DE1493050A1 - Process for the production of unsaturated derivatives of the pregnane series - Google Patents

Description

PATENT ADVOCATE PATENT ADVERTISEMENT DiPL.-iNG. ADOLF SPREER graduate phys. DR. W. JUNIUS

3 HANOVER

AIIESTKASSE 20 TELEVOK 13 43 30

April 22, 1965

SPOFA, Sdruzeni podniku pro zdravotnickou v ^ robu, Praha

"Process for the preparation of unsaturated derivatives of the Pregnan series "

The invention relates to a process for the preparation of unsaturated derivatives of the Pre? Nan series of the general Formula I.

CCH ₂ K ₃

wherein R ₁ denotes a hydrogen atom, an OL ~ or ^ -methyl group or a methylene group, _{R 1 and R 3} , identical or different, denotes a hydrogen atom or an acyloxy group with 1-6 carbon atoms, it being possible for there to be a double bond in the 16, 17-position ·

The introduction of a double bond in the 6, 7-position represents a very important synthetic step in the production of therapeutically valuable 3-keto-A »-pregnadiene derivatives.

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With the technically applicable methods known up to now

"4 6 J ren for the preparation of compounds having the 3-keto.. '-C.en moiety starting from the corresponding A -3-KetonreTnanverbindungen and the double bond is direct in the 6,7-position, either by means of or The direct methods include dehydrogenation with substituted quinones, e.g. with chloranil (J.Am. Chem. Soc. 79,1257,1957; ibid. 12, 4293, 1960), with 2,3-dichloro-5, 6-dikyanbenzoquinone in the presence of hydrogen chloride (Chemistry anctlndustry 1962, 211) or with chloranil and acidic catalysts using 3-enol acetates or 3-ketones (3-acyloxy-il " ^f -rrcnadienes) as starting materials. A common disadvantage of these methods is that the unconverted agent (ie the corresponding quinone) and its conversion products (in particular the corresponding substituted quinone) can only be removed from the reaction mixture with great difficulty and with great difficulty. Extraction with dilute solutions of alkali metal, lethal hydroxides, appears to be expedient; however, in the case of compounds sensitive to alkalis (e.g. esters) the result of this is their partial decomposition and reduction in the yield of the desired product.

The indirect methods are based on the introduction of bromine into the 6-position and on the splitting off of the hydrogen bromide with symra. Collidine. The bromination of the 6-position can either be carried out directly by so-called allyl bromination with N-bromosuccinimide or with analogous N-bromamides, or by conversion of the &. -3-ketones into the 3-enol ether and through addition of sub-bromic acid, which one develops directly in the reaction mixture (J. Am. Chem. Soc. 81, 3485, 3712, 1959). The indirect methods mentioned give consistently low yields.

It was found that the disadvantages of the previous methods can be eliminated by using the process »

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Production of unprecise derivatives of the Prernan series •• cmjiss of the present I: rfindunp used. This method is characterized in that a substituted S-acyloxy-Δ * -prerrnadiene der narciellcn alleemei formula II

wherein Ri cine acyloxy «rrunpe means with 1 - 6 carbon atoms, halogenated, the resulting starting product hydrolyzed and the resulting ö / i-üaloqen-Ä -3-ketone dehydrohalopenicrt.

The halogenation is carried out by means of an anlarerunf. of elemental chlorine or bromine in the presence of an inert one organic solvent, such as a halogenated aliphatic hydrocarbon with 1-2 carbon atoms, advantageous dichloromethane through. As a reaction medium Anhydrous alinatic monocarboxylic acids with 2-3 carbon atoms can also be used, advantageously Lisessip, or a mixture of one of the named S.Uuren with one Halopened aliphatic hydrocarbon with 1 - 2 carbon atoms, optionally with the addition of an alkali metal salt the acid used.

Halogenation can also be carried out at the present time aliphatic or heterocyclic amines, at temperatures from - 30 C to 50 ° C, advantageously at a temperature of 0 to 20 ° C.

To the Jlydrplyse des halojreniertep Anlaperunirsproduktes, which at .JJj, r, 25 ° C, you can use water.

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The dehydrohalogenation of the o / i-IIalop.en-4 -3-ketone takes place best in dimethyl formamide, in the presence of alkali metal or alkaline earth metal carbonates, advantageously lithium or calcium carbonate, also in the presence a mixture of lithium carbonate with a lithium halide, the ljalopen of which corresponds to the split-off Ilaloqen, at temperatures from 20 ° C to the boiling point of the reaction mixture.

