DE1161883B - Process for the preparation of 3-oxo-14-hydroxy-11ª ‡, 19-diacetoxycardadiene (1,4) -olide - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

German KL: 12 ο -25/01

Number:
File number:
Registration date:
Display day:

S 77280 IVb / 12 ο
December 23, 1961
January 30, 1964

The inventive method for the preparation of 3-oxo-14-hydroxy-lla ^ -diacetoxy-cardadiene- (1,4) -olide the formula below

CH, COO

CHoCOO

is characterized in that 1 ", 1 la-epoxy-3 [beta], 5,14,19-tetrahydroxy-cardene- (20:22) -olide (I) is catalytically hydrogenated, the resulting l", ll «-Epoxy-3 / 3-5,14,19-tetrahydroxycardanolide (II) is selectively dehydrated, the 3 - oxo -1 α, 11 oc - epoxy - 5,14,19 - trihydroxycardanolide (III) obtained as the main product 3 -Oxo-5,1 loc-14,19-tetrahydroxy-carden- (I) -olide (IV) acetylated and the resulting 3-oxo-5,14-dihydroxy-11α, 19-diacetoxycardene- (5) -olide (V) Dehydrated in 4,5-position by treatment with glacial acetic acid.

The new steroid possesses a grouping in ring A, which is characteristic of numerous therapeutic is significant corticosteroids, and exhibits pronounced mineralcorticiode and glucocorticiode properties on. It is also said to be an intermediate for the manufacture of chemotherapeutically interesting products Find corticoid analogs use. According to the invention, the starting material used is from Ouabain, 1,19-isopropylidene-ouabagenin or ouabagenin obtained by treatment with dilute hydrochloric acid in aqueous alcohol 19-tetrahydroxy-cardene- (20:22) -olide (I).

Process for the production of

3-oxo-14-hydroxy-lla, 19-diacetoxy-

cardadiene (1,4) solid

Applicant:

Sandoz A. G., Basel (Switzerland)

Representative:

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

Dipl.-Ing. G. E. M. Dannenberg

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

Frankfurt / M., Große Eschenheimer Str. 39

Named as inventor:

Dr. Christoph Tamm, Riehen (Switzerland),

Dr. Gert Volpp, Cambridge, Mass. (V. St. A.)

Claimed priority:

Switzerland of December 29, 1960 (No. 14 533)

The new synthesis proceeds according to the reaction scheme (see formula sheet). The individual process steps are in per se using customary methods carried out in a known manner.

The catalytic hydrogenation is z. B. with Pt in glacial acetic acid, the selective dehydration z. B. with O ₂ —Pt in aqueous acetone and the acetylation carried out, for example, with acetic anhydride — pyridine. The 5-hydroxy group can be selectively split off by boiling with glacial acetic acid for 30 minutes, as a result of which 3-oxo-14-hydroxy-11, 19-diacetoxycardadiene- (1,4) -olide (VI) is obtained.

HO

OH

309 807/441

HO

OH

OH

CH _a

HO
H ₂ C

OH

OH

III

OH

IV

O.

OAc

H-!

AcO

H ₉ C

OH

OAc

H-

CH,

AcO

H ₂ C

OH

OH

OH

VI

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

example

a) 1 ", 1 la-Epoxy-S / ^ MJii-tetrahydroxy-cardano-Hd (II) from l ", ll" -epoxy-3 ^, 5,14,19-tetrahydroxycardene- (20:22) -olide (I).

