1.ApplicationNumber: US-26649163-A
1.PublishNumber: US-3351639-A
2.Date Publish: 19671107
3.Inventor: JR. GEORGE RODGER ALLEN,
WEISS MARTIN JOSEPH

4.Inventor Harmonized: ALLEN JR GEORGE RODGER()
JOSEPH WEISS MARTIN()

5.Country: US
6.Claims:

7.Description:
(en)United States Patent l 3,351,639 17-ALKYL-20-KETO SUBSTITUTED PREGNENES,
PREGNADIENES AND METHODS OF PREPAR- ING THE SAME George Rodger Allen, In, Old Tappan, and Martin Joseph Weiss, Oradell, N.J., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Filed Mar. 20, 1963, Ser. No. 266,491 2 Claims. (Cl. 260-3973) This invention relates to new organic compounds. More particularly, it relates to 17-alkylated pregnenes, pregnadienes and methods of preparing the same.
The new steroids of the present invention may be illustrated by the following formula:
wherein R is an alkyl radical; R is selected from the group consisting of hydrogen, hydroxyl, halogen and alkanoyloxy radicals; R is selected from the group consisting of hydrogen, lower alkyl and chlorine; and:
| R1 C4 (CBRB) is a radical selected from the group consisting of:
then R is selected from the group consisting of hydrogen 3,351,639 Patented Nov. 7, 1967 and halogen and when:
then R is hydrogen.
Also included within the purview of the present invention are 17a-alkyl3-alkoxy-6-hydrogen or lower alkylpregna-S-en-ZO-ones which are described in the examples hereinafter.
The present compounds are, in general, white crystalline solids. They are substantially insoluble in water and somewhat soluble in the usual organic solvents such as benzene, petroleum ether and the like.
A number of compounds of this invention can be prepared by treatment of the corresponding A -3fi-ols (I) with appropriate reagents. Thus, treatment with [i-chloroa,a,fi-trifluoroethyldiethylamine produces the 3,8-fluoroderivatives (II), treatment with thionyl chloride gives the 3B-chloro derivatives (III), and treatment with potassium t-butoxide and an alkyl halide furnishes the 3,8- alkoxy derivatives (IV). The B-unsubstituted methylene derivatives can be obtained by treatment of the corresponding A -3 3-chloro (V) derivative with sodium and an alcohol such as amyl alcohol, a procedure which also usually reduces the ZO-keto group to a 20-01. The desired ZO-ketone (VI) is then obtained by oxidation of the 20-01. The A derivatives can be prepared by reduction of the corresponding A -3-ketone (VII), preferably with a metal hydride to the A -3B-ol (VIII), which with acetic acid undergoes dehydration with the formation of the A -diene (IX). When lithium aluminum hydride is utilized as the reducing agent, the ZO-keto group also undergoes reduction and it is necessary to oxidize, after formation of the 3,5-diene, to a ZO-ketone (XI). With metal hydrides, such as sodium borohydride, in the presence of an alcoholic solvent, such as methanol, as the reducing agent preferential reduction of the 3-ketone can be achieved and an oxidation step is not necessary. Thus, use of the latter reagent also affords the A -3fl-ol-20- ketones (X). Similar treatment of a A -3-ketone will produce the M' -3 601 (XIII). This novel method for the preferential reduction of a 3-carbon1yl group in a 17- alkylpregnl-ene (or 4,6-diene)-3,20-dione to give the corresponding A or A -3,8-ol is to be considered part of this invention. Reaction of the A -3B-ols or the A 3/3-ols with alkanoylating agents will furnish the corresponding Bfi-alkanoyloxy derivatives. These reactions are illustrated by the following equations, and more specifically, by the examples which follow.
F- \p t no I O:
XIII NaBH l CHgOH l il 1 HO-- I XIV The compounds of the present invention possess progestational activity and are useful in place of known progestational steriods, such as progesterone, in the treatment, for example, of habitual abortion. These compounds have an additional utility in that they are effective when administered by the oral route. Furthermore, these compounds are also useful by oral administration for the inhibition of conception.