The hnol esters (3-acyloxy

_.3.5

-dienes) are produced in a manner known per se from corresponding Δ -3-ketones, usually by the action of a fatty acid anhydride with 1-6 carbon atoms with acid catalysis (J.Ain.Chem.Soc. 76, 747, 1954). It is particularly advantageous that, in parallel with the alcohol acylation, some desired conversions of other SuI) substituents also take place, e.g. the acylation of the 17dC-hydroxyl, the acetolysis of the 16f-methyl-16 (i, 17 & -epoxide to 16-methylene-17 ^ -acyloxyderivat, enolacylation of the 20-

17/20 / Ketorrunne with formation of the 20-acyloxy-A derivative etc., or that in part the changes in the molecule occur spontaneously with inolacylic run, the Δ -5-keto group present can be derived. In the halogenation, the chlorine or bromine in an equimolecular amount is gradually and after either in elemental form or in the form of a solution add in a solvent serving as a reaction medium. The reaction temperatures can vary proportionally; As mentioned above, in most FUllons the temperature must be from 0 ° to 15 - 20 ° C.

To prevent the undesirable substitution halopenation in the vicinity of the 20-iCeto group, it is useful if you add an agent to the reaction mixture

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which neutralizes any hydrogen chloride formed and thereby removes the catalyst of this undesired reaction. These agents include for example sodium or potassium acetate, ^p yridin, tcrci'ire amines, etc. Under these conditions, the reaction verliiuft selectively such that less reactive double bonds, for example, are not attacked by the 16-methyl group.

If particularly reactive double bonds in the molecule, e.g. of the unolacylate type, the addition takes place at the same time of the halogen and there the halogen must be used in a corresponding excess. Proof that you can This course of the reaction can be used with advantage in some cases is given in Example 9.

The resulting primary addition product , which can be represented by the following partial formulation (III)

4 X

H ₁ O

♦ AcOH * HX

where R ^ is the same as in formula II, X is a halogen atom and Ac is the radical of an acid split off from the substituent R. in the 3-position, spontaneously splits off HX and the acyl radical in the presence of water and goes into the corresponding Δ -6 ^ -Halo-3-ketone (IV) via. Since, after the addition of halogen, the product is usually isolated from the reaction mixture by shaking with the aqueous phase or by dilution with water, the hydrolysis takes place spontaneously and the unsaturated one is obtained

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.v ■■ »» «■ ..

Ilnlo enketone (IV) in a degree of purity sufficient for the subsequent dehydrohalogenation. This l! Alo "renketone can, of course, be recovered in the pure state, but when the process according to the invention is carried out, the crude reaction product can be used directly, which avoids losses in purity and simplifies the method of operation. ^T enviromed from dimethyl formamide; alkali metal or alkali metal carbonates are used to bind the hydrogen chloride to be split off. As an example of a peptic agent, precipitated calcium or lithium carbonate may be mentioned, with the addition of a lithium halide, its alcopene with the same from the stcroid molecule The halo-ening reaction takes place at normal temperature and without the carbonates mentioned. For the purpose of completion and sufficiently rapid course of the reaction, however, it is advisable to work at an elevated temperature, namely up to the boiling point of the reaction mixture. This reaction is extremely selective, no usual functional groups present in the molecule are attacked, reactive ualopene atoms except, for example, in a rC-HalofienketOfrrupnierunsT. In such a case, their simultaneous splitting takes place.Synthetic utilization of this isebic reaction is described in Example 9.

The following examples are intended to explain the invention in more detail without restricting its scope in any way.

Examples 1.

A solution of 4.14 g of SjiTöC-Diacetoxy-A. '-pregnadien-20-on in a mixture of 25 ml of dichloromethane, 25 ml of glacial acetic acid and

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and 1 ml of pyridine cools down to ⁰ ° C. and "gives a solution of '), 8 " within 3½ minutes. Add chlorine in ml of chlorine ethane. IUc Rcaktionsmir.chunf shakes nan with V'asscr, with a 3 ^! * -i ^r .cn KMCO solution? and again with no water, the orange phase is dried with anhydrous magnesium sulphate and the solvent is distilled off. The raw residue is subjected to a hydrochlorination process. Example 3.

'.i'cnn it is necessary to isolate ilas b / & -Chlorderivat in pure form, the residue was crystallized from ether-^ entan in, whereby the UAN "roduct with F. 22) - 222 ° C. 2 ° = - ¹⁾ ° »1 ^{i: ton 239 nm} ( ^lo ° ^ε 4.17), which with üor

IT! 1 X

the substance described in the literature is identical.

