DE1593452A1 - Method of making steroids - Google Patents

Description

PATENT LAWYERS

: DR. W. SCHALK · DIPL-INC. PETER WlRTH 1593452

DIPL-ING. G. E. M. DANNENBERG · DR. V. SCHMIED-KOWARZIK FRANKFURT AM MAIN SK / SK IF. E "CHINHIIMI" "TR. 89 PA 1 05

Syntex Corporation
Apartado 7386
Panama, Panama

Method of making steroids

The present invention relates to a process for the production of the known steroidal pupation hormone for insects, ecdysone ("moulting hormone") and to the production of structure derivatives thereof. The synthesis of ecdysone, ie 2β, 3β, 14dyr 22β, 25-pentahydroxy-5β-cholest-7-et-6-one is, for example, in Journ.Am.Ghem Soc, 88, 862 (1966); "Tetrahedron-letters" 13, 3457 (1966) and in the Erie patent Hr. 726/65. In each of these syntheses was did Heir ^H ydroxy 1 group by the use of selenium dioxide (or selenious acid) introduced into compounds that encountered in ecdysone core 2ß £ ß-dihydroxy-6-keto £ ^ - have dehydro-structure. Furthermore, in several of these syntheses given, the compounds subjected to this ^ -hydroxylation contained the 5 [beta] configuration.

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BATH ORIGINAL

OÜiÄ29 / Uai

According to the invention it has now been found that one. improved yields and higher purities are obtained if one uses the 14i <»- hydroxylation at 2ß, 3ß-dihydroxy-6-keto-A -dehydroverbindungen with of the 5iC configuration, the substituent in the 5cfc position either an acyloxy group, generally acetoxy group, or is a hydrogen atom. Bas 5 # t-steroid comes with Selenium dioxide in an organic, inert to the reaction.

-.vie B & iizol, öler Äuiierii,
Solvents, such as dioxane, letrahydrofuran, etc.

preferably in the presence of an acid such as acetic acid at reflux temperatures for a period of about 4-6 hours. The 140ir-hydroxy-5c $ steroid obtained is isolated by filtering, washing and evaporating the reaction mixture.

Depending on the choice of the other process steps used, this reaction can be carried out with compounds in which the ecdysone side chain has not yet been worked out, for example an alkyl ester of 6-keto-2β, 3β, 5 <^ - triacetoxy-22,23-bisnor -5 ^ -chol-7-enoic acid, or with compounds which already contain the fully or partially worked out side chains, for example 2ß, 3ß-isopropylidenedioxy-22ß-hydroxy-25- (tetrahydropyran-2-yloxy) -5 # tr-cholest -7-en-6-one. In cases where the 5ft-position is substituted by an acetoxy group, this may be after the introduction of 14arHydroxygruppe by treatment with Ohromochlorid in an aqueous or ketonic solvent such as acetone _y, are selectively removed. This selective removal of the tertiary acetoxy group takes place with the steriospecific entry of the hydrogen atoms and gives only the corresponding «trane-A / l condensed product» ζ · Β · 2ß, 3ß-diacetoxy-1 ^ (- hydroxy-6-ketor 22,23- bis-nor-5 ^ -ehol-7-en-säurealkyleeter.

009829/1481

Whether the 1 ^ hydroxylation occurs on a steroid that is a Contains hydrogen atom in the 5d position, or on a steroid, which contains a 5J ^ -Ae etoxygruppe, then as above is selectively eliminated, the configuration of the 5o (, - hydrogen atom is inverted by treatment with a base, for example, by allowing the compound to stand in methanolic potassium bicarbonate for 20 or more hours. In the course aoyloxy groups, e.g. in the 2- and 3-position, hydrolyzed · The base-resistant groups, such as acetonide or tetrahydropyranyl ether, remain intact. These are known in Way removed by acid treatment. The hydrolysis of the acyloxy groups can also be done first with a short base treatment, and the inversion at C-5 is then carried out by prolonged treatment with a base.

