DE1618998A1 - New 6-keto-20-hydroxysteroids - Google Patents

Description

New 6-keto-2Q-hydroxysteroids

The invention relates to compounds of the general formula

wherein E, hydrogen, a preferably lower alkyl radical or acyl radical, R _{2 is} hydrogen or a hydroxyl group, Z is hydrogen or -CH ,, Y is a straight or branched-chain alk ;; l-, vinyl or alkynyl radical, which if desired also z. B. can be substituted by free or functionally modified hydroxyl groups and / or by a keto group, and C «i_ütLCg a saturated or unsaturated carbon-carbon bond, A ^ / mean the Α ring in the steroid skeleton, and the other in the molecule against the invention applied reactants may contain inert substituents, and wherein the 5-hydrogen atom

10 9 8 2 5/1898

Documents (Art. 7 § I Abe. 2 Mr rSatf 3 de ·; Änaerünöeges. V. 4. 9..19G7)

SCHERING AG .. fri - October 27, 1969

α- or ß ~ can be configured, and a method of manufacturing of these compounds, characterized in that the 20-keto group of a corresponding 6,20-diketo steroid is selected selectively with Y * MgX, where Y is the radical indicated above and X is chlorine, bromine or iodine, or a metal acetylide converts, and if in the obtained primary product Y is an alkynyl radical means, if desired, to the carbon-carbon triple bond with formation of a 22-keto group in the presence of acidic catalysts, water is added and, if desired hydroxyl groups other than the 14a-OH group esterified or etherified, acyloxy groups present saponified or cleaves ether groups and - if Rp is hydrogen if desired, by methods known per se in a purely chemical or biological way by means of 14oc-hydroxylating agents Microorganisms or their enzymes introduce a hydroxyl group in the 14-position. As additional substituents, the The reactants to be used according to the invention are inert to the following in particular: lower alkyl radicals, preferably the methyl radical in e.g. l-, 7- or 16-position, hydroxy- or acyloxy groups in e.g. B. 1-, 2-, 3-, 11-, 16- or 17-position, or functionally ζ. Β. modified as ketal Keto groups in e.g. B. 11- or 3-position or additional double bonds z. B. in 1 (2) - and / or 3 (4) position.

The radical Y in the process products which can be prepared according to the invention can be, for example, propyl, isopropyl,

10 9825/1898

SCHERING AG. - 3 - October 27, 1969

Butyl, isabutyl ", butynyl, pentyl, isopontyl, pentynyl, iBopentinyl-, 2 ~ methyl-2 ~ hydroxy ~ 5 ~ butyn ~ 4-yl--, 2-ethyl-2-hydroxy-4-pentiii-5-yl ~, 2-methyl-2 ~ hydroxy-5-oxo-pcnt-5-yl, 2-methyl-1-hydroxy ~ 5-oxo-pent ~ 5-yl and similar residues. Contains the radical Y to be introduced according to the invention is a hydroxyl group y such as the 2-methyl-2-hydroxy-4-peritin-5-yl listed, for example, or 2-methyl-2 ~ hydroxy-3-butyn ~ 4-yl, so this hydroxyl group is expediently protected before introduction, for example as tetrahydropyranyl ether, whereby this If desired, protective group after implementation again, can be split off · -.

The feasibility of the process according to the invention was • surprising, in some cases it was not to be expected that, in spite of the 6-keto group present at the same time in the starting product, only the 2o-keto group would react and thus a selective introduction of the radical Y in the 2o-position would be possible " It was also surprising that this selective introduction of the radical Y still takes place stereospecifically with the formation of a 2o-hydroxyl group practically only in 20OCj ₁ division. This is important because the compounds of the present type are generally only active if the 2o-hydroxyl group is 2oap-configured

The selective formation of the oxo group in the 22-position by water addition to the carbon-carbon triple bond of a primarily introduced alkynyl side was also surprising.

• ·
"109825/1898

SCHERING AG ·. - 4 - October 27, 1969

chain. According to the rules of organic chemistry, one would have must have expected that this formation of the oxo group could have taken place in both 22 and 23 studs.