The following examples illustrate in detail the preparation of the compounds of the present invention.
Example 1 .--Preparatiorz 0 f 1 7 u-ethy l-3 ,B-fluoropregn-S en-ZO-one (II) A solution of 340 mg. (1 mmole) of 17ot-ethylpregnenolone [Tetrahedron Letters, [11], 489 (1962)] and 200 mg. (1.06 mmoles) of ,B-chloro-a,a,fi-trifluoroethyl diethylamine in 10 ml. of methylene chloride is allowed to stand in the refrigerator 17.5 hours. The solution is diluted with methylene chloride, washed with sodium carbonate solution and water, dried over magnesium sulfate and evaporated. Crystallization of the residue from methanol gives white crystals, melting point 178- 180 C.; [ch 64 (c. 0.69, chloroform);
A533; 5.91; Example 2.Prepamti0n of 3 3-flu0ro-17u-methylpregn- -en-20-0ne (II) Treatment of 146 mg. (0.44 mmole) of 17amethylpregnenolone [Helv. Chim. Acta, 32, 270 (1949)] with 94 mg. (0.5 mmole) of fl-chloro-a,u,fl-trifiuoroethyldiethylamine in ml. of methylene chloride as described in Example 1 gives, after recrystallization from dilute methanol, white crystals, melting point 129131 C.; [a1 57.5 (c. 1.1, chloroform);
methylpregn-5-en-20-0ne (II In the manner described in Example 1, 500 mg. of 17a-ethyl-6-methylpregnenolone [Chemistry and Industry, 118 (1963)] is treated with 300 mg. of fi-chloro-a,a,fltrifiuoroethyldiethylamine. The product is chromatographed on silica gel, and the solids eluted by benzene XII are recrystallized from dilute methanol to give white crystals, melting point 127 C.; [ch -73 (c. 1.1, chloroform) max.
Example 4.Preparati0n 09 3acet0xy17a-0ctylpregna- 3,5-dien-20-0=ne A solution of 2.00 g. of 17a-octylprogesterone [Chemistry and Industry, 118 (1963)] in 30 m1. of acetic anhydride and 30 ml. of acetyl chloride is heated on the steam bath for 2 hours. The resulting solution is chilled in ice and poured with stirring onto cracked ice. After the excess reagents hydrolyze, the mixture is extracted with methylene chloride. The extract is washed repeatedly with water, dried over magnesium sulfate and the solvent removed. The residue has m2 235 m ((218,000) and KBr max.
Example 5.-Preparati0n of 17ot-0ctylpiregnen0l0ne (I) A solution of 2.00 g. of 3-acetoxy-l7w-octylpregna-3,5- dien-20-one (Example 4) and 2.00 g. of sodium borohydride in 125 ml. of methanol and 60 ml. of tetrahydrofuran containing 5 ml. of water is kept at room temperature for 18 hours. The solution is diluted with Water and extracted with methylene chloride. The organic solution is dried over magnesium sulfate, and the solvent is evaporated to give material which has no appreciable ultraviolet absorption at 20 7/ ml. and has Treatment of 17a-octylpregnenolone (Example 5) with ,fl-chloro-a,oz,B-trifiuoroethyl diethylamine in the manner of Example 1 produces 3fl-fiuoro-17a-octylpregn-5-en-20- one.
7 Example 7.-Preparatin of 3,8-chl0r0-17a-e2thylpregn-5- en-ZO-one (III) Example 8.Preparati0n of SB-chloro-I 7a-0ctylpregn-5- en-ZO-one (111) When l7a-octylpregnenolone (Example is reacted with thionyl chloride in the manner of Example 7, the product 3 fl-chloro-17a-octylpregn-5-en-20-one is obtained.
