DE1593480A1 - Pregnan series 12alpha-halogen steroids and process for their preparation - Google Patents

Description

DR. ELISABETH JUNG. DR. VOLKER VOSSIO'3, DIPL.-1NG. GERHARD COLDEWEY

β MÖNCHEN 23 · CLEMENSSTRASSE 30. TELEPHONE 345087. TELEGRAM ADDRESS: INVENT / MONCHEN. TELEX 5-29688

Oct. 27, 1969

UoZ ₀ ; C 504 (Vo / kä)

Case 515 747 - S.

EoRo SQUIBB k SONS, IWC,
New York, Ν.Υ _β> V.StoA «,

"12 öf-Halogen Steroids of the Pregnan Series and Processes for Their

Manufacture ⁿ .. ^: . ... ■.

• ■ ·· ■ -. »■■ ·

Priority i 22 «December 1965, V.St.A.,» r. 517 747

The invention relates to new 12 oMialogensteroide of the Pregnanrei he of the general formula; '

or their 1,2-dehydro-, 6,7-dehydro- or 1,2,6,7-Ietradehydro- derivatives, in which R is a water atom, R ^{1 is} a hydroxyl or aoylozy group or R and R ^f aueaomen. Carbonylsauerstoffatoa, X a Halogenatoa, Z a Waieeretoffatoa, a Hydroxyl-

_BA0 o? = G

OO9842J / 1850

or mean aoyloxy group »

The preferred acyloxy radicals are derived from carboxylic acid less than every 12 carbon atoms «& · Β« lower! fatty acids, such as Acetic acid »propionic acid, butyric acid and tert-pentanecarboxylic acid, lower olefinisoh unsaturated carboxylic acids »monocyclic aromatic carboxylic acids «such as phenylacetic acid and e-phenylpropionic acid, cyoloalkanoarboxylic acids and cyoloalkencarboxylic acids

bonsäurenι

The compounds are made from 16 Of-methyl-3Ctf _t 12O / -dihydroxy-5ß-pregnan-2O-one. The preparation of this compound is described below in Examples Ί and 2

The process according to the invention can be explained by the following reaction aaa

009843/1856

Χ = Br

CH ₂ Z

.-CH:

BB

BATH

0098A3 / 1856

CH;

CH ₂ Z

C = O

--CH

, CH-

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HO!

CH-

H or J

CH ₂ Z

C = O

... CH-

--CH,

0098A3 / 1856

For the production of those compounds in which Z is a Hydro "Xyl or acyloxy eats _t is 16Of-methyl ~ 30i, 12Gf-dihydroxy-5ß-pregnane-20-one in the presence of acetic acid or chloroform, or another suitable organic solvent to 21- Bromderivat B bromier », which is then reacted with iodine to form the 21-iodine derivative BB. This compound is then converted to the 21-acyloxy compound A by treatment with acetate ions, propionate ions or other lower aliphatic acyloxy ions.

The compounds of the general formula A are then oxidized to the 3-keto compounds of the formula C with K-bromosucoinimide, N-bromoacetamide or H-chlorosuceiniraid. The reaction of compound C with a sulfonyyl halide, such as p-toluenesulfonyl chloride or methanaulfonyl chloride, in the presence of an organic base, such as pyride in, gives the corresponding 12-sulfonyloxysteroid (compound D), which can be obtained either by heating in collidine or can be converted into the 11-dehydrocompound by means of adsorption on an activated adsorbent, such as aluminum oxide, heating and subsequent elution an acid, such as perchloric acid, p-toluenesulfonic acid or trichloroacetic acid, gives the 11β-hydroxy-12C ^ "bromine compound of the general formula?. Brominating compound P gives _{the dibromine compound G 9} which, when reacted with idthium bromide or xithium chloride, gives dimethyl 1 -foraamid at elevated temperature with elimination of halogen waaetretoff gives the 4-dehydro compound H »

Q098A3 / 1856

BATH ORIGINAL

The reaction of the compound H with potassium carbonate gives the lin, 12β "epoxies of the general formula I, in which Z is a hydrogen atom or a hydroxyl group, which after esterification with the corresponding acid anhydride or acid halide in the presence of an organic base such as pyridine, the compounds of the general formula I, in which Z is an acyloxy group. The reaction of compound 1 with hydrogen chloride to form hydrogen fluoride gives the 12tf-halogen compounds J ₁ in which X is a chlorine or fluorine atom.