The selective introduction of the radical Y by means of Y · MgHaI is in a solvent inert to Grignard reagents, such as z. B. tetrahydrofuran, ether, dioxane, benzene and the like. by slowly combining the Grignard reagent solution and the solution of the starting steroid, preferably with stirring If it is in principle also possible to carry out the Grignarding at an elevated temperature, we recommend However, it calibrates - in order to guarantee the most quantitative, selective reaction possible - the reaction temperature to choose low. The Grignarding is expediently at -15 to. + 15 ° C, preferably at 0 ° -5 °. Surprisingly, especially in the specified temperature range, neither the 6-keto group nor optionally present acyloxy groups attacked by the Grignard reagent. As a rule, the selective Grignardization is after about 5 - 10 minutes ended * However, undesirable side reactions occur practically not even when the Grignarding reagent for a long time, z. B, about 50 - 90 minutes, to the exit steroid acts.

If the desired radical Y is an alkynyl radical, it is introduced also feasible, by ethynylation of the 2o-

«109825- / 918-9 8

SCHERIWG AG - 5 - October 27, 1969

Keto group by means of metal acetylide, preferably by means of alkali acetylide, such as. B. K- or Li-acetylide in ₅ z, B, liquid ammonia or inert against the Eeagenz .Lösungsmitteln, such as especially tetrahydrofuran, dioxane or - as far as the solubility of the starting materials e3 permitted ~ hydrocarbons such as benzene ₉ "

The addition of water to the triple bond of the alkynyl radical takes place according to the working methods customary for this purpose in the presence of acidic catalysts. Examples of catalysts are in question mineral acids such as sulfuric acid, Lewis acids such as boron trifluoride etherate, mercury compounds such as mercury sulfate or Que eks via oxy d, or also acidic ion exchangers » The reaction is preferably carried out at room temperature, but can also be carried out at a lower or higher temperature will.

X -

The gewünsehtenfalls connected! ^ - hydroxylation is carried out according to conventional methods of steroid chemistry, "On a purely chemical way it is done in particular by the action of Selenäioxyd or" selenious Säura _o takes place on biochemically the ^ - hydroxylation or in particular by the action of microorganisms * of the enzymes formed by them, which are known to be preferentially prone to 14 "Bydrö3 £ ylieming", like % & B ". Enzjme from OCE genus Curroiaria _p weiae Ciirinilaria _lunate? o & bt- the G-attung A ^ sIdIa ₉

103825/18
BATH ORIGINAL

SCHERIlG AG "- 6 - 27.10.1969

wise Absidia regnieri, or especially of the genus Ilelio " costyluni, preferably Heliocostylum pirifornie, or the cat- ' tung Mucor, preferably Mucor griseocyanus.

The esterification or etherification of hydroxyl groups present or the saponification of acyloxy groups or the splitting off of ether groups or other protective groups, e.g. in the selective hydrogenation - determined by the nature of the substituent R p R ₂ is a 14a-Hydrcxylgruppe are reaction conditions, where known tertiary hydroxyl groups easily eliminated with elimination of water, to avoid "the optionally subsequent • esterification of other hydroxyl groups as the 14ct-0H The group then takes place, for example, by means of carboxylic acid anhydrides or carboxylic acid halides in the presence of pyridine.

As already stated above, the selective and stereospecific course of the introduction of the radical Y and the selective water addition to a carbon-carbon triple bond in the radical Y with formation of a 22-keto group was not due to the working methods known to the person skilled in the art expected * These two sr ~ fahrens'Ecliritt © 'ainci thus new and erfinderiθqh _s why for them in Eataeii ies Torliegendon erfindungsgeniäSsii process

