1.0 g of 6a-trifluoromethyl-17"-acetoxy-progesterone, 45 mg of p-toluenesulfonic acid and 20 ml of 2-methyl-2-ethyl-1,3-dioxolane was heated for 5 hours, and 2- the butanone released during the reaction was slowly distilled through a Vigreux column at atmospheric pressure in mixture with dioxolane. The cooled reaction mixture was diluted with ether, and the solution was washed with a solution of sodium bicarbonate and then with water and finally dried over MgSO 4 . The solvent was distilled off in vacuo, and the residue crystallized from methanol containing 0.5% pyridine, whereby 0.75 g of the desired substance was obtained with a melting point of 172-175°C. After recrystallization from the same solvent, the melting point was 178-182°C.

Analysis:

Calcd: C: 64.45; H: 7.28%. Found: C: 64.28; H: 7.29%.

(b) 6-trifluoromethyl-A4 fi-pregnadiene-17α-ol-3,20-dione-17-acetate.

A mixture of 727 mg of 6α-trifluoromethyl-17α-acetoxy-progesterone-3-cycloethyl-enketal, 300 mg of N-bromosuccinimide and 30 ml of tetrachloromethane was refluxed for 10 minutes under irradiation with light from a 250 Watt photolamp (Philips type 13103 E/ 99). After cooling, the succinimide was removed by filtration and the filtrate evaporated to dryness in vacuo. The residue was dissolved in 10 ml of boiling γ-collidine, and the resulting solution was refluxed for 30 minutes. After cooling, the collidine hydrobromide, which had been formed during the reaction, was filtered off, whereupon the filtrate was diluted with 30 ml of ether, washed with dilute hydrochloric acid and then with water and dried over MgSO 1 . The solvent was distilled off in vacuo, the residue was dissolved in a mixture of 9 ml of methanol and 1 ml of 4 N sulfuric acid, and the solution was refluxed for 30 minutes. After cooling, the desired product is precipitated by adding water. By recrystallization from acetone/hexane, the desired substance was obtained with a melting point of 231-233°C. The ultraviolet spectrum showed a maximum at 270 m^i (E=20,000).

Analysis:

Calcd: C: 65.73; H: 6.67%. Found: C: 65.50; H: 6.76%.

Example 2.

6-trifluoromethyl-Al Ac>-pregnatriene-17a-ol-3,20-dione-11'-acetate.

150 mg of selenium dioxide was added to a solution of 300 mg of 6-trifluoromethyl-A<4-0->pregnadien-17a-ol-3,20-dione-17-acetate in 10 ml of tertiary butanol containing 0.04 ml of pyridine. The mixture was refluxed for 24 hours and then cooled and filtered through Hy flo Supercel to remove solid selenium constituents. The filtrate was evaporated to dryness, and the residue was triturated with water;

After filtration and drying over P2O5, the product was chromatographed on a column of silica gel with a yield of 170 mg of the desired substance.

Analysis:

Calculated: C: 66.00; H: 6.20; F: 13-10%. Found: C: 65.92; H: 6.31; F: 13 24%.

Example 3— 10.

By following the procedure described in the preceding examples 1 and 2 and using the starting materials mentioned in the following table, the reaction products were obtained which are shown in the last column of the table.

Claims (1)

Process for the production of therapeutically effective 3-keto-A<4>'°-6-trifluoromethylsteroids and 3-keto-A1'4'n-6-trifluoromethylsteroids of the androstane series. The 19-nor-androstane series, the pregnane series and the 19-nor-pregnane series, characterized in that a 3-keto-A<4->6a-trifluoromethylsteroid of one of the aforementioned series, where the 3-keto group has been converted into a cyclic ketal group. is reacted with N-bromosuccinimide under be irradiation with light, whereupon the reaction product is dehydrobrominated and then the ketal group is removed by an acid hydrolysis, after which, if a 3-keto-A<1.4.fl->6-trifluoromethylsteroid is desired, the obtained 3-keto-A<4.>° is dehydrated -6-trifluoromethylsteroid in known manner.