DE1192200B - Process for the preparation of A-nor-B homo 6-Oxo ostrenen - Google Patents

Description

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FEDERAL REPUBLIC OF GERMANY GERMAN AL ^ PATENT OFFICE

EDITORIAL

Int. Cl .:

_C07c

co?

6-3 / äü

German class: 12 ο - 25/07

Number: 1192 200

File number: R 32938IV b / 12 ο

Filing date: June 18, 1962

Opening day: May 6, 1965

The invention relates to a process for the preparation of new A-nor-B-homo-6-oxo-oestrenes of the general formula IV

OR

IV Process for the preparation of
A-nor-B-homo-6-oxo-estrenes

wherein R is a hydrogen atom or a lower one Means acyl radical.

The process according to the invention for the preparation of compounds of the general formula IV consists in that a 3,6-dioxo-17 /? - acyloxy-A-nor-B-homo-oestran in enolic form (I a or I b) is carried out catalytic hydrogenation in the presence of an organic acid at room temperature selectively reduced, the resulting mixture of the corresponding 3 - oxo - 6ξ - hydroxy - 17/3 - acyloxy-A-nor-B-homo-estran (II) and the corresponding 3f-hydroxy -6-oxo-17 / 3- acyloxy-A-nor-B-homoöstran (III) separates by fractional crystallization and chromatography, the latter compound is dehydrated by known methods, in particular by heating in methanolic alkali hydroxide, and the 6-oxo-17 obtained / Miydroxy-zl ³ < ⁵ > A-nor-B-homo-oestrene (IV; R = H) optionally esterified with a functional derivative of a lower organic carboxylic acid in a manner known per se.

According to a preferred embodiment of the process according to the invention, the catalytic Hydrogenation carried out in the presence of palladium-carbon and in acetic acid.

The new products obtained according to the invention are distinguished by their particular hormonal properties. They are more active than the classic stem steroids from which they are derived and show less dangerous side effects. For example, 6-oxo-17 / i-hydroxy-J ^{3 (51} -A-nor-B-homoestrous has an androgenic and anabolic effect. The solubility of these compounds also allows them to be used more widely. However, they are also valuable intermediates for the production of others A-nor-B-homo-steroids according to known chemical or microbiological processes.

Applicant:
Roussel-Uclaf, Paris

Representative:

Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann and

Dipl.-Chem. Dr. R. Koenigsberger,

Patent Attorneys, Munich 2, Bräuhausstr. 4th

Named as inventor:

Georges Muller, Nogent, Marne;

Jacques Martel, Bondy, Seine (France)

Claimed priority:

France of June 19, 1961 (865 322)

The S-oxo-of-hydroxy-H / i-acyloxy obtained as by-products of the process according to the invention - A - nor - B - homo - oestrane (II) are valuable intermediate connections for the production of others physiologically active products, namely the A-nor-B-homo-3-oxo-oestrene, which are described in patent application R 32939IVb / 12 o.

The following example serves to explain the method according to the invention in more detail. The instant ones Melting points were determined on the Kofler bench. The scheme gives an overview about the reaction sequence.

example

Production of 6-Oxo-J ^{3 | 5)} -17j8-hydroxy-A-nor-B-homo-oestrene (IV; RH)

Stage A. Catalytic hydrogenation
the enolic form of 3,6-dioxo- 170-acetoxy-A-nor-B-homo-estran (Ia or Ib; R = COCHe)

2.68 g of S.ö-dioxo-H ^ -acetoxy-A-nor-B-homo-estran are dissolved (M.p. - 168 ° C), which is disclosed in patent 1 161889 is described, in 25 ecm acetic acid, adds 1.3 g of palladium-carbon with 20% palladium and hydrogenated Hours at room temperature. It is filtered, added ecm methylene chloride and washed until Neutrality with water. It is dried over magnesium sulphate and evaporated to dryness in a vacuum.

$ 50 5M / 4S5

This gives 2.7 g of a compound which consists essentially of a mixture of 3-oxo-6f-hydroxy-17 / i-acetoxy-A-nor-B-homo-oestran (II; R = COCH3) and Sf- Hydroxy-o-oxo-n ^ -acetoxy-A-nor-B-homoöstran (III; R = COCH ₃ ).

One takes up in 20 ecm of ether and lets the ethereal solution stand until crystallization. After suction filtration, washing with ether and drying, 520 mg of crystalline compound II (R = COCH 3), mp = 200 ⁰ C. [a] i ° = -145 ° (c = 0.5 ° / o, chloroform) .

The compound Π (R = COCH ₃ ) is new.

Its structure is confirmed by the values of infrared analysis: the presence of a hydroxyl is indicated by a broad band at 3598 to 3611 cm " ¹ .

The 3 - oxo - 6ί - hydroxy - Πβ- acetoxy - A - nor-B-homo-estran (II; R = COCH3) is soluble in acetone, benzene, chloroform, alcohol and ether and insoluble in water.

Analysis: C ₂₀ H ₃₀ O ₄ = 334.44
Calculated ... C 71.82%, H 9.04%;
found ... C 71.7%, H 9.0%.

The 3ξ - hydroxy - 6 - oxo -17/3 - acetoxy - A - nor-B-homo-estran (III; R = COCH ₃ ) is obtained by chromatography of the ethereal mother liquors of the 3 - oxo - 6ξ - hydroxy -17 /? - acetoxy - A - nor - B - homoöstrans (II; R = COCH3) separated on aluminum oxide in benzene. After recrystallization from hexane, 250 mg of the crystallized compound III (R = COCH ₃ ) with a melting point of 148 ° C. are obtained. [a] l ° = - + 125 ° (c = 0.5%, chloroform).

