DE1064058B - Process for the preparation of 21-alkyl derivatives of 17beta-hydroxy-17alpha-pregn-20-y - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY
 PATENT OFFICE

KL. 12 O 25/05

INTERNAT. KL. C 07 C EXPLAINING PUBLICATION 1064 058

B 47549 IVb / 12 ο

REGISTRATION DATE: JANUARY 22, 1958

NOTICE THE REGISTRATION AND ISSUE OF THE DISPLAY: AUGUST 27TH 19 5 9

21-A] kyl derivatives of 17 / S-hydroxy-17a-pregn-20-yns of formula I below

OH

CH,

C = CR

(I)

(R ~ an alkyl group with 1 to 8 carbon atoms, R ₁ = CH ₃ or H)

are of particular pharmaceutical importance. The manufacture of these substances according to the invention takes place in the Way that the 17-position hydroxyl group of a 17 /? - Hydroxy-17a-pregn-20-yn of the general formula II

ao

Method of manufacture

of 21-alkyl derivatives of 17 | 3-hydroxy-17a-pregn-20-yns

Applicant: The British Drug Houses Limited, London

Representative:

Dipl.-Ing. F. Weickmann and Dr.-Ing. A. Weickmann, Patent Attorneys, Munich 2, Brunnstr. 8/9

Claimed priority: Great Britain January 25, 1957 and January 17, 1958

Suzanne Patricia Barton, Dorek Burn, George Cooley,

Bernard Ellis, Vladimir Petrow

and Isobel Ann Stuart-Webb, London,

have been named as inventors

(Π)

by transferring it into an ether protects the 21st Carbon atom alkylated and then the 17 /? - position Hydroxyl group regenerated again.

Protection of the 17 / J hydroxyl group in Compounds of the above form] II is effected in the usual way by reacting with a vinyl ether, z. B. isopropyl vinyl ether or 2,3-dihydropyran, condensed. In practice, the hydropyran mentioned will be preferred because it is commercially available.

The condensation of the compounds of the formula II with 2,3-dihydropyran to give the tetrahydropyranyl ether of the following formula III

25th

an excess of 2,3-dihydropyran, preferably in an organic solvent such as chloroform or Tetrahydrofuran, and in the presence of a catalytic amount of an acidic reagent, such as hydrochloric acid or phosphorus

oxychloride. Purification of the resulting tetrahydropyranyl ether of formula III is generally not necessary. The raw material can be used directly for the next process stage can be used.

The 21-alkylation of the tetrahydropyranyl ether

Formula III takes place by converting the compound of this formula into a C ^ metal derivative. This is z. B. ' condensed with an alkyl halide or sulfate. A 21-alkylated tetrahydropyranyl ether is obtained Formula IV below

λ

O -

(III)

takes place by mixing the compound of formula II with O-I

To carry out the method according to the invention the compound of formula III is in a solution

909 609/433

medium, like ether, solved. Lithium amide is added to the solution, Sodium amide or potassium amide in liquid ammonia too. An alkyl halide, e.g. B. Ethyl bromide or iodide, added.

To regenerate the 17 /? - hydroxyl group you can use the 21-alkylated tetiahydropyranyl ether with an acidic reagent such as hydrochloric acid, toluene-p-sulfonic acid or oxalic acid, in a solvent such as ethanol, either at room temperature or below Treat reflux conditions, depending on the nature of the substituents in the 21-alkylated tetrahydropyranyl ether.

The method can be applied to a wide variety of 17 /? - Hydroxy-17a-pregn-20-yne (I). These may contain substituents and unsaturated bonds in the molecule. Such substituents can e.g. B. be: oxo, hydroxyl (in addition to the 17th hydroxyl group), phenolic hydroxyl and methyl groups.

