DE2059839A1 - Process for the production of halogenated pregnans - Google Patents

Description

Dr. Ing, A, van der Werft Dr. Franz Lederer

PATENT ADVOCATE!

, Dec 1970

RAN -UO4 / 97K

F. HofFmann-Lä Hoche & Co. Aktiengesellschaft, Basel / Switzerland Process for the production of halogenated pregnans

The present invention relates to a method for Production of halogenated pregnans of the formula I.

Ί ^R »

wherein R ₁ and R represent chlorine or bromine and R .. NiederallcyLidon represent,

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Green / 2 ^ .11.70

BATH

as well as new intermediates for it.

The term lower alkyl includes straight and branched ones Hydrocarbon radicals with up to 6 carbon atoms, such as Methyl, ethyl, t-butyl and n-pentyl. The term Miedera ": ky ~ iiden denotes a straight-chain or branched hydrogen radical, the two free bonds on a carbon atom having. Examples are methylene, ethylidene and Isopropylideri. A preferred lower alkylidene radical is methylene.

The compounds of formula I are available as ProgestatJ.va of value (see for example Belgian patent specification no. 719049).

The method according to the invention is characterized in that that he

a) a compound of the formula II

R ₂

where R, which has the above R ^ doutiing, H _} chlorine or bromine and η represent the number O- ^l j ,

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treated with chlorine or bromine and - a proton acceptor, b) d ^ e go ^ ö forms connection; of formula III

CHR ₄ (CH ₂ ) _n H.

^R 4
where R, R ^ / and η have the above meaning

in an inert organic solvent with an alkali iodide heated to reflux in the presence or with the subsequent addition of a Niederal ^ a "carboxylic acid.

The conversion of a compound of the formula II into a compound of the formula III according to reaction step a can either directly or via an intermediate of the formula IV

CHR ₂₁ (CH ₂ ) H

1 2

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IV

BATH ORIGINAL

where R ,, R _? , Rj, and η have the above meanings ,

take place. A compound of formula II can by treatment be converted with chlorine or bromine into a compound of the formula IV. This reaction step can be carried out by adding catalytic Amounts of anhydrous mineral acid or organic acids are facilitated. It is preferred to use hydrogen halides for this purpose, e.g. hydrogen chloride. The reaction is carried out in an inert organic reaction medium, e.g. in ethers such as Lower alkyl ethers, e.g. ethyl ether or dioxane, in halogenated Hydrocarbons such as chloroform, carbon tetrachloride, ethylene chloride or methylene chloride carried out. Preferred The solvent for this reaction are the halogenated hydrocarbons. The halogen can according to the usual methods can be introduced into the reaction medium, e.g. a solution of the halogen in an organic solvent in the reaction mixture can be introduced. A solution of the halogen in a halogenated one, for example, is suitable for this purpose Hydrocarbon, e.g. a solution of chlorine in carbon tetrachloride. The halogen treatment becomes appropriate at low temperatures, preferably between -40 C and Room temperature, in particular between -30 ° and 0 C carried out.

A compound of formula IV can be converted into a compound of formula III by treatment with a dehydrohalogenating agent will be convicted ». Examples of dehydrohalogenating agents for this reaction are proton acceptors such as nitrogen-containing heterocyclic bases, e.g. pyridine or Picoline i lower alkylamines, e.g. triethylamine and alkali metal bases such as alkali hydroxides, e.g. sodium hydroxide, or alkali bicarbonates, e.g. sodium bicarbonate. A suitable one The base itself can be the solvent for this reaction. But you can also use other solvents, e.g. inert organ! -

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BATH

Niche solvents such as ethers, e.g. diethyl ether or Use dioxane or chlorinated hydrocarbons such as chloroform or carbon tetrachloride. The dehydrohalogenation is expedient at temperatures between 0 and 100 C, preferably carried out between 0 and 50.degree. Used as a base one preferably uses a nitrogen-containing heterocyclic base, in particular pyridine.

