CH626635A5 - Process for the preparation of pregnan-21-oic acid derivatives - Google Patents

Description

626635

2nd

; , - -îf PATENT CLAIM f

Process for the preparation of Pregnan-21-acid derivatives of the general formula I.

. COOR

C = 0

(i),

10th

in which R is an alkyl radical having 1 to 8 'coolant atoms and X is a hydrogen atom, fluorine or chlorine atom, characterized in that an 11 / 3,17a, 21-trihydro-xy-l, 4-pregnadiene-3.20- dione of the general formula II

CHo0H; i 2

C = 0

OH j

-.Sdl),

wherein R is an A.lkylrest: with 1: tjis-8 carbon atoms and,. X denotes a hydrogen atom "Ffuór-" or "chlorine atom,

•• Pregn "äri-21 ^ ätfre-Derivatfc of the general: Fönnel I" are known to be pharmacologically active substances which, when applied topically, are characterized by a pronounced anti-inflammatory. , jn ^ tonsehe Wifksadikett.- (German | Disclosure * 2-250,268 and.2 260,303.) ...

The previously known processes for producing the Pre-gnan-21-sam; p-JDerij.ate ii had the disadvantage that jup.c ^^ ej & óéìflhren $ n | 9 «x, ï | / 3,21rDihy-droxy as the starting connection -l, 4-pregnadien-3,20-dione, in which X has the meaning given above, substances whose syn-

this is very complex •••; •

It has now been found that the Pregnan-21-acid,,: 15 derivatives can also be obtained from the easily accessible 9 "X, II /?, 17a, 21-trihydroxy-l, 4-pregnadiene-3,20-dione , in which X has the abovementioned meaning, can be prepared in surprisingly high yields by means of a simple two-stage synthesis.

The invention thus relates to a process for the production of PrégnànP2'f4aure-DèriVaten of the àlîgfeînëiâen formula I, which is characterized in that an 11 /?, 17a, 21-trihydroxy-l, 4-pregnadien-3,20-dione of the general formula II

CHo0H

! c.

Y- 'Z'i

20th

25th

30th

wherein X has the meaning given above with zinc acetate with elimination of water to an aldehyde of the general formula III

35

■ OH

(II),

(III) r wherein X is the above-mentioned meaning with sinec acetate under water separation to form a mdfehyde of the general formula III

CHO

ft sot gijHîiafcrtsfl sas ^

Where-XOdip ^ ofaen mentioned meaning. Has, .allocation. And this. Oxidized with oxidizing heavy metal oxides in the presence of • alcohols. Of the formula ROH and, cyanide ions with simultaneous esterification, - ..

45

50

■ A ^

(HI),

The invention relates to éln Veffàîireîi'zûr'IHërsteliiiiig of Pregnan-21-acid derivatives of the general formula I.

(I)

wherein- X 'has the abovementioned meaning and rearranges it with oxidizing heavy metal oxides in the presence of 55% alcohols of the formulas ROH and cyanide ions with simultaneous ^ Sregtenin'g î & yxjjejï .- *'

The first stage of the process according to the invention can be carried out in such a way that 11 /?, 17a, 21-trihydroxy-l, 4-pregriMien ^ 3 ', 2'0-âÎôn of the'aiîgBïiièihen formula 60 II in a lower carboxylic acid - such as formic acid, acetic acid, propionic acid or butyric acid with zißkacetatjUipsetzf ^ This reaction is preferably carried out in

The second reaction procedure of the method according to the invention is carried out with oxidizing heavy metal oxides in the presence of alcohols of the formula ROH and cyanide ions.

Alcohol for this ReäRfiühäsreltriu Alko

3rd

626635

20th

30th

get the general formula RÖH! —woriii'iR. which has the 'glëichë meaning as in formula I - •' used; ' Bésondeir's preferred alcohols are lower and 1 middle "primary or secondary saturated aliphatic 'Aikbhblë: with 1 to 8; ßlöK- :: ■ ienstóffatomén in the alcohol residue. As alcohols' séiefï hëispiëls-' s weise'igënânnt; methanol, Äthananol; , Isòprdjfànbì; * 'Bütanol, 1 ìsobutanoi, sèk.-Buta'nol, amyl alcohol; -Isbamflällcb-hol, HeXänbl,' Heptanol or Ocf ahoy it is also possible to add other inert solvents to the reaction mixture in addition to the alcohols. Such inert solvents are, for example: hydrocarbons, such as benzene, cyclohexane or Tólùol, chlorinated hydrocarbons; such as'Métfryfen-cMbfid, Chloroform oder Tetftbhlorätliän, '' Äther,% vie DP Kâtfiylâth'èr, Diisopropylathei ;, GÎ ^ koldimèïhylâ & éT ^ Tètra- "''" '' 'hydrofuran or Dioxan, öder dìpolère apr Dimethylformamide, N-methylacetamide or N-methyl-pyrrolidone.

