CH475224A - Process for making new 9B, 10x steroids - Google Patents

Description

  

  



  Process for the production of new 9ss, 107alpha; -steroids
The invention relates to the preparation of new 9ss, 10α-steroids of formula I (I)
EMI1.1
 in which R1 is a halogen atom and R2 is a carbonyl group or one of the groups
EMI1.2
 mean. where OR is a hydroxy, alkoxy or acyloxy group, X is hydrogen, a halogen atom or a hydroxy or acyloxy group; Y represents hydrogen or a hydroxy, an alkoxy or acyloxy group and Z represents hydrogen or a lower alkyl, a lower alkenyl or a lower alkynyl group, as well as A6 derivatives thereof.



   A halogen atom represented by the symbol R1 is preferably a fluorine, chlorine or bromine atom, and a halogen atom represented by the symbol X is preferably a fluorine atom. Any alkoxy group present in the 17-position is preferably an aliphatic, cycloaliphatic or araliphatic alkyl group having 1-10 carbon atoms. Examples of such groups are: methyl, ethyl, propyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl, cyclopentene- (l) -yloxy, 1-ethoxy-cyclo- pentyloxy and tetrahydropyranyloxy.



   Any acyloxy group present in the 17- or 21-position is preferably derived from a saturated or unsaturated aliphatic, cycloaliphatic, an araliphatic or an aromatic carboxylic acid having 1-20 carbon atoms. Examples of such acids are: formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, oenanthic acid, oleic acid, palmitic acid, stearic acid, succinic acid, malonic acid, benzoic acid. The lower alkyl, alkenyl and alkynyl groups represented by the symbol Z preferably contain 1-5 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, vinyl, allyl, 1'- and 2'-methallyl, ethynyl and propargyl.



   The method according to the invention is characterized in that a 9, ss, 10oc steroid of the formula
EMI1.3
 wherein R4 represents hydrogen or an esterified carboxyl group, or a # 6 derivative thereof is treated with a halogenating agent in the presence of a base.



   To prepare the starting material, a 3-keto-A4 or a 3-keto- # 4,6-9ss, 10α-steroid is used with an oxalic acid ester or with a formic acid ester, especially the ethyl ester, in solvents, e.g. aromatic hydrocarbons, such as benzene, toluene, xylene, or in pyridine, at temperatures between room temperature and the boiling point of the solvent, preferably at 60-700, in the presence of a base such as sodium methylate or ethylate, sodium hydride or pyridine.



   The 2-methylene compounds mentioned are then, optionally with the protection of a 20-keto group present, with a halogenating agent, e.g. an N halogen amide or imide, such as N-bromo- or N-chlorosuccinimide, N-bromoacetamide, chloramine T or dimethylchlorohydantoin in a solvent such as acetone, alcohol or dioxane, at about - 200 to +200, in the presence of a base, e.g. an alkali alkoxide, such as sodium methylate, or an acetate, such as potassium acetate.



   The new 9ss, 10α-steroids of the formula I obtainable according to the invention are hormonally or antihormonally active. For example, the 2ss-fluoro-17ss-hydroxy-9ss, 10α - -androst-4-en-3 -on uterotrophic and the 2ss-fluoro-17α - -methyl-17p-hydroxy-9, ss, 10sc-androsta-4 , 6-dien-3-one anti-gonadotropic effectiveness. The products of the process can be used as medicaments in the form of pharmaceutical preparations which they contain as a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration. The pharmaceutical preparations can be in solid or liquid form.

   They may contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.



   In the following examples, the temperatures are given in degrees Celsius.



   Example I.
500 ml of benzene were added to a solution of 4.01 g of sodium and 70 ml of methanol. The excess methanol was then distilled off azeotropically. The resulting suspension was treated with 13.2 ml of ethyl formate and a solution of 25 g of 9ss, 10α-androst-4-en-3,17-dione in 250 ml of benzene and refluxed for 20 minutes. After cooling, it was filtered, the residue was washed with benzene and dried, giving 24 g of the sodium salt of 2-hydroxymethylene-9ss, 10α-androst-4-ene-3,17-dione, UV: Anax 244 and 303 nm, which was uniform by plate chromatography , s = 8300 and 14700.



