IL23183A - 13beta-n-propyl-18,19-bis-nor-progesterone and process of preparation thereof - Google Patents

Description

C O H E N Z E D E K & S P I S B A C H REGD. PATENT ATTORNEYS 24, LEVONTIN STR., P. O. B. 1169 T E L - A V I V P A T E N T S & D E S I G N S O R D I N A N C E 13036/65 SPECIFICATION 13β-η-ϊ¾0ΡΏι-18#19HBIS-H0R-iK0QESm01iE ABB PROCESS OF PBEPARA!PIQH r' 'i WE, ROUSSBL-UCLAF, a FreiMih Body Corporate § ί of 35» Boulevard des Iimilides, Paris 7e» France, O HEREBY DECLARE the nature of this invention and in what manner the same is to be performe to be particularly described and ascertained in and by the following statement :¾ ί I which comprises the steps of: a) reacting 5-methoxy-13£-n-propyl-A * -des-A-gonatrlene-173-ol with an oxidizing agent, b) ethynylating the resulting 5-methoxy-13£-n- 57 Q propyl-Δ ' -des-A-gonatriene-17-one by the action of an ethynylating agent, c) esterifylng the resulting 5-methoxy-13£-n- 579 propyl-17a-ethynyl-A ' -des-A-gonatriene-17j5-ol by the action of an esterifylng derivative of an organic carboxyllc acid having from 2 to 7 carbon atoms, -. d) hydrating the ethynyl function of the resulting ester of the formula wherein Ac represents the acyl of an organic carboxyllc acid having from 2 to 7 carbon atoms, by the action of water in the presence of a hydration catalyst, of the ormula wherein Ac represents the acyl of an organic carboxylic acid having from 2 to 7 carbon atoms, by the action of an alkali metal in liquid ammonia and subjecting the resulting product to an acid hydrolysis, f) reacting the resulting 13£-n-propyl-18,19- 9 bis-nor-Δ -des-A-pregnene-20-ol-5-one with an oxidizing agent, g) reacting the resulting 13£-n-propyl-18,19-bis-nor-A^-des-A-pregnene-5,20-dione with a secondary amine j of the formula NH wherein R and It, are members selected from the group consisting of alkyl having from 1 to 8 carbon atoms and, when taken together with the nitrogen, pyrrolidyl, piperidyl and morpholyl, h) reacting the resulting enamine of the formula consisting of alkyl having from 1 to 8 carbon atoms and, when taken together with the nitrogen, pyrrolidyl, piperidyl and morpholyl, with l-halo-3-chloro-2-butene in an organic solvent, i) reacting the resulting 3-chloro-13j3-n-propyl- 2 9 18,19-bis-nor-4,5-seco-A ' -pregnadiene-5,20-dione with an acid hydrolyzing agent, j) reducing the resulting 13£-n-propyl-18,i9-bis- Q nor-4,5-seco-A -pregnene-3,5,20-trione by the action of hydrogen in the presence of a hydrogena ion catalyst, k) cyclizing the resulting 13£-n-propyl-18,19-bis-nor-4,5-seco-pregnane-3,5,20-trione by the action of a cyclizing agent selected from the group consisting of acidic and basic cyclizing agents, and 1) recovering-said 13j3-n-propyl-18,19-bis-nor-progesterone, A further object of the invention is the obtention of the novel intermediates : a) 5-methoxy-13j3-n-propyl-A^'^'^-des-A- gonatriene-17-one 579 A * - r together with the nitrogen, pyrrolidyl, piperidyl and morpholyl, h) 3-chloro-13jB-n-propyl-18,19-bis~nor- ,5- 2 9 seco-Δ ' -pregnadiene-5,20-dione, i) 13j3-n-propyl-18,19-bis-nor- ,5-seco-A^- pregnene-3,5,20-trione i) 13p-n-propyl-18,19-bis-nor- ,5-seco-pregnane- 3,5,20-trione "" 3 5 k) 3-pyrrolidyl-13£«n-propyl-18,19-bis-nor-Δ ' -I pregnadiene-20-one.