2. 0/3 -15ron-17 (? C_-acetoxyprooesterone

i-.ine Ltfsunn of 4.14 r 3.17 ^, - lltacctoxy- ^ "'-nrernadien-20-one in 20 nl of chloroform is stirred with cooling with 10 ml of Hisessif and 5 ml of triethanolamine and under water is added dropwise Within 15 minutes a solution of 1.61 "bromine" in 10 ml "isessi", in addition, after 1 minute of the bromine, the reaction mixture is diluted with 20 ml of chloroform and shaken with water, a 3% solution of KHCO, and again with water until the reaction is neutral, the orange phase dries and chloroform is distilled off. The residue can either be used directly for the dehydrobromic run, or recrystallized from ether-pentane, if the product can be made pure. Then it melts at 17P - 180 ° C, ^ ⁰

* t °° ιλ Hi !! ¹¹ 247 mn, (1οσ £ 4.14) in Obercinstimmunj »with

IHrIX

Literature in % aben.

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3. IT ^ -Acetoxy-o-dehydroprogesterone

a) It is suspended in a solution of 3.6 g of i-chloro-17iC-acetroxyprogesterone (from Example 1) in 25 ml of dimethylformamide, 1 g of lithium chloride and 1 g of lithium carbonate, after which the reaction mixture is refluxed for 3 hours. After cooling, the inorganic salts are filtered off and the solvent is distilled off until the first crystals appear. After cooling, the precipitated product is filtered off with suction and the mother liquor is diluted with water. By recrystallizing the first portion and the precipitate of the second portion from methanol, 2.56 g (78t) of the product "it F. 220-221 ° C, & Ü ρ ^0-3 °, Xj; ^" 283 nm (log £ 4.41), in accordance with the same product manufactured in a different way.

When the reaction is carried out under exactly the same conditions with the crude substance from Example 1, one obtains the desired compound with the above constants in a yield of 2.81 g (76t).

b) The crude evaporation residue of the bromine derivative from Example 1 is dissolved in 25 ml of dimethylformamide and the solution is left to stand at room temperature overnight. According to thin-layer chromatography, it transforms under these conditions converts a considerable proportion of the starting material into the desired product. The reaction is completed after adding Von 1.2 g lithium bromide and 1.2 g lithium carbonate by heating for 2 hours in a boiling water bath. Next »Refurbishment as in example 3a. The procedure is analogous with pure a ^ -Bromo-iftt-acetoxyprogesterone.

4. o / l-chloro-io-methylene-WoC-acetoxyprogesterone

A solution of 2.5 g of 3.174 t ~ DUeetoxy-16 * «ethylene-4 ^S ' ⁵ -

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Pregnadien-20-one in 15 el chloroform is mixed with 3 ml glacial acetic acid and 2 ml triethylamine and cooled to 0 ° C. A solution of 0.456 g of chlorine in 9 ml of glacial acetic acid is slowly added dropwise to the reaction mixture. After 15 minutes, the reaction mixture is concentrated in vacuo, the residue is diluted with 15 ml of glacial acetic acid and 10 ml of water, added dropwise. The crude product crystallizes out overnight , which is recrystallized from ether. This gives the new compound in pure form, with a temperature of 144 - 146 ° C, JLJJJ ^M 240 na (log 6 4.16). The Eleraentar analysis results correspond to the calculated values and the roast formula,

5. 6ye * -Bromo-16-methylene-17tfO »acetoxyprogesterone

In the same way as in Example 4, but using a solution of 1.03 g of bromine in 8 ml of glacial acetic acid, the desired new compound with P. 148 - 149 ° C (with decomposition) is obtained after recrystallization from ether, λη £ ^χ Η ^{248 n} * ^{ilog ε 4 "17)} · ^Dio elemental analysis corresponds to the calculated values and the empirical formula.