Example 9.-Preparati0n of 17a-ethyl-3B-meth0xy-6- mefhylpregn-5-en-20-0ne (IV) To a solution obtained by the interaction of 59 mg. of potassium with 20 ml. of t-butyl alcohol is added 358 mg. of 17a-ethyl-6-methylpregnenolone, 15 ml. of t-butyl alcohol being used to aid in the transfer. The solution is heated at reflux temperature with mechanical stirring and a solution of 5 ml. of methyl iodide in 20 ml. of t-butyl alcohol is added dropwise over 2 hours. Heating and stirring are continued for an additional 2 hours. The cooled mixture is distributed between Water and methylene chloride. The organic solution is washed with saline,
dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel. The material eluted by the first 125 ml. of a benzene-ether (99:1) solution is recrystallized from dilute methanol to give White needles, melting point 162l64 C.;
Example 10.Preparation of I 7m-ethyl-3/3-0ctyl0xypregn- 5-en-20-one (IV) Treatment of 17u-ethylpregnenolone with potassium t-butoxide and octyl iodide as described in Example 9 produces 17a-ethyl-3,B-octyloxypregn-Sen-20-one.
Example I1.Preparati0n of 3fl-eth0xy-I7a-00tylpregn- 5-en-20-0ne (IV) When 17a-0ctylpregnenolone is reacted with potassium t-butoxide and ethyl iodide in the manner of Example 9 the product 3p-ethoxy-17a-octylpregn-5-en-20-one is obtained.
Example 12.Preparati0n of I7a-ethyl-3/3,20-dihydr0xypregn-4-ene (VIII) A mixture of 692 mg. of 17a-ethylprogesterone [Chemistry and Industry, 118 (1963)] and 130 mg. of lithium aluminum hydride in 30 ml. of ether is heated at reflux temperature for 30 minutes with magnetic stirring. Ethyl acetate is added slowly, followed by water. The organic solution is dried over magnesium sulfate and evaporated to give a solid which has no appreciable ultraviolet absorption and no absorption in the carbonyl region of its infrared spectrum.
Example 13.Preparation of I7a-ethyl-3/3-hydr0xypregn-4-en-20-one (X) A solution of 500 mg. of l7a-ethylprogesterone and 500 mg. of sodium borohydride in 25 ml. of methanol, 15 ml. of tetrahydrofuran and 1 ml. of water is kept at room temperature for 21 hours. The solution is distributed between water and methylene chloride. The organic solution is dried over magnesium sulfate and evaporated to give a solid residue which is absorbed onto silica gel.
The solid contained in the benzene-ether (:5) eluates is recrystallized from acetone-hexane to furnish white plates, melting point 179l8l C.; [111 +43 (c. 1.48, chloroform); no appreciable ultraviolet absorption at 20 /ml.;
max.
Example I4.Preparati0n of 3B-hydr0xy-17a-0ctylpregn-4-en-20-one (X) Treatment of 17a-octylprogesterone with sodium borohydride in the manner of Example 13 gives the product 3fl-hydroxy-17a-octylpregn-4-en-ZO-one.
Example 15.-Preparati0n 0) I7a-ethyl-20-hydr0xypregna-3,5-diene (IX) MoOH m.
228, 234, 242 mp and x53; 3.0a
Example 16.Preparati0n of 17a-ethylpregna-3,5- diene-ZO-one (XI) To an ice-chilled slurry of 700 mg. of chromium trioxide in 10 ml. of pyridine is added a solution of 17aethyl-20g-hydroxypregna-3,5-diene (Example 15) in 15 ml. of pyridine. The mixture is then magnetically stirred for 30 minutes and then kept at room temperature for 22 hours. The mixture is poured into water and extracted with methylene chloride. Filtration is necessary to remove some undissolved solid. The organic solution is dried over magnesium sulfate and evaporated. The residue is extracted with hot benzene and the extract is adsorbed onto silica gel. The column is washed with benzene and the solid remaining on evaporation of the solvent is recrystallized from dilute methanol to give white crystals, melting point 155157 C.;
228, 234, 248 m, and W max.
Example I 7.Preparati0n of I 7 ot-ethylpregna-3 ,5 dien-ZO-one (XI) A solution of 17a-ethyl-3fl-hydroxypregn-4-en-20-one (Example 13) in ml. of 50% acetic acid is heated at reflux temperature for 45 minutes. After 10 minutes a solid separates from the solution. The mixture is chilled and filtered to give 360 mg. of white crystals, melting point -458 C. This material is recrystallized from methanol to give white needles, melting point 155l57 C. The identity of this material with that of Example 16 is shown by melting point and infrared and ultraviolet spectral comparisons.