According to the invention, the compound of the formula II can also be converted directly into a compound of the formula III if one considers the halogenation in the presence of a proton acceptor and a lower alkanecarboxylic acid such as propionic acid. This is where the ones described above come in Halogenation conditions into consideration. Regardless of whether the compound of the formula II is in the compound of the formula III is transferred directly or via the intermediate IV, 1 mole of halogen is required per mole of the compound of formula II. However, it has been found that the use a molar excess of halogen, i.e. the use of at least 1.5 moles of chlorine or bromine per mole of the compound of formula II, leads to higher yields and purer products. It is preferred to halogenate with 1.5-2 mol of halogen per mole of compound of formula II.

In step b of the process according to the invention, one can proceed in such a way that the compound of the formula III with an alkali iodide, preferably sodium iodide, to reflux heated and then a lower alkanecarboxylic acid is added. You can also use the compound of formula III in the presence of a Heat lower alkali carboxylic acid, preferably acetic acid, with an alkali iodide. Preferred solvents for this reaction are ketonic solvents such as acetone and methyl ethyl ketone. .

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The compounds of formula II can as follows illustrated by an example:

Production of l6e-chloromethyl-6- chloro-l6q, lja-epoxy pregna 4,6-diene-3,20-dione;

Ss To a solution of 50 g of 3, IJa- dihydroxy-l6-methylenpregn-5-en-20-one-3 ~ acetate in 1 liter of dry benzene containing 17 ml of dry Fyridin be over one hour at 0 C 264 ml of a 1.08 molar solution of chlorine in carbon tetrachloride. The mixture is stirred for 30 minutes at OC, filtered and the white precipitate is washed thoroughly with benzene. The benzene wash solutions are combined and set aside. The precipitate is dried under reduced pressure, stirred into 200 ml of water and filtered again. 28 g of crude product are obtained in this way.

The benzene solutions are then washed with 10 % sodium thiosulphate solution, 1N hydrochloric acid, 57 ° sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure, additional crude product being obtained. The entire crude product is dissolved in methylene chloride, the insolubles are filtered off and the solution with. Coal treated. The residue obtained after removal of the solvent is crystallized from methylene chloride-methanol and gives 16β-chloromethyl-5tf, 6β-dichloro -3β-hydroxy-16tt, r7a-epoxypregnan-20-one acetate. Concentration of the mother liquors gives additional product.

To a suspension of 41 g of 16β-chloromethyl-5c (, 6p> dichloro-3f> -hydroxy-16c (, 17ct-epoxypregnan-20-one acetate in 800 ml of tetrahydrofuran are 615 ml of a 1 ^ igon solution of Potassium hydroxide in 95% / ethanol. The mixture is

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stirred at room temperature, whereupon most of the Solvent is removed under reduced pressure. The residue is mixed with 500 ml of ice water and the resulting Precipitate filtered, washed with water and dried under reduced pressure for 2 hours. The product obtained is dissolved in benzene, the solution is over magnesium sulfate dried and concentrated. The residue is with diethyl ether triturated and yields 16β-chloromethyl-5c {16p-dichloro-5β-hydroxyepoxy pregnan-20-one.

To a solution of 32 g of 16P ~ chloromiethyl-5c (>6p> -dichloro- M 3P ~ hydroxy-16 «, 17c (-epoxypregnan-20-one in 320 ml of acetone (previously by refluxing with permanganate until the violet color persists and subsequent distillation) are added in the course of 15 minutes at OC 29.3 ml (10 $ excess) Jones reagent (made from 13 * 36 S chromium trioxide and 11.5 ml concentrated sulfuric acid and make up to 50 ml with water) The reaction mixture is stirred for a further 10 minutes at 0 ° C. and most of the acetone is removed under reduced pressure at 25-30 ° C. 2 liters of ice-water are then added, the mixture is filtered and washed with 3 liters of water. The product is dried under reduced pressure for 2 hours - J net and delivers
pregnan-3,2O-dione.