These and other objects of the invention will become more apparent as the description thereof proceeds.

The compound of formula I, 13j8-n-:propyl-18,19- bis-nor-progesterone having a specific rotation /oc/p = II +149.5° ± 1 (c » QA7 in methanol) presents the stereochemical configuration of the natural steroids.

This compound- possesses interesting physiological properties. 130-n-propyl-18,19-bis-nor-progesterone is devoid of all progestomimetic activity at customary doses 1 when administered orally, on the other hand, it has a remarkable anti-androgenio effect. Thus, when administered I at the same time as a product having an androgenic and an anabolic activity such as testosterone acetate, it reduces the effects of the latter on the sexual receptors by about . !| 50 without modifying the anabolic effect.

The process of preparing the 13£-n-propyl-18,19- bis-nor-progesterone, also an object of the invention, is summarized by the flow diagram of the Table. c represen s e acy o an organ c car oxy c ac having from 2 to 7 carbon atoms.

R and ^ are members selected from the group consisting of alkyl having from 1 to 8 carbon atoms and, when taken together with the nitrogen, pyrrolidyl, piperidyl and morpholyl.

This process is essentially characterized in 7 9 that ~5-methoxy-13B-n-propyl-A -des-A-gonatriene-17/3-ol is subjected to the action of an oxidizing agent under the · usual conditions to oxidize the hydroxy group to a ketone.

An ethynylating agent is reacted with the resultant 7 -methoxy-138-n-propyl-A -des-A-gonatriene-17-one (II), 7 9 thus obtaining 5-methoxy-138-n-propyl-17a-ethynyl-A ' ' -des-A-gonatriene-178-ol (III). This latter compound is esterified with the aid of a functional derivative of an organic carboxylic acid, having from 2 to 7 carbon atoms to give a 5-methoxy-13 -n-propyl-17iS-acyloxy-17 t~ethynyl- 5 7 9" Δ -des-A-gonatriene (IV). The ethynyl function of this ester is catalytically hydrated to give a 5-methoxy-13jS- 5 7 n-propyl-17j3-acyloxy-17a-acetyl-A ' ·' -des-A-gonatriene (V).

This compound V is reduced by means of an alkali metal in liquid ammonia; next an acid hydrolysis is effected, thus q ' giving 135-n-propyl-18,19-bis-nor-A -des-A-pregnene-20-ol-5-one (VI), which is subjected to the action of an oxidizing agent. The resultant 138-n-propyl-18,19-bis-nor-A^-des-A-pregnene-5,20-dione (VII), is reacted with a secondary amine of the formula: in which, as well as in the following,- R and which may e en ca or eren , are mem ers se ec e rom e group consisting of alkyl having from 1 to 8 carbon atoms, and, when taken together with the nitrogen, pyrrolidyl, plperidyl and morpholyl, which leads to the 5-enaraino-13p-n-propyl-18, 19-bis-nor-A^^10^^^11^-des-A-pregnadiene-20-one (VIII). This enamine is condensed with a l-halo-3-chloro-2-butene to give 3-chloro-138-n-propyl-18,19-bis- " 2 9 nor- ,5-seco-A * -pregnadiene-5,20-dione (IX). This last product is reacted with an acid hydrolyzing agent to obtain 135-n-propyl-18,l9-bis-nor-4 •,5-seco-A9-pregnene-3,5,20-trione (X), which is reduced by catalytic hydrogenation to 13j3-n-propyl-18,19-bis-nor- ,5-seco-pregnane-3,5,20-trione (XI). This latter is subjected to the action of an acid or basic cyclizating agent and the desired 13S«-n-propyl-18,19-bi3-nor-progesterone, I, is obtained.