The unsaturated compounds L may be prepared from the compounds H and J by reaction with a benzoquinone of the corresponding fiedox potential, such as 2,3-Dlcyan ~! _T T 6-dichlorobenzoquinone · in a neutral solvent such as dioxane be prepared. Similarly, the 6-dehydro M i are prepared by reaction of the compounds H or J with EJJ-dicyano-StB-dichlorobenzoquinone in dioxane, hydrogen chloride containing "The 1,6-Tetradehydroderivate (Compound N) may be prepared from compounds M in the same Ways to be made * the connections L.

The il-ketones of the general formula K, in which the 1,2- and 6,7-positions are saturated and / or unsaturated, are obtained from the compounds of the general formula H, J, L, H and ^; B obtained by ChroA acid oxidation.

The steroids which can be prepared according to the invention are psyeiological • ktlv and they have anti-inflammatory activity. ~ ^ -,

bad original 0098A3 / 1856

The examples illustrate the invention.

Example 1 .

3 Qf, 12 Of ~ dihydroxy »5ß" Prefin ~ 16-en-2o-one Bin Gemisoh of 200 mg 3Ci _f 12tf-Diaöeto:

20-one in 4 ml of a 2N potassium hydroxide solution in methanol and

4 ml of water is refluxed for 3 hours, then allowed to cool and extracted with chloroform. The chloroform extract is washed with water and then evaporated. To Recrystallization of the residue gives the desired one Link.

Example 2

16 of ~ Me thy 1-3 Of «12of -aihydroxy-üß ^ pregnan ^ O-op (α) A solution of methylmagnesium iodide, which was prepared from 12 g of magnesium turnings and 70 ml of methyl ^ odide in ether, is mixed with a solution 10 g of 3 (X, 12or- »diaoetoxy-5β-P * egnl6-en-20 ~ one in 250 ml of anhydrous toluene are added. The ether is distilled off and the remaining solution is refluxed for 16 hours. The reaction mixture is then refluxed Poured into a mixture of ice and aqueous ammonium chloride solution and then diluted with ether. The organic solution is separated off, washed thoroughly with water, dried over sodium sulfate and evaporated to dryness under reduced pressure -3a

009 · «Ι / 1Ι ·«

(b) Following the procedure of Example 2, but using -from 3c / »^ 12c -DihyoLroxy-5ß-pregn-16-en-20-one there is obtained the

Case 3

16 et -Ke thy 1-12 & ~ hydro3cy-5β-pregna-3 ₁ 20-dione

A solution of 100 ing.l6öf-Methyl-3 pr, 12ö ^ ₇ dihydroxy-5ß-

pregnan «20 * -one in 8 ml of tert.utanol and 0.8 ml of water is mixed with 112 mg of N-bromosuocinimide are added, and the Gemisoh is 2 hours Stirred at barely any temperature · Then a little phenol crystal added and the solution slowly diluted with water.

Here the desired connection is separated; away. She is going to

filtered, washed with water and dried «

Example 4

tosyloxy ~ 5fl '»pregna» 3 * 20-dione

A 500 mg l6ci-methyl ~ 12Of "hydroxy-5ß-pregna-3> 20-dione and 500 mg of p-Ioluolsulfonylchlorid in 20 ml of anhydrous iyridin containing solution is allowed to stand for 6 days at 45 ⁰ C. The solution is then slowly poured into a mixture of bis and water. The Gemisoh is extracted with chloroform. The Chlorofora extract is first washed with 2N hydrochloric acid / 5% sodium bicarbonate solution and then with water and then evaporated under reduced pressure. The desired compound is obtained after conversion of the residue.