* 109825/1898 " ^? " *

'·. BATH ORIGINAL

SCHERING AG -7- October 27, 1969

Element ens chut s "is claimed *

The method that can be produced by the method according to the invention Some ns products have valuable pliarmacological ones themselves Properties or serve as intermediate products for the production of active ingredients of the most varied of hormonal agents Activity · The products of the process are particularly suitable as intermediate products for the production of insect and crustacean metamorphic hormones, such as, for example, «2o-hydroxy-ecdysone ·

. A preferred starting product of the inventive method

driving is the previously not previously described Δ -5a-pregnen-2ß, 3ß-diol-6,2o-dione diacetate. The production, for which no protection is sought in the context of the present application, takes place "z · B, in the following way:

49o ml of acetic anhydride are cooled to about -lo ° C. and 295 ml of nitric acid (D = 1.51) are added dropwise; 100 g of 5a-pregnan-2oss-ol-5,6-dione - dissolved in 59o ml of chloroform - are slowly added dropwise to this mixture, with stirring and under nitrogen, so that the temperature does not rise above -5 ° C. The reaction mixture becomes 2o Minutes at · -5 ° to ~ lo ° C and poured into ice water «, the chloroform solution is separated _s the aqueous phase with '

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SCHERING AG - 8 - October 27, 1969

Extracted methylene chloride and the combined organic extracts washed neutral and evaporated in vacuo «. After recrystallization from isopropyl ether methylenoliloride, 96 g of 5a-pregnane-2oss-ol-3 _f 2o-dione nitrate were obtained; M.p. 19o.5-191.5 ° C (Sers.).

To 19 g 5cc-pregnan-2oß-ol-3,6-dione-nitrate in 4oo ml of dry tetrahydrofuran under cooling, a solution of 2.68 ml of bromine and 3.9 g of potassium acetate in 5o ml of glacial acetic acid are added dropwise The reaction solution is in _β Sodium acetate-containing ice water is stirred in, the precipitated 2a-bromo-5a ~ pregnan-2oss-ol-3 »6-dione nitrate is suctioned off and recrystallized from isopropyl ether at 152-153 ° ö (decomposition).

18.2 g of 2a-bromo-5a-pregnan-2oss-ol-3,6-dione-nitrate are in 150 ml of frozen tetrahydrofuran at ο - 5 ° C with a solution of 2ο g lithium aluminum tri-tert »-butoxyhydride in 90 ml of reduced tetrahydrofuran "It is stirred into ice-water with sulfuric acid, the bromohydrin which has precipitated out is suctioned off, dried and acetylated in 80 ml of pyridine with 40 ml of acetic anhydride for 15 hours at room temperature. The reaction mixture is stirred into ice water, the precipitate which has separated out is filtered off with suction, washed with water, dried and recrystallized from acetone. The 2oc-bromo-5apregnan-3β, 2oss-diol-6-one-3-acetate-2o-nitrate obtained in this way melts at 23o - 231 ° 0 (Zerso),

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BATH ORIGINAL

SCHERIITG AG - g - October 27, 1969

5o g 2a ~ bromo-5cc-pregnan ~ 3ßs.2oss ~ diol-6 ~ one ~ 3-acetate ~ 20 ~ nitrate. are refluxed for 3 hours in 600 ml of glacial acetic acid and 12 ml of water with 19 g of silver acetate. The precipitate is filtered off with suction, and getrocloiet in 12o ml of pyridine with 6o ml of acetic anhydride nachaeetyliert _e The crude product is chromatographed on silica gel. The 5x-pregnane-2β, 3β _r 2oss-triol-6-one-2,3-diacetate-20-nitrate is eluted with methylene chloride and recrystallized from acetone-hexane; F · 221-222 ° 0 (dec.).