Example I8.Preparali0n of I 7ot-0ctylpregna-3,5- dien-ZO-one (XI) Treatment of 3B -hydroxy-l7a-octylpregn-4-en-20-one (Example 14) with acetic acid as described in Example 17 produces 17a-octylpregna-3,5-dien-20-one.
Example I9. Preparation of 3fl-acet0xy-17a-ethylpregn-4-en-20-0ne (XII) Treatment of 3B hydroxy-17a-octylpregn-4-en-20-one (Example 14) with acetic anhydride by the procedure of Example 19 gives 3,8-acetoxy-17a-octylpregn-4-en-20-one.
When 17a-ethyl-6a-methylprogesterone [Chemistry and Industry, 118 (1963)] is reacted with sodium borohydride by the procedure described in Example 13 the product 17oz ethyl-3 8-hydroxy-6a-methylpregn-4-en-20- one is obtained.
Example 23.Preparatin of 3fl-acet0xy-I7ot-ethyl6amethylpregn-4-en-20-0ne (XII) Treatment of 17ot-ethyl-3fi-hydroxy-6ix-methylpregn-4- en-20-one (Example 22) with acetic anhydride in the manner of Example 19 is productive of 3p-acetoxy-17aethyl-6wmethylpregn-4-en-20-one.
Example 24 .Preparation of 1 7oc-etl2yl-6-mellzylpregna-3 ,5 -dien-20-0ne (XI) When 17oz ethyl-3,8-hydroxy-6ot-methylpregn-4-en-20- one (Example 22) is treated with acetic acid in water according to the procedure described in Example 17, the product is 17a-ethy]-6-methylpregna-3,5-dien-20-one.
Example 25.Preparatian of I 7at-ethyl-3 8-hydroxypregna-4,6-dien-20-0ne (XIV) A solution of 400 mg. of 17rx-ethylpregna-4,6-diene- 3,20-dione [Chemistry and Industry, 118 (1963)] in 150 ml. of methanol, 10 ml. of tetrahydrofuran and 2 ml. of water is treated with 400 mg. of sodium borohydride and kept at room temperature for hours. Most of the solvent is removed and the concentrate is distributed between water and methylene chloride. The organic phase is dried over magnesium sulfate and evaporated. The residue is recrystallized from methanol to give white needles, melting point 198205 C.;
McOI-I 2 2 23 247 2.80, 5.95, 6.10, 6.2071
Example 26.-Preparation 0f 3fi-aceloxy-I 70t-Llllylpregna-4,6-clien--one (XV) Treatment of 60 mg. of 17a-ethyl-3fl-hydroxypregna 4,6-dien-20-one (Example with 1 ml. of acetic anhydride in 10 ml. of pyridine in the manner described in Example 19 produces White crystals. This solid is recrystallized from dilute methanol to give white crystals, melting point 176-178 C.;
Example 27.Preparazz'on 0f l7u-ethyl-6-methylpi egna-4,6-dien-3,20-di0ne (XIII) AKBr max.
max.
10 The extracts are washed successively with water, 1% sodium hydroxide solution and finally with saline. Removal of the solvent gives a residue which crystallizes from acetone-hexane to give White needles, melting point 182-183 C.; +51 (c. 0.97, chloroform);
290 H1,u (623,600); AH; 5.91, 6.00, 6.15, 6.30
Example Z8.Preparali0n 0] I7u-etl1yl'3,B-hydr0xy- 6-m tlzylpregna-4,6-dien-20-0ne (XIV) Treatment of 17a-ethyl-6methylpregna-4,6-diene-3,20- dione (Example 27) with sodium borohydride in the manner of Example 25 is productive of 17u-ethyl-3fl-hydroxy- 6-methylpregua-4,6-dien-20-one.