BATH

009843/1856

Example 5 .

16 Ot -Hetnyl-5ß-pregn ~ ll-en-3,20-dione

(a) A solution of 100 mg 160 <-Methyl-12of -tosyloxy-Sfl-pregna-3,20-dione in 5 ml anhydrous collidine and 10 ml anhydrous Xylene is refluxed for 36 hours. After that, the fctfaung evaporated to dryness under reduced pressure and the Residue taken up in chloroform. The chlorine of ormlb'Bund will Successively with 2N hydrochloric acid, 5% sodium bicarbonate solution and then washed with waeeer and finally to dryness evaporated. Recrystallization of the residue provides the desired connection.

(b) A solution of 16 e (-Methy 1-12 Of-toeyloxy-5ß-pregna-3 _# 20-

in benzene is adsorbed on aluminum oxide (activity I). Solvent is allowed to evaporate and then the

Aluminum oxide ^{heated to 50 °} C. for 5 hours. The aluminum oxide is then treated with chloroform and filtered. The filtrate is evaporated to dryness. After recrystallization, the residue yields the desired 16tf-methyl-5ß-pregn ~ ll-en-3,20-dione. . '

Example 6

llfl-hydroxy-12 y-bromo-16 # -methyl-50-pregna-3. 20-diön - ■■ A solution of 100 g of LöOf-Methyl-Se-pregn-ll-en- ^ iSOi-dioß in 3 liters of dioxane in a 5 liter bottle is mixed with 1.7 liters of 0.167 η perchloric acid. Then throw 50.1 g of N-bromooetamide under your sugars and dissolve it. Since "Q" mixes

009843/1856 bad originai

becomes with 5 $ £ -iger < Treated sodium sulfite solution until the color changes to light yellow, and then diluted with water and with Chloroform extracted The chloroform extract is washed with water and evaporated under reduced pressure eur Trookene Wake up recrystallization of the residue gives the desired one

Link· Example 7

4fl « l2 Of ~ dibromo-llg ~ hydroxy-16fl (Hmethyl-5ß-pregnä-3 _f 2 Chdlon Jäine solution of 199 mg of Ui3-hydroxy-12 0f-bromo-l6 (X-methyl-5B-pregna, -3, 0.72 ml of a solution containing 112 mg / ml bromine in acetic acid is added dropwise to 20-dione in glacial acetic acid, after it has first been mixed with a drop of 11% hydrobromic acid in acetic acid Pour cold water in, the precipitate is filtered off / washed with water, 5 C sodium bicarbonate solution and again with water and then dried. The desired compound is obtained.

Example 8

llß -H.vdroxy-12a ^f -brom ~ 16 of -methylprogesteron A hot solution of 285 mg of lithium bromide in 27 ml of dimethylformamide is 67 mg of 40.12 <y-Dibroe-llß-hydroiy-16 OT-methyl-5ß ^ pregna -3,2O-dione vertetst, and the solution is heated in a nitrogen stream on the steam bath for 4 hours. Danaoh will reet the hot water with water. and cool jelly · Here the usual compound separates out in crystalline form · The crystals · are filtered off, washed with water and dried;

009843/1886

«12 -

Example 9

llß, 12ß-Oxldo-16o (-methylprofleateron

A mixture of 35 g of 11β-hydroxy-12Oi-bromine-16 Of-methy! Progesterone in 2.5 ladder methanol is stirred with 185 ml 10 J & -i £ er Potassium carbonate solution was added dropwise over the course of 20 minutes. After standing for 30 minutes at room temperature, the solution is diluted with 1.2 liters of water, with 10 # acetic acid neutralized and then evaporated under reduced bridging until 1 liter of solvent has distilled off o With further dilution crystals separate out with water. These are filtered off t, washed with water and dried desired connection. ·. ·· '■■■'

Example 10 .

