DE1171911B - Process for the preparation of 21-low-acyloxy-17ª ‡ -hydroxy-16ª ‰ -methyl-pregna-1, 4, 9-triene-3, 20-dione - Google Patents

Description

Process for the preparation of 21-lower-acyloxy-17α-hydroxy-16β-methyl-pregna-1,4,9-triene-3,20-dione The invention relates to a method for the production of 16-methyl steroids, the Carry double bonds in the 1- and 4-positions and a keto group in the 3-position.

One has recently been on various steroids with methyl groups in 16 position, paying particular attention to the field of anti-inflammatory steroids, since the presence of a 16-methyl substituent was found to be the physiological Can significantly affect properties. It therefore became important to have procedures for Manufacture of compounds in the steroid range, especially the anti-inflammatory ones Series to develop with 16-methyl substituents.

A process for the preparation of 21-acyloxy-17 Jx-hydroxy-16β-methyl-5 has been used proposed a-pregn-9-en-3,20-dione by dichlorinating a 3ß-acyloxy-16-methyl-5x-pregn-9 (11) -en-20-one compound with formation of a 3β-acyloxy-9a, 11β-dichloro-16-methyl-5-x-pregnan-20-one, acylation of this compound to form a 3ß, 20-diacyloxy-9a, llß-dichloro 16-methyl-5x-pregn-17 (20) -en or Enolacylation of 3ß-acyloxy-16-methyl-5oc-pregn-9 (11) -en-20-one with formation a 3β, 20-diacyloxy-16-methyl-5x-pregna-9 (11) 17-diene dichlorination of this compound with formation of a 3ß, 20-diacyloxy-9a, llß-dichloro-16-methyl-5a-pregn-17 (20) -en, Epoxidation of the enol acylate obtained in one of the two ways with formation of a 3β, 20-diacyloxy-9x, 11β-dichloro-17 (20) -epoxy-16-methyl-5x-pregnane, hydrolysis this latter compound to form a 3ß, 17.x-dihydroxy-9.x, l Iß-dichloro-16-methyl-5x-pregnan-20-one, Brominating this compound in the 21-position, acyloxylation of the bromine compound obtained with formation of 21-acyloxy-9, x, llß-dichloro-3ß, 17a-dihydroxy-16-methyl-5x-pregnan-20-one, Oxidation of this compound in the 3-position to the corresponding keto compound and Cleavage of chlorine from the 3-keto compound with formation of 21-acyloxy-17ca-hydroxy-16-m ethyl-5x-pregn-9 (11) -en-3,20-dione or, optionally, splitting off of chlorine from the 21-acyloxy-9x, 11β-dichloro-3β, 17x-dihydroxy-16-methyl-6a-pregnan-20 -on and oxidation of the latter compound in the 3-position to form the corresponding one 3-keto compound.

It has now been found that those obtainable from these compounds 21-acyloxy-2,4-dibromo-17ahydroxy-16β-methyl-5a-pregn-9-en-3,20-diones to the desired ones 41,4-3-ketones can be dehydrobrominated. The process-manufacturable 41,4-3-ketones can in turn become a pharmacologically active compound, e.g. B. 16ß-methyl-9x-fluoro-prednisolone, are processed. According to the invention from a 21-lower-acyloxy-2,4-dibromo-17oc-hydroxy-16β-methyl-5x-pregn-9-ene-3,20-dione by heating in the presence of an inert Lewis base with a high dielectric constant, d. H. over 15, which corresponds to the general formula R1 - CO - NR2 - R3, where R1 a hydrogen atom or an alkyl group with 1 to 5 carbon atoms and R2 and R3, the can be the same or different, in each case an alkyl group having 1 to 5 carbon atoms or optionally together a divalent aliphatic group which together with the adjacent nitrogen atom form a heterocyclic ring, where the base is liquid at the temperature of the elimination of hydrogen bromide, or of N-formylmorpholine and in the presence of calcium carbonate, preferably using an alkali or alkaline earth metal halide, hydrogen bromide, which is soluble in the reaction mixture cleaved. The dielectric constant of the base is advantageously between 30 and 40.

Bases suitable for the process according to the invention are, for. B. N, N-dimethylformamide, N, N-diethylformamide, N, N-dipropylformamide, N, N-dibutylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N, N-dimethylvaleramide, N, N-dimethylpropionamide, N-formylpiperidine and N-formylmorpholine. This group of compounds is preferably N, N-dimethylacetamide used.

The inventive method is carried out in the presence of calcium carbonate performed against the reacting steroid and the desired end steroid product is inert. Its function is obviously to be the educated in the implementation To bind hydrogen bromide.

