GB1594197A - 17a,21-dimethyl-19-nor-pregna-1,3,5(10),6-tetraenes processes for preparing them and their use in the synthesis of tritiumlabelled steroids - Google Patents
17a,21-dimethyl-19-nor-pregna-1,3,5(10),6-tetraenes processes for preparing them and their use in the synthesis of tritiumlabelled steroids Download PDFInfo
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Abstract
The compounds correspond to the formula <IMAGE> in which R is hydrogen, alkyl, tetrahydropyranyl, trityl or trimethylsilyl and R1 is hydrogen, acyl or tetrahydropyranyl. They are prepared from 17 alpha -methyl-3-methoxy-19-norpregna-1,3,5(10)-trien-20-one by a synthesis in eight, nine or ten stages depending on the meaning of R and R1. Compounds I may be used for the synthesis of steroids labelled with tritium in positions 6 and 7.
Description
(54) NEW I 7a,2 1-DIM ETHYL-I 9-NOR-PREGNA- 1,3,5(10)-,6-TETRAENES, PROCESSES FOR
PREPARING THEM AND THEIR USE IN THE
SYNTHESIS OF TRITIUM-LABELLED STEROIDS
(71) We, ROUSSEL-UCLAF, a French
Body Corporate, of 35 Boulevard des
Invalides, Paris 7eme, France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to new 17a,2l dimethyl - 19 - nor - pregna 1,3,5(10)6-tetraenes, processes for preparing them and their use in the synthesis of tritium-labelled steroids.
In one aspect this invention provides the new steroids of the general formula:
wherein R represents a hydrogen atom, an alkyl group having from I to 4 carbon atoms, a tetrahydropyran - 2 - yl radical, a trityl radical or a trimethylsilyl radical and
R1 represents a hydrogen atom, an acyl radical having from 1 to 5 carbon atoms or a tetrahydropyran - 2 - yl radical. The wavy line in the general formula indicates that the 20-OR, group may be in the a or ,B configuration.
When R represents an alkyl group it may be a methyl, ethyl, n - propyl, isopropyl, n butyl, sec - butyl or t - butyl radical. The methyl radical is preferred.
When R1 represents an acyl radical it may, for example, be derived from formic, acetic, propionic, butyric or valeric acid. A preferred acyl radical is the acetoxy radical.
The following compounds of general formula I are especially preferred: 3,20g - dihydroxy - 17a,21 dimethyl - 19 - nor - pregna - 1,3,5(10),6 tetraene;
3 - - methoxy - 17a,21 - dimethyl 20g - hydroxy - 19 - nor - pregna - 1,3,5 (10),6 - tetraene; 3 - methoxy - - l?a,21 - dimethyl - 20t - acetoxy - 19 - nor - pregna - 1,3,5 (10),6 - tetraene; and
3 - hydroxy - l?a,21 - dimethyl 205 - acetoxy - 19 - nor - pregna - 1,3,5 (10),6 - tetraene.
The invention also provides in another aspect a process for preparing the compounds of general formula I. Those compounds wherein R represents a hydrogen atom may be prepared by dehydrohalogenation of a 2,6 dihalogeno - 17a,21 - dimethyl - 20- OR, - 19 - nor - pregn - 4 - en - 3 - one, and preferably this dehydrohalogenation is effected using an alkali-metal halide in dimethylformamide. A particularly preferred alkali-metal halide is lithium chloride.
The formed compound of general formula I may thereafter be reacted with a blocking agent selected from alkylation agents, dihydropyran, trityl chloride and trimethylsilyl chloride to form the corresponding compound of general formula I wherein R does not represent a hydrogen atom.
An alkylation agent used in this conversion must be capable of introducing the desired alkyl group having from 1 to 4 carbon atoms. To introduce a methyl group the alkylation agent is preferably dimethyl sulphate employed in the presence of sodium hydroxide.
If necessary, the compounds of general formula I wherein R1 represents a hydrogen atom may in turn be prepared by reacting the formed compound I wherein R and R, do not represent hydrogen atoms with a base or an acid so as to release the 20 - hydroxy group. Preferred bases for use in releasing the 20; - hydroxy group include alcoholic potassium hydroxide and sodium hydroxide solutions. A preferred acid for this purpose is aqueous acetic acid.
If desired, the 3 - hydroxy function may then be released by reacting the formed compound with an acid to form 3,205 - dihydroxy - 17a,21 - dimethyl - 19 - nor pregna - 1,3,5(10),6 - tetraene. Aqueous acetic acid or a hydracid such as hydrochloric acid is a preferred reagent for releasing the 3-hydroxy group.
The 2,6-dihalogeno - 17cur,21 - dimethyl 20t - OR, - 19 - nor - pregn - 4 - en - 3 one starting material may be prepared by reacting 17a,21 - dimethyl - 20t - OR, 19 - nor - pregn - 4 - en - 3 - one with a halogenation agent. When it is desired to form the 2,6 - dibromo compound, the halogenation agent is preferably bromine in acetic acid and the reaction is advantageously carried out in diethyl ether.