13.7 g of 5cc-pregnane-2β, 3β, 2oss-triol-6-one-2,3-diacetate-2o-nitrate are * in 3oo ml of tetrahydrofuran and 3oo ml of glacial acetic acid with 2o g Zinc dust stirred for 10 minutes at room temperature. The zinc dust is filtered off, then the filtrate in vacuo concentrated and poured into ice water. The precipitated 5α-pregnane-2β, 3β, 2oss-triol-6-one-2,3-diacetate is filtered off with suction land recrystallized from ^ methylene chloride isopropyl ether;

8.67 g of 5α-pregnane-2β, 3β, 2oJ3-triol-6-one-2,3-diacetate dissolved in 2oo ml of glacial acetic acid, treated with 1.075 ml of bromine in 2o ml of glacial acetic acid and 2 hours at 5o ° C · the mixture is stirred, stirred into ice water, the potassium acetate was added, the precipitate filtered off with suction, washed neutral and dried · the crude product is chromatographed on silica gel ohromatographiert © with methylene chloride / ether {1% 3), the 7 "~ bromo-5a ~ ppegnan-2i3, 3ß | _i 2oß-triol ™ 6-on ~ 2 _i 3-diacetate eluted and ame isopropyl

BAD ORfGlNAI.

• SCHERING AG - 10 - October 27, 1969

etherealized; 198-199 ° C (Zerso).

2.7 g of the 'oMgen 7' bromoketone are dissolved in 54 ml of glacial acetic acid, 5.4 ml of water added, "at f 5-lo ° C 6.75 ml Chromium saxir solution (2 ^ .6 g CrO, in 2 ml HpO and 23 ml AcOH) added dropwise and 0.32 ml of cone "sulfuric acid added" Hach Stirring is added for 10 minutes and with methylene chloride extracted. The methylene chloride solution is washed neutral, dried and evaporated. The 7a-bromo-5a-pregnane-2β, 3β-diol-6,2o-dione diacetate obtained in this way After recrystallization from acetone-hexane, it melts at 173.5-174 »5 °.

2.4 g of the oMgen bromodione are stirred in 25 relative dimethylformamide, o.72 g lithium carbonate and o.44 g lithium bromide for 3 »5 hours at 12 ° _G» Then poured into ice water, extracted with methylene chloride and the methylene chloride solution washed neutral and evaporated. The Δ ~5α-pregnene-2β, 3β-diol-6,2o-dione diacetate obtained in this way is recrystallized from methylene chloride / isopropyl ether; P · 225-226 ° C; UY: B ₂ ^ _B 13 4oo,

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0 9 8 25/1898
BAD ORIGINAU

SCHERIUG AG. ■ - 11 '- October 27, 1969

Be ispiel 1. -

2.7 ml of 2-methyl-4-pentyn-2-ol-tetrahydroyl) yranyl ether (made from 2-methyl-4-pentyne) are added to an ethyl magnesium bromide solution (made from 517 mg magnesium, 1.1 ml ethyl bromide in 20 ml ether) -2-ol / ~ a "Mondon Ann _o 577, was added dropwise (by Yerätherung with dihydropyran, Kp. ₁ 92 -94 ° C 1952J7) in 2ο ml of tetrahydrofuran and 131 1 hour at room temperature naehgerührto This Grignard solution in an ice-cooled

«7

Solution of 600 mg of Δ -5α-pregnen-2β,; 5β-diol-6,2o-dione diacetate added dropwise to 60 ml of tetrahydrofuran and 1 hour at about 5 ° C ■ stirred · The reaction mixture is washed with saturated am- " monium chloride solution decomposed, taken up in ether and the Ether extract washed with water and evaporated in a yakuum After purification by preparative thin-layer chromatography 5a-ChQlest-7-en-22-yn-2ß, 3ß, 2oap, 25-tetrol ~ 6-one-2,3-diacetate-25-tetrahydropyranyl ether isolated·

^{UV: e} 244 ^{= 15} ^ ⁰ '"^ - ■." ■ - ..

Example 2:.

28o mg of mercury oxide and 5.6 ml of 2N sulfuric acid Heated for 5 minutes on the steam bath, cooled to 20 ° C and with a solution of 53o mg 5a-Cholest-7-en-22 - in-2ß, Sß ^ ooCp, 25-tetrol ~ 6-one-2,3-diacetate-25-tetrahydropyranyl ether in. 56 ml of methanol are added and the mixture is at room temperature for 2.5 hours.