The performance of the process of invention may be characterized advantageously by the following points. a) The oxidizing agent utilized to oxidize the hydroxyl 57 ' group of 5-methoxy-13j3-n-propyl-A ' * -des-A-gonatriene- 17j3-ol into the 17 ketone, is preferably chromic acid anhydride, and the reaction is conducted in the presence of sulfuric acid In an acetonic media; b) The ethynylating agent, which is allowed to act upon ' the 5-niethoxy-13£-n-propyl-A * * -des-A-gonatriene-17- one (II) can be any ethynylating agent conventionally used to ethynylate a 17 ketone steroid, .however it is preferable to utilize an alkali metal acetylide in an organic solvent, such as lithium acetylide in a benzene-tetrahydrofuran media. - · g e secon ary amine which is reac ed wi h .8-n-propy - 18, 19-bis-nor-A^-.des-A-pregnene-5,20-dione (VT ), is preferably pyrrolidine and the reaction is conducted at an elevated temperature up to the reflux temperature. h) The 1-h 1 o-3-chl or0- -butene which is condensed with the 5-enamino-13£-n-propyl-18, 19-bis-nor-A^ ( 10) ' ^ ( H ) des-A-pregnadiene-20-one (VIII ) is l,3-dichloro-2- butene and the reaction is conducted in dimethylformamide in the presence of potassium iodide. i ) The acid hydrolyzing agent which is reacted with 2 9 3-chloro-13j3-n-propyl-18, 19-bis-nor-4, 5-seco-A ' - pregnadiene-5,20-dione (IX), is a strong mineral acid such as sulfuric acid, j ) The catalytic hydrogenat ion of 13S-n-propyl-18,19-bis- Q nor-4,5-seco-A -pregnene-3, 5,20-trione (X), is accomplished in a hydroxylated solvent suc as ethanol, in the presence of a small quantity of a basic reacting compound, such as a tertiary amine,' for example, triethylamine and by utilizing a palladized carbon black hydrogenation catalyst. k) The acidic cyclizating agent which is reacted with 13|3-n-propyl-18, 19-bis-nor-4, 5-seco-pregnane-3, 5,20- trione (XI), is preferentially hydrochloric acid, the reaction being conducted in an acetic acid media. 1 ) The basic cyclizating agent which is reacted with 13j5-n-propyl-18, 19-bis-nor- , 5-seco-pregnane-3, 5,20- trione is preferentially pyrrolidine, which leads to an intermediary compound, 3-pyrrolidyl-13£-n-propyl-18, 19- bis-nor-Δ 3 ' 5 -pre nadiene-20-one (XII) . An acid hydrolysis of this compound, preferably by acetic acid j . gives the desired 130-n-propyl-18,19-bis-nor-progesterone; The starting product for the process described, or 5-methoxy-13£-n-propyl-A-*' ^ ' ^-des-A-gonatriene-17j3-ol, may be prepared according to the process described in United States Patent No. 3, 115, 507, issued December 24, 1963.

The following example illustrates the invention. It is to be understood, however, that it presents no limiting characteristics .

EXAMPLE ς 7 Q Step I: 5-methoxy-13g-n-propyl-A -des-A-gonatriene- 17-one, II.

A solution of 24 gm of 5-methoxy-13p-n-propyl- des-Α-Δ 5 7 9 -gonatriene-17j3-ol in 480 cc of pure acetone was cooled to +2°C. and within a space of 5 minutes the following solution was introduced : · Chromic acid anhydride. . . 7.65 gm Water .'·. . 76.5 cc Concentrated sulfuric acid. ... 7.6 cc Next the reaction mixture was agitated for 3 hours at +20*C , then 8.5 cc of methanol were introduced. The mixture was further agitated for another 15 minutes, then poured into 4, 750 cc of water. The aqueous mixture was extracted with methylene chloride. The extracts were washed first with an aqueous saturated solution of sodium bicarbonate, and thereafter with water until the wash waters were neutral and finally dried. The extract was then evaporated under vacuum to dryness, and the solid residue obtained was crystallized from isopropyl ether.

After vacuum filtering and drying 19.2 gm of 5-methoxy-13£-i n-propyl-Δ 5 ' 7 * 9 -des-A-gonatriene-17-one (II), were i isolated. This product occurred, in the form of colorless ys s, v ng a me ng po n o . an a spec c rotation a D - +67.7° (c » 0.5 in methanol).

