DE1211192B - Process for the preparation of 11alpha, 19, 21-triacet-oxy-14-hydroxy-delta 1,4-14betagnadiene-3, 20-dione - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

German class: 12 ο - 25/05

Number: 1 211192

File number: S 86018IV b / 12 ο

Filing date: July 5, 1963

Opening day: February 24, 1966

The present invention relates to a process for the preparation of lla ^^ l-triacetoxy-W-hydroxy-zl ^ -l ^ -pregnadiene-S ^ O-dione, which is characterized in that according to methods known per se 3/3, 5,14,19,21 - Pentahydroxyla, Ila-oxido-5 / S, 14ß-pregnan-20-one (II) acetylated, the monoacetate of the formula III and the diacetate of the formula IV are isolated from the resulting mixture, these are catalytically dehydrated , the obtained A ¹ S-Ke tone of the formulas V and VI acetylated and the obtained Ila, 19,21 - triacetoxy - 5,14 - dihydroxyzl ¹ -5 / S, 14 /? - pregnen-3,20-dione (VII ) in 4 (5) -Stelhing by treatment with an organic acid, preferably with glacial acetic acid, dehydrated.

The new steroid possesses a grouping that is characteristic of numerous therapeutically significant ones Is corticosteroids, and has pronounced mineralcorticoid and glucocorticoid properties on. For example, a zl ^ -S-keto structure of ring A is characteristic of the prednisolone series. It is also said to be an intermediate for the production of chemotherapeutically interesting products Find corticoid analogs use.

The process according to the invention uses 3 ^, 5,14,19,21 - pentahydroxy - la, lla-oxoido-5 ^, 14 ^ -pregnan-20-oh (II), which by O ₃ degradation of 3.19 -Di-O-acetyl-la, lla-oxido-strophanthidol and subsequent saponification is available.

The new synthesis proceeds according to the reaction scheme.

According to the invention one obtains the previously unknown compound of formula I by treating, for example, the ketol of the formula II with 1.5 mol of acetic anhydride in pyridine-dioxane at 0 ⁰ C. The result is a mixture of the mono- and diacetates of the formulas III and IV and of the triacetate of the formula VIII, which can be separated by chromatography on silica gel (using the modification by GR Duncan). Duncan's method consists in the direct transfer of thin-layer chromatography according to Stahl to the ratios of column chromatography. 100 times the amount of adsorbent, based on the amount of substance, is used. The solvent or solvent mixture used in thin-layer chromatography, which is not changed, is used for elution. The same column can therefore be used for several chromatographies. In addition to a little triacetate of the formula VIII, the mono- and diacetates of the formulas III and IV are formed in equal parts. The two last mentioned substances process for the preparation of IIa, ^{19,21-triacetoxy-14-hydroxy-1} J ^'i -14 _/ ö-pregnadien-3,20-dione

Applicant:

Sandoz A. G., Basel (Switzerland)

Representative:

Dr. W. Schalk, Dipl.-Ing. P. Wirth,
Dipl.-Ing. GEM Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Named as inventor:

Dr. Christoph Tamm, Riehen (Switzerland)

Claimed priority:
Switzerland of 6 July 1962 (8143)

are then dehydrated directly, preferably with 02-Pt in aqueous acetone, the corresponding zfi-S-ketones of formulas V and VI form. These are acetylated by customary methods, the two substances being the same Triacetyl derivative VII is formed. The latter is then refluxed by heating with glacial acetic acid the double bond in the 4-position was introduced by splitting off the 5-hydroxy group. After cleaning of the crude product on the silica gel column, the new steroid of the formula I becomes uniform and crystallized Form won.

The compound can be used as a remedy, e.g. B. in the form of pharmaceutical preparations, use. These contain the compounds mentioned mixture with one for enteral, parenteral or local Application of suitable organic or inorganic carrier material. Such come for the same Substances in question that do not react with the new compound, such as B. gelatine, milk sugar, starch, Magnesium stearate, talc, vegetable oils, benzyl alcohols, gum arabic, polyalkylene glycols, petrolatum, Cholesterol or other known excipients. The pharmaceutical preparations can e.g. B. as tablets, coated tablets, powders, creams, suppositories or in liquid form as solutions, suspensions or emulsions are present. If necessary, they are sterilized and / or contain auxiliary materials, such as preservation, stabilization, network

609 509/415

or emulsifiers. They can also contain other therapeutically valuable substances.

The ratios for solvents in the following examples always relate to Volumes.

In the following examples, all temperatures are given in degrees Celsius. The melting points are corrected.