11ß-Hydroxy-12 Of -chlor-16 Qf «« methylprogesterone A solution of 200 mg of llß, 12ß-oxido-16O (-methylprogeeterone in 50 ml of chloroform is cooled in an ice bath and a solution of hydrogen chloride and chloroform is added dropwise Standing for one hour at ⁰ ° C., the solution is neutralized with 5 point sodium carbonate solution, washed with old water and evaporated to dryness under reduced pressure. After recrystallization of the residue, the desired compound is obtained. ·. '. "._. ■■.

Example 11

11 fl-Hydroxy-12 of-fluoro-16 Cf-niethylprogeBteron 50 mg llß, 12ß-Oxido-16 or -methyprogeBteron are dissolved in a portion of 5 ml of chloroform and 2.5 ml of anhydrous tetrahydrofuran, which in a Poiyäthylenflasohe are included.

009843/1856

BAD ORiGiNAL

■ i '· - υ -

The solution is cooled in an Adeton-dry ice bath to -80 ⁰ C. Then the solution is slowly set before stirring with 2.0 ml of hydrogen fluoride with the aid of a PolyäthyZenpipette · The Reaktionsgemiseh 10 minutes at -80 ⁰ C is then maintained. Subsequently, the acetone-tfrockeneis bath is replaced by a üis-Kochsalskühlmisohung and the temperature maintained for 6 hours at -10 ⁰ C. The reaction mixture is then pipetted into a stirred mixture of chloroform and white water in a polyethylene glass and carefully neutralized with sodium bicarbonate. The chloroform solution is separated off, washed with water and dried under reduced pressure. Uncrystallization of the residue provides the desired connection. ,. ■.

Example 12

lß-t-hydroxy-12 Qf-fluoro-16 (V-methylpregna-1,4-dlen-3 «20-dione 100 mg 2 _y 3-Diohlor * 5 "6 ^ dicyano * benzochinos added, and the mixture a stream of nitrogen heated for 6 hours at 100 ⁰ C .. Vaoh cooling, the mixture is filtered and the Tilterrüokstand with chloroform washed off. the combined Piltrat and The Wasohlüsungen are then passed through aluminum oxide (activity I), which is then washed out with chloroform. The piltrate is evaporated under reduced pressure and the residue is recrystallized. The desired compound is kept.

In a similar way, using / corresponding 12 βί-Ciller- οάφν IZiV-BrtmrerbinduüÄ do "

009843/1856 bathroom

16 (rf-methylpregna-1,4-diene-3 | 20-dione and the llo-hydroxy-12 <«■ bromo-16 O? -Methylpregna-1,4-diene-3 , 20-dione.

Example 13 .

llß ~ Hydroxy-12 Ct ~ fluor-16 tf ~ mothylprefina "4» 6-diene ~ 3.20-dione A solution of 100 mg Hß-Hydro3cy-12 ^ ~ fluor-1 & ^ - iaethyl- = progesterone ¹ in 10 ml of chloroform is Treated with hydrogen chloride gas for 3 minutes, and then the mixture is left to stand for 2.5 hours at room temperature. The mixture is then filtered off and the filtrate is washed with 5 # strength hatriuric carbonate solution and water and then evaporated under reduced pressure 'Aluminum oxide the desired compound.

In a similar way, the 12 dr-chlorine and 12oM3rom compounds. the llß- ^ ydroxy-12 o ^ -chlor-16 Of-methylpregna-1,4-diene * 3 »20-dione and the 11ß-hydroxy-12 Ot -bromo-16Oi-methylpregna-1,4-diene- 3ι20-dione produced.

Example 14

12 Qf -fluoro-16 or ~ methylpregn '"4 ~ 8n« »3.11 * 20-trione A solution of 11β-hydroxy-12 (X -fluoro-16 Oi -methylprogesterone in pure acetone is added dropwise with an aqueous solution which 200 mg chromic anhydride and 320 ag sulfuric acid in ml, which does not immediately decolorize. After that, excess oxidant is reduced by adding a few drops of methylol, the mixture is diluted with water and extracted with chloroform. The chloroform extrusion Λ is washed with water and , turned under reduced pressure

009843/1856

steams. Crystallization of the residue is obtained . Desired connection.