Silver oxide, lead (IV) oxide, Menninge, vanadium (V) oxide or manganese (IV) oxide, for example, can be used as oxidizing heavy metal oxides for the second process step. The reaction is usually carried out in such a way that preferably 0.5 g to 50 g and in particular lg to 10 g of heavy metal oxide per g of steroidal aldehyde are used. Cyanide ions are used as catalysts for this reaction step. Alkali cyanides, such as sodium or potassium cyanide, are preferably used as reagents which supply cyanide ions. Preferably 0.01 to 10 mol and in particular 0.1 to 1 mol of cyanide are used per mol of steroid aldehyde. If you use e.g. For example, as reagents that supply cyanide ions, alkali metal cyanides, the reaction is expediently carried out in such a way that the amount of mineral acid required for neutralizing the alkali metal cyanide (such as, for example: sulfuric acid, phosphoric acid or hydrogen chloride), sulfonic acid (such as p-Toluoisulfonic acid) or carboxylic acid (such as formic acid or acetic acid).

The reaction is expediently carried out at a reaction temperature between −20 ° C. and + 100 ° C. and preferably at a reaction temperature between 0 ° C. and + 50 ° C. The reaction time depends on the reaction temperature and the choice of the reactants, it is preferably on average 15 minutes to 120 minutes. In individual cases, the optimal response time can easily be determined in 4J in the same way as in the first process step.

The following examples serve to explain the process according to the invention:

50

example 1

a) The solution of 10.0 g prednisolone in 100 ml conc. 1.0 g of zinc (II) acetate is added to acetic acid. The mixture is refluxed at 120 ° C. for 90 minutes, the reaction mixture is cooled to 60 ° C. and the acetic acid is distilled off in a vacuum. The residue is dissolved in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo. 10.0 g II /?, 20-dihydroxy-3-oxo-l, 4.17 (20) -prednatrien-21-al are obtained as a solidified foam. 60

b) The aldehyde thus obtained is dissolved in 50 ml of butano !, mixed with 150 ml of dimethylformamide, 15 g of active magnesium (IV) oxide, 16 ml of acetic acid and 3.5 g of potassium cyanide. The mixture is stirred vigorously at room temperature for 20 minutes. The reaction mixture is sucked into ice water through a frit and the residue is washed with a little acetone. The precipitate is 'filtered off,' washed out with water and taken up in dichloromethane. The solution is over

Dried sodium sulfate; filtered and the solvent removed in vacuo. The raw product; 10.2 g of foam is chromatographed on: silica gel With 17- ^ 24 "/" acetone-hexane, after recrystallization from Aeeton gasoline (60 to 80 p), 5.9. g Ai> ß-Hydrox <y ^ 3; 20-dioxö-1 j4-! pregnadien-21-acid-

butylésterisoliërt. Melting point 1'56 °: G; [3} +; 167 ° • ■

(c = 0.5 in chloròforafr). UV: "2": = 15,900 '(methanol) ;. ':

'Example ^

i -; a); 5.0; g, prednisolone, are heated to boiling with 50: ml of zinc; - acetic acid and,, 5 g of zinc (II) -? acetate 9 ö: minutes. ■ -, After / cooling to room temperature, the mixture is stirred into 750 mb ice water. The precipitate that has failed is filtered, washed with water and dried; : One obtains' 4.9! GslljS <20-dihydroxyf3-oxo- <1, 4; 17 (20): - pregnatrien-2 / Uatalsî> nlyër ^ K; i • .i. •. -

b) The aldehyde thus obtained is dissolved in 25 ml of ethanol and 75 ml of dimethylformamide. 7.5 g of active manganese (IV) oxide, 8 ml of acetic acid and 1.75 g of potassium cyanide are added to the solution and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is filtered, water is added to the filtrate, the precipitate is isolated and chromatographed on silica gel. With 23-27% acetone-hexane, 3.49 g are obtained, which are recrystallized from acetone-hexane. Yield 2.25 g ll /? - Hydroxy-3,20-dioxo-l, 4-pregnadien-21-acid-

ethyl ester. Melting point 187 ° C. [a] 25 = + 182 ° (c = 0.5

in chloroform). UV: £ 242 = 15,700 (methanol).