6. lo-methylene-δ-dehydro-njC-acetoxyprogesterone

a) In an analogous manner to Example 3a is obtained from o ^ chloro-ie-methylene-ntft'-acetoxyprogesteron the desired compound "it P. 230-233 ° C, (*) ⁰ J ■ - 132 °, Jt 22 " nm (log £ 4.5o), which is identical to the authentic sample.

b) The bromine derivative used as the starting material is prepared by bromination of a solution of 50 g of 3.17 ** -diacetoxy-16-methylen-A · -pregnadien-20-one in 300 ml of chloroform, 40 ml

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TriUthylamine and 60 ml of glacial acetic acid, with a solution of 20.6 g of bromine in 100 ml of glacial acetic acid at 0 ° C. and by working up as in Examples 1 and 2. The raw evaporation residue, which still contains about 50 g of chloroform, is dissolved in 250 ml of dimethylformamide, 16 g of anhydrous, powdery material is added Calcium carbonate and refills with dimethylformamide to a volume of 450 ml. The reaction mixture is heated to boiling under nitrogen and slowly distilled until the Temperature is the boiling point of the pure dimethylformamide (146 ° C) reached. The reaction mixture is boiled at this temperature for a further 1 hour, then allowed to cool, the precipitated calcium carbonate is filtered off and the solvent is distilled in vacuo until it separates from the first crystals. After cooling, the crystals of the 1st product are filtered off, the mother liquor is concentrated, whereby the II. product is obtained. The remaining mother liquor is supplied by precipitation with a five-fold volume Water the impure III. Product. By recrystallizing the individual components from acetone, if necessary using decolorizing agents, 30.8 g (60t) are obtained of the product, the constants of which correspond to those of the substance from Example 6a.

7. 16-methylene-6-dehydro-17 ^ -capronyloxyprogesterone a) The preparation of the 3, n-dikapronyloxy-io-methylene A ' -pregnadien-20-one consists of warming 5 g of 16 / fl-methyl-16flC, 13 * -epoxyprogesterone in SO al caproic anhydride • with 0.025 g of sulfosalicylic acid in vacuo with gradual distillation, so that 40 ml of the liquid within 20 minutes pass over. 0.1 »1 pyridine is added to the residue and the distillation continues as long as the distillate passes over the vacuum of the water jet pump up to a temperature of 200.degree. The oily residue is mixed with 5 ml of old pyridine and the unreacted anhydride decomposes aan 50 ml of water. The oily layer niaat aan in ethyl acetate, after the usual work-up it yields 8.0 g (10Ot)

- 11 -

of the pure dikapronate Aj ^ f 234 rna (log C 4.28), which can be used for further operations.

b) Broadening and dehydrobromination of enol capronate

A solution of 8.0 g of enol capronate from Example 7a in RO ml of anhydrous propionic acid and 5 g of sodium propionate is cooled to ⁰ ° C. and brominated with a solution of 2.35 g of bromine in 15 ml of propionic acid. After the bromine has decolorized, the reaction mixture is concentrated in vacuo, the residue is diluted with 25 ml of water, taken up in chloroform and worked up in a known manner. The crude residue is subjected directly to a dehydrobromination according to Example 6b, whereby 4.35 g (671, based on the starting epoxide) of the desired product with F. 143-144 ° C, (ÖC) o ° "* ¹²⁶ °»% mix ^{H 283 nm} (log £ 4.47), with appropriate elemental analysis, obtained. The compound has not yet been described in the specialist literature.

8. 21-Acetoxy-A * ⁶ -pregnadiene-ITdO-ol-S 1 O-dione

A solution of 9.52 g of 3.17 «t, 21-triacetoxy- λ -pregnadien-20-one in 50 ml of dichloroethane, 10 ml of glacial acetic acid and 10 ml of N-ethylpiperidine are brominated in an analogous manner to in Example 2 with a solution of 3.25 g of bromine in 15 ml Dichloroethane. The crude residue obtained by working up according to Example 2 is heated in 90 ml of dimethylformamide with 5 g of pulverulent calcium carbonate for 3 hours boiling water bath. After cooling, the precipitated inorganic strings are filtered off with suction and the filtrate is poured one in 450 g of a water-ice mixture and the deposited precipitate is filtered off with suction. While it is still moist, it is suspended in 20 nl methanol, filtered if necessary the solution and, under nitrogen, a solution of 0.30 g of sodium in 15 el of methanol is added dropwise. After 1 hour of standing at the temperature of the free tea, it settles down Solution with 1 tablespoon of glacial acetic acid and the solvent is distilled in the vacuum «off. By diluting the residue with 30 «1 Precipitation from water is absorbed in Bentol,

the solution is shaken with water, a sodium bicarbonate solution and again with water and, after drying, the solvent is distilled off. Dissolves the residue in 80 ml of pyridine, 20 ml of acetic anhydride are added and left the reaction mixture at room temperature overnight. hen. Ice broken by pouring it to 400 ρ a precipitate is obtained which, by crystallization from methanol, yields the desired product of 6.0 g (79%) provides. M.p. 218-219 ° C / LJjJax " ^{283 nm} (log £ 4.41), which agrees with the literature.