A solution of 600 mg Ia ₅ IIiX-EpOXy-SjS ₅ S, 14,19-tetrahydroxy-carden- (20:22) -olide (I) with a melting point of 306 to 316 ° in 30 ecm glacial acetic acid is mixed with 165 mg PtOg- H ₂ O hydrogenated at 22 °. The H ₂ uptake (156 ecm H ₂ ) comes to a standstill after 60 minutes. The Kedde reaction is negative. The Kedde reaction is carried out as follows: A solution of 0.02 to 0.05 mg of substance in 0.01 ecm of methanol is dropped onto filter paper and treated with a solution of 2 g of 3,5-dinitrobenzoic acid in 100 ecm of methanol plus 5, 6 g of KOH sprayed in 100 ecm of water. If the reaction is positive, the spot turns blue. After filtering off the Pt catalyst and evaporating the filtrate in vacuo, the residue is taken up in chloroform-ethanol (3: 1), _{washed with 2N Na 2} CO ₃ and water, _{dried over Na 2} SO ₄ and evaporated. The crude product (598 mg) gives 535 mg of crystals from methanol-ether with a melting point of 223 ° to 231 °. After recrystallization, prisms from double melting point 230 to 234 ° / 253 to 259 °; _[A] "= + 31.5 ° ± 2 ° (c = 1.303 in methanol). Rf == 0.59 in the water-butanol system (9 hours). Development with SbCl ₃ in chloroform. Transparent in the UV. In the IR (KBr) bands at around 2.9 μ (OH) and 5.63 μ (C == O, γ-lactone).

b) Selective dehydrogenation and acetylation of 1 χ, 11 a-epoxy-3 / ?, 5,14,19-tetrahydroxy-cardanolide (II).

A solution of 585 mg of l «, ll« -epoxy-3 / J, 5,14,19-tetrahydroxy-cardanolide (II) with a melting point of 230 to 234 ° in 100 ecm of acetone and 80 ecm of double-distilled water is freshly extracted with Pt 240 mg PtO ₂ · H ₂ O prepared by hydrogenation, shaken for 19 hours in an Ojj atmosphere. It is then filtered through a layer of kieselguhr (trade name Celite No. 535 and evaporated. The crude product (646 mg) shows at least four spots in thin-layer chromatography (system chloroform + 2% methanol) Acetic anhydride left to stand for 16 hours at 35 ° C. Customary work-up with chloroform gives 686 mg of brown-colored crude product which, in the thin-layer chromatogram (system chloroform + 12% methanol), showed the three spots, designated A, B and C. It is chromatographed on 30 g of silica gel 60 ecm of solvent per fraction are used for rewashing.

Fractions 1 to 8 [eluted with chloroform and chloroform-methanol (99: I)] give only traces of amorphous material. Fractions 9 and 10 [eluted with chloroform-methanol (98: 2)] give 38 mg of amorphous material which, according to thin-layer chromatography, shows the pure spot A (Rf value: 0.9). UV spectrum : X _max = 265 ηιμ; log ε = about 3.0 (ethanol). In the IR spectrum (CH ₂ Cl ₂ ) bands at 2.76 μ (OH); 5.66 µ (C = O, six-membered ring ketone + acetyl).

Fractions 11 and 12 [eluted with chloroform-methanol (98: 2)] give 53 mg of amorphous mixture.

Fraction 13 [48 mg, eluted with chloroform-methanol (98: 2)] contains according to the thin layer chromatogram the pure spot B (Rf value: 0.56) and gives 35 mg of di-O-acetyl-1 from methanol-ether ", 11" -epoxy-3 / ?, 5,14,19-tetrahydroxy cardanolide in needles with a melting point of 219 to 228 °. According to the mixed melting point, thin-layer chromatogram, UV spectrum (transparent) and IR spectrum: identical to authentic material.

Fractions 14 to 21 [eluted with chloroform- Methanol (98: 2)] give 139 mg of amorphous mixture which still contains spot B.

Fractions 22 to 30 [323 mg, eluted with chloroform-methanol (97: 3)] contain pure spot C (Rf value: 0.28) according to the thin-layer chromatogram. UV spectrum: X _max = 232 ηιμ;

log ε = 3.95 and λ _ηιαχ = 316 πιμ; log ε = 1.60 (ethanol). In the IR spectrum (CH ₂ Cl ₂ ) bands at 2.78 μ and 2.88 μ (OH); 5.65 µ (C = O, γ-lactone); 5.77 µ (C = O, acetyl); 5.96 µ (C = O, Δ ! -3-ketone); 6.21 μ (C = C, J! -3-KiStOn) and 8.13 μ (COC, acetate). It is the Δ ¹ -3-ketone.