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109825/1898

BAD ORIGINAL '

SCHERING AG. · - κ - 27.10.1969

stirred * The undissolved Qiieokuilborvorbindiuigen were filtered off, the filtrate is extracted with methylene chloride, ncu-

Neutral washed and evaporated in vacuo. Do Δ -5a-Cholesteii-2ß, 3ß, 20a, _a ,, 25-tetrol-6,22-dione -2,3-diacetate _β UVi ε ₂ . s 13 2oo ₀

B e i _mj s..ρ i ,, "ο ,,, 1 3»,

152 rag A ⁷ -5α-oil residues ~ 2β, 3β, 2oa _I , _f 25-tetrol-6.22 "dione-2,3-diacetate are dissolved in _{0.5 ml of dioxane with 48 mg of SeO 2 for} 20 minutes at 90 ° stirred C »The reaction solution is freed directly by preparative thin layer of selenium The so_erhaltene A'-5a-0holesten-2ß _r 3ßfl4a, 2oap, 25-pentol- 6,22-dione 2,3-diacetate melts at 293-294 ° Ow .

^{UV: e} 24o ^ ^{11 5oOe} '·'''

Example 4: ' ^:

20 mg A ^ "-5a-bholesten-2ß, 3ß, 14cx, 2oa _II , 25-pentol-6,22-dione-2,3-diacetate are stirred in 1 ml of methanol with 3» 5 mg of potassium hydroxide for 3 hours at room temperature and heated under reflux for 5 minutes. The reaction solution is neutralized with acetic acid, evaporated in vacuo and the resulting Ä ⁷ -5ß-Chole3ten-2ß, 3ß, 14α, 2οα _ρ , 25-pentol-6,22-dione isolated by preparative thin-layer chromatography · UTi e _{2 /} , ₂ β 12 loo,

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scheiotg- ag - 13 - "27.10.1969

B is ρ ie 1 5 ^ ₁

~ —————

20 mg Δ -5α

2,3-diacetate are stirred in 1 ml of methanol with 3.5 mg of potassium hydroxide for 30 minutes at room temperature. The reaction solution is neutralized with acetic acid, concentrated in vacuo *

7th
evaporates and the resulting Δ -5ct ~ Cholesteii ~ 2ß, 3ß, 14a, 2oap, • 25-pentol-6,22-dione isolated by preparative thin film chromatography ". '·', ■. · J

B e i s ρ i e 1 6ϊ

39o mg of 5α-Cliolesten-7- "en" -22-in-2β _r 3β, 2oap, 25-tetrol-6-one-2,3-diacetate-25-tetrahydropyranylether are dissolved in 8 ml of oil-tetrahydrofuran and after addition stirred by o, 8 ml of 2N sulfuric acid l'hour at 2o O. The reaction solution is diluted with Essigester and dissolution washed with sodium bicarbonate and sodium chloride! and evaporated in Yakuum * Hach Umlirist alii sat ion "are llexan from acetone / 28o mg 5a-eiio = read-7-en-22-yne ~ 2β, 36.2Oa ^ ₁ 25 ~ tetrol ~ 6-one-2,3-diacetate obtained from melting point 2o8.5 - 21o C "

example

2οο ing 5 ^ -Choleot-7- * en-22 ~ in ~ 2ß, 3ß <, 2οαρ _y 2 $ diacetate are in 2o ml of afes © Mothanol with 2o © mg Quec3c0ii ~

BATH ORIGINAL '

SCHERIEfG AG - October 14-27, 1969

Stirred over II acetate and 0.1 ml of boron trifluoride etherate for 5 minutes at room temperature.After adding 1 ml of pyridine and 2oo ml of ice water, the extract is extracted with ethyl acetate evaporated. 19o mg of A ⁷ -5ct ~ Cholesteii-2ß, 3ß, 2Oa ^, 25-tetrol ~ 6,22 ~ dione-2,5-diacetate · UV: ε ₂ ^ α 15 are obtained