9. 16-methyl- _Δ ⁴ » ⁶ » ¹⁶ -pregnatriene-S ^ o-dione

a) Enol acetylation of 16 ec-methylprogesterone

A solution of 6.56 ς 16Ä-methylprogesterone in 60 ml Toluene and 7.5 ml of acetic anhydride with the addition of 35 mg of sulfosalicylic acid are boiled under reflux, the solvents being gradually distilled off via a column. After 3 hours (35 ml of distillate), 0.15 ml of pyridine is added and the solvent is evaporated to dryness in vacuo away. The residue is dissolved in 50 ml of chloroform, the solution is washed with water, with an NaHCO. Solution and again with water until the reaction is neutral. After drying and filtering, the chloroform solution is used in the following stage.

b) bromination and dehydrobromination

The chloroform solution from Example 9a is mixed with 5 ml of glacial acetic acid and 3 ml of triethylarain and brominated at 5-10 ° C. with a solution of 3.2 g of bromine in 10 ml of glacial acetic acid. the After the usual work-up, the reaction mixture gives a solid residue which is dissolved in 100 ml of dimethylformamide and with 1.5 g lithium bromide and 1.5 g lithium carbonate in dehydrobrominated in a manner analogous to that in Example 6a. Recrystallization of the crude product from methanol is obtained 4.85 g (75t) of the desired new, still in the specialist literature

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product not described with a temperature of 217 - 218 ° C, 251 and 283 nm (log £ 4.23 and 4.42).

In an analogous manner, but using 16/3 methylprogesterone, the same product was significantly lower Yield obtained, which is probably caused by sterically unfavorable dehydrobronation in the D-ring.

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Claims (1)

Claims 1. Process for the preparation of unsaturated derivatives the pregnancy series of the general formula I. where R _{1 is} a hydrogen atom, an edC- or / 6-Me thy Ig rup- pe or a methylene group, R ₂ and 3, identical or different, denote a hydrogen atom or an acyloxy group with 1-6 carbon atoms, where there may be a further double bond in the 16, 17-position, characterized in that a substituted 3-acyloxy - Δ ³ » ⁵ -pregnadiene of the partial general formula II II where R. denotes an acyloxy group with 1-6 carbon atoms, halogenated, the adduct formed is hydrolyzed and the 6/9 -halogen-A -3-ketone obtained is dehydrohalogenated. 909847/1067 - 45 BATH ORIGINAL , Method according to claim 1, characterized, that one can halogenation by addition of elemental chlorine or bromine in the presence of an inert organic . Solvent, such as ZiB. of a halogenated hydrocarbon with 1-2 carbon atoms, advantageously FIi- caloromethane, chloroform or dichlorohthane. 3. The method according to claim 1, characterized in that the halogenation in anhydrous aliphatic monocarboxylic acids with 2-3 Carbon atoms, advantageously in glacial acetic acid. 4. The method according to claim 1 and 2, characterized, that halogenation can be carried out in an organic inert solvent such as a halogenated aliphatic hydrocarbon with 1-2 carbon atoms in the Mixture with an anhydrous aliphatic monocarboxylic acid with 2-3 carbon atoms. 5. The method according to claim 1 and 3, characterized in that the halogenation in the presence of an alkali metal salt of an aliphatic monocarboxylic acid with 2-3 Carbon atoms. 6. The method according to claim 1, 2 or 3, characterized in that that the halogenation is carried out in the presence of tertiary aliphatic or heterocyclic amines. 909847/1067 - 16 - 7. The method according to claim 1 to 5, characterized in that the halogenation at Temperatures from -30 ° C to 50 ° C, advantageously at 0 to 20 ° C, carries out. 8. The method according to claim 1, characterized, that the hydrolysis of the halogenated adduct with Performs water at a temperature of IS to 25 ° C. 9. The method according to claim 1, characterized, that the dehydrohalogenation of the 6/0 -halogen-A -3-. ketones in dimethylformamide, in the presence of alkali metal or alkaline earth metal carbonates, advantageously lithium ·· or Calcium carbonate. 10. The method according to claim 1 and 9, characterized, that the dehydrohalogenation of the 6-halogen-A -3-ketone in the presence of a mixture of lithium carbonate “it” a lithium halide, the halogen of which corresponds to the split off halogen, carries out. 11. The method according to claim 1 and 9 characterized, that nan the dehydrohalogenation at temperatures of 20 ° C drive through to the boiling point of the reaction mixture. 909847/1067