Example 3

Under the conditions given in Example 1b, but with methanol instead of butanol, 2.0 g of 11ß, 20-dihydroxy-3-oxo-1, 4.17 (20) -pregnatrien-21-al in 11 /? - Hy -droxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid methyl ester transferred. Yield 0.98 g. Melting point 187 ° C. [a] ^ 5

= + 175 ° (c = 0.5 in chloroform) UV: £ 242 = 15 700 (methanol).

Example 4.

Under the conditions given in Example 1b, but with propanol instead of butanol, 2.5 g of 11ß, 20-dihydroxy-3-oxo-l, 4.17 (20) -pregnatrien-21-al are converted into 11 / J-hydroxy -3,20-dioxo-l, 4-pregnadiene-21-acid-propyl ester transferred.

Yield: 1.34 g. Melting point 181 ° C. Ea] ^ 5 = + 175 °

(c = 0.5 in chloroform). UV: «242 = 15,700 (methanol).

Example 5

a) The solution of 4.0 g of 9a-fluoro-ll /?, 17a, 21-trihydroxy-l, 4-pregnadien-3,20-dione in 40 ml conc. 400 mg of zinc (II) acetate are added to acetic acid and the mixture is heated to boiling for 90 minutes. The mixture is cooled to 60 ° C. and the acetic acid is largely distilled off in vacuo. The back sand is dissolved in dichloromethane, the solution washed with water, dried over sodium sulfate and evaporated in vacuo. 4.0 g of 9a-fluoro-II /?, 20-dihydroxy-3-oxo-l, 4.17 (20) -preg-natrien-21-al are obtained as a foam.

b) 1.5 g of the aldehyde thus obtained are dissolved in a mixture of 10 ml of methanol and 25 ml of dimethylformamide. 1.5 g of active manganese (IV) oxide, 2.2 ml of acetic acid and 480 mg of potassium cyanide are added, and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is sucked into ice water via a frit, the precipitated product is isolated and chromatographed. After recrystallization from ethyl acetate, 535 mg of 9a-fluor-ll /? - hydroxy-3,20-dioxo-l, 4-pregnadiene-21-acidic acid methyl ester is obtained. Melting point! 84- ° -G -.- [a] ™ _.- t-163 °. , (c _—- 0.5. in .Chloroform) ...

UV: "39 = 16,600 (methanol).

626635

4th

Example 6

Under the reaction conditions given in Example 1b, 2.5 g of 9a-fluoro-11 /?, 20-dihydroxy-3-oxo-1, 4, 17 (20) -pregnatrien-21-al are in 9a-fluoro-II /? -hydroxy-3,20-dioxo-l, 4-pregnadfen-21-acid-butyl ester transferred. Yield 1.06

Grams. Melting point 198 ° C. [a] ^ = + 151 ° (c = 0.5 in

Chloroform). UV: su s = 16 200 (methanol).

Example 7

a) 7.5 g of 9a-chloro-II /?, 17a, 21-trihydroxy-l, 4-pregnadien-3,20-dione and 750 mg of zinc (II) acetate are heated to boiling in 75 ml of acetic acid for 90 minutes . After cooling to 60 ° C, the acetic acid is largely distilled off in vacuo. The residue is dissolved in dichloromethane and the solution washed neutral with water. The organic phase is then dried and the solvent is evaporated completely in vacuo. 7.5 g of 9œ-chloro-11 /?, 20-dihydroxy-3-oxo-1,4,17 (20) -pregnatrien-21-al remain as a residue.

b) 2.5 g of the aldehyde thus obtained are dissolved in 16 ml of butanol and 40 ml of dimethylformamide. 5 5 g of active manganese (IV) oxide, 3.6 ml of acetic acid and 800 mg of potassium cyanide are added, and the mixture is stirred at room temperature for 35 minutes. The reaction mixture is sucked into ice water via a frit. The resulting precipitate is isolated and chromatographed. 980 mg of 9a-chloro-II /? - hydroxylo 3.20-dioxo-l, 4-pregnadiene-21-acidic acid butyl ester are obtained.

Example 8

Under the conditions given in Example 5b, 2.5 g of 9a-chlorine-II /?, 20-dihydroxy-3-oxo-l, 4.17 (20) pregnatrien-21-al in 9a-chlorine -ll /? - hydroxy-3,20-dioxo-l, 4-pregna-dien-21-acidic acid methyl ester.

M