The product was insoluble in water, and soluble in acetone, benzene and methylene chloride.

This compound is not described in the literature. 7 9 Step II: 5-methoxy»133-n-propyl-17a~ethynyl-A ' ' -des-A- gonatriene-173-»ol (III).

A solution of lithium acetylide in a benzene-tetrahydrofuran media was prepared by allowing acetylene to bubble through a mixture of 1560 cc of tetrahydrofuran and 1560 cc of a normal solution of butyl-lithium in benzene over a period of 3 hours < at.30-35°C This solution was heated to 50°C. and, over a period of 5 minutes, 12.5 gm Of 5-methoxy-13j6-n-propyl-Δ -des-A-gonatriene-17-one (II), dissolved in 175 cc of tetrahydrofuran, were introduced. The mixture was heated to reflux for 2 hours, then cooled to 0°C , and within a period of 30 minutes, without exceeding 20°C, 3000 cc of an aqueous saturated solution of ammonium chloride were introduced therein.

The solution was decanted. The aqueous phase was separated and extracted with ether. The combined organic phases were washed with water, dried over sodium sul ate and evaporated to dryness .

A resin was thus obtained, which was dissolved in methylene chloride and subjected to chroma ography through silica gel. On elution with methylene chloride containing 2% of acetone, 12.17 gm of 5-methoxy-13j3-n- 5 7 9 propyl-17cx-ethynyl-A * -des-A-gonatriene-17£-ql (III), - · were ob ained. This product was utilized as such fo e following step.

This compound is not described in the literature.

Step III: 5-methoxy-13β-n-p opy 1 — 7/5-ace oxy-17α-e hynyl- Δ^'^* ^-des-A-gonatriene (IV, Ac = CH^CO).

To a solution of 12.11 gm of 5-methoxy-13/3-n- opyl-17a-ethynyl-A 5 7 pr ' 9-des-A-gonatriene-17jS-ol (III), in 121 cc of acetic acid anhydride, 6.055 gm of p-toluene sulfonic acid monohydrate were added at a temperature of 25°C. For a period of 20 hours this mixture was agitated at a temperature of 20-25°C. Then, 600 cc of water were introduced in the reaction mixture and it was agitated for 2 hours at 20-25°C. The aqueous mixture was extracted with methylene chloride. The combined organic phases were washed successively with water, then with a saturated solution of sodium bicarbonate and finally with water until the wash waters were neutral, dried over sodium sulfate and evaporated under vacuum to dryness. In this manner a resin was obtained, which was dissolved in methylene chloride and subjected to chromatography through silica gel. On elution with methylene chloride containing 1 of acetone, 11.91 gm of 5-methoxy-13/S-n-propyl-17i3-acetoxy-17a-ethynyl-A5,7,9-des-A-gonatriene-(IV, with Ac = H^CO) were recovered. The product obtained was utilized as such for the following step.

This compound is not described in' the literature.

- - - - . (V, with Ac a CH^CO), were recovered. The product was utilized as such for the following step.

This compound is not described in the literature.

Step V: 13ff-n-propyl-18 , 19÷~bis-nor-A^-des -A-pregnene-5 , 20- dione (VII) . 625 cc of anhydrous ammonia were condensed at a temperature of -75°C , and, within the space of 15 minutes, 1.75 g» of lithium, cut into small pieces, were introduced therein. The mixture was agitated for a period of 30 minutes at -70°C , then, within a period of 10 minutes, 125 cc of anhydrous ether were added thereto. Thereafter, within a period of 10 minutes, a solution of 2.5 m of -methoxy pr toxy 5 * 7 -13£-n- opyl-17j5-ace -17ct-acetyl-A ' 9 -des-A-gonatriene (V, with Ac =» CH CO) in 125 cc of anhydrous ether was added. Finally, within a period of 10 minutes, another 125 cc of anhydrous ether were added. The reaction mixture was then subjected to a vigorous agitation, first for 2 hours at -70*C , then for 3 hours at - 0°C. Then, at - 0*C. , 75 cc of methanol were added within a period of 30 minutes . The ammonia was distilled from the reaction mixture and the temperature was allowed to rise to +20°C . Then, under agitation, first 625 of methylene chloride, then 2 0 cc of water were added. The mixture wa§ allowed to separate, the organic phase was decanted and washed 3 times with 250 cc of water.