For example

a) Acetylation of 3 / 3,5,14,19,21-pentahydroxy-1 α, 11 a-oxido-5 / S, 14jS-pregnan-20-one (II)

A solution of 59 mg of pure 3,3,5,14,19,21-pentahydroxy - Ια, ΙΙα -oxido - 5 / S, 14j8 - pregnan - 20 - one with a melting point of 201 to 202 ° in 1.0 ml of dioxane and 0.5 ml of absolute pyridine is mixed with 0.025 ml of acetic anhydride (= 1.5 mol) and left to stand for 20 hours at 0 °. It is then evaporated in vacuo, and the residue is evaporated twice more with acetone. 64 mg of crude product result, which shows three spots in the thin-layer chromatogram. It is chromatographed on 75 g of silica gel together with 9 mg of analogous material from another experiment (a total of 73 mg). Methylene chloride-methanol (9: 1) (100 ml fractions) is used for elution. Fraction 1 gives 3 mg of triacetate VIII. Fraction 2 gives 29 mg of amorphous material which is uniform by thin layer chromatography, diacetate IV, IR spectrum in CH ₂ Cl ₂ : bands at 2.9 μ (OH); 5 75 μ (C = O, acetyl) and inflection at 5.80 μ (C = O, 20-ketone). Fraction 3 yields 29 mg of amorphous, uniform material according to thin layer chromatography (a single homogeneous spot), monoacetate III. IR spectrum in the CH ₂ Cl ₂ : bands at 2.95 μ (OH) (very strong); 5.72 µ (C = O, acetyl), 5.28 µ (C = O, 20-ketone).

b) Partial catalytic dehydrogenation
of the diacetate IV

40

A solution of 28 mg of the diacetate IV in 10 ml of acetone and 7.5 ml of water is added to a suspension of freshly prepared Pt (from 17.5 mg of PtO ₂ ) in 2.5 ml of water and in an O ₂ atmosphere for 30 hours shaken. Filtration and evaporation result in 30 mg of crude product, which is chromatographed on 30 g of silica gel. Methylene chloride-methanol (95: 5) (10 ml fractions) is used for elution. Fractions 1 to 6 give only traces of material. Fractions 7 to 13 give 20.5 mg of amorphous material; according to thin-layer chromatogram mixture (contains VI). Fractions 14 to 21 give 13 mg of amorphous I ^ I material, which shows only one spot in the thin layer chromatogram (visible in the UV), the ζμ-3-ketone VI.

IR spectra in CH ₂ Cl ₂ : bands at 2.78 and 2.88 μ (OH); 5.74 µ (C = O, acetyl), inflection at 5.80 µ (C = O, 20-ketone) and 5.94 µ (C = O, A ^ -ketone).

c) Partial catalytic dehydrogenation
of the monoacetate III

One. Solution of 28 mg of the monoacetate III is _{treated with Q 2} -Pt exactly as described in the above experiment and the crude product (29 mg) is chromatographed analogously on 30 g of silica gel. 14 mg of ^ -S-ketone V result.

d) lla, 19,21-triacetoxy-5,14-dihydroxyzl ¹ -5 _i S, 14 / S-pregnen-3,20-dione

The fractions containing the zI ¹ -3-ketones IV and V are left to stand at 37 ° for 18 hours with 3 ml of pyridine and 3 ml of acetic anhydride. After evaporation in vacuo, it is taken up in chloroform and the solution _{is washed twice each with 2N HCl, 2N Na 2} CO 3 and water, _{dried over Na 2} SO 4 and evaporated. 43 mg of the crude product thus obtained are chromatographed on 35 g of silica gel. Methylene chloride-methanol (97: 3) (10 ml fractions) is used for elution. Fractions 1 to 7 give 22 mg of crude VII, which still shows an accompanying stain in the thin-layer chromatogram. Fractions 8 to 16 give 23 mg of amorphous Ila, 19, 21-triacetoxy-5,14-dihydroxy-z) ¹ -5jS, 14/3-pregnen-3,20-dione (VII) which is uniform by thin layer chromatography. [a] g = + 60 + 3 ° (c = 0.830 in chloroform). UV spectrum in ethanol: X _m ax = 231 πΐμ (log _ε = 4.00; calculated C ₂₇ H ₃₆ Oi _0). IR spectrum in CH ₂ Cl ₂ : bands at 2.80 and 2.95 μ (OH); 5.76 µ (C = O, acetyl), inflection at 5.82 µ (C = O, 20-ketone); 5.96 µ (C = O, ^ -3-KeIOn), 6.24 µ (C = C, / M-ketone) and 8.20 µ (CO = C, acetate).