The calcium carbonate is preferably in finely powdered form, advantageously with a particle size of less than 10 microns was used.

In addition, an alkali metal or Alkaline earth metal halide, especially a bromide, in the reaction mixture is soluble, e.g. B. lithium bromide, sodium bromide or calcium bromide can be added. The presence of such a halide often enables the reaction to take place at lower temperatures and can lead to higher yield. Also enables the halide shortening the reaction time at lower temperatures.

The reaction time required for splitting off hydrogen bromide depends on a certain steroid depends on the temperature used, and a suitable one The balance of these factors can easily be determined experimentally. That can can be conveniently performed by putting the steroid in the chosen organic base optionally with the added inorganic basic substance or the halide heated. The reaction mixture should be kept at a certain temperature, and aliquots are removed at certain time intervals. One can progress implementation by observing an appropriate physical identifier, such as z. B. the UV absorption, measure. A graphic table thus recorded shows clearly the minimum time required. Analysis of the product for bromine content is also possible cheap.

The elimination of hydrogen bromide can expediently by heating at temperatures carried out between 80 and 1.80 ° C in the presence of the base and the calcium carbonate will. At temperatures in the lower part of the specified range, e.g. B. from 80 up to l35 ° C, is the presence of an alkali metal or alkaline earth metal halide particularly favorable to reduce the time required for implementation and a obtain better yield of 41,4-3-ketone; these conditions are preferred Working method.

If you at higher temperatures, such as. B. 135 to 180 ° C, it may be advantageous to carry out the reaction at the boiling point of the mixture. Working at these higher temperatures can lead to considerable damage to the 17-position side chain and thus make a rather laborious purification necessary so that the desired 41,4-3-ketone can be isolated. In view of this loss, the yield may be relatively low, e.g. B. of the order of 400% of the theory for the isomer mixture and about 46% of the theory for the crystalline 2: x, 4x isomer. You can reduce the reaction rate at higher temperatures through the use of an alkali metal or alkaline earth metal halide, such as. B. lithium bromide; however, this can lead to the optimal response time becoming inexpediently short. If you work at lower temperatures, the 2,4-dibromo steroid can be added with stirring to a mixture of the base with the calcium carbonate and an alkali metal halide or alkaline earth metal halide, maintaining the reaction temperature until the UV spectrum and the bromine content of an isolated sample show that the implementation is practically complete. At 100 ' C the required time can e.g. B. be about 20 hours for the crystalline 2-N, 4, N-dibromo isomer (as 21-acetate) and more for the isomer mixture. Although the reaction time is significantly longer than the time required at higher temperatures, the 17-position side chain is only slightly attacked and the product is cleaner and therefore easier to clean. In addition, the yield is greater, e.g. B. about 65 "/ o the theory for the crystalline 2x, 4-t-isomer and about 45% of the theory for the isomer mixture.

The following examples explain the process according to the invention.

The side chain determinations were made with cortisone acetate as the reference compound. They are corrected due to the differences in molecular weight. The method was described by Mader and Buck (Analyt. Chem., 1952, 24, p. 666). The homogeneity of the products was also checked by paper chromatography and IR spectoscopy. Elimination of hydrogen bromide from 21-acetoxy-2x, 4 @ x-dibromo-17 x-hydroxy-16f-methyl-5 z-pregn-9-en-3,20-dione Example 1 With calcium carbonate and lithium bromide in dimethylacetamide at 95 ° C Mixture of 5 g of 21-acetoxy-2x, 4ß-dibromo-17a-hydroxy-16ß-methyl-5x-pregn-9-en-3,20-dione with calcium carbonate (5g) in tablet form was with vigorous stirring to a suspension of Calcium carbonate (2 g) and lithium bromide (2.3 g) in dimethylacetamide (62.5 ml) were added under nitrogen at 95 ° C. The mixture was stirred at 95 ° C. for 22 hours, cooled and poured into ice-cold n-hydrochloric acid (11) with rapid stirring. After stirring for 30 minutes, the product was filtered off, washed successively with water, dilute sodium bicarbonate solution and with water until neutral and then dried at 100 ° C. in vacuo. The crude product weighed 3.315 g (93%). A portion of the product (3.258 g) in benzene (110 ml) was chromatographed on a column of charcoal (7.2 g, 38 x 1.26 cm), benzene (II) eluted a white solid (2.989 g) which from Acetone (25 ml) was recrystallized. The first crop (1.804 g, 50.6%) had the F. (K of 1 er) = 218 to 224 ° C; 7 .. "z - 238 mu. (Egg" = 405); [x] D. = + 69 @ (c --- 0.58 in dioxane) (found: side chain = 900/0). The second crop (0.355 g, 10.0 %) had the F. (K of 1 er ) = 215 to 223 ' C and A. ", = 238 m # L (E,'! = 412); [ x] D, _ + 69 ° (c = 1.29 in dioxane).

