DD268954A1 - PROCESS FOR THE PREPARATION OF 9ALPHA HALOGEN 11BETA FORMYLOXYSTEROIDS OF THE PREGNANIUM SERIES - Google Patents

Abstract

The invention relates to a process for the preparation of steroids of the pregnane series, which contain as a characteristic feature a 9a-halogen-11b-formyloxy group. Steroids with these structural elements are precursors to corresponding 11b-hydroxy steroids, which have been known to show topically strong anti-inflammatory effects. The process is such that 21-acyloxy-17-hydroxy-pregn-9 (11) -en-20-ones, which may be further substituted or unsaturated, by means of halogenating agent in dimethylformamide with the addition of a strong acid in the corresponding 9a -Halogen-11b-formyloxyderivate and acylated these in the 17-position according to known methods. The halogenating agents used are preferably N-haloamides or imides.

Description

Field of application of the invention

The invention relates to a process for the preparation of steroids of the pregnane series, in which the characteristic feature comprises a 9a-halogen-11β-formyloxy group.

Steroids with these structural elements are precursors to corresponding .beta.-hydroxystero: which have been known in recent years to have topically strong anti-inflammatory action with at the same time low systemic side effects.

These drugs, including the well-known beclomethasone dipropionate, may find application in the local treatment of inflammatory processes in warm-blooded animals.

Characteristic of the known technical solutions

17-Acylate the pregnane series with 9a-halogen-11 ß-formyloxy are not yet known. The precursors according to the invention for the entlastenden agents with 11 ß-hydroxy groups are therefore new.

Object of the invention

The object of the invention is to find a reaction sequence which, starting from 9 (11! -Saturated-steroids, leads to the corresponding 17-acylates with 9a-halo-11β-formyloxy group.

Explanation of the essence of the invention

It has been found that the transition to the corresponding 9a-bromo-11β-formyloxy derivatives described for specific 20,20-bis (nitratomethyl) -pregna-4,9 (11) -diene derivatives also in 9 (11! -Unsaturated pregnanes with Dihydroxyacetone side chain can be realized.

Furthermore, it has been found that when using an N-chloroamide or N-chloroimide in dimethylformamide, the valuable 9a-chloro-11β-formyloxy grouping can be directly introduced, which is a very big step forward if 9a-chloro-steroids are aimed at as target compounds.

Finally, it was surprising that in these 9a-bromo or 9a-chloro-11β-formyloxysteroids the formyloxy group is reduced below e.g. acid acylation conditions is sufficiently stable to acylate the relatively difficult acylatable 17a-hydroxy group in dihydroxyacetone steroid steroids. The overall process for the preparation according to the invention of 9a-halo-11β-formyloxy-α-acylates of the pregnane series is therefore such that 21-acyloxy-17-hydroxy-pregn-9 (1 D-en-20-one, which is described in more detail in US Pat substituted or unsaturated by means of halogenating agent in dimethylformamide with the addition of a strong acid into the corresponding 9a-halogen-11 ß-formyloxyderivate and acylated in the 17-position according to known methods acylated as halogenating agent preferably N-haloamides or imides used.

Exemplary embodiments

example 1

1.1. Formyloxyoctanoic halogen-addition

15 g of 21-acetyloxy-17-hydroxy-pregna-1,4,9 (11) -triene-3,20-dione are suspended in 170 ml of dimethylformamide at room temperature and admixed with 5 ml of 70% perchloric acid. The total required 6.75 g of N-bromoacetamide are added with stirring in 3 portions of 2.25 g each at the beginning of the reaction, after 10 minutes and after 20 minutes.

Shortly after adding the last portion results in a clear reaction solution, which is stirred after a total of 30 min in 31 cold water, the reaction product precipitates. It is filtered off, washed with water until KJ starch paper remains colorless and sucked dry.

This gives 18.2 g of air-dry 21-acetyloxy-9-bromo-11β-iormyloxy-17-hydroxy-pregna-1,4-diene -?, 20-dione from mp

223 "C, which shows less than 2% by-products when tested by thin-layer chromatography (OC)

Recrystallization from ethyl acetate is found [ajg ³ = 160 ° in dioxane.

1.2. Acylation of the 17-hydroxy group

2g air-dry 21-acetyloxy-9-brom11 (3-formyloxy-17-hydroxy-pregna-1,4-diene-3,20-dione is brought to 35 ⁰ C in 40ml Chloroformsuspendiert, and with stirring, in the course of o> wa With 40 ml of acetic anhydride for 10 minutes, containing 1% of 5%

Sulfosalicylic acid containing a clear solution is formed. After a reaction time of 4 h is stopped by adding 480 ml Cloroform with 2% ethanol with moderate cooling over the course of

Be stirred for 20 minutes. Thereafter, at room temperature, much saturated NaHCO ₃ solution is slowly stirred in until pH about 8 is reached.