The 17a,21 - dimethyl - 20N - OR, - -19 - nor - pregn - 4 - en - 3 - one starting materials wherein R, is other than a hydrogen atom may be prepared by reacting 17a,21 - dimethyl - 20t - hydroxy - 19 nor - pregn - 4 - en - 3 - one with appropriate esterification agents or etherification agents to form the desired 20t - OR, groups. For example, to form the compound wherein R, is an acetoxy group the 20 - hydroxy compound is preferably reacted with a functional derivative of acetic acid, such as acetic anhydride, as an esterification agent and this reaction is desirably carried out in pyridine. When it is desired to introduce, for example, a tetrahydropyran - 2 - yl radical as R, the 20 - hydroxy compound is preferably reacted with dihydropyran as an etherification agent.
17a,21 - dimethyl - 20g - hydroxy 19 - nor - pregn - 4 - en - 3 - one is conveniently prepared by isomerising l7,2J - dimethyl - 20t - hydroxy - 19 nor - pregn - 5(10) - en - 3 - one by the action of a strong acid. A suitable strong acid is hydrochloric acid and the isomerisation is preferably carried out in methanol.
A convenient method of preparing 17a,21 - dimethyl - 20g - hydroxy - 19 nor - pregn - 5(10) - en - 3 - one is by subjecting 3 - methoxy - 17cm,21 dimethyl - 20t - hydroxy - 19 - nor pregna - 1,3,5(10) - triene to lithium in ammonia. This reaction is carried out in an analogous manner to the Birch reaction, and is preferably performed in the presence of ethanol.
3 - Methoxy - 17a,21 - dimethyl - 19 nor - pregna - 1,3,5(10) - trien - 20 - one may be reacted with a reducing agent to form the 20 - hydroxy compound used as starting material for the Birch-type reaction. Preferred reducing agents are the alkali-metal borohydrides and especially sodium borohydride.
The 3 - methoxy - 17a,21 - dimethyl 19 - nor - pregna - 1,3,5(10) - trien - 20 one starting material for this reduction may in turn be prepared by methylation of 3 methoxy - 17a - methyl - 19 - nor pregna - 1,3,5(10) - trien - 20 - one at the 21 - position using a methyl halide.
Preferably methyl iodide is employed, most desirably in the presence of a tertiary base such as potassium t - butylate and in an aromatic hydrocarbon medium such as toluene.
3 - Methoxy - 17a - methyl - 19 - nor pregna - 1,3,5(10) - trien - 20 - one is a known compound, being described, for example, in French Patent No. 1,480,247.
The compounds of general formula I are useful starting materials for the synthesis of steroid derivatives labelled with tritium.
In another aspect this invention provides a process for preparing tritium-labelled steroids, in which a compound of general formula I is reduced by tritiated hydrogen in the presence of a catalyst to form (6,7-3H) 3 - OR - 20g - OR, - 17a,21 - dimethyl 19 - nor - pregna - 1,3,5(10) - triene which is thereafter treated::
either. when R represents a methyl radical and R, represents a hydrogen atom, an acyl radical having from 1 to 5 carbon atoms or a tetrahydropyran - 2 - yl radical, directly with lithium in ammonia in the presence of ethanol, according to a Birch-type reaction, to obtain (6,7-3H) 3 - methoxy - 17a,21 - dimethyl - 205 - hydroxy - 19 - nor pregna - 2,5(10) - diene (when R, represents a hydrogen atom or an acyl radical) or (6,7-3H) 3 - methoxy - 17a,21 dimethyl - 205 - tetrahydropyranyloxy - 19 - nor - pregna - 2,5(10) - diene (when
R, represents a tetrahydropyran - 2 - yl radical),
or, when R does not represent a methyl radical or a hydrogen atom and R, does not represent hydrogen, with an acid, preferably an organic carboxylic acid such as acetic acid or a hydracid such as hydrochloric acid, to obtain (6,7-3H) 3 - hydroxy - 17a 21 - dimethyl - 205 - OR, - 19 - nor pregna - 1,3,5(10) - triene which product is thereafter treated with a methylation agent, such as dimethyl sulphate, and the formed (6,7-3H) 3 - methoxy - 17a,21 - dimethyl 20t - OR, - 19 - nor - pregna - 1,3,5(10) triene is subjected to the action of lithium in ammonia in the presence of ethanol, according to a Birch-type reaction, to obtain (6,7-3H) 3 - methoxy - 17a,21 - dimethyl - 20- hydroxy - 19 - nor pregna - 2,5(10) - diene (when R, represents an acyl radical) or (6,7-3H) 3 methoxy - 17a,21 - dimethyl - 20g tetrahydropyran - 2 - yloxy - 19 - nor pregna - 2,5(10) - diene (when R, represents - a tetrahydropyran - 2 - yl radical).