Example 2 With calcium carbonate in dimethylacetamide under reflux A mixture of 5 g of 21-acetoxy-2x, 4x-dibromo-17a-hydroxy-16ß-methyl-5t-pregn-9-en-3,20-dione] with calcium carbonate (4 g) was added with stirring and under reflux to a suspension of calcium carbonate (1.5 g) in dimethylacetamide (40 ml) under nitrogen. Heating under reflux was continued for 20 minutes, the reaction mixture cooled and poured into ice-cold 5N hydrochloric acid (500 ml) with rapid stirring. Isolation in the manner described in Example 1 gave a crude product (3.333 g) of Amax = 239 m # t (Eil = 363) (found: Br = 1.6%, side chain 87%). A portion of this product (3.27 g) in ethanol (90 ml) and acetic acid (5.4 ml) was refluxed with Girard P reagent for 15 minutes, the solution concentrated in vacuo to about half its volume and in Pour 4% sodium bicarbonate solution; the unreacted substance was extracted with ethyl acetate (50 ml-8), the combined extracts were washed with sodium bicarbonate solution and water, dried over magnesium sulfate and the solvent was evaporated off. The foam-like product obtained (2.980 g) had @max = 238 m # L (El l = 398); it was dissolved in boiling benzene, cooled, and a small amount of insoluble residue (0.094) g filtered off. The filtrate was chromatographed on a column of charcoal (4 g). When eluting with benzene and benzene-ethyl acetate (9: 1), a white solid substance (2.495 g) of Am "" = 238 m # t (El @ . = 366) was obtained. On recrystallization from acetone, the desired 16β-methyltriene (1.632 g, 460/1) was obtained in three crops.

Example 3 Elimination of hydrogen bromide with calcium carbonate in dimethylacetamide under reflux in example 2, with calcium carbonate (10 g) in dimethylacetamide (50 ml) under reflux for 30 minutes, the crude 16β-methyl-trienone acetate (4.95 g), Amdx = 237 m # t (E111 = 376) .This After treatment with Girard P reagent (see Example 2) and the removal of a benzene-insoluble product (0.589 g) by chromatography on charcoal (30 g), the product gave a crude material which, when crystallized from acetone, gave the desired 16β-methyltriene (2.235 g) in five portions.

The IR spectra of the fourth and fifth crops showed traces of contamination; @max = 1800 cm- ', which could be an oxide (17.21 -oxide?); otherwise they were all similar to the standard sample.

Example 14 The bromination of 21-acetoxy-17a-hydroxy-16ß-methyl-5a-pregn-9-en-3,20-dione Dibromosteroid (7.386 g) obtainable in glacial acetic acid-dioxane was treated with calcium carbonate (6.96 g) intimately mixed and with stirring to a mixture of lithium bromide (3.2 g) and calcium carbonate (2.8 g) in dimethylacetamide (87 ml), under nitrogen was kept at 95 ° C, was added. The reaction mixture was at for 34 hours stirred at this temperature. Isolation of the steroid revealed after chromatography and the Girard separation (see Example 2) a yellow solid substance (3.915 g) of% max = 238 m # t (Ei '! = 375). This solid was passed through a column in benzene (100 ml) sent from charcoal (not ground charcoal) (2 g) and with benzene (500 ml) eluted. Upon removal of the benzene, an off-white solid (3.84 g) obtained, which was recrystallized from acetone, 21-acetoxy-17x-hydroxy-16ß- methyl-5a-pregna-1,4,9-triene-3,20-dione (2.840 g) was obtained in three crops.

Example s Elimination of hydrogen bromide from 21-acetoxy-2x, 4ß-dibromo-17x-hydroxy-16ß-methyl-5ca-pregn-9-en-3,20-dione 21-acetoxy-2a, 4ß intimately mixed with calcium carbonate (1 g) -dibromo-17x-hydroxy-16β-methyl-5a-pregn-9-ene-3,20-dione (1 g) was added with stirring to a mixture of lithium bromide (0.46 g) and calcium carbonate (0.4 g) in Dimethylacetamide (12m1) kept under nitrogen at 95 ° C was added. The reaction mixture was stirred at this temperature for 22 hours, then cooled and poured into ice-cold 1N hydrochloric acid (250 ml) with vigorous stirring. The white precipitate was filtered off, washed and dried (0.646 g, 910/0). M.p. = 224 to 227 ° C (K of 1 er); M.p. = 206 to 210 ° C (capillary); @max = 238 m # t (Ei2, = 398) (found: side chain = 96 ° / a).