Thereafter, 5 cc of a 2 :1 per volume mixture of methanol and concentrated hydrochloric acid were added and the mixture was heated to +70°C. to remove the ether and - ' e me y ene c or e. e mix ure was he a + . o. 10 minutes, cooled to room temperature and an aqueous solution of sodium bicarbonate was added. The mixture was extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness under vacuum. In this manner, 2.34 gm of a resin were obtained, which was dissolved under atmosphere of nitrogen in 42.5 cc of methanol. 4.7 cc of concentrated hydrochlori acid were added thereto and the mixture was heated at reflux for 10 minutes. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of sodium bicarbonate. This aqueous mixture was then extracted with methylene chloride. The organic phase was washed with water and dried.

The extract was then evaporated to dryness and a resin. as obtained which was dissolved in 43.6 cc of pure acetone. To this solution, cooled to 0°C, within a period of 3 minutes, the following solution was added: Chromic acid anhydride........ 665 mg ' Concentrated sulfuric acid.... 0.66 cc Water... 6.6 cc This reaction mixture was agitated for 3hhours at 20-25°C. 7.4 cc of methanol were then Introduced into this mixture, which was agitated for a further 5 minutes. Then the mixture was poured into 400 cc of water. The aqueous mixture was extracted with methylene chloride.

The organic phase was washed, first with a saturated aqueous- solution of sodium bicarbonate, then with water and dried. The organic phase was then evaporated to dryness under atmosphere of nitrogen and 1.15_^gm of resin was obtained. , methylene chloride, 250 cc of a saturated aqueous solution of sodium chloride were added, and the solution was again extracted with methylene chloride. By an identical treatment, a further 0.85 gm of resin was recovered.

The two resins were combined by dissolving them in 4 cc of isopropyl ether heated to reflux. On cooling, 440 mg of crystals were separated, which, recrystallized from isopropanol, yielded 370 mg of 13^-n-propyl-18,19-bis-nor-A^-des-A-pregnene-5,20-dione (VII). This product had a melting point of 167°C. and a specific rotation a D « +46.6° + 0.5 (c « 0.8 in methanol).

The product occurred in the form of colorless crystals insoluble in water, slightly soluble in hot isopropanol and soluble in methylene chloride.

This compound is not described in the literature. isolated, having a melting point of 171°C. and a specific rotation /a/D » +213* ± 1 (e « 0.66 in benzene).

The product occurred in the form of yellow crystals, insoluble in water, methanol, and soluble in benzene.

This compound is not described in the literature.

Step VII: 3-chloro»-13.e-n-propyl'-18>19-'bis-nor-4,5~seco» A2 Q-pregnadiene-5» 0-dione (IX).

While operating in the absence of' light and at a minutes, then 0.21 cc of freshly distilled 1,3-dichloro-2-butene were added. The mixture was agitated for 4 hours at 0°C. under atmosphere of nitrogen. Next, 0.4 cc of water was added thereto and the temperature was raised to 90°C. within a period of 30 minutes and maintained at this temperature for 2 hours. The mixture was then cooled to room temperature, diluted with 20 cc of water and extracted with methylene chloride. The extract was washed with water, dried and evaporated to dryness. The residue was dissolved in methylene chloride and purified by passing it through "Plorisil". After evaporation, 50Q mg of product were obtained.