A preferred product of this process is (6,7-3H) 3 - methoxy - 17cr,21 - dimethyl 20N- hydroxy - 19 - nor - pregna 2,5(10) - diene, which is a compound described in our copending Application 51,969/77 (Serial No. 1,578,900). This product is an important intermediate in the synthesis of (6,7-3H) 17a,21 - dimethyl
19 - nor - pregna - 4,9 - diene - 3,20 dione.The synthesis is described in our aforementioned copending Application, and in this synthesis (6,7-3H) 3-methoxy 17a,21 - dimethyl - 205 - hydroxy - 19 nor - pregna - 2,5(10) - diene is reacted with an aqueous weak acid to form (6,7-3H) 17a,21 - dimethyl - 20N - hydroxy - 19 nor - pregn - 5(10) - en - 3 - one which is reacted with pyridinium perbromide; and the formed (6,7-3H) 17a,21 - dimethyl 20N - hydroxy - 19 - nor - pregna - 4,9 dien - 3 - one is then reacted with an aqueous sulphochromic solution to form (6,7-3H) 17a,2l - dimethyl - 19 - nor pregna - 4,9 - diene - 3,20 - dione.
(6,7 - 3H) 17cr,21 - Dimethyl - 19 - nor pregna - 4,9 - diene - 3,20 - dione enables the progesterone specific receptor to be measured easily in the uterine cytosol, in the cytoplasm of tumour cells (such as found in cancer of the womb) and in induced tumours caused by DMBA (9,10-dimethyl 1,2 - benzanthracene) in rats. The compound has the advantage, relative to progesterone, that it does not become attached to the transcortina while having an affinity for the progesterone receptor 6 to 8 times greater than progesterone.
The use of (6,7-3H) 17cur,21 - dimethyl 19 - nor - pregna - 4,9 - diene - 3,20 dione to characterise the progesterone receptor has been described in numerous publications-for example, J. P.
Raynaud and D. Philibert, Steroids, July 1973, pp. 89-97.
Certain of the intermediates in the process described hereinbefore for preparing the compounds of general formula I are believed themselves to be new compounds useful in synthesis. These are as follows:
3 - methoxy - 17a,21 - dimethyl - 19 nor - pregna - 1,3,5(10) - trien - 20 - one;
3 - methoxy - 17a,21 - dimethyl - 20g hydroxy - 19 - nor - pregna - 1,3,5(10) triene;
17a,21 - dimethyl - 20t - hydroxy - 19 nor - pregna - 5(10) - en - 3 - one; 17a,21 - dimethyl - 20t - hydroxy - 19 nor - pregn - 4 - en - 3 - one;
17a,21 - dimethyl - 20g - acetoxy 19 - nor - pregn - 4 - en - 3 - one; and
2,6 - dibromo - 17a,21 - dimethyl 20g - acetoxy - 19 - nor - pregn - 4 - en 3 - one.
Furthermore, certain of the tritiated intermediates formed in the process for preparing tritium-labelled steroids are also believed to be new and useful compounds.
The tritiated intermediates concerned are those of the general formula:
wherein R and R, are as defined hereinbefore, and especially (6,7-3H) 3 methoxy - 17a,21 - dimethyl - 20N hydroxy - 19 - nor - pregna - 1,3,5(10) triene.
The following Examples are now given, though only by way of illustration, to show certain aspects of the invention.
Example 1: 3-Methoxy-17a,21 -dimethyl-205-
hydroxy- I 9-nor-pregna- 1,3,5(10),6-tetraene.
Stage a: 3-Methoxy- 17a21 - dimethyl - 19 - nor
pregna - 1,3,5(10) - trien - 20
one.
126 g of potassium tert-butylate were introduced into 1840 ml of toluene, agitating for 15 minutes at ambient temperature under inert atmosphere, and then over 15 minutes 306 g of 3 - methoxy - 17cz - methyl - 19 - nor - pregna - 1,3,5(10)- trien - 20 - one in 900 ml of toluene was introduced. The mixture was rinsed with 300 ml of toluene, and left for one hour under agitation at ambient temperature, before being cooled to about 0 C. 600 ml of methyl iodide were introduced and the reaction mixture left for 20 hours under agitation at a temperature close to OOC. 6000 ml of water were then added, and the aqueous phase was separated and extracted several times with chloroform.The combined extracts were washed with water, then dried on sodium sulphate and evaporated to dryness under reduced pressure. 312 g of 3methoxy - 17a,21 - dimethyl - 19 - nor pregna - 1,3,5(10) - trien - 20 - one were obtained. This product was purified by chromatography on silica gel with elution by a mixture of cyclohexane, benzene and ethyl acetate (5:3.5:1.5), M.Pt~97 C.
The product was used as it was for the following stage of the synthesis.
Stage B: 3 - Methoxy - 17a,21 - dimethyl - 205 - hydroxy - 19 - nor - pregna
1,3,5(10) - triene.
Under agitation at ambient temperature, 60 g of the product obtained in Stage A and 17.5 g of sodium borohydride were introduced into 300 ml of ethanol and 90 ml of water. The reaction mixture was refluxed under agitation for about 5 hours, then cooled to about 50"C and poured, under agitation, into 900 ml of water. The crystalline product was vacuum-filtered, washed with water and dried.