3I g of 16β-chloromethyl-5aj6P-dichloro-16ci, 17a-epoxypregnan-3,20-dione are added to a suspension of > 1 g of sodium acetate in 1550 ml of 95% ethanol, and the mixture is refluxed for one hour. The solvent is then removed under reduced pressure and the residue treated with one liter of ice water. The precipitate is filtered off and washed with 3 l of water. After drying and trituration with dietary ether, β-chloro-IGβ-chloromethyll6rt, 17ci-epoxypregn-4-ene-3,20-dione is obtained.

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"- r

BATH ORIGINAL

To a solution of 22.6 g of 6ss-chloro - L6P ~ thylox chlorine, 17o: ~ ~ epoxypregn 4-en-3> 20 'dione in 226 ml of dry dioxane is 22.6 ml redestillierton Orthoarneisensäuretriätliylester and 1.13 ß Snlfosalicylic acid monohydrate. The solution is stirred for 5 hours under nitrogen at room temperature. It is then cooled to 0 ° C., 7 * 5 ml of pyridine and an insole-lessend tropfenviej.se are added with 600 ml of ice water over the course of 30 minutes. The mixture is stirred for 2 hours at room temperature, the precipitate is filtered off, washed with water and dried overnight. One receives' ß-chloro-loß-chloromethyl-3-ethoxyl6ci, 17c / -

9, Q. g activated manganese dioxide The mixture is stirred vigorously for half an hour and then stirred

filtered through diatomaceous earth. The pestilents are made with methylene chloride washed and the filtrate is reduced under reduced

Pressure (bath temperature about 40 C) concentrated. The remaining acetic acid is removed under high vacuum at ho C. The oily residue is treated with 250 ml ice water, filtered, α and thoroughly washed wi th water. After drying, one obtains

-Chlorine thy 1-6-chloro-l6cf, l7cc-epoxypregna-4,6-diene-3i20-dione. 2 g of this crude product are treated with 10 ml of benzene and the colloidal suspension thus obtained is with 500 ml of benzene through 20 g of neutral aluminum oxide (activity 1) flushed. The solvent is removed under reduced pressure, giving 16 (3-chloromethyl-60-chloro-16a, rfa-epoxypregna-4,6-diene-3,20-dione obtained as a colorless foam.

The following examples explain the invention Procedure:

BATH ORIGINAL

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example 1

A. To a solution of 1.3 g of 16β-chlorinethyl 6-ch.ior-, 17er-epoxypregna-ii -., 6-diene-3,20-dione in 10 ml of chloroform is added at 0 C 2.8 ml of a 1.13 molar solution of chlorine in carbon tetrachloride. The reaction mixture is stirred at OC for 1 hour , then the solvent is removed under reduced pressure. The residue is treated with 10 ml of hexane and the solvent is removed again. This gives 16β-Chlorine thy 1-44,6,7C * - trichloro-lec ^ Tfa-eppxypregn-5-en ~ 3.20 - dione as a pale yellow foam. This is mixed with 5 ml of A dry pyridine and stirred for 2 hours at room temperature. The light yellow solution is poured into 100 ml of diethyl ether and the ethereal solution is extracted several times with 1N sulfuric acid in order to remove all of the pyridine. The ethereal solution is then dried over magnesium sulfate and the solvent removed under reduced pressure. 1.2 g of a light yellow foam are obtained. This is dissolved in 10 ml of benzene and filtered with 300 ml of benzene over 10 g of neutral aluminum oxide (activity 1). The residue obtained after removal of the solvent is triturated with diethyl ether and yields 16p-chloromethyl-4,6-dichloro-16u, 17c (-epoxypregnail-, 6-diene-3,20-diGn.

B-. To a suspension of 3 g of sodium iodide in 20 ml Acetone is added, with stirring, to 300 mg of 16β-chloromethyl-4,6-dichloro6cc, r / ct-epoxypregna-ij - ^ - dien - ^^ O-dione and then heated the Reflux mixture for 24 hours. Then 0.5 ml of glacial acetic acid is added added, and it is heated to reflux for a further 2 hours. The dark solution is after cooling with 15 ml of 0.1 N Sodium thiosulphate solution is added and the acetone is removed under reduced pressure. Water is added to the residue, and the precipitate is filtered off and washed with water. The product thus obtained is 2 hours under reduced Pressure dried and then dissolved in as little ether as possible.