Influence isolated, unsaturated bonds, e.g. in the 9 (ll) position generally not the method of the invention. Methyl groups, e.g. B. in 2-, 6- or 16-position, generally do not affect the process either. Hydroxyl groups, e.g. B. in the 5-, 6- or 11-position, as well phenolic hydroxyl groups are usually converted into the tetrahydropyranyl ether protected. This is followed by regeneration. So z. B. the 6 ^ -Methyi-17a-pregn-20-yn-3 | e, Sa, 17 ^ -triol der Formula V

OH

acid the desired 21-alkyl-17a-pregn-20-yn-3β, 5a, 17β-triol formula VII below

OH

HO -

CH C. H r HO CH ₃ = Alkyl) (R =

^l (VII)

Oxo groups are protected in the usual way, e.g. B. by ketal or enol ether formation. After that is regenerated. So z. B. 17 /? -Hydroxy-6a-methyl-17a-pregn-4-en-20-yn-3-and formula VIII below

OH

HO -

O = ¹

<■ C = CH

(VIII)

CH,

(V)

35

HO

into the ethylene ketal of formula IX below

OR '

CH,

in the tri-tetrahydropyranyl ether of the formula VI

OR '

40

45, -Ο

(IX)

(VI)

R'O-

in this formula VI, R '=

(R = R '= H)

convicted.

The said substance is made with 2,3-dilydropyran condensed. The ketal tetrahydropyranyl ether of the formula IX is obtained

55 R = H, R '=

convicted. This ether is then, e.g. B. by

Action of ethyl iodide on the lithium derivative, the latter compound is alkylated, and one obtains alkylated in the 21-position. This makes the 21-alkyl derivative the 21-alkyl derivative

obtained tetrahydropyranyl ether

/ / \ \ ⁶ 5 I formula IX; R = alkyl; R '=

Formula VI; where R = alkyl, R '=. \

ν '~ V /

By treating this compound with diluted oxalic acid, this ether gives the desired 21-alkyl- 70 acid in ethanol.

Formula X below

H ₉ C

O =!

OH

(X)

CH ₃

(R = alkyl)

Pharmaceutical preparations of the end product, namely the substance of the formula I or of 6a, 21-dimethyl-17 /? - hydroxy-17a-pregn-4-en-20-yn-3-one and of 21 - ethyl -1 7 β - hydroxy -6 α - methyl -17 a - pregn-4-en-20-yn-3-ons, can be in the form of tablets, cachets, capsules, tablets for tongue absorption, liquids, and suppositories. The substances can be combined with solid or liquid carriers. The following examples illustrate the process according to the invention.

example 1

Preparation of 3ß, i7ß - dihydroxy - 21 - methyl-17a-pregn-5-en-20-yn of the following structural formula XI (R = CH ₃ )

OH

H _a C

(XI)

HO -

10 g of a solution of.,. ,, _ ____, _____ ^ _. _ _Γ _ _Ο _ 5-en-20-yn in 85 ml of tetrahydrofuran are mixed with 25 ml of 2,3-dihydropyran. 0.2 ml of phosphorus oxychloride are added. After 2 l / _t hours, the mixture is poured into ^{2 l of water.} The solid obtained is collected and crystallized from aqueous acetone containing traces of pyridine. The 3ß, 17 /? - bis - Tetrahydropyranyl ether des 1, 7β - dihydroxy-17ct-pregn-5-en-20-yns has a melting point of 173 to 174 ° C; [a] ² _D '= -120 ° (c = 0.61 in chloroform).

4.1 g of the product thus obtained in 165 ml of ether are added in \ ^r erlauf one hour, dropwise to a stirred solution of 0.2 g of ferric nitrate and 0.45 g of lithium 110 ml ammonia. A temperature between -35 and -40 ° C is maintained. After a further 2 _^1/2 hours of stirring, a solution is added of 11 ml of methyl iodide in 50 ml of dry ether over a period of 30 minutes. Stirring is then continued for a further 3 hours. Finally 5 g of ammonium chloride are added to the mixture and the ammonia is allowed to evaporate. The product isolated with ether is triturated with methanol. A material is obtained which has a melting point of 120 to 125 ° C. 400 mg of this material in 50 ml of ethanol are treated with 150 mg of toluene-p-sulfonic acid. The mixture is treated on the steam bath for 30 minutes. After concentrating and adding water, the 3 / ?, 17 /? - dihydroxy-21-methyl-17a-pregn-5-en-20-yn is obtained, which is purified from aqueous methanol. Plates from melting point 177 to 179 ° C; [α] * "= -124 ° (c - 1.0 in chloroform).