The following examples illustrate the present invention, without restricting them

example \

A mixture of 140 mg selenium dioxide, 10 ecm dry dioxane and 265 mg 2β, 3β, 5dL-triacetoxy-6-keto-22,23-bis-nor-5et-chol-7-enoic acid methyl ester was refluxed for 4 hours, the reaction mixture then cooled, filtered and the filtrate washed with dilute aqueous potassium bicarbonate and extracted with methylene chloride. The ethylene chloride extracts were washed with a saturated sodium chloride solution, dried and filtered through diatomaceous earth. The piltrate was concentrated to dryness and gave the 2β, 3β, 5th% -triacetoxy-6-keto-14j ^ -hydroxy-22,23-bis-nor-5blrchol-7-enoic acid methyl ester with a P. of 230 -232 ° 0. / W ₁ ) - + 75 °.

009829/1481

4 ecm of a 25- A solution of chromochloride in 1N hydrochloric acid was added. The solution was allowed to stand for 2 minutes, after which it was poured into a water / methylene chloride solution. The organic layer was separated and washed successively with dilute aqueous potassium bicarbonate, water and saturated sodium chloride solution sodium sulfate and evaporated to dryness? so of 2ß, 3ß-diacetoxy-6-keto-14tf-hydroxy-22,23-bisnor-chol-5.7-7-en-säuremethylester was having a melting point of 250-254- ⁰ Cj

^{= +510? Ν} · ^Μ · ^Ε · 40.7 (18- ^H ) »59.7 Ü9-H), 120.6 and 124.3 (2XOAc), 275-310 (3tt-H), 319, HBW 7 (2 · ς-Η), 356 (J 2.5 cps, 7-H).

A mixture of 1 g of 2β, 3β-diacetoxy-14tf, -hydroxy-6-keto-22,23-bis-nor-5ol-chi-7-enoic acid methyl ester, 0.33 g potassium carbonate and 100 ecm 90% aqueous methanol was left to stand at room temperature for 20 hours. Then, ethyl acetate and a saturated sodium chloride solution were added to the mixture and the layers were separated. The organic layer was neutralized, washed with water, dried over sodium sulfate and concentrated to dryness at room temperature; a mixture of the 2β, 3β, 14 <£ -trihydroxy-6-keto-22,23-bis-nor-5β-chol-7-enoic acid methyl ester RD / OyZ ₅₄₁ = +60, / 0 ^ 40 = -224 ; NMR (d ₅ -Pyrdidn), 40.8 (18-H), 60.5 (19-H), 365! Palette (J 2.5 cps, 7-H) and the 5 «t-epimer, N, MR (d ₅ -pyridine), 40.8 (18-H), 77.5 (19-H), 365 - / a-.Ie ^ e
(J 2.5 cps., 7-H), which separated by chromatography

009829 / U81

became. The 5e (r epimer was used for the further production of the 5β-compound returned.

Example 2

A mixture of 140 mg selenium dioxide, 10 ecm trocleiem dioxane and 483 mg of 2β, 3β-isopropylidenedioxy-22β-hydroxy-25- (tetrahydropyran-2-yloxy ) -5 <* i-cholest-7-en-6-one was refluxed for 4 hours. The reaction mixture was then cooled, filtered and the piltrate washed with dilute aqueous potassium bicarbonate and extracted with methylene chloride. The methylene chloride extracts were washed with saturated sodium chloride solution and dried and filtered through Oelite diatomaceous earth. The filtrate was concentrated to dryness and yielded 2ß, 3ß-Isopropylidenedioxy-14ot, 22β-dihydroxy-25 - (tetrahydropyran-2-yloxy) - ^ - cholest-7-en-6-one with a P. of 251-253 C.