The connection ΙΠ (R = COCH3) is new.

Its structure is confirmed by the values of infrared analysis: presence of a hydroxyl, presence of a carbonyl which ^{absorbs at 1685 cm "1} in chloroform and at 1688 cm" ¹ in carbon disulfide.

The 3 | - Hydroxy - 6 - oxo -170- acetoxy - A - nor-B-homo-estran (III; R = COCH3) is soluble in acetone, benzene, chloroform, alcohol and ether and insoluble in water.

Analysis: C20H30O4 = 334.44
Calculated ... C 71.82%, H 9.04%;
found ... C 72.2%. H 9.0%.

Stage B. Dehydration of

Sf-Hydroxy-o-oxo-n ^ -acetoxy-A-nor-B-homo-estran

(III; R - COCH ₃ )

500 mg of the 3S-hydroxy-6-oxo-170-acetoxy-A-nor-B-homo-estran (III; R = COCH ₃ ) obtained in the previous stage are dissolved in 5 ecm of methanol and 0.5 ecm of 10 normal aqueous Caustic soda. The mixture is heated to reflux for 45 minutes, after cooling, 20 ecm of methylene chloride are added and the mixture is washed with water. It is dried over magnesium sulphate and evaporated to dryness in a vacuum. The residue is taken up in 25 ecm of methylene chloride and chromatographed on 25 g of aluminum oxide (activity II to III according to Brockmann). It is eluted first with methylene chloride, then with methylene chloride containing 2% methanol. When the chromatogram is eluted with a mixture of methylene chloride and 2% methanol, a resin is obtained which crystallizes after being taken up in a little ether. The 6-oxo-7β -hydroxy-d ³ < ⁵ > -A-nor-B-homo-estrous (IV; R = H) with a temperature of 153 ° C. is thus obtained after suctioning off and drying. [a]? = + 42 ° ± 3 (c = 0.5%, chloroform).

The infrared spectrum shows the presence of a band at 1670 cm ^-1 , which indicates the presence of a carbonyl group on a heptagonal ring that is conjugated with a double bond.

Analysis: Ci ₈ H ₂₆ O ₂ = - 274.4

Calculated ... C 78.8%, H 9.6%;
found ... C 78.6%, H 9.5%.

The product is new.

The 17/3-hydroxylated obtained in stage B Product can be acylated by known methods using functional derivatives lower organic carboxylic acids, ζ. B. the ants, vinegar, propion, butter, isobutter, Valerian, Isovalerian, trimethyl acetic, ß-trimethyl propion, capryl, cyclopentyl acetic, cyclohexyl acetic, cyclopentyl propion, Phenylacetic, 2,4-dinitrobenzoic or phenoxyacetic acid.

Stage C. Manufacture of

6-Oxo-17/3-benzoyIoxy-J ^{; i} < ⁵ > -A-nor-B-homo-oestren _2J (IV; R - COC ₆ H ₅ )

30 mg of the 6-oxo-1 Iß -hydroxy-Λ ³ < ⁵ > -A-nor-B-homo-estrous (IV; R = H) obtained in stage B are dissolved in 2 ecm anhydrous benzene and 0.6 ecm Pyridine. It is cooled in an ice bath, 0.25 ecm of benzoyl chloride is added and the mixture is left to stand for a few hours at room temperature. 0.2 ecm of formic acid is then added with cooling, the mixture is taken up in methylene chloride, washed with 1 η hydrochloric acid, with water, with an aqueous sodium bicarbonate solution and then with water. It is distilled to dryness and the residue thus obtained is chromatographed on aluminum oxide. By eluting with methylene chloride, which contains 2% methanol, 6-oxo-17 /? - benzoyloxy- / 1 ^{3 <5} > -A-nor-B-homo-esters with a melting point of 145 ° C. are isolated.

The compound is insoluble in water and soluble in ether, acetone, benzene and chloroform. That IR spectrum is consistent with the proposed structure.

The product has not yet been described in the literature.

According to the process, you can also use other catalysts and the type of solvent and change the reaction temperatures.

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Claims (2)

Patent claims: 1. Process for the preparation of A-nor-B-homo-6-oxo-oestrenes the general formula OR wherein R is a hydrogen atom or a lower one Acyl radical means, characterized in that that you have a 3,6-dioxo-l 70-acyloxy- A-nor-B-homo-estran in enolic form is selectively reduced by catalytic hydrogenation in the presence of an organic acid at room temperature, the resulting mixture of the corresponding 3-oxo -6ξ- hydroxy -Π / ϊ-acyloxy-A-nor-B -homo-estran and the corresponding 3 £ -hydroxy-6-oxo-17 / if-acyloxy- A-nor-B-homoöstran by fractional crystallization and chromatography separates the latter compound according to known methods, in particular by heating in methanolic alkali hydroxide, dehydrated and the 6-oxo-17 / S-hydroxy- / J ^{3 <5)} -A-nor-B-homo-esters obtained, optionally esterified with a functional derivative of a lower organic carboxylic acid in a manner known per se. 2. The method according to claim 1, characterized in that the catalytic hydrogenation carried out in the presence of palladium-carbon and in acetic acid. 1 sheet of drawings SOf 568/465 4.65 β Bimdeadrucker "Berlin