59.6 g of 3 - methoxy - 17a,2l dimethyl - 20g - hydroxy - 19 - nor pregna - 1,3,5(10) - triene were obtained and purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (7:3), M.Pt700C. The produce was used as it was for the following stage of the synthesis.
Stage C: 17cur,21 - Dimethyl - 20g - hydroxy - 19
nor - pregn - 5(10) - en 3 - one
Over 40 minutes at --400C, a solution of 85 g of the product obtained in Stage B in 850 ml of tetrahydrofuran were introduced into 1400 ml of ammonia. With agitation at -400C under inert atmosphere, 42 ml of ethanol were added, then over about 40 minutes, 8.940 g of lithium were added and the reaction mixture was agitated for a further 15 minutes at about -40"C.
This operation of adding ethanol and lithium was repeated twice more. Then 127.5 ml of ethanol were added and the ammonia was distilled off under an inert atmosphere until the internal temperature reached 15"C. 850 ml of water were then added and the reaction mixture was agitated for about 1 hour, then left for about 20 hours at rest under inert atmosphere at 20"C. The precipitate was vacuum-filtered off, rinsing with ether and the organic phases were recovered and distilled under vacuum. The formed residue was taken up with 85 ml of tetrahydrofuran, and 255 ml of acetic acid were added to the solution obtained, which was then left under agitation for I hour at 20"C in inert atmosphere.
The solution was poured into a mixture of water, ice and ammonia. The precipitate formed was vacuum-filtered, washed with water, taken up with 850 ml of ether, dried over sodium sulphate, and then evaporated to dryness under vacuum.
The residue was made into a paste with 170 ml of petroleum ether (B.Pt 640-750C) under agitation, then vacuum-filtered and dried. 70.7 g of 17a,21-dimethyl-20g- hydroxy - 19 - nor - pregn - 5(10) - en 3 - one were obtained, M.Pt-129"C.
This product was used as it was for the following stage of the synthesis.
Stage D: 17a,21-Dimethyl - 205 - hydroxy - 19
nor - pregn - 4 - en - 3 - one
7.85 g of the product prepared in Stage C were introduced into 78.5 ml of methanol, and to the resultant solution 7.9 ml of IN hydrochloric acid were added, and the reaction mixture was refluxed for about I hour.
After cooling, the precipitate was vacuum-filtered, washed with methanol and with petroleum ether (B.Pt. 400-700C), and dried under vacuum to yield 6.68 g of
17a,21 - dimethyl - 20g - hydroxy - 19 nor - pregn - 4 - en - - one.
The product was purified by chromatography on silica gel eluting with a mixture of methyl chloride and ethyl acetate (9: 1) to give a purified product, M.Pt.=221 C.
Stage E: 17a,2l - Dimethyl - 20g - acetoxy - 19
nor - pregn - 4 - en - 3 - one
6.68 g of the product prepared in Stage D were introduced into 33.5 ml of pyridine and
16.5 ml of acetic anhydride. The reaction
mixture was agitated for about 24 hours at 700 C, then poured into a mixture of 200 ml of IN hydrochloric acid and ice, and
extracted several times with methylene chloride. The extracts were washed with IN hydrochloric acid, with water and with a
saturated aqueous solution of sodium bicarbonate, then dried on sodium sulphate, treated with active charcoal and alumina, filtered and concentrated to dryness under vacuum.
The formed residue was taken up with isopropyl ether, vacuum-filtered and dried under vacuum to obtain 6.3 g of 17a,21 dimethyl - 20g- acetoxy - 19 - nor pregn - 4 - en - 3 - one which was purified by chromatography on silica gel eluting with a mixture of methylene chloride and ethyl acetate (95:5) and recrystallization from a mixture of methylene chloride and isopropyl ether, M.Pt.=222 C.
Analysis: (C24H38O3) Calculated: C% 77.37 H% 9.74
Found: C% 76.9 H%9.7
Stage F: 2,6 - Dibromo - 17a,21 - dimethyl - 20g acetoxy - 19 - nor - pregn - 4 - en
3 - one
4.88 g of the product prepared in Stage E were suspended in 50 ml of ether, then, at about 15"C, 27 ml of bromine in 15.6% solution in acetic acid were introduced slowly.The reaction mixture was agitated at about 150C for 15 minutes, then 100 ml of methylene chloride were added and the whole poured into water, washed with an aqueous solution of sodium bicarbonate, then with water, dried on sodium sulphate and filtered to obtain a solution of 2,6 dibromo - 17a,2I - dimethyl - 20E acetoxy - 19 - nor - pregn - 4 - en one which was used as it was for the following stage of the synthesis without being isolated.