Example 2

5 g of a solution of 17/5-hydroxy-17a-pregn-4-en-20-yn-3-one in a mixture of 110 ml of benzene and 6 ml of ethylene glycol are distilled until the distillate is no longer cloudy. Thereupon 0.1 g of toluene-p-sulphonic acid is added admitted. The mixture is refluxed for 4 hours. The one that settles when it cools down. product is crystallized from aqueous pyridine. The obtained 3,3-ethylenedioxy-17 ^ -hydroxy-17a-pregn-5-cn-20-yn

ίο forms soft platelets with a melting point of 258 to 259 ° C; [α] «= -69 ° (c = 0.75 in pyridine).

3.8 g of the substance mentioned in 200 ml of tetrahydrofuran are treated with 10 ml of 2,3-dihydropyran. 0.08 ml of phosphorus oxychloride are added. After 2 ¹ J ₂ hours the mixture is poured into a dilute aqueous solution of sodium bicarbonate. The precipitated solid is purified from aqueous acetone which contains traces of pyridine. It is the 17 /? - tetrahydropyranyl ether of 3,3-ethylenedioxy-17 ^ -hydroxy-17a-

ao pregn-S-en-20-yns, melting point 170-174 ° C; [α] * = -92 ° (c = 0.77 in pyridine).

4 g of the compound obtained above in 100 ml of tetrahydrofuran are added dropwise over the course of one hour to a moving solution of 0.2 g of ferric nitrate and 1.55 g of lithium in 400 ml of liquid ammonia. The temperature is maintained between -35 and -40 ° C. After a further 2 _^1/4 hours of stirring, the solution 11 ml of methyl iodide in 50 ml of dry ether was added over 30 minutes. Stirring is continued for 2 _^3/4 hours. Finally, 5 g of ammonium chloride are added to the mixture and the ammonia is then allowed to evaporate. The product isolated with ether is triturated with ethanol. A crude product with a melting point of 145 ° to 146 ° C. is obtained after purification from aqueous acetone containing a little pyridine. The 17 /? - tetrahydropyranyl ether of SS-ethylenedioxy - ^ / miydroxy-21-methyl-17a-pregn-5-en-20-yns crystallizes in the form of needles; Melting point 148 to 149 ° C; [α]? = -84 ° (c = 0.99 in pyridine).

200 mg of the above substance in 20 ml of ethanol are treated with 10 ml of 2 ° / ₀ aqueous solution of oxalic acid. The mixture is refluxed for 45 minutes. Dilution with an equal volume of water (30 ml) gives a small amount of crystalline material which is removed by filtration. A further addition of water to the filtrate gives the 17 /? - hydroxy-21-methyl-17a-pregn-4-en-20-yn-3-one in the form of platelets with a melting point of 100 to 104 ° C.

After cleaning from acetone / hexane, 17 /? - Hydroxy-21 -methyl-17a-pregn-4-en-20-yn-3-one separates into Shape of prismic needles with a melting point of 151 to 152 ° C.

Example 3

(Formula XI, R = C ₂ H ₆ )

6 g of a solution of the 3 / ?, 17 / J-bis-tetrahydropyranyl ether des 3ß, ^ / J-dihydroxy-na-pregn-S-en - ^ - yns

(prepared according to Example 1) in 100 ml of dry ether are added dropwise over the course of one hour to a moving solution of 0.3 g of ferric nitrate and 1.1 g of lithium in 200 ml of liquid ammonia. The temperature is maintained between -35 and ⁰ -4o C. After a further 2 _^1/2 hours of stirring, a solution of

21 ml of ethyl iodide in 100 ml of dry ether were added over a period of 30 minutes. The stirring will continue Continued for 3 hours. Ammonium chloride is added to the mixture. The ammonia is allowed to evaporate.

The product isolated with ether is dissolved in 60 ml of ethanol and refluxed for 30 minutes with 0.6 g of toluene-p-sulfonic acid. It is isolated with ether and crystallized from acetone / Hxan. The S / S ^ ß-dihydroxy ^ l-ethyl-na-pregn-S-en ^ O-yn separates out in the form of fine needles with a melting point of 78 to 80 ° C; [a] ² _D ² = -107 ° (c = 0.4 in pyridine).