_{The 12Qf-UuOr-Ieei-methylpregn-1 f} 4-dlen-3i 11,20-trione and the 12 0 ^ -Iluoro-16C (-nethylpregn-4,6-diene are obtained in a similar manner from the corresponding 11β-hydroxy compound -3,11,20-trione and the corresponding 12% chlorine * and 12% bromine compounds.

Example 15

3 SQM 2 Ct -Bihydroxy-16 Qf HCBethyl-21-l) roa-5fl-pregnan-20-one 3.2 g of bromine in 30 μl of acetic acid are added dropwise with stirring to a mixture of 9.9 g of 3 <V, 12 0T-J) ihydroxy-16Qf'-oethyl-5β pregnan-20-one given in 3fcO el ether within 50 minutes. At- As a result, the gel is stirred for another 30 minutes, then washed out with sodium bicarbonate solution and with hater · The

Ether solution is dried over sodium sulphate and

Reduced pressure below 3O ⁰ O evaporated "Mach Uakristalli sation you get the connection you want.

Example IS 3

A solution of 3 _f 3 g 3 ^ 'f2.2cy-Dihydroa3r-16Of-ethyl-21-bromo-5ß-pregna-20-one in 100 ml of benzene is mixed with 6.6 g of sodium iodide in 45 ml of anhydrous alcohol and 16 Left to stand for hours at room temperature. Fold addition of water is separated and washed successively the Benuolschicht "3 JC-strength Katriumthio- ulfatl8sung and water gewasohen evaporated _f and dried under reduced ^ nmek 'within 4O ⁰ C. The residue delivers

»098 * 3/1856

after Urakriatallisatioa the desired connection

Example.

3 C ( _t 120 ( -dihydgoxy-16

3 g 3 ofp12 <* ~ Mhydroxy «16ctf-" methylol "•;) Qd-5Ö-pregn-2Q ~ one in 30 ml. Acetone is added to a gene made from 6 g of calcium carbonate and 3.8 ml of acetic acid and Boiled under reflux for 24 hours "After the addition of water, the precipitate which separates is filtered off" washed with water and recrystallized.

■ ^v

12, Of f H y droxy «» l6 d "methy l ^ glf» a cetoky ^ Sß ' -pre ^ na "^. 20-dione öemäss Example 3, but using 3 Of "12 <V-dihydroxy '16 ^ HDftethyl-> 21 ~ ~ acetosy 5ß- * pregna-20 © n obtains the ge" wished connection ·

Example 19.

12 Qf-gos ylpaqr ^ ieof -methyl ^ l ^ a qetoxy-SB-pregna-S »20 ^ dion C-emäsö Example 4, but using 12 Of» Hydroxy-Ib Oi'-metliyl '^ I-acetoxy- ^ ß-pragna-J ^ O-äion you get the desired. Link· . .

Example 20

16 Qf "-Methyl -""21-a setoxy -" 5ß "pregn a-ll-en-3. 2Q-dione According to Example 5 $ However, using 12 0f-Toayloxy ~ looC-ffiethyi- ^ l ^ aeetoxy-Sfi-pregiia-JpSC-dione one obtains the obtained compound »*,

009843/1856

BAD OfHGINAL

Example 21 ■. "

Example 6 bia θ _£ but using each of the 21 Äcetoxyderivats anat @ ll © the 21-Deso ^ derivative obtained DL® desired compound · ■ '.

llflplgfl ^ Oxido ^ ieffi ^ and his

21 ^ Aqetat ^

According to Example 9, but using methylcprtico9teron * 21-acetate; and in the presence of nitrogen al © protective gas to the 21S receives _{p-12B-oxido-IOOF} methy1-21-hydroxyprogesteronο

A solution of 200 mg
progesterone in 1 ml of acetic anhydride and 3 ml of anhydrous Pjridin% fird at Haumtemperatur 16 hours left "äanaoh- is di © lösuBg poured into Siswasser and @ with Chlorof9m 3Etrahi0rte D®r Chloroformextralct successively with ₉ 5 s £ ~ ig @? Hodium bicarbonate solution and dried over ITatriusisulfet with water and evaporated.