A mixture of 1 g of 2ß, 3ß-isopropylidenedioxy-14 $, 22ß-dihydroxy-25- (tetrahydropyran-2-yloxy) -5oC-cholest-7-en-6-one, 0.33 g of potassium carbonate and 100 ecm 90- Aqueous methanol was allowed to stand at room temperature for about an hour. Then, ethyl acetate and saturated sodium chloride solution were added to the mixture and the layers were separated. The organic layer was neutralized, washed with water, dried over sodium sulfate and concentrated to dryness at room temperature; a mixture of 2β, 3β-isopropylidenedioxy-140C, 22β-dihydroxy-25- (tetrahydropyran-2-yloxy) -5β-cholest-7-en-6-one (F. 198-20O ⁰ G.) and the 5 «f epimers obtained, which were separated by chromatography. The 50i-epimer was recycled for further preparation of the 5β-compound. The hydroxylysis of the 5β-epimer with 0.1N hydrochloric acid in aqueous tetrahydrofuran and purification of the product by chromatography and recrystallization from tetrahydrofuran and then

• 0 09829 / U81

BAD OmWM

Water afforded the 2ß, 3ß-22ß 14 ^, 25 ^ pentahydroxy-5ß-cholest'-7-en-6-one having a melting point of 237-239 »5 ⁰ C. (Phaaenveränderung 165-167 ⁰ C.

00 9829/1481

V -ft?

Claims (3)

Bate nt a ns ν r ü c Ii e 7 1.- Process for the production of a 6-keto-A'-denydrc-14flr hydroxy-5i3-steroide3, characterized in that a 6-keto- ^ ⁷ -deii7dro-5i <.- steroid with a water atoixato:.: or an acetoxygrappe. Treated in the ^ -position with selenium dioxide, if the 5 ^ -steroid has an acetoxy group in the 5 ^ -position, this 5 <fc-acetoxy group is replaced selectively by treatment with ohromohydrate by an iJ ^ pyahydrogen atom and the configuration of the 5 ^ -water3toi ^v i.'atoias inverted into a 5 ^ hydrogen atom by treatment with a base. 2.- Procedure for making a 2i:, 3ß, 14 ^: Trihydrox _a ^^^ - 6-keto-22 _t 23-bis- ^! 'nor-5ii ~ Ciiol-7-enoic acid ethyl ester, which is designated by the fact that 2i; _f 'iii, 5 ^ -Triacetox / -ö-3ceto-22 _f 23-bis-riGr-5e ^ chol-7-enoic acid methyl ester to the £ ir.fäi.run _t ; a 14 (^ - Hydroxyl ^ ruxjpe mit Seleiidioxyd "Deiielten, the ρβί, -Acetoxygx'uppe by treatment with Ghromochlorid to the formation eiaea ^ ü ^ ü-Diacetoxy-o-iceto-i ^ - hydroxj ^r -22 _f ^ 3-bis-iior-r? ^ - chol-7-ensätireniethylester3 ■ "select ir eliaiiniert and the configuration as Cp is inverted by treatment with a ... base, whereby the acce.toxygroupeii a: .. 'ü-c aud Cj hydrolyzed vverden » 3.- Process for the production of: _ ^, 5ii, i4oC ~ 22ü, 25-rentar-ydrOxy-Oholeate-T-en-o-oii, thereby geicermzeichest, daw iLan a ^ r, 3 _ώ , 22J2-25- 'Tetra ^ ^ -droxy- ^ cHrcholest-7-en-6-one, in -.Velciien know the aydroxylgruppen may be protected by ester, ketal or ether formation, to introduce eixwr i4 <-hydrox / l group with selenium dioxide Ge-a-delt, the configuration to C- ^ 5 inverted by treatment of a base and ^ at the same time any verea hydroxyl groups and, xall_ the hydroxyl. λ ^ .ΜΑ »009829/1481 BAD ORIGINAL ■ ■ groups are protected by ketal or ether formation, the ketal or hydrolyze the ether by treatment with an acid. · The patent attorney: BAD ORlGWAL 009829/1481