When a portion (0.598 g) was recrystallized from acetone, the pure 16ß-methyltriene (0.405 g) was obtained in two yields.

Example 6 The rubbery dibromosteroid obtainable by bromination of 21-acetoxy-17a-hydroxy-16ß-methyl-5a-pregn-9-en-3,20-dione in the presence of p-toluenesulfonic acid was dissolved in dimethylacetamide (30 ml) and the resulting solution was added to a refluxing suspension of calcium carbonate (30 g) in dimethylacetamide (200 ml) and, as described in Example 2, to a crude product (16.0 g) of 21 maz = 238.5 mp. (El;, = 374) implemented.

This crude product was dissolved in methanol (300 ml) and acetic acid (15 ml) treated with Girard reagent P (5.0 g) at reflux for 15 minutes. The cooled reaction mixture was dissolved in 4% aqueous sodium bicarbonate solution poured and the product as described in Example 2, including isolated by chromatography on charcoal (60 g) and crystallization from acetone. The product (8.87 g, 44%) that was isolated in one yield had the F. = 205 to 206 ° C (capillary) and @max = 238 m # t (Elem = 395).

EXAMPLE 6 Splitting off of hydrogen bromide from mixed dibromo isomers at 130.degree. C. Crude, 2a, 4ß-dibromo compound prepared from 21-acetoxy-17a-hydroxy-16ß-methyl-5xpregn-9-en-3,20-dione (20 g) was dissolved in Dimethylacetamide (70 ml) was added to a mixture of calcium carbonate (40 g) and lithium bromide (6.5 g) in dimethylacetamide (100 ml) at room temperature under nitrogen with stirring. The temperature of the reaction mixture was raised to 130 ° C. in 80 minutes, and after heating to 130 ° C. for 3 hours, the reaction mixture was cooled and poured into ice-cold In hydrochloric acid (1700 ml) with stirring. After stirring for 30 minutes, the precipitated crude trienone (19.12 g) was filtered off, washed with dilute hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water and dried over phosphorus pentoxide.

A portion (18.0 g) of the crude trienone was refluxed for 1 hour with Girard reagent P (4.5 g) in methanol (300 ml) and acetic acid (15 ml). The solution was cooled and poured into a mixture of aqueous sodium hydrogen carbonate (4 ° / a, 21) and ethyl acetate (300 ml) with stirring. The ethyl acetate layer was separated off and the aqueous layer extracted with further ethyl acetate (3-200 ml); the combined ethyl acetate extracts were washed with aqueous 4% sodium hydrogen carbonate solution (2-100 ml) and water (2-100 ml). When the dried extract was evaporated to dryness in vacuo, the crude, solid trienone (13.7 g) of the) .. "x (in ethanol) = 238 m # t (EI % = 363) remained.

The solid substance (13.6 g) was dissolved in ethyl acetate (400 ml) stirred with charcoal (7.0 g) at room temperature for 3 hours. The charcoal was filtered off and extracted with further ethyl acetate. When constricting of the ethyl acetate filtrates, the trienone was obtained in three yields. the first crop (6.86 g) had the F. = 213.5 to 219-C (capillary) and [x] D. _ -E- 70 ° (c = 1.17 in dioxane) and ATnaz (in ethanol) = 238 m #t (Ei ', = 390); the second crop (2.27 g) had a m.p. = 211 to 216 ° C and [x] D. = + 70.5 ° (c = 1.2 in dioxane); A "taz (in ethanol) = 238 m # t (egg ';, = 371); the third crop (0.81 g) obtained after a second charcoal treatment the F. = 207 to 215 ° C and [x] D. = T 71.4 ° (c = 1.4 in dioxane); @@ "ax (in ethanol) = 238.5 m # t (Ei m = 382). The overall yield was 53%.