Stage G: 3 - Hydroxy - 17a,21 - dimethyl - 20g acetoxy - 19 - nor - pregna 1,3,5(10),6 - tetraene
4.88 g of lithium chloride were introduced into 50 ml of dimethylformamide, and heated by means of an oil bath to 1200C, then over about 35 minutes whilst distilling, the solution of the dibrominated product obtained in Stage F was added. Once the methylene chloride has been eliminated the reaction mixture was maintained for about 15 minutes at 1000C, then allowed to cool to ambient temperature. Methylene chloride was added and the whole poured into water, washed with a saturated aqueous solution of sodium bicarbonate and with water and extracted with methylene chloride. The combined organic phases were dried on sodium sulphate and concentrated under vacuum.The formed residue was taken up with methanol and purified by chromatography on silica gel, eluting with a mixture of methylene chloride and isopropyl ether (95:5), to obtain 2.65 g of 3 hydroxy - 17a,21 - dimethyl - 20g acetoxy - 19 - nor - pregna - I,3,5(10),6 tetraene, M.Pt.=246 C.
Stage H: 3 - Methoxy - 17a,21 - dimethyl - 20g acetoxy - 19 - nor - pregna
1,3,5(10),6-tetraene
1.92 g of the product prepared in Stage F were introduced into 29 ml of methylene chloride and 19 ml of water, then at 200C 13 ml of 1N sodium hydroxide, 1.45 ml of dimethyl sulphate and 190 mg of tetrabutylammonium iodide were added.
The reaction mixture was agitated for 3 hours at 200C, then poured into 100 ml of 0.1N sodium hydroxide and extracted with methylene chloride several times. The organic phases were separated, washed with hydrochloric acid and with water, dried on sodium sulphate and concentrated.
Isopropyl ether was added and the whole concentrated, then cooled, vacuum-filtered, washed with isopropyl ether and dried under vacuum to obtain 1.87 g of 3 - methoxy 17a,21 - dimethyl - 20g - acetoxy - 19 nor - pregna - 1,3,5(10),6 - tetraene, M.Pt=162 C. The product was purified by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (85:15).
Stage I: 3 - Methoxy - 17a,21 - dimethyl - 20- hydroxy - 19 - nor - pregna
1,3,5(10),6-tetraene
1.87 g of the product prepared in Stage H und 7.5 ml of 3N ethanolic potassium hydroxide were refluxed under agitation for 6 hours, then poured into 30 ml of water and extracted several times with methylene chloride. The combined extracts were washed with hydrochloric acid then with water, dried on sodium sulphate, treated with alumina and concentrated to dryness under vacuum.The formed residue was taken up with isopropyl ether, cooled and the crystalline product vacuum-filtered off, washed with isopropyl ether and dried under vacuum to obtain 1.13 g of crude 3methoxy - 17a,21 - dimethyl - 20g hydroxy - 19 - nor - pregna - l,3,5(10),6 tetraene, which was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (90:10).
The purified product had a melting point of 141"C.
Example 2:
Stage A: (6,7-3H) 3 - methoxy - I7a,21 - dimethyl - 20g - hydroxy - 19 - nor - pregna
1,3,5(10) - triene
A reaction mixture constituted by 65 mg of 3 - methoxy - 17a,21 - dimethyl - 20g hydroxy - 19 - nor - pregna -1,3,5(10),6 tetraene, 20 mg of palladised charcoal and 2.5 ml of ethyl acetate was cooled with liquid nitrogen, then under vacuum 7.95 ml of tritium having an activity of 20 Ci were introduced. The reaction mixture was allowed to return to ambient temperature, agitated for 3 hours cooled again with liquid nitrogen and the excess tritium was recovered. The reaction mixture'was again allowed to return to ambient temperature, and the catalyst was filtered off and washed with ethyl acetate.The filtrate was evaporated under vacuum to obtain 65 mg of crude product in the form of a resin.
The crude product was purified by thinlayer chromatography on silica gel eluting with a mixture of methylene chloride and acetone (1:1). The eluate was filtered, evaporated to dryness and the residue was taken up with a mixture of benzene and ethyl acetate (10:1). After evaporating off the solvent 55 mg of the desired product,
Rf=0.38, were obtained having a specific activity of 56.5 Ci/m mole.
Stage B: (6,7-3H) 3 - methoxy - 17cr,21 - dimethyl 20t - hydroxy - 19 - nor - pregna
2,5(10) - diene
To 25 ml of liquid ammonia (cooled to between -35"C and -40"C) were added 55 mg of (6,7-3H) 3 - methoxy - 17a,21 - dimethyl - 20 - hydroxy - 19 - nor pregna - 1,3,5(10) - triene in solution in 5 ml of tetrahydrofuran and 0.5 ml of ethanol, then in small portions 200 mg of lithium were introduced. The reaction mixture was agitated for I hour at about -35"C, then 10 ml of ethanol were slowly added. The ammonia was eliminated by bringing the reaction mixture back to ambient temperature, 50 ml of water were added, and the whole was extracted several times with benzene.The organic bases were dried on sodium sulphate and evaporated to dryness under vacuum to obtain 55 mg of (6,7-3H) 3 - methoxy - 17cz,21 - dimethyl 20g - hydroxy - 19 - nor - pregna 2,5(10) - diene in the form of a resin which was used as it was for the following stage of the synthesis of(6,7-3H) 17a,21 - dimethyl 19 - nor - pregna - 4,9(10) - diene - 3,20 dione, not here described.