Example 2

Production of lla, 19,21-triacetoxy-5,14-di-

hydroxy-zl! -5 / J, 14 / J-pregnen-3,20-dione

the mixture of the monoacetate III

and diacetats IV

A solution of 192 mg of 3ß, 5,14,19,21-pentahydroxy - Ια, ΙΙα - oxido - 5 / 3.14 /? -pregnan-20-one in 2 ml of dioxane and 1 ml of pyridine is mixed with 0.10 ml of acetic anhydride (= 2.2 mol) at 0 ° and left to stand for 18 hours at 0 °. The crude product (190 mg) resulting from the work-up as described in Example 1 is chromatographed on 10 g of Al2O3. 10 ml of solvent per fraction are used for elution. The fractions eluted with methylene chloride, which contains 2 to 30% methanol, give 80 mg of crude product, which consists mainly of III and IV. A solution of 130 mg of such a mixture in 40 ml of acetone and 30 ml of water is added to a suspension of Pt, which has been freshly _{prepared from 65 mg of PtO 2} by hydrogenation, in 10 ml of water and in O for 15 hours at 22 ° ₂ atmosphere shaken. After filtering off the catalyst and evaporating the solution, 124 mg of crude product result, which is _{chromatographed on 6 g of A1 2} Ü3. 10 ml of solvent per fraction are used for elution. The fractions eluted with methylene chloride containing 1% methanol give 79 mg of crude product, which consists of a mixture of V and VI. In the UV spectrum it shows an absorption maximum at 233 ηΐμ (log ε = 3.89 in ethanol), which is typical for the / !! - S-ketone group. 65 mg of the crude product are left to stand at 22 ° for 18 hours with 1 ml of pyridine and 1 ml of acetic anhydride. The solution is chromatographed directly on 7 g of AUO3. 10 ml of solvent per fraction are used for elution. The fractions eluted with pure methylene chloride give 41 mg of crude VII. In the IR spectrum (CH ₂ Cl ₂ ) it shows bands at 2.85 and 2.95 μ (OH); "5.75 μ (C = O, acetyl) ; 5.95 μ (C = O, / μ-3-ketone) and 6.20 μ (C = C,

zJ! -3-KeUm). For further purification, 35 mg of crude VII are _{chromatographed again on 1 g of Al 2} Os. 3.5 ml of solvent per fraction are used for elution. The fractions eluted with pure methylene chloride and methylene chloride containing 0.5% methanol give 25 mg of pure VII.

Example 3

HcU ^ l-Triacetoxy-M-hydroxy-

didO) from VIl '

25 mg of pure llcU ^ l-triacetoxy-SJ ^ -dihydroxy - ^ - SftMjS-pregnen-S ^ O-dione, prepared according to one of the preceding examples (VII) are refluxed with 1.5 ml of glacial acetic acid for 30 minutes and then completely evaporated in vacuo.

The residue gives 15 mg of crude crystals from methanol-ether. The mother liquor residues are chromatographed on 16 g of silica gel. Methylene chloride-methanol (98: 2) (10 ml fractions) is used for elution. Fractions 4 and 5 provide a further 3 mg of crude crystals. After recrystallization from methanol, pure I is obtained in rods with a double melting point of 121 to 124 ° / 211 to 215 °. After recrystallization from acetone-ether, rods with a melting point of 210 to 216 °; [a \ l ⁵ = + 64 + 2 ° (c = 0.943 in chloroform). UV spectrum in ethanol: maxima at 241 ηΐμ (log ε = 4.26) and 320 ηΐμ (log ε = 1.67). IR spectrum (solid * in KBr): bands at 2.89 μ (OH); 5.70 to 5.74 µ (C = O, acetyl); 5.80 µ (C = O, 20-ketone); 5.99 µ (C = O, zl ^ ketone); 6.14 and 6.21 μ (C = C, / d ^ -O-ketone) and at 8.11μ (Ο - Ο —C ₅ acetate).

CH ₂ OH C =

OH II

AcO Λ H ₂ C

HO

CH ₂ OAc
OH I
AcO IC = O

OH

OH

VI

CH ₂ OAc
OAc I
AcO j C = O

OAc

CH ₂ OAc

c - π

VII

AcO

OH

VIII

Claims (1)

7 8 Claim: Mixture of the monoacetate of formula III and the Diadetate of the formula IV isolated, this catalytically Process for the production of lla, 19,21-tri-dehydrogenated, the corresponding / M-Ke- acetoxy-14-hydroxy-z! ¹ ' ⁴ -14 ^ -pregnadien-3,20-dione-clays of the formulas V and VI acetylated and that (I), characterized in that 5 obtained lla.l ^ l-triacetoxy-5,14-dihydroxy one according to known methods 3 / 3,5,14, / l ¹ -5 / 9,14 / S-pregnen-3,20-dione (VII) in 4 (5) -Stel- 19,21-pentahydroxy-la, lla-oxido-5ß, 14 | S-prelung, by treatment with an organic gnan-20-non (Π) acetylated, dehydrated from the resulting acid, preferably with glacial acetic acid. 609 509/415 2.66 © Bundesdruckerei Berlin