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The yellow ethereal solution is made with 0.1 N sodium thiosulphate solution washed, dried over magnesium sulfate and evaporated. 4,6-dichloro-17a-hydroxy-16-methylenepregna-4,6-diene-3,20-dione is obtained.

Example 2

To a solution, cooled to 0 C, of 20.47 g of 6-chloro16P * -chloromethyl-16cX, 17o-epoxypregna-4,6-diene-3.20-dione in 200 ml of chloroform is added 75.5 ^ra l of a 0.995 molar solution of chlorine in carbon tetrachloride. The reaction mixture is stirred at 0 ° C. for half an hour, then the solvent is removed under reduced pressure at 50 ° C. and 150 ml of pyridine are added to the residue. The mixture is stirred for 1 hour at room temperature and then diluted with 600 ml of diethyl ether. The organic phase is washed with 4,400 ml portions of 1N hydrochloric acid, 400 ml of 5-fold sodium bicarbonate solution, 400 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated at 50.degree. 24.15 g of crude 16β> chloromethyl-4,6-dichloro-16fi-17c (-epoxypregna-4,6-diene-3 _i 20-dione, which is dissolved in 60 ml of benzene and dried over 182 g of silica gel (0.005 - 0.2 mesh), eluting as follows:

Fraction: Eluent: 5 1 benzene Product quantity: 1 2, 25th 1 π 9.63 2 0, 25th 1 Il 0.87 3 0, 1 CH ₀ Cl ₀ 0.78 4th 5 11.16

Fractions 2-4 are combined and poured into 150 ml Dissolved methylene chloride. The solution is concentrated to 100 ml, mixed with 200 ml of methanol, concentrated to 180 ml and after Allowed inoculation to crystallize. After cooling to -20 ° C. for 4 hours, filtering and washing with ice-cold methanol one 9.18 g loess-chloromethyl ^ G-dichloro-loq ·, 17cc-epoxy-

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pregna-4,6-diene-3 , 20-dione.

This product is used in the example 1, section B. described way in 4,6-DiChIOr-I ^ x-hy droxy-lö-methylen - * - pregna-4,6-diene-3,20-dione transferred.

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Claims (1)

Claims e / 1, / Process for the production of halogenated pregnans of formula I. CH. C = O where R. and R represent chlorine or bromine and R., lower alkylidone, characterized in that one a) a compound of the formula II CH. (CHJ _n H ₂ ) II where R has the above meaning, R _{2 is} chlorine or bromine and η is the number 0-5, 109825/2098 and b) treated with chlorine or bromine and a proton acceptor, / the compound of formula III thus formed III ^R 4
where R, R ^ / and η have the above meaning, in an inert organic solvent with an alkali iodide heated to reflux in the presence or with the subsequent addition of a lower alkanecarboxylic acid. 2. The method according to claim 1, characterized in that that a compound of formula II as defined in claim 1 by treatment with chlorine or bromine in an inert organic solvent into a compound of formula IV IV 109 825/2098 in which R, R, R. and η are the same as in claim 1, convicted. 3. The method according to claims 1 and 2, characterized in that that a compound of the formula IV as defined in claim 2 with a dehydrohalogenating agent treated in order to obtain a compound of the formula I as defined in claim 1. 4. The method according to claim 3, characterized in that the dehydrohalogenating agent is pyridine. 5. The method according to claim 1, characterized in that in step a 1.5 ^ MoI halogen per mole of the compound Formula II used. 6. The method according to claim 1, characterized in that the alkali iodide in step b is sodium iodide. 7. Process according to claims 1-6, characterized in that the compound of formula II is the
ß-chloromethyl-o-chloro-ISci, 17c (-epoxypregna-4,6-diene-3,20-dione used. 1 09825/2098