The product obtained can be purified by chromatography on silica eluting with a mixture of benzene and ethyl acetate (10:1),
Rf=0.38.
The product was found to be identical to that described in our copending Application
No. 51,969/77. (Serial No. 1,578,900.
WHAT WE CLAIM IS:
1. A compound of the general formula:
wherein R represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, a tetrahydropyran - 2 - yl radical, a trityl radical or a trimethylsilyl radical and
R, represents a hydrogen atom, an acyl radical having from 1 to 5 carbon atoms or a tetrahydropyran - 2 - yl radical.
2. 3,20- Dihydroxy - 17a,21 dimethyl - 19 - nor - pregna - 1,3,5(10),6 tetraene.
3. 3-Methoxy - 17cz,21 - dimethyl -205 hydroxy - 19 - nor - pregna - 1,3,5(lO),6 tetraene.
4. 3 - Methoxy - 17a,21 - dimethyl 20t - acetoxy - 19 - nor - pregna 1,3,5(10)6 - tetraene.
5. 3 - Hydroxy - 17her,21 - dimethyl 20g - acetoxy - 19 - nor - pregna 1 ,3,5(10),6-tetraene.
6. A process for preparing the compounds of general formula I wherein R represents a hydrogen atom, in which a 2,6 diahalogeno - 17a,21 - dimethyl - 20g ORt - 19 - nor - pregn - 4 - en - 3 - one is dehydrohalogenated.
7. A process as claimed in claim 6, in which the dehydrohalogenation is effected with an alkali-metal halide in dimethylformamide.
8. A process as claimed in claim 7, in which the alkali-metal halide is lithium chloride.
9. A process as claimed in any of claims 6 to 8, in which the formed compound of general formula I is thereafter reacted with a blocking agent selected from alkylation agents, dihydropyran, trityl chloride and trimethylsilyl chloride to form the corresponding compound of general formula I wherein R does not represent a hydrogen atom.
10. A process as claimed in claim 9, in which to introduce a methyl group as substituent R, the blocking agent is dimethyl sulphate employed in the presence of sodium hydroxide.
11. A process as claimed in claim 10, in which a formed compound of general formula I wherein R and R1 do not represent hydrogen atoms is reacted with a base or an acid so as to release the 20g hydroxy group and form a compound of general formula I wherein R1 represents a hydrogen atom.
12. A process as claimed in claim 11, in which the base is selected from alcoholic potassium hydroxide and sodium hydroxide solutions.
13. A process as claimed in claim 11, in which the acid is aqueous acetic acid.
14. A process as claimed in any of claims
11 to 13, in which the formed compound of general formula I wherein R, represents a hydrogen atom and R does not represent a hydrogen atom is reacted with an acid to form 3,205 dihydroxy - 17a,21 dimethyl - 19 - nor - pregna - 1,3,5(10),6 tetraene.
15. A process as claimed in claim 14, in which the acid is aqueous acetic acid or a hydracid.
16. A process as claimed in any of claims 6 to 15 in which the 2,6 - dihalogeno 17a,21 - dimethyl - 20t - OR1 - 19 - nor pregn - 4 - en - 3 - one starting material is prepared by reacting 17a,21 - dimethyl 20g - OR1 - 19 - nor - pregn - 4 - en - 3 one with a halogenation agent.
17. A process as claimed in claim 16, in which to form the 2,6 - dibromo compound, the halogenation agent is bromine in acetic acid.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (34)
1. A compound of the general formula:
wherein R represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, a tetrahydropyran - 2 - yl radical, a trityl radical or a trimethylsilyl radical and
R, represents a hydrogen atom, an acyl radical having from 1 to 5 carbon atoms or a tetrahydropyran - 2 - yl radical.
2. 3,20- Dihydroxy - 17a,21 dimethyl - 19 - nor - pregna - 1,3,5(10),6 tetraene.
3. 3-Methoxy - 17cz,21 - dimethyl -205 hydroxy - 19 - nor - pregna - 1,3,5(lO),6 tetraene.
4. 3 - Methoxy - 17a,21 - dimethyl 20t - acetoxy - 19 - nor - pregna 1,3,5(10)6 - tetraene.
5. 3 - Hydroxy - 17her,21 - dimethyl 20g - acetoxy - 19 - nor - pregna 1 ,3,5(10),6-tetraene.
6. A process for preparing the compounds of general formula I wherein R represents a hydrogen atom, in which a 2,6 diahalogeno - 17a,21 - dimethyl - 20g ORt - 19 - nor - pregn - 4 - en - 3 - one is dehydrohalogenated.
7. A process as claimed in claim 6, in which the dehydrohalogenation is effected with an alkali-metal halide in dimethylformamide.