Example 29.-Preparalion 09 I 7 a-eth yl-6 -metlzy l- 3fi-0ctan0yl0xypregna-4,6-dien-2 0-0ne (XV) Treatment of 17ot-ethyl-3[3-hydroxy G-methylpregna- 4,6-dien-20-one with caprylic anhydride in pyridine solution in the manner described in Example 19 gives 17aethyl-6-methyl-3B-octanoyloxypregna-4,6-dien-20-one.
Example 30.- Preparati0n 0 I7ot-0ctylpregna- 4,6-diene-3,20-di0ne (XIII) Treatment of 17a-octylprogesterone [Chemistry and Industry, 118 (1963)] in dioxane saturated with hydrogen chloride with dichlorodicyano-p-benzoquinone in the manner described in Example 27 gives 17a-octylpregna- 4,6-diene-3,20-dione.
Example 31.-Preparati0n of 3fl-hyd'r0xy-I7a-octylpregna ,6-dien-20-one (XIX) Treatment of 17ot-octylpregna 4,6-diene 3,20-dione (Example 30) with sodium borohydride according to the procedure of Example 25 furnishes 3B-h ydroxy-17ot-octylpregna-4,6-dien-20-one.
Example 32.Preparati0n of 3/3-acel0xy-I7ot-0ctylpregna-4,6-a ien-20-ane (XV) Treatment of 3p-hydroxy-17ot-octylpregna-4,6-dien-20- one (Example 31) with acetic anhydride in pyridine in the manner of Example 19 furnishes 3fi-acetoxy-l7aoctylpregna-4,6-dien-20-one.
Example 33.Preparation of 6:1,706-6POW-1 7a-etlzylpregn-4-ene-3,20-dione A solution of 2 g. of 17ot-ethylpregna-4, 6-diene-3,20- dione, 260 ml. of methylene chloride and a solution of 6.43 g. of monoperphthalic acid in 134 ml. of ether is kept at room temperature, protected from moisture, for 72 hours. The resulting phthalic acid is removed by filtration. The filtrate then is diluted with 300 ml. of methylene chloride, washed with saturated sodium carbonate solution, saline and then with water, dried with anhydrous magnesium sulfate and evaporated to dryness. Trituration with. ether followed by filtration gives 81% mg. (40%) of product, melting point 218-222 C. Two recrystallizations from methylene chloride-ether gives white crystals, melting point 226-230 C. [111 +49 (0.99% in CHCl A3152 21-1 m (614,650); Ail; 5.86, 5.95. 6.11
Example 34.-Preparati0n 0f 17a-0ctylpregna- 4,6-diene-3,20-di0ne Treatment of 17a-0ctylprogesterone (7.7 g.) with 2,3- dichloro-5,6-dicyano-p-benzoquinone in the manner described in Example 27 is productive of crude 17ot-octylpregna-4,6 -diene-3,20-dione (7.74 g.) which is subjected to partition chromatography on diatomaceous earth. The system heptanezZ-methoxy ethanol is used; the column is packed with 750 g. of diatomaceous earth. The first 950 ml. of eflluent contains a negligible amount of material; the next 950 ml. of efiluent contains the major peak which on evaporation gives 2.5 g. of product; [111 (0.40% in CHCl max. 283 mp. (619,500); Affif; 5.88, 5.98, 6.17, 6.3;; Example 35.Preparation of 6a.,7tx-ep0xy-17a-0ctylpregn-4-ene-3,20-di0ne max. Example 36.-Preparati0n of 6-chI0r0-17a-ethylpregna-4,6-diene-3,20-dione A solution of 30 ml. of glacial acetic acid saturated at room temperature with hydrogen chloride is added 500 mg. of 6a,7a-epoxy-17a+ethylpregn 4-ene-3,20-dione (Example 33). After standing for four hours, the solution is poured onto 60 ml. of iced water and stirred for minutes. The amorphous material is collected by filtration and recrystallized from ether-petroleum ether to give 203 mg. (39%) of product, melting point 157160 C. Recrystallization from methylene chloride-ether gives white crystals, melting point 166170 C., [aJ +28 (0.78% in CHCl W 285 mp (618,200); x55; 5.89, 6.02, 6.24, 6.31,.