Example 4

The 17/9 tetrahydropyranyl ether of 3,3-ethylenedioxy'-17 /? - hydroxy-17a-pregn-5-en-20-yns, prepared according to Example 2, is ethylated according to a method similar to Example 2. The 17 / S-tetrahydropyranyl ether of 21-ethyl-3,3-ethylenedioxy-17/5-hydroxy-17a-pregn-5-en-20-yns, which is obtained from acetone containing traces of pyridine in the form of needles with a melting point 120 to 121 ⁰ C crystallizes; [α] * '= -105 ° (c = 1.01 in pyridine).

2 g of the aforementioned compound in 200 ml of ethanol are refluxed for 55 minutes with 100 ml of 2 ⁰ I ^ gBr aqueous oxalic acid. The product is isolated with ether. The benzene solution is filtered through an alumina column. The product obtained is 21-ethyl-17 / J-hydroxy-17a-prcgn-4-cn-20-yn-3-ori, which crystallizes from acetone / hexane in the form of plates with a melting point of 118 to 119 ° C.

Example 5

3β, 17 /? - Dihydroxy-21-n-propyl-17α-prcgn-5-en-20-yn

(Formula XI, R = n-propyl)

8 g of a solution of the 3 / J, 17 / J-bis-tetrahydropyranyl ether of S / l ^ / J-dihydroxy- ^ a-pregn-S-cn ^ O-yns (prepared according to the example!), Dissolved in 200 ml of dry ether , are added dropwise to an agitated solution of 0.2 g of ferric nitrate and 1.5 g of lithium in 300 ml of ammonia over the course of one hour. The temperature is maintained between -35 and ⁰ -4o C. After a further 2 _^1/4 hours of stirring, a solution of 13.5 ml of n-PropyJjodid in 100 ml of dry ether is added, namely in the course of 30 minutes. Stirring is continued for an additional 3 hours. Ammonium chloride is added to the mixture. The ammonia is allowed to evaporate. The product isolated in ether is dissolved in 80 ml of ethanol and refluxed with 0.8 g of toluene-p-sulfonic acid for 30 minutes. The product is isolated with ether and crystallized from ether / petroleum ether. It consists of 3 / ?, 17 / $ - dihydroxy-21-n-propyl-17a-pregn-5-en-20-yn. It separates out in the form of fine needles with a melting point of 70 to 71 ° C; \ 'a \ i> ~ -110 ° (c = 1.002 in chloroform).

Example 6

The 17 / i-tetrahydropyranyl ether of 3,3-ethylenedioxy-17 / I-hj'droxy-l 7 a-pregn-5-en-20-yns, prepared according to example 2, is n-propylated according to a methylation process according to example 1 similar procedure. The 17 / J-tetrahydropyranyl ether of 3,3-ethylenedioNy-17 / J-hydroxy-21-n-propyl-17a-pregn-5-en-20-yns is obtained. This crystallizes from acetone containing traces of pyridine in the form of needles with a melting point of 104 to 106 ° C .; [α] ² / = -134 ° (c = 1.07 in chloroform).

The protective groups present in the abovementioned compound are removed with aqueous ethanolic oxalic acid under conditions as described in Example 2. The 17/5-hydroxy-21-n-propyl-17a-pregn-4-en-20-yn-3-one is obtained, which crystallizes from acetone / hexane in dense prisms with a melting point of 86 to 87 ° C; [d% = + 8 ° (c = 0.72 in chloroform).

Example 7

21-n-Butyl-17/5-hydroxy-17a-pregn-4-en-20-3-n-3-one

The 17/3 tetrahydropyranyl obtained according to Example 2

äther des S.S-Äthylendioxy - ^ / J-hydroxy- ^ a-pregn-S-en-

20-yns becomes n-butyl-text. The crude product obtained is treated with hot, aqueous ethanolic oxalic acid.

21-n-Butyl-17/5-hydroxy-17a-pregn-4-cn-

20-yn-3-one. This product was crystallized from ether / light petroleum in the form of prisms having a melting point 80-81 ⁰ C; [α] *, '= + 2 ° (c = 1.0 in ethanol).