The usual further processing by separation, post-extraction, washing and concentration gives virtually quantitative 17.21- Diacetyloxy-9-bromo-11β-formyloxy-pregna-1,4-diene-3,20-dione, be! 4 DC test less than 3% by-products

recognize.

After recrystallization from methanol to give the pure compound with mp.: 200 to 207 ⁰ C and (α) "= 102 ° in CHCl ₃ . Example 2

2.1. Formyloxyoctanoic halogen-addition

10 g of 21-acetyloxy-17-hydroxy-pregna-1,4,9 (11) -triene-3,20-dione are suspended in 110 ml of dimethylformamide and admixed with 3.5 ml of 70% perchloric acid.

At room temperature, 5 g of N-chlorosuccinimide are added in several portions with stirring over the course of 20 minutes. After about 40 minutes, a clear solution has been created. After 60 minutes, work-up is begun by cooling to about 5 ° C

and slowly adding 10% sodium sulfite solution while cooling until the pH reaches about 7 (about 300 ml). Finally, the reaction mixture is stirred into 2.5 L of ice-water, whereupon the reaction product precipitates. It is suctioned off, washed with water and dried.

This gives 10.5 g (corresponds to 90% of theory) of 21-acetyloxy-9-chloro-1-β-formyloxy-17-hydroxy-pregna-1,4-diene-3,20-dione of Mp .: 247 ^° C., which is suitable for further processing. After further purification by Umkristaiiisation of much 2-propanol or Methanol, the compound with mp.: 262 ⁰ C and [a] § ³ = 170 ° can be obtained in dioxane.

2.2. Acylation of the 17-hydroxy group

10g 21 acetyloxy-9-chloro-1β-formyloxy-17-hydroxy-pregna-! 4-diene-3,20-dione are suspended in 200 ml of chloroform, brought to 35 ° C and with stirring with 200ml propanoic anhydride containing 1% 5-sulfosalicylic acid, added. The mixture is kept for 5 h at 35 ⁰ C, wherein after about 2 h a clear solution results. For working up, the mixture is brought to room temperature and within about 20 minutes to 2.41 chloroform transmitter · containing 4% ethanol. The mixture is stirred for 2 h, then cooled to about ^{0 0} C and added as much saturated NaHCO ₃ solution that pH is reached about 8.

The usual further processing by separation, post-extraction, washing and concentration gives virtually quantitative 21 · acetyloxy ^ -chlor-i 1 ß-formyloxy-17-propanoyloxy-pregna-1,4-diene-3,20-dione, which is suitable for further processing , For purification, it is possible to recrystallize from chloroform + methanol or acetone + methanol. One finds for this compound m.p .: 198-200 ⁰ C and (a] g ³ = 96 ° in dioxane.

Example 3

3.1. Formyloxyoctanoic halogen-addition

1 g of 21-acetyloxy-17-hydroxy-pregna-4,9 (11) -diene-3,20-dione are mixed with 34 ml of dimethylformamide and 66 ml of chloroform, dissolved with heating, brought to room temperature, with 0.4 ml of 70% perchloric acid and then with 156mg N-

Chlorosuccinimide (NCS). After 10 and 20 minutes, a further 156 mg of NCS are added to the stirred suspension. When a clear solution has formed (70 to 100 minutes), another 156 m of NCS is added. Workup begins when

the thin-layer chromatographic examination reveals only 2% starting steroid.

Add 10% Na ₂ SO ₃ solution until KJ starch paper no longer turns blue. Then iV is concentrated to about 60ml, with

20 ml of water and distilled again until the remaining CHCl _{3 has} gone over together with a little water. Finally add 60 ml of water, cool, suction, wash neutral and dry.

1.06 g = 90% of theory 21-acetyloxy-9-chloro-11β-formyloxy-17-hydroxy-pregna-4-ene-3,20-dione of m.p .: 183 ° C to

187 ⁰ C, which is suitable for further processing. To obtain analyte is recrystallized from ethanol. The

Compound shows then mp .: 202 to 205 ⁰ C and [al "= 175 ° in dioxane.

3.2. Acylation of the 17-hydroxy group

1 g of 21-acetyloxy-9-chloro-11ßformyloxy-17-hydroxy-pregna-4-ene-3,20-dione is dissolved in 9 ml of CHCl _3, 9ml propanoic und90mg sulphosalicylic acid at the boiling point and then kept at 50 ⁰ C 60min. It is then cooled to room temperature, diluted with 15 ml of CHCl ₃ and shaken with saturated NaHCO ₃ solution until the propanoic anhydride is decomposed. Thereafter, it is separated, nachextraiert, washed, dried and iV ae.igt.