Example 37.Preparati0n of 6-chl0r0-17a-0ctylpregna-4,6-diene-3,20-di0ne A333 284 my. (627,600); x219 5.91, 6.02, 6.10, 0.22,.
Example 38.Preparati0 n 0f 6-chl0r0-l7a-ethyl- 3,8-hydroxypregna-4,6-dien-20-one To a solution of 200 mg. of 6-ch1oro-l7a-ethylpregna- 4,6-dien-3,20-dione (Example 34) in 75 ml. of methanol, 5 ml. of tet-rahydrofuran and 1 ml. of water is added 200 mg. of sodium borohydride; the solution is kept at room temperature for 16 hours. The solvents are removed, and the residue is distributed between methylene chloride and a 1% sodium hydroxide solution. The organic layer is washed with saline, dried over magnesium sulfate and evaporated. The residue crystallizes from acetone-hexane to give white crystals, melting point 192193 C.,
235, 242, 250 mp; x335; 2.85, 5.02,.
Example 39.Preparati0n of 6-chl0r0-17a-0cryl-3B- hydroxypregna-4,6-dien-20-0ne XIVIcOH max.
Treatment of 6-chloro-17a-octylpregna-4,6-diene-3,20- dione (Example 37) with sodium borohydride in the manner described in Example 38 produces 6-ChlO'f0-17ozoctyl-3fl-hydroxypregna-4, 6-diene-20one.
E 2 Example 40.Preparati0n of 3,8-acet0xy-6-chl0ro- 1 7 a-ethyl pregna-4,6-dien-20-0ne Treatment of 6-chloro-17a-ethyl SB-hydroxy-pregna- 4,6-dien-20-one (Example 38) with acetic anhydride in pyridine as described in Example 19 is productive of 3,9- acetoxy-6-chloro-17a-ethylpregna-4,6-dien-20-one.
Example 41.Preparati0n of 3 B-acet0xy-6-chl0r0- I 7 a-octyl pregna-4,6-dien-20-0ne Treatment of 6-chloro-17a-oetyl 3B-hydroxypregna- 4,6-dien-20-one (Example 39) with acetic anhydride by the procedure of Example 19 produces 3fi-acetoxy-6- chloro-17a-octylpregna-4,6-dien-20-one.
Example 42."reparati0n of I7a-ethylpregn-S-en-ZO-one To a solution of 360 mg. of 3,8-chloro-17a-ethylpregn- 5-en-20-one (Example 7) in 15 ml. of boiling amyl alcohol are added small pieces of sodium metal. Each addition is made after all metal has dissolved and a total of 2 g. of metal is added. The amyl alcohol is removed, and the residue is distributed between water and methylene chloride. The solvent is removed from the organic layer and the residue is dissolved in 5 ml. of pyridine. This solution is added to an ice-chilled slurry of 300 mg. of chromium trioxide in pyridine. The mixture is kept at room temperature for 16 hours and then poured into water. The product is isolated with ethyl acetate to give material which has and no appreciable absorption at 207/1111. in the ultraviolet region.
We claim.
1. The compound 17a-ethyl-35-fluoro 6-methylpregn- 5-en-20-one.
2. A 17-lower alkyl pregn-5-en-20-one of the formula:
wherein R is lower alkyl.
References Cited Bowers et a1.: J.A.C.S., 84, p. 1050-53 (1962).
Djerassi et aL: J. Org. Chem. 16, p. 754-60 (1951).
Gut: J. Org. Chem. 21, p. 1327-28 (1956) Kupfer: Tetrahedron 15, p. 193-196 (1961).
Lowenthal: Tetrahedron, vol. 6, No. 4, p. 269303, June 1959.
Romo et al.: J.A.C.S. 73, p. 152833 (1951.).
Weiss et al.: Chem. and Industry, p. 118-119, January 1963 LEW-IS GOTTS, Primary Examiner.
H. FRENCH, J. R. GENTRY, Assistant Examiners.