   A solution of 2.1 g of sodium and 85 ml of methanol was added to a solution of 24 g of this compound in 750 ml of methanol at -200 and then perchloryl fluoride was passed in over 80 minutes. Then, after removing the cooling bath, the excess perchloryl fluoride was blown out of the solution with nitrogen.



  The reaction solution was then concentrated to half, mixed with 47 g of anhydrous potassium acetate and refluxed for 90 minutes. After filtration, the solution was extracted with ethyl acetate, the extract was washed with water, 0.5 N sodium hydroxide solution and water, dried and evaporated. The yellow oil obtained (9.5 g) was chromatographed on silica gel (25 ml fractions). Fractions 195-310 contained a mixture of the 27alpha; and the 2ss-fluoro-9ss, 10α-androst-4-en3,17-dione.



  Fractions 311-488 contained almost pure 2p isomer which, after recrystallization from ethyl acetate isopropyl ether, contained pure 2ss-fluoro-9ss, 10? - androst-4-en-3,17- -dione delivered. Melting point: 132-133, UV: A. mnx 240 nm, n = 15,700 [a] 25D = -1040 (in dioxane).



   Example 2
A solution of 5.8 g of 9b, 10α-testosterone in 70 ml
Pyridine was treated with 20 ml of ethyl formate and after
Addition of a solution of 940 mg sodium and 10 ml
Methanol was stirred for 24 hours at room temperature. The
Reaction mixture was taken up in ether. Of the
The extract was washed with 200 ml of 20% strength acetic acid and then drawn out with three times 200 ml of 4% strength sodium hydroxide solution. The alkaline extract was acidified with acetic acid and re-extracted with ethyl acetate. After working up the ethyl acetate extract, 5.0 g of crude 2-hydroxymethylene-17ss-hydroxy-9b, 10α-androst-4-en-3-one were obtained, UV: #max 243 and 304 nm, s = 8800 and
14200.



   Treatment of this compound with perchloryl fluoride according to Example 1 gave 2ss-fluoro-17ss-hydroxy-9P, 10a-androst-4-en-3-one. Melting point: 164-1660 (from methylene chloride-isopropyl ether), UV: #max 242 nm, # = 15,000 [α] 25D = 153 (in dioxane).



   Example 3
Analogously to the procedure described in Example 1, 17a-ethynyl-9P, 10a-testosterone was converted into the sodium salt of 2-hydroxymethylene-17α-ethinyl-17ss-hydroxy-9ss, 10α-androst-4-en-3 -on transferred. By treating this compound with perchloryl fluoride as in Example 1, 2ss-fluoro-17α-ethinyl-17ss-hydroxy-9ss, 10α-androst-4-en-3-one was obtained. Melting point: 146-150, UV: #max 241 nm, # = 14,200.



   This compound was also obtained by reacting the 2ss-fluoro-9ss, 10α-androst-4-en-3-one described in Example 1 with acetylene-potassium in liquid ammonia.



   Example 4
Analogously to the procedure described in Example 1, the sodium salt of 2-hydroxymethylene-17j3- -hydroxy-9ss, 10α-andandrosta- was obtained from 17ss-hydroxy-9ss, 10α-andandrosta-4,6-dien- -3-one. Melting point 4,6-dien-3-one (crude) 244-2460 (dec.); UV: #max 288 nm, s =
11020 obtained with perchloryl fluoride 2α-fluoro-17ss- -hydroxy-9ss, 10α-andandrosta-4,6-dien-3-one, melting point
164-165, UV:

     #max 295 nm, # = 25,300, [α] 25D = - 566 (in dioxane) and 2ss-fluoro-17ss-hydroxy-9ss, 10α-andandrosta--4,6-dien-3-one, melting point 146-147, UV: #max 287 nm, ± = 25,500, [a125 = -6430C (in dioxane) provided.



   Example 5
34.42 g of 17α-methyl-17ss-acetoxy-9ss, 10α-andandrosta-4,6- -dien-3-one were added with 1.5 ml of ethyl formate and 1.1 g
Sodium methylate in 40 ml of benzene heated under reflux for 5 minutes. After cooling the reaction mixture, the precipitated mixture of the sodium salts was the
Hydroxymethylene compounds filtered off and dissolved in water. The solution was acidified with 4N hydrochloric acid and extracted with methylene chloride.