After repeated absorption in acetone finally 1.15 g = 90% of theory a solid residue of 21-acetyloxy

9-chloro-11β-formyloxy-3,17-dipropanoyloxy-pregna-3,5-dien-20-one which is suitable for further processing.

For cleaning can be cold-moistened with acetone and vacuumed. The product thus obtained shows mp. 163 bis

174 ⁰ C and [a] g ³ = -24 ° in dioxane.

Example 4

4.1. Formyloxyoctanoic halogen-addition

42g 17-hydroxy-21-propanoyloxy-pregna-1,4,9 (11) -triene-3,20-dione are suspended in 500 ml of dimethylformamide at 20 to 25 ⁰ C with 14,5ml 70% perchloric acid and 6.9 g N-chlorosuccinimide (NCS) added.

After 10 and 20 minutes, additional portions of 6.9 g NCS each are added. When the suspension is in a clear solution

is transferred (40min) is stirred for a further 10min and thin at S 1O ⁰ C, the excess of NCS by means of 10% Na ₂ SO ₃ -

Solution destroyed (70 ml). Then the reaction product is precipitated with 1.51 of water with little cooling, finally

sucked off, washed and dried.

This gives 49 g = 98% of theory g-chloro-Hss-formyloxy-tf-hydroxy ^ i-propanoyloxy-pregna-M-diene-S ^ O-dione, m.p .: 248 to 253 ⁰ C, which is suitable for further processing.

After recrystallization from CHCl ₃ + methanol = 1 + 1, the compound is obtained with mp: 257-259 ⁰ C and [a] 8 ³ = 163 ° in CHCl ₃ 4.2. Acylation of the 17-hydroxy group

12 g of S-chloro-Hβ-formyloxy-U-hydroxy- ^ i-propanoyloxy-pregna-i ^ -diene-α ^ O-dione are mixed with 36 ml CHCl ₃ , 36 ml propanoic anhydride and 360 mg sulfosalicylic acid, brought to 7O ⁰ C and stirred until a clear solution is obtained (»1.5h). After another 10 min, brought to s2O ⁰ C and treated with 120ml CHCl ₃ + 5ml ethanol. By stirring with • χ 150ml of saturated NaHCO ₃ solution is neutralized. Thereafter, it is separated, nacbextraiert, washed, to »120ml i. Concentrated, mixed with 120ml of methanol and concentrated again until abundant crystallization. It is cold, sucks and receives 11.4 g = 85% d. Th. ChIoM 9-1 beta-formyloxy-17,21 -dipropanoyloxy-pregna-1,4-diene-3,20-dione, mp .: 223-226 ⁰ C. To prepare an analysis sample from a methanol-Chlorofcrm- Mixture redissolved. The compound is obtained with mp: 224 to 227 ⁰ C and [a] g ³ = 97 ° in CHCl ₃ .

Example 5

5.1. is performed as 4.1.

5.2. Acylation of the 17-membered hydroxy group

3g 9-chloro-11.beta.-formyloxy-17-hydroxy-21-propanoyloxy-pregna-1,4-diene-3,20-dione, together with 9 ml of CHCI _3, heated 9ml hexanoic anhydride and 90mg sulphosalicylic acid at 75 ⁰ C and stirred until a clear solution emerges («1.5h). After a further 30 minutes, the mixture is brought to room temperature and concentrated by evaporation until sufficient for crystallization. After standing overnight at -i0 ° C is filtered off with suction, washed and dried. 2.5 g = 85% of theory is obtained as 1st fraction. 9-chloro-11-β-formyloxy-17-hexanoyloxy-21-propanoyloxy-pregna-1,4-diene-3,20-dione which is suitable for further processing. For the purpose of obtaining an analytical sample, it is recrystallized from a methanol-CHCl ₃ mixture. The compound then displays m.p .: 193 to 195 ⁰ C and (a] g ³ = 88 ° in CHCI. ₃

Claims (2)

1. A process for the preparation of 9a-halo-11ß-formyi-oxysteroiden the pregnane series, characterized in that 2i-acyloxy-17-hydroxy-pregn-9 (11) -en-20-one, the further substituted and / or can be unsaturated by means of halogenating agent in dimethylformamide with the addition of a strong acid in the corresponding 9a-halogen-11ß-formyloxyderivate and acylated in the 17-position according to known methods. 2. A process for the preparation of 9a-halo-11ß-formyloxysteroiden the pregnane series according to item 1, characterized in that as halogenating agent preferably N-haloamides or imides are used.