Example ? Elimination of hydrogen bromide from 21-acetoxy-2x, 4x-dibromo-17a-hydroxy-16ß-methyl-5rx-pregn-9-en-3,20-dione at 130 ° C Crystalline 21-acetoxy-2: x, 4x-dibromo- 17x-hydroxy-16ß-methyl-5x-pregn-9-en-3,20-dione (1.0 g) was ground in a mortar with calcium carbonate (1.0 g) and under nitrogen and with stirring to form a suspension of Calcium carbonate (0.40 g) and lithium bromide (0.46 g) which had been heated to 130 ° C were added. After heating at 130 ° C. for 4 hours, the cooled reaction mixture was poured into ice-cooled In hydrochloric acid (120 ml) with stirring. After 30 minutes the crude trienone (659 mg) was filtered off, washed with dilute hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water. Recrystallization from ethyl acetate (with charcoal) gave the trienone in two yields. The first crop (470 /,) had the m.p. = 214 to 218 ° C (capillary) and [a] D. _ '-, 69 ° (c = 1.4 in dioxane) and lm "" (in ethanol) = 238 mp. (El l '. = 397); the second crop (13%) had the m.p. = 211 to 215 ° C (capillary) and [x] D. _ + 68 °; a, "4, (in ethanol) = 239 m # L (Ei! = 389). Example 8 Splitting off of hydrogen bromide in the presence of calcium bromide The procedure of Example 1 was repeated, except that lithium bromide was replaced by an equimolar amount of calcium bromide; the crude trienone became with i. "" (in ethanol) = 238 m # L (egg, -. = 389).

Example 9 Splitting off of hydrogen bromide in the presence of sodium bromide The procedure of Example 1 was repeated except that lithium bromide was used replaced by an equimolar amount of sodium bromide; the raw Trienon was rated 2 "" x (in ethanol) = 238 m # £ (E ". = 375).

Example 10 Effect of lithium bromide on the rate of elimination of hydrogen bromide from 21-acetoxy-2, x, 4x-dibromo-17x-hydroxy-16β-methyl-5 x-pregn-9 (I 1) -ene-3.20- dione In these experiments the dibromo compound (1 g) was added with stirring to a mixture of dimethylacetamide (12 ml), calcium carbonate (1.40 g) and, if indicated, lithium bromide (0.46 g); the mixture was preheated to the reaction temperature. The "reaction time" is the time required to obtain a crude product that contains less than 10% bromine. reaction time Temperature without with Lithium bromide lithium bromide 100` C ....... > 24 hours * 24 hours 115 ° C ....... 7 hours 130 ° C ....... 6 hours 4 hours 150 ° C ....... 30 minutes 170 ° C ....... 25 minutes <10 minutes * The product contained 3.9% bromine after 24 hours.

Claims (6)

Claims: 1. Process for the preparation of 21-low-acyloxy-17 x-hydroxy-16ß-methyl-pregna -1, 4, 9-triene-3,20-dione, characterized in that that you have a 21-low-acyloxy-2,4-dibromo-17x-hydroxy-16ß-methyl-5x-pregn-9-en-3,20-dione by heating in the presence of an inert Lewis base of the general formula R1-CO-NRZ-R3 wherein R1 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms and R2 and R3, which may be the same or different, each represent an alkyl group with 1 to 5 carbon atoms or optionally together a divalent aliphatic Group which, together with the neighboring nitrogen atom, forms a heterocyclic Ring forms mean having a high dielectric constant, i.e. H. over 15, has and is liquid at the temperature of the splitting off of hydrogen bromide, or of N-formylmorpholine and in the presence of calcium carbonate, preferably with additional use of an alkali or alkaline earth metal halide soluble in the reaction mixture, dehydrobrominated. 2. The method according to claim 1, characterized in that the base N, N-dimethylformamide, N, N-diethylformamide, N, N-dipropylformamide, NN-dibutylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N, N-dimethylvaleramide, N, N-dimethylpropionamide, N-formylpiperidine or N-formylmorpholine used. 3. The method according to claim 1, characterized in that calcium carbonate is used with particle size smaller than 10 microns is used. 4. The method according to claim 1, characterized in that one is used as an alkali or alkaline earth metal halide Bromide used. 5. The method according to claim 4, characterized in that one used as bromide lithium bromide, sodium bromide or calcium bromide. 6. The method according to claim 1 to 5, characterized in that a 21-acyloxy-2a, 4ß-dibromo-17 cc-hydroxy-16ß-methyl-5 ca-pregn-9-en-3,20-dione or a 21-acetoxy-2,4-dibromo-17ahydroxy-16β-methyl-5a-pregn-9-en-3,20-dione was used as starting compounds. References considered: U.S. Patents Nos. 2,873,284, 2,837,542, 2,904,564; JACS, 75 (1953), 4432 ff .; 80 (1958), 4428 ff, 4431 ff; J. Org. Chem., 24 (1959), 1600ff., 1617ff; Bull. Soc. Chim. France, 1958, 366f .; German interpretative document No. 1 040 546.