8. A process as claimed in claim 7, in which the alkali-metal halide is lithium chloride.
9. A process as claimed in any of claims 6 to 8, in which the formed compound of general formula I is thereafter reacted with a blocking agent selected from alkylation agents, dihydropyran, trityl chloride and trimethylsilyl chloride to form the corresponding compound of general formula I wherein R does not represent a hydrogen atom.
10. A process as claimed in claim 9, in which to introduce a methyl group as substituent R, the blocking agent is dimethyl sulphate employed in the presence of sodium hydroxide.
11. A process as claimed in claim 10, in which a formed compound of general formula I wherein R and R1 do not represent hydrogen atoms is reacted with a base or an acid so as to release the 20g hydroxy group and form a compound of general formula I wherein R1 represents a hydrogen atom.
12. A process as claimed in claim 11, in which the base is selected from alcoholic potassium hydroxide and sodium hydroxide solutions.
13. A process as claimed in claim 11, in which the acid is aqueous acetic acid.
14. A process as claimed in any of claims
11 to 13, in which the formed compound of general formula I wherein R, represents a hydrogen atom and R does not represent a hydrogen atom is reacted with an acid to form 3,205 dihydroxy - 17a,21 dimethyl - 19 - nor - pregna - 1,3,5(10),6 tetraene.
15. A process as claimed in claim 14, in which the acid is aqueous acetic acid or a hydracid.
16. A process as claimed in any of claims 6 to 15 in which the 2,6 - dihalogeno 17a,21 - dimethyl - 20t - OR1 - 19 - nor pregn - 4 - en - 3 - one starting material is prepared by reacting 17a,21 - dimethyl 20g - OR1 - 19 - nor - pregn - 4 - en - 3 one with a halogenation agent.
17. A process as claimed in claim 16, in which to form the 2,6 - dibromo compound, the halogenation agent is bromine in acetic acid.
18. A process as claimed in claim 17, in
which the reaction is carried out in diethyl
ether.
19. A process as claimed in any of claims
16 to 18, in which the 17a,21 - dimethyl 20g - OR1 - 19 - nor - pregn - 4 - en - 3 one starting material wherein R1 is other than a hydrogen atom is prepared by reacting 17a,21 - dimethyl - 20- hydroxy - 19 - nor - pregn - 4 - en - 3 one with appropriate esterification agents or etherification agents to form the desired 20g - OR, group.
20. A process as claimed in any of claims
16 to 19, in which the 17xx,21 - dimethyl 20g - hydroxy - 19 - nor - pregn - 4 - en 3 - one is prepared by isomerising 17a,2l dimethyl - 20g - hydroxy - 19 - nor pregn - 5(10) - en - 3 - one with a strong acid.
21. A process as claimed in claim 20, in which the strong acid is hydrochloric acid.
22. A process as claimed in claim 21, in which the isomerisation is carried out in methanol.
23. A process as claimed in any of claims 20 to 22, in which the 17cur,21 - dimethyl 20g - hydroxy - 19 - nor - pregn - 5(10) en - 3 - one is prepared by subjecting 3 methoxy - 17a,21 - dimethyl - 20g hydroxy - 19 - nor - pregn - 1,3,5(10) triene to lithium in ammonia.
24. A process as claimed in claim 23, performed in the presence of ethanol.
25. A process as claimed in either of claims 23 and 24, in which the 3-methoxy 17a,2l - dimethyl - 20g- hydroxy - 19 nor - pregna - 1,3,5(10) - triene is prepared by reacting 3 - methoxy - 17cur,21 dimethyl - 19 - nor - pregna - 1,3,5(10) trien - 20 - one with a reducing agent.
26. A process as claimed in claim 25, in which the reducing agent is an alkali-metal borohydride.
27. A process as claimed in claim 26, in which the reducing agent is sodium borohydride.
28. A process as claimed in any of claims 25 to 27, in which the 3- methoxy 17a,2l - dimethyl - 19 - nor - pregna
1,3,5(10) - trien - 20 - one is prepared by methylation of 3 - methoxy - 17a - methyl - 19 - nor - pregna - 1,3,5(10) trien - 20 - one at the 21 - position using a methyl halide.
29. A process as claimed in claim 28, in which the methyl halide is methyl iodide.
30. A process as claimed in claim 29, in which the methylation is effected in the presence of a tertiary base and in an aromatic hydrocarbon medium.
31. A process for preparing a compound of general formula I substantially as described herein with reference to Example 1.