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BATH ORIGINAL
109825 / T838

Claims (1)

Claims 1. Process for the preparation of compounds of the general formula , *. «.. * ,. * ög a wherein R _{1 is} hydrogen, a preferably lower alkyl radical or acyl radical, R _{2 is} hydrogen or a hydroxyl group, Z is hydrogen or -CH ,, Y is a straight or branched chain alkyl, vinyl or alkynyl radical which, if desired, also z. B, can be substituted by free or functionally modified hydroxyl groups and / or by a keto group, ₅ nnä saturated or unsaturated carbon-carbon bond, A ^ 3 ^ denote the At ring in the steroid skeleton, and which contain further substituents inert to the reactants used according to the invention in the molecule can, and in which the 5-position hydrogen atom can be α- or ß-configured, characterized in that one se- - 16 - BATH ORIGINAL 109825/18 98 Untfc.rla .'on ^ίΛ ■ - ■ * · * S-V. 4.9. AG - 16 - 27.10.1969 selectively the 2o-keto group of a corresponding 6,2o ~ Di ~ ketosteroids with Y «> MgX, where Y is the remainder indicated above and X is chlorine, bromine or iodine, or a me- - Talacetylid converts, and if in the obtained primary product Y is an alkynyl radical, if necessary, on the carbon-carbon triple bond with the formation of a 22-keto group in the presence of acidic catalysts Adds water and, if necessary, other hydroxyl groups esterified or etherified as the 14oc-OH group, any acyloxy groups present are saponified or ether groups are cleaved and - if R "is hydrogen - if desired according to methods known per se in a purely chemical or biological way using 14oc-hydroxylating microorganisms or whose enzymes introduce a hydroxyl group in the 14-position · "· 2. The method according to claim 1, characterized in that the introduction of the radical Y by Y-MgX in -lo ° to 4- 3o ° C. 3. Process according to Claim 1, characterized in that the water is deposited on the carbon-carbon triple bond of the radical Y in the presence of sulfuric acid / mercury oxide *. '' · 109825 / 1Ö98
BASS ORIGINAL SGHElIFG- AG- 10/27/1969 4 * Method according to spoke 1, characterized in that the subsequent "introduction of a! ^ hydroxyl group takes place by means of selenium dioxide or * selenious acid " 5 # method according to claim 1 to 3, characterized in that that -dione-diacetate is used as the starting product used· β * Sa-Oholest-T-en-Sa-in-aß, 50,2oaj ,, 25-tetrol-6-one-2,5 -. 'diacetat-SS-tetrahydropyranylether * Δ ^T »-saacetates -2ß, 35ß _f 2οα ^, 25-tetrol-6,22-dione-2,3-di- , 25-pentol-6,22-d ± on-2,3- aiacetati 9 ♦ & «5ß-Chole8te" n-20,30,14a, 2οβ | ,, 25-pentol-6,22-dione, Io * V ^ ieMndungea of the general formula Rr '- 18 - BATH ORIGINAL 109825/18 98 SCHERING AG - ^ - 27.10.1969 wherein R-, hydrogen, a preferably lower alkyl radical or acyl radical, Rp hydrogen or a hydroxyl group, Z hydrogen or -CH ,, Y a straight or branched »chain alkyl, vinyl or alkynyl radical, which if desired also z. B. can be substituted by free or functionally modified hydroxyl groups or by a keto group, and C ₁₇ ^ -Jt-A-CkCg a saturated or unsaturated carbon-carbon bond, A ^) mean the A ring in the steroid skeleton, and the other in the molecule may contain substituents inert towards the reactants used according to the invention, and in which the 5-position hydrogen atom can be α- or ß-configured. 11, 5α-Cholest-7-en-2β, 3β, 140-2Oa ₁ ,, 25-pentol-6,22-dione 12. 5a ~ Cholest-7-en ~ 22-in-2β, 3β, 20a _i ,, 25-tetrol-6-one-2,3 dia.ce tat 109825/1898
BATH ORIGINAL