DE1768116A1 - Process for making 20-ketosteroid compounds - Google Patents

Description

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Our no. 14 569

The Upjohn Company Kalamazoo, Mich., V.Pt.A.

Process for making 20-ketosteroid compounds

This invention relates to a method of creation of progesterones or pregnenolones through a specially catalyzed oxidation, using copper or Iron compounds as catalysts, in a liquid medium in the presence of a base. The starting compound

for progesterone is a 3 ~ ketobisnor-4-cholenaldehyde, Ä

while the starting compound for pregnenolone has a 3-hydroxy-5-ene structure which is characteristic of pregnenolone; the 3-hydroxyl group can be esterified be protected by known methods, and one can use, for example, the modified 3-acetate.

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Stigmastadienone was obtained by reaction with ozone [Herr et al., J.A.C.S. 72, 2167 (195O)] in 3-ketobisnor-4-cholenaldehyde convicted. This compound was used as a starting material for the synthesis of progesterone, using 22-enamine as an intermediate. The oxidation was carried out with chromic acid [Shepherd et al., P J.A.C.S. 77, 1212 (1955)]. Both connections, namely 3-Ketobisnor-4-cholenaldehyde and 3-acetoxy-bisnor-5-cholenaldehyde are known starting materials for the preparation of progesterone with ozone (Heyl et al., J.A.C.S., 72,2617 0.95O)].

This invention relates to a method of making 20-keto steroids. The procedure is through characterized in that one has a 22-aldehyde steroid in the presence of catalytic amounts of copper ions and an organic fc base subjected to the action of molecular oxygen and isolating the 20-keto steroids thus formed from the reaction mixture.

The method according to the invention is applicable to a number of 22-aldehyde steroids which have a 17-side chain and have the following D-ring configuration:

.CHO

/
22.3.68

- 2 -

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The remainder of the steroid molecule M ₁ in relation to the formula given above can have a number of core substituents and combinations of unsaturated double bonds. So z. B. the starting compound can have a 22-aldehyde or 7-substituent such as α- or ß-alkyl or oc- or p-halogen. It can have oxygen substituents in the> and / or 11-position such as α- or β-hydroxyl or keto groups. In addition, substituents in the m

A-, 9- and 12-position be present, namely substituents such as alkyl groups or halogen. Double bonds may be present, such as in the Z ^ -3 structure ^ the 3-keto-1,4-diene structure _; the 3-keto-1,4,6-triene structure or the 3-keto-4,6-diene structure. Double bonds in the 9 (H) position, 5 (6) position or 7 (8) position can also be present.

This invention includes the discovery that the 22-aldehyde structure of the above formula easily into the 20-keto structure j

can be converted:

(II)

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This conversion takes place by means of base-catalyzed oxidation, carried out in the presence of catalytic amounts on copper or iron compounds. The products of this invention, e.g. B. progesterone, are valuable intermediates in the production of a number of biologically active steroids, such as cortisone, hydrocortisone, prednisolone, 6 <z-methylprednisolone and others.

The starting compounds can be given by the following

Formula can be represented:

.CHO

R '' I.
I.
I. j If I. T

where R is carbonyl, OH, O-alkyl _r O-acyl or (O-alkyl) ₂ } R 'denotes H, CH ₃ or ρ'; and R "is H, OH, carbonyl

or O-acyl; the dashed lines represent the presence or absence of double bonds .

The compounds obtained in the present invention are represented by the following formula

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wherein R, R ', R ^1f and the dashed lines have the same meaning as above. The metal compounds used as the catalyst are copper (II) salts or iron salts.

Because of their great reactivity, copper salts are used preferred. The presence of copper or iron ions, which characterize the process according to the invention, can be caused by the use of the following compounds can be achieved:

Copper (II) acetate, copper (II) sulfate, copper (II) chloride, %

Copper (II) nitrate, copper (I) acetate, copper (I) sulfate, Iron (III) sulfate, iron (III) acetate, iron (II) sulfate and Ferrous acetate.

Copper (II) acetate is particularly preferred. The copper (II) and iron (III) compounds are in front of the Copper (I) and iron (II) compounds are preferred. Under the The low-valued compounds are oxidized in the reaction into the higher quality connections.

The reaction is in the presence of organic solvents g

medium executed. Polar aprotic solvents are preferred, such as. B. dimethylformamide (DMF), hexamethylphosphoramide (HBIPA), cDLmethylsulfoxide (DMSO) _; Tetramethylurea and dimethylacetamide. Other organic solvents can also be used, such as alkanols such as methanol or ethanol and other oxygen-containing solvents such as

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Tetrahydrofuran} dioxane and the like, or hydrocarbon solvents such as benzene.