Claims (1)

1. c ) esterifying the resulting 5-methoxy-13j3-n--propyl -17a-ethynyl -Δ 5 7 9 -des-A-gonatriene-17j8-ol by the action of an esterifying derivative of an organic carboxylic acid having from 2 to 7 carbon atoms, d) hydrating the ethynyl function of the resulting ester of the formula wherein Ac represents the acyl of an organic carboxylic acid having from 2 to 7 carbon atoms, by the action of water in the presence of a hydration catalyst, e ) reducing the resulting 17a-acetyl-gonatriene of the formula wherein Ac represents the acyl of an organic carboxylic acid having from 2 to 7 carbon atoms, by the action of an alkali metal in liquid ammonia and subjecting the resulting product to an acid hydrolysis, 73 k) cyclizing the resulting 13j3-n-propyl-18,19' 7 bis-nor- ,5-seco-pregnane-3J,5J20-trione by the action of a j 75 cyclizing agent selected from the group consisting of 76 acidic and basic cyclizing agents, and 77 1) recovering said 13]3-n-propyl-18J,19-bis-nor-78 progesterone. 5. The process of claim , step a) wherein said oxidizing agent is chromic acid anhydride and the reaction is conducted in the presence of sulfuric acid in an acetonic media. 6. The process of claim 4, step b) wherein said ethynylating agent is lithium acetylide in a benzene- tetrahydrofuran media. 7. The process of claim 4, step c) wherein said esterifying derivative of an organic carboxylic acid having from 2 to 7 carbon atoms is acetic acid anhydride in the presence of p-toluene sulfonic acid as a catalyst. 8. The process of claim 4, step d) wherein said hydration catalyst is a mercuric catalyst selected from the group consisting of the mercury salt of p-toluene sulfonamide and an ion exchange resin containing mercuric cations and the reaction is conducted. in an aqueous- alkanolic media. 9. The process of claim 4, step e) wherein said alkali metal is lithium and the reducing reaction is conducted in the presence first of diethyl ether and then of methanol and the subsequent acid hydrolysis is effected j ! by a strong mineral acid. j ■ i! I . I I 10. .The process of claim 4, step f ) wherein said oxidizing agent is chromic acid anhydride and the reaction is conducted in the presence of sulfuric acid and in an acetonic media. 11. The process of claim 4, step g) wherein said secondary amine is pyrrolidine and the reaction is conducted at elevated temperatures up to the reflux temperature. 12 . The process of claim 4, step h) wherein said l-halo-3-chloro-2-butene is lj, 3-dichloro-2-butene and the reaction is conducted in dimethylformamide in the presence of potassium iodide. 13. The process of claim 4, step i) wherein said acid hydrolyzing agent is concentrated sulfuric acid. 14. The process of claim 4, step j) wherein said hydrogenation catalyst is palladized carbon black and the ί reaction is conducted in the presence of a small amount of triethylamine in an alkanolic media. 15. The process of claim 4, step k) wherein said cyclizing agent is hydrochloric acid in acetic acid and 13jS-n-propyl-18, 19-bis-nor-progesterone is recovered. 16. The process of claim 4, step k) wherein said cyclizing agent is pyrrolidine and 3-pyrrolidyl-13jS- 3,5 n-propyl-18, 19-bis-nor-A -pregnadiene-20-one is recovered, which compound is. subjected to an acid hydrolysis to give 13jS-n-propyl-18, 19-bis-nor-progesterone. 3. 13£-n-propyl-18,19-bIs-ηοΓ-Δ^-des-A■ pregnene-20-ol-5-ofte. 24. 13£-n-propyl-18,19-bis-nor-^-des-A-pregnene-5,20-dione. 25. An enamine of the formula wherein R and are members selected from the group consisting of alkyl having from 1 to 8 carbon atoms and, when taken together with the nit ogen, pyrrolidyl, piperidyl and morpholyl. 26. 5-pyrrolidyl-13jB-n-propyl-18,19-bis-nor 5(10),9(11) Δ -des-A-pregnadiene-20-one. 3-chloro-13j3-n-propyl-18,19-bis-nor- 2,9 seco-Δ -pregnadiene-5 O-dione. 9 28. 133-n-propyl-18,19-bis-nor-4,5-seco^ -pregnene- , ,20- ione. DATED THIS 18th day of COHEN ZBDBK & SPISBACH P.O.BOX 1169, TEL AVIV Attorneys for Applicants,