32. A compound of general formula I whenever prepared by a process as claimed in any of claims 6 to 31.
33. A process for preparing tritiumlabelled steroids, in which a compound of general formula I is reduced by tritiated hydrogen in the presence of a catalyst to form (6,7-3H) 3 - OR - 20g - OR1 - 17a,21 dimethyl - 19 - nor - pregna - 1,3,5(10)- triene which is thereafter treated::
either, when R represents a methyl radical and R1 represents a hydrogen atom, and acyl radical having from 1 to 5 carbon atoms or a tetrahydropyran - 2 - yl radical, directly with lithium in ammonia in the presence of ethanol to obtain (6,7 - 3H) 3 - methoxy 17a,21 - dimethyl - 205 - hydroxy - 19 nor - pregna - 2,5(10) - diene (when R1 represents a hydrogen atom or an acyl radical) or (6,7-3H) 3 - methoxy - 17a,21 dimethyl 20g - tetrahydropyran - 2 yloxy - 19 - nor - pregna - 2,5(10) - diene (when R1 represents a tetrahydropyran - 2 yl radical),
or, when R does not represent a methyl radical or a hydrogen atom and R1 does not represent hydrogen, with an organic carboxylic acid or a hydracid to obtain (6,73H) 3 - hydroxy - 17a,21 - dimethyl - 20g OR1 - 19 - nor - pregna - 1,3,5(10) - triene which product is thereafter treated with a methylation agent and the formed (6,7-3H) 3 - methoxy - 17a,21 - dimethyl - 20g- OR, - 19 - nor - pregna - 1,3,5(10) - triene is subjected to the action of lithium in ammonia in the presence of ethanol to obtain (6,7-3H) 3 - methoxy - 17a,21 dimethyl - 20g - hydroxy - 19 - nor pregna - 2,5(10) - diene (when R1 represents an acyl radical) or (6,7-3H) 3 methoxy - 17a,21 - dimethyl - 20g tetrahydropyran - 2 - yloxy - 19 - nor pregna - 2,5(10)-diene (when R, represents a tetrahydropyran - 2 - yl radical).
34. A process as claimed in claim 33 substantially as described hereinbefore with reference to Example 2.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7709907A FR2385737A1 (en) | 1977-04-01 | 1977-04-01 | NEW STEROIDS, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THE SYNTHESIS OF STEROIDS TRADEMARKS WITH TRITIUM |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1594197A true GB1594197A (en) | 1981-07-30 |
Family
ID=9188911
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB12605/78A Expired GB1594197A (en) | 1977-04-01 | 1978-03-31 | 17a,21-dimethyl-19-nor-pregna-1,3,5(10),6-tetraenes processes for preparing them and their use in the synthesis of tritiumlabelled steroids |
Country Status (10)
| Country | Link |
|---|---|
| JP (2) | JPS53124254A (en) |
| AU (1) | AU516015B2 (en) |
| BE (1) | BE865555A (en) |
| CA (1) | CA1122590A (en) |
| CH (1) | CH629826A5 (en) |
| DE (1) | DE2814048A1 (en) |
| FR (1) | FR2385737A1 (en) |
| GB (1) | GB1594197A (en) |
| IT (1) | IT1101860B (en) |
| SE (1) | SE432425B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2430953A1 (en) * | 1978-07-13 | 1980-02-08 | Roussel Uclaf | NOVEL 3,20-DIOXO 4,9-DIENE 21-HYDROXYL DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
| JPS63126499U (en) * | 1987-02-10 | 1988-08-18 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2077877B1 (en) * | 1970-02-20 | 1974-02-01 | Roussel Uclaf | |
| FR2149302A1 (en) * | 1971-08-19 | 1973-03-30 | Roussel Uclaf | 21-methyl pregnadienes prepn - used as progestomimetics |
-
1977
- 1977-04-01 FR FR7709907A patent/FR2385737A1/en active Granted
-
1978
- 1978-03-16 SE SE7803051A patent/SE432425B/en not_active IP Right Cessation
- 1978-03-30 IT IT7848677A patent/IT1101860B/en active
- 1978-03-31 DE DE19782814048 patent/DE2814048A1/en not_active Ceased
- 1978-03-31 CA CA300,224A patent/CA1122590A/en not_active Expired
- 1978-03-31 BE BE186452A patent/BE865555A/en not_active IP Right Cessation
- 1978-03-31 CH CH348878A patent/CH629826A5/en not_active IP Right Cessation
- 1978-03-31 GB GB12605/78A patent/GB1594197A/en not_active Expired
- 1978-03-31 JP JP3693378A patent/JPS53124254A/en active Granted
- 1978-04-03 AU AU34691/78A patent/AU516015B2/en not_active Expired
-
1986
- 1986-01-31 JP JP61018244A patent/JPS62281894A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6126798B2 (en) | 1986-06-21 |
| DE2814048A1 (en) | 1978-10-12 |
| AU516015B2 (en) | 1981-05-14 |
| IT1101860B (en) | 1985-10-07 |
| JPS641480B2 (en) | 1989-01-11 |
| JPS62281894A (en) | 1987-12-07 |
| SE7803051L (en) | 1978-10-02 |
| SE432425B (en) | 1984-04-02 |
| FR2385737B1 (en) | 1980-03-21 |
| JPS53124254A (en) | 1978-10-30 |
| BE865555A (en) | 1978-10-02 |
| FR2385737A1 (en) | 1978-10-27 |
| IT7848677A0 (en) | 1978-03-30 |
| CA1122590A (en) | 1982-04-27 |
| AU3469178A (en) | 1979-10-11 |
| CH629826A5 (en) | 1982-05-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930331 |