   After working up the extract, it was chromatographed on silica gel, where 2 - hydroxymethylene-17-methy1-17 -acetoxy-9p, 10 -androsta-4, 6-dien-3-one, melting point: 1280 (from ether),
UV: #max 293 nm, # = 18,300, and 2-hydroxymethylene -17α-methyl-17ss-hydroxy-9ss, 10α-andandrosta-4,6-dien-3-one,
Melting point: 135-1380 (from ether), UV: = 296 nm, # = 16,500, [α] 25D = -418 (in dioxane).

   From the latter compound, according to Example 1, 2α-fluorine-17α-methyl-17ss-hydroxy-9ss, 10α-and-and-sta-4,6-dien-3-one, melting point: 122-1230 (from isopropyl ether) , UV: lmax 295 nm, ± = 25 100, [a] 25D = -58QO (in dioxane) and 2ss-fluoro-17α-methyl-17-hydroxy-9ss, 10α-andandrosta-4,6-diene -3-one, melting point: 150-153 (from isopropyl ether), W: #max 288 nm, E = 25000, [α] 25D = -672 (in dioxane).



   Example 6
Analogously to the procedure described in Example 5, 2-hydroxymethylene-17α-ethinyl-17ss-hydroxy was obtained from 17α-ethynyl-17ss-acetoxy-9ss, 10α-and-and-sta-4,6-dien-3-one -9ss, 10? -Androsta-4,6-dien-3-one. This compound was fluorinated as the sodium salt according to Example 1 and gave 2ss-fluoro-17α-ethinyl-17ss-hydroxy-9ss, 10α-andandrosta-4,6-dien-3-one, melting point: 215-218 (from methylene chloride -Isopropyl ether), UV: #max 287 nm, ± = 26,000 [α] 25D = -7520 (in dioxane).



   Example 7
To a suspension of 1.19 g of sodium methylate in 120 ml of benzene, 5.0 g of diethyl oxalate were added at 250. The solution thus obtained was added with 3.12 g of 9ss, 10? -Pregna-4,6-diene-3,20-dione and stirred for 18 hours. The reaction mixture was then diluted with 150 ml of ether, the precipitate was filtered off, washed with ether and dried at 50 in vacuo.



  The crude product thus obtained was fluorinated according to Example 1. From the reaction mixture, 2ss-fluoro-9ss, 10α-prepregna-4,76-diene-3,20-dione, melting point: 156-1570, UV: #max 286 nm, s = 26000; [a] = 5110 (in dioxane) isolated.



   Example 8
Analogously to the procedure described in Example 7, 2P-fluoro-9P, 10a-pregn-4-ene-3.20-dione was obtained from 9ss, 10α-Pregn-4-en-3,20-dione. Melting point: 162-164, UV:: lm3x 242nm, ± = 15300.



   Example 9
Analogously to Example 7, 17α-hydroxy-9ss, 10α-prepregna-4,6-diene-3,20-dione was converted into 2ss-fluoro-17α-hydroxy-9ss, 10α-prepregna-4,6 -diene-3,20-dione. Melting point: 232-2380.



   Example 10
Analogously to Example 7, 17α-acetoxy-9ss, 10α -pregna-4,6-diene-3,20-dione was converted into 2ss-fluoro-17α-acetoxy-9ss, 10α-prepregna-4,6 -diene-3,20-dione. Melting point: 204-205, UV: #max 287 nm, # = 26,100.



   Example 11
Analogously to Example 7, 21-acetoxy-9ss, 10a-prepregna-4,6-diene-3,20-dione was converted into the 2? - Fluoro- 21 - acetoxy- -9ss, 10 - pregna - 4,6 - diene -3,20-dione obtained melting point: 166-168, UV: #max 286 nm, # = 25,000.

 

Claims (1)

PATENT CLAIM Process for the preparation of new 9ss, 10α-steroids of the formula EMI3.1 in which R1 is a halogen atom and R2 is a carbonyl group or one of the groups EMI3.2 denote, where OR is a hydroxyl, alkoxy or acyloxy group, X is hydrogen, a halogen atom or a hydroxyl or acyloxy group; Y represents hydrogen or a hydroxy, an alkoxy or acyloxy group and Z represents hydrogen or a lower alkyl, a lower alkenyl or a lower alkynyl group, as well as # 6 derivatives thereof, characterized in that a 9ss, 10α-steroid of the formula EMI3.3 in which R4 represents hydrogen or an esterified carboxyl group, or an A6 derivative thereof is treated with a halogenating agent in the presence of a base.