Alternatively, you can use a solution of 26 mg 1 «, 1 l« -Epoxy-3 / S, 5,14,19-tetrahydoxy-cardanolide (II) in 8 ecm acetone and 6 ecm double-distilled water with Pt, fresh from PtO ₂ · H ₂ O prepared by hydrogenation, shake _{in 0 2 atmosphere for 24 hours.} It is then filtered through a layer of kieselguhr (Celite No. 535) and evaporated. The crude product shows two spots in the thin-layer chromatogram and bands at 2.91 μ (OH) in the IR (KBr); 5.68 µ (C = O, γ-lactone); 5.84 µ (C = O, six ring ketone); 5.99 µ (C = O, J ^a -3 ketone) and 6.21 µ (C = C, J ^ ketone, weak). UV spectrum: X _ma x = ηιμ 238; log ε = 3.69 and shoulder at 295 to 320 ηιμ; log ε = 1.74 (ethanol). From the ε value of the maximum of 236 πιμ it follows that the crude product consists of about 45% saturated 3-oxo-1 «, 11α-epoxy-5,14,19-trihydroxycardanolide (III) and about 55% 3-oxo -5, Ila-14,19-tetrahydroxy-carden- (I) -olide (IV), which; as described above, then acetylated with formation of 3-oxo-5,14-dihydroxy-II «, 19-diacetoxycardene- (I) -olide (V).

c) Dehydration of the 3-oxo-5,14-dihydroxylla, 19-diacetoxy-cardden- (l) -olids (V) to 3-oxo-14-hydroxy-II «, 19-diacetoxy-cardadiene- (1,4) -olide (VI).

230 mg of amorphous 3-oxo-5,14-dihydroxy-IIIa, 19-diacetoxy-cardden- (I) -olide (V) (spot C) are refluxed with 10 ecm of glacial acetic acid for 30 minutes. It is then evaporated, the residue is taken up in chloroform and filtered through a layer of kieselguhr (Celite No. 535) and evaporated. The crude product (239 mg) gives 178 mg of crystals from acetone-ether with a melting point of 202 ° to 216 °. After recrystallization from acetone-ether, prisms with a melting point of 210 to 215 °; [oc] l ¹ = + 22 ± 1.5 ° (c = 1.765 in chloroform). UV spectrum: λ _ηα χ - 243 πιμ; log ε = 4.18 and 330 ΐημ; log ε = 1.67 (ethanol). In the IR spectrum (CH ₂ Cl ₂ ) bands at 2.73 μ (OH); 5.65 µ (C = O, γ-lactone); 5.67 µ (C = O acetyl); 6.01 µ (C = O, ΛΜ -3-ketone); 6.15 µ and 8.08 µ (COC, acetate).

Claims (1)

Claim: Process for the preparation of 3-oxo-14-hydroxy-11 x, 19-diacetoxy-cardadiene- (1,4) -olide of the formula below CH ₃ COO
CHoCOO characterized in that Ia ₅ IIa-EpOXy-SzS ₅ S ₅ M ₅ W-tetrahydroxy-carden- (20:22) -olide (I) is catalytically hydrogenated in a manner known per se, the resulting Ια, ΙΙα-Εροχν-3 / 3 to 5.14, 19-tetrab.ydroxy-cardanolid selectively dehydrogenated (II) which, besides the _3-oxo-5 Ia-IIa CpOXy-S M _{5 5} W-trihydroxy-cardanolid (III) 3- obtained as a main product Oxo-5 ₅ l la-14,19-tetrahydroxy-carden- (l) -olide (IV) acetylated and the resulting 3-oxo-5,14-dihydroxy -11 α, 19-diacetoxy-carddene - (5) - olide ( V) dehydrated in 4,5-position by treatment with glacial acetic acid. 309 807/441 1.64 © Bundesdruckerei Berlin