The desired residue is obtained from the residue

Procedure of Examples 10 to 14 »However, under V @ r-

21-JU> 6toxyderlm $ e © r is obtained

■ ■ ', -:> 00S8-43 / 1Bg8

/8th

Turns

In accordance with Example 12, but using the products of Example 13 and their corresponding 21-acetoxy derivatives, which were prepared according to Example 21, the ^ 1 ^ »greens of the formula N are obtained,

Claims

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- * "BAD GRiG IN

Claims (4)

■ g atentane P ^ rJJLg ₇ AJt I. 12fli ** Halog®net @ rolde der Pregnanreifae vline X « ² or their 1,2-dihydric, 6 _s 7-33 hydro- ode? l _p 2 _i 6 _g 7-Setradehydro-'derivate «in which E is a hydrogen atom, Ε» a hydroxyl or Aejlosqrgruppe, or H ₁ and B ⁹ together © is eerbonyleaueretoff * X is a halogenaioia and Z is a hydrogen atom, in hydroxyl-i ¹ 'loyloxy group meaning to the Edretellune 'of the connections after. Claim 1 ur, ο h- 'g e-'lc e nase i β h'n.et _p that aas. © in Stero oh?% * Z has the ■ Torgtetoeade Befieutiasg. ₉ ^ e © inern steroid of the BAD OBiGSMAL-3 documents {An.? δ ι para. 2 w. t βββ 3 ae ₃ IO oxidized ,, the compound obtained through. Implementation with a Sulfonyl halide into a compound of the formula CH ₉ Z
CSu I *
^1st 0 = <0 ,-Oh, in the SuIfonylrest means, converted, dissolved compound under heating into a compound of the formula GHpZ • »•• Cn? transferred, this compound duroh reaction with an N-bromo- amide or H-bromimide au a compound of the formula brominated, the compound obtained from a compound of the formula '. . 0 0 98A3 / 1856 BAD ORIGlMAi Hi 2.1 < Br fh ^Z C = O —CH, brominated, and from the compound obtained Halogenwasßerötoff forming a connection of the 3 sleeves -. · ■■■■■ '■: - ■■■■■ - ■■ · ■' ■ * ■?% »■■ ■ · ■ '■■■'" ■ ■ ί C = O splits off «this compound with potassium carbonate Bpoxide of the formula -w CH, converts, and the epoxy through .Treatment with hydrogen chloride or hydrogen fluoride in the corresponding 12 OC-Halogen ^ llß "-liydroxyrerbinduhg iimwf, in which X is a chlorine * or fluorine atom., and this compound or the compound in which X is a Bromatom means »with @inea BenzocMnon 8U a pre · - ' feiüdung of the formula.' BAD O «OILNAl 0098437) 858 dehydrated. 3. The method according to claim 2 »marked thereby draws that nan a compound of the formula in which X is a halogen atom and Z is a Waeeeretoffatoa, a hydroxyl or Aoyloacygruppe iet, mit Z.J-Dicyan-Sferdiohlorbenaochinon in Bi-Bioxane containing hydrochloric acid to form a compound of the formula .JBl ₃ dehydrated and the compound obtained with «inen Bensoohinon forming a connection of the form »! 009843/1856 BATH ORIGINAL HO -CH, treated. 4. The method naoh claim 2, characterized g β ke η η a e 1 oh net, daea one connection of SOrael In which X «in halogenated and Z is a hydrogen clay, a hydroxyl or acyloxy group, or its 1,2-dehydro, 6,7-dehydro or 1,2,6,7-tetradehydrogenate, with chromium acid tu a compound of omel oxidized. 0098 ^ 3/1856