The reaction is carried out in the presence of a base. A diazobieycloalkane such as x is preferably used. B. Diazocyclooctane (DABCO) (PK ^ 11.5) is used. Tertiary ininines such as triethyl, trimethyl, tripropylaxin, etc., amines, Ν, Ν'-dimethylpiperizine, N-methylpyridine, N-methylpyrrolidine, quinuclidine and others can advantageously be used.

The reaction is aided by the aameno "- '* of certain agents which form complexes with iron or copper. Such compounds are, for example, 1,10-phenanthroline and 2,2'-bipyridyl. By using these agents , it has been found that the yield may increase 2-6 $, ie compared to reactions where no complex-forming agents are used. It is preferably such an amount of the copper complex used forming agent corresponding einerfrenge which is approximately necessary to the present copper ions in the reaction mixture associate.

The reaction can be carried out at a temperature at which the reaction mixture is liquid. Preferably, temperatures of 20 ° C are preferably to 65 C, and it was found that to get the best Besultate the oxidation at a temperature of 45 ° to 50 ° C.

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The inventive method can essentially in .der Absence of water run, but it has been found that small amounts of water, less than

un IO yolum ~? 4 of the reaction mixture, no favorable influence to have the reaction. In the case of the use of HMPA, the presence of 10% by volume of water should reduce the yield of the Increase 20-keto compound and accelerate the rate of reaction.

The following examples are intended to explain the invention in more detail.

Example 1 : Conversion of 3-ketobisnor-4-cholenaldehyde (bisnoraldehyde) into _t progesterone.

CD

Oxygen aisin base

To a suspension of 25 g bisnoraldehyde in 75 ml hexamethylphosphoramide (HMPA) to 10 "g Diazar bicyclooetan (DABCO) A g of copper gave (II) acetate and 1 ml of water. This slurry was heated to 5O ⁰ C and initiated 5 1 / 2

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Oxygen in the reaction vessel for hours. Man cooled the reaction mixture and precipitated the product by adding water. The pest substances were by a small amount of silica gel eluted with ethyl acetate and the eluate was analyzed quantitatively by gas chromatography (85.6% $ 86.6 progesterone). The solvent was evaporated ^ and the obtained pesticide was recrystallized from acetone Fe. You got two shots of progesterone, together 20.42 g ($ 85.5 theory).

Melting point = 125.5 - 128.5 ° C [a] _D = -175 °

The bisnoraldehyde of this example can be replaced by 6-methyl-3-ketobisnor-4-cholenaldehyde are substituted and 6-methylprogesterone is obtained. 3-ketobisnor-4,7 (8) choladienaldehyde yields 7 (8) dehydroprogesterone and 3-ketobisnos-4,6-choladienaldehyde provides 6-dehydroprogesterone.

Example 2 : Conversion of 3-ketobisnor-4-cholenaldehyde | (Bisnoraldehyde) to progesterone.

The procedure was the same as in Example 1, but dimethylformamide was used as the solvent. 3.3 g of 2,2 * -bipyridyl were added as a copper complex-forming agent. Oxygen was passed into the reactor for 3 1/4 hours. The reaction mixture was worked up in the same way as in Example 1, and progesterone bit one was obtained

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Yield of 86.7 # melting point = 126.5-127.5 C. Γα-L = 173.9 °

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Claims (7)

Claims 1. A process for the preparation of 20-ketosteroids, characterized in that that a 22-aldehyde steroid in the presence of catalytic amounts of copper ions and an organic base of the action of molecular oxygen and the 20-ketosteroids formed in this way isolated from the reaction mixture. 2. The method according to claim 1, characterized in that the reaction is carried out in a polar aprotic solvent. a 3 · method according to claim 2, characterized in that as a solvent Dimethylformamide is used. 4. The method according to claim 1, characterized in that the reaction is carried out in a polar aprotic solvent in the presence of 1,10-phenantroline or 2,2'-bipyridyl. 5. The method according to claim 2, characterized in that the base Diazobicyclooctane is used. 6. The method according to claim 2, characterized in that copper (II) acetate is used as the copper compound. 7. The method according to claim 2, characterized in that for production of druggesterone as a starting material bis-noraldehyde is used. For The Upjohn Company Kalamazoo, Mich., V.St.A. 101141/1768 Lawyer