Example 8

21 -Methy.1-19-nor-l 7 ct-pregn-1,3,5 (1O) -trien-

20-yn-3.17 / S-diol

OH

HO-I

H ₃ C

= S CR

(XII)

2 g of 19-nor-17a-pregn-l, 3,5 (10) -trien-20-yn-3,17 / i-diol in 17 ml of dry tetrahydrofuran and 5 ml of 2,3-dihydropyran are mixed with 0.04 ml of phosphorus oxychloride treated. After 2 ¹ / _ä hours of standing at room temperature, the mixture is treated with an excess of very dilute aqueous sodium bicarbonate. The product is isolated with ether. It crystallizes from aqueous traces of acetone containing pyridine and consists of the 3.17 / S-bis-tetrahydropyranyl ether of 19-nor-17a-pregn-l, 3.5 (10) -trien-20-yn-3.17 / 5-diols. The product is in the form of needles with a melting point of 155 to 157 ° C.

Ig of the above compound in 30 ml dry ether, in the course of 30 minutes, a moving solution of 0.05 g ferric nitrate and 0.2 g Lithium added in 50 ml of liquid ammonia. The temperature is kept just below the boiling point.

The mixture is stirred for ^{2 1} _{2 hours.} 3 ml of methyl iodide in 10 ml of ether are added over a period of 30 minutes. Stirring is continued for an additional 3 hours. Finally ammonium chloride is added. The ammonia is allowed to evaporate. The product, isolated with ether, is refluxed for 30 minutes with 100 mg of toluene-p-sulfonic acid in 12 ml of ethanol. Chromatography of the product gives 21-methyl-19-nor-17a-pregn-1,3,5 (10) -trien-20-yn-3,17 /? - diol. The product crystallizes (as a monohydrate) from aqueous methanol in the form of plates with a melting point of 110 ° C; [α] »= + 3 ° (c = 0.37 in chloroform).

Example 9

21-ethyl-19-nor-17a-prcgn-1,3,5 (10) -trien-20-yn-3,17 / 3-diol

(Formula XII; RC ₂ H ₅ )

The product mentioned is obtained by the process of Example 8 if the methyl iodide mentioned there is used for the alkylation of ethyl iodide. On crystallization from aqueous methanol, the compound separates out as a monohydrate in the form of prisms with a melting point of 80 ° C T> ; Mf / = -1 ° (c = 0.45 in chloroform).

9 10

Example 10 resinous mass in 200 ml of dry ether and 50 ml

21-n-propyl-19-nor-17 "-pregn-l, 3,5 (10) -triene-tetrahydrofuran is over * / ₄ hour

20-V11-3 17 # diol dropwise a suspension of litluumamide (from

3.6 g of lithium) in 600 ml of liquid ammonia, which (Formula XII, R = n-propyl) contains _{5 g Q6 Fcrrinitrat} added. After 2 _^1/2 hours

The above-mentioned compound is after stirring at -30 to -40 ° C, a solution of 30 ml

game 8 produced when ethyl iodide in 150 ml of dry ether in the course of a

added instead of the methyl iodide mentioned there every half hour. The mixture is then

Alkylation of n-Propyljodidcs served. From ether / further 3 hours at the same temperature.

Purified hexane, the compound crystallizes in the form of io Finally, 20 g of ammonium chloride are added,

of needles with a melting point of 107 to 108 ⁰ C; The ammonia is evaporated. Water and ether

[α] *, '= -5 ° (c = 0.33 in chloroform). are incorporated into the residue. The organic

Layer is separated, with dilute sulfuric acid,

Example 11 dilute aqueous potassium bicarbonate and water

21-n-butyl-19-nor-17a-pregn-1,3,5 (10) -tricn- * 5 washed. It is made over anhydrous sodium sulfate

20-yn-3.17 // - dried diol. The solvent is reduced under

VTT r> υ pressure removed. 16.6 g of the residue in 150 ml of Me-

(Formcl XIl, R = η-butyl) _{ethanol and 15 ηύ water are treated for} 1 hour with 15 g of oxaline

According to Example 8, the above-mentioned compound has been treated with acid at the reflux. The solution obtained is prepared by concentrating under reduced pressure in place of the 20 used there and using vcr-methyl iodide of n-butyl iodide with water. The compound is thinned and extracted with ether. The extract is washed with manure, crystallized from ether / hydrogen in the form of needles, water, over anhydrous sodium sulfate with a melting point of 98 ° C; [a]% = -3 ° (c = 0.32 dries and under reduced pressure to dryness in chloroform). evaporated. The crystallization of the resinous return Example 12 ⁸ 5 land from aqueous methanol gives 21-ethyl-6/3-me-

thyl-17a-pregn-20-yn-3 / i, 5a, 17 / i-triol in the form of needles 6 / ^ 21-dimethyl-17a-pregn-20-yn-3 / ?, 5oc, 17 / ii- tnol _a melting point of 168 to 170 or 110 to

A suspension of 1.2 g of 6 /? - methyl-17a-pregn-20-yn-112'C (dimorphic form); [a] ^l _D ° = -66.2 ° (c = 0.72 in 3 / S, 5a, 17/3-triol in 100 ml of dry ether and 2 ml of chloroform).
2,3-Dihydropyran are treated with five drops of phosphorus-30
oxychloride treated. After 1 hour, the homogeneous example 14

Solution washed with dilute, aqueous sodium bicarbonate 21-n-propyl-6 _/ 3-methyl-17a-pregn-20-yn-3j3,5a, 17i3-triol and then with water. It is dried.

The solvent is removed under reduced pressure. The 3 / 3.5 α, 17 / S-tri- (tetrahydropyranyl) ether is removed. The residue in the form of 2.15 g of a resinous 35 6 /? - methyl-17a-pregn-20-yn-3 / 5.5a, 17 / i (-triols (10 g) becomes like, clear substance without Further purification for prepared according to Example 13. A solution of the raw material used in the next process step. Product in 150 ml of dry ether and 50 ml of tetra-10 g of this substance in 150 ml of dry liydrofuran is added in the course of half an hour to an ether in the course of * / ₄ hours was added dropwise to a suspension of lithium amide (prepared from 3.6 g of lithium) in a solution of 0.4 g of ferric nitrate and 2.4 g of lithium 40 in 600 ml of liquid ammonia, which was added to 0.6 g in liquid ammonia. the temperature is contains ferric nitrate. the mixture is kept for another 2 hours between -30 and -40 ° C. After further stirred at -30 to · ■ 40 ° C. a solution of 30 ml of 2 _^1/2 hours of stirring, a solution of 21 ml of methyl n-propyl iodide in 150 ml of dry ether becomes verjodid in 100 ml of dry ether in the course of 30 Mixture added for half an hour and the mixture added. Stirring is continued for a further 3 hours 45 is continued at the same temperature for a further 3 hours. Then 20 g of ammonium are added to the mixture. The crude product isolated with ether is added to 150 ml of chloride, and. the ammonia is allowed to evaporate. Methanol and 15 ml of water, which evaporate 15 g of oxalic acid. The product is isolated with ether and, as hold, refluxed for 1 hour. The concentration of resinous substance gained. 9.2 g of the product are refluxed in the solution under reduced pressure and the subsequent 1 hour with 10 g of oxalic acid dihydrate in 100 ml of 50 dilution with water give a resinous product, methanol and 10 ml of water. That which is given in ether. The ether solution is washed with crystalline product is obtained by concentrating the water solution, obtained over anhydrous sodium sulfate under reduced pressure. It is dried from aqueous and evaporated under reduced pressure, like ethanol and consists of 6 / 3,21-dimethyl- The product crystallized from aqueous methanol is 17a-prcgn-20-yn-3 / 3,5a, 17 / $ -triol. It is in the form of 55 21-n-propyl-6 / S-methyl-17 «-pregn-20-yn-3 / ?, 5a, 17i9-triolin needles with a melting point of 219 to 221 ° C. in the form of needles a melting point of 177 to set before; [α] * '= -63 "(c = 0.88 in chloroform). 179 ° C.

The dimorphic form has a limestone point of

Example 13 92 to 94 ° C; [a) ^! _D ³ = -46.9 " (c = 0.82 in chloroform).

21-ethyl-6 /? - methyl-17a-pregn-20-yn-3 / S, 5a, 17 /? - triol ⁶ ° _{Example 15}

To 10g of a suspension of 6 /? - methyl-17a-pregn- <■ 01 iv _1Ί _ ι , - , - on ια, ια τ ,

in iac ! Ta ,. · 1 · rcn ι-. ι / xi_nt 6,21-dimethyl-17a-pregn-5-en-20-yn-3 / 3.17 / J-diol

20-yn-3p, 5a, 17p-triolm550ml dry ether, which ^J * ° ^J ''

Contains 16 ml of 2,3-dihydropyran, 0.5 ml of phos-acetylene is allowed to purify phosphorus oxychloride given. After standing for 3 hours at 65 acetone / carbon dioxide separator and two concentrated The homogeneous solution with washing bottles containing sulfuric acid will pass through at room temperature. Soda thin cm, aqueous potassium bicarbonate and water. Then the acetylene is passed through a bottle with stirrer washing, then over anhydrous sodium sulphate and a mercury seal, which dry 100 ml dries. It will contain ether at reduced pressure to dryness, flow through it for 30 minutes. 2 g one evaporated. The residue (17 g) in the form of a clear, 7 ° solution of potassium in 30 ml of tert-amyl alcohol (ge

Claims (2)

dries by standing over calcium sulfate and distillation over potassium) and 2 g of 6-methyldehydroepiandrosterone acetate in 100 ml of dry ether and 10 ml of dry benzene are added dropwise over 30 minutes. Stirring is continued for 5 hours. Acetylene is blown through continuously. The reaction mixture is acidified with a few drops of saturated ammonium chloride solution containing hydrochloric acid, and the product is isolated with ether. 6-Methyl-17a-pregn-5-en-20-yn-3 / ?, 17ß-diol is obtained in the form of a solid substance with a melting point of 190 to 194 ° C. Purification from a small amount of methanol gives platelets with a melting point of 203-2070C. Said diol in 10 ml of tetrahydrofuran and 3 ml of 2,3-dihydropyran is treated with 0.02 ml of phosphorus oxychloride. After standing overnight at room temperature, the mixture is poured into 300 ml of water containing a small amount of sodium bicarbonate. The oil thus obtained is isolated with ether and recrystallized from acetone containing a trace of pyridine. The bis-tetrahydropyranyl ether of 6-MethyH7 "-pregn-5-en-20-yn-3 / J, 17/3-diol is obtained in the form of fine needles with a melting point of 178 to 180 ° C; [α] Γ = -122.2 ° (c = 0.450 in chloroform). 700 mg of said bis-tetrahydropyranyl ether in 40 ml of dry ether are added to a stirred suspension of lithium amide (made from 400 mg of lithium) in 75 ml of liquid ammonia at -35 to -40.degree. The liquid ammonia contains 50 mg of ferric nitrate. After 21 hours of stirring, 2.5 ml of methyl] odide in 15 ml of ether are added over the course of 25 minutes. Stirring is continued for 3 hours. An excess of lithium amide is decomposed with ammonium chloride. The ammonia is allowed to evaporate overnight. The product is isolated with ether. Crystallization from aqueous acetone containing a trace of pyridine gives the hydrate of bis-tetrahydropyranyl ether of 6,21-dimethyl-17a-pregn-5-en-20-yn-3 / ?, 17-diol in the form of needles with a melting point of 160 to 161 ° C; [α] »• = -117.0 ° (c = 0.282 in chloroform). The aforementioned bis-tetrahydropyranyl ether of 6,21-dimeth} 'l-17a-pregn-5-cn-20-yn-3 / S, 17/3-diol is dissolved in ml of ethanol and then boiled for 1 hour with 1, Treated 4 g of oxalic acid dihydrate in 50 ml of water. Dilution to cloudy and long standing results in 6,21-dimethyl-17α-pregn-5-en-20-yn-3 / J, l 7j? -Diol in the form of needles with a melting point of 164 or to form). 1120C; [α] «= -102.6 ° (c = 0.604 in CMoro- PATIiNTANSPRl) CHE: 1. Process for the preparation of 21-alkyl derivatives des 17 /? - Hydroxy-17a-pregn-20-yns the general Formula -I; OH C = CR in which R denotes an alkyl group with 1 to 8 carbon atoms and R ₁ denotes CH ₃ or H, from a corresponding 17 / S-hydroxy-17a-pregn-20-yn, characterized in that the hydroxyl group in the 17JÖ position is used as the starting compound 17 /? - Hydroxy-17a-pregn-20-yns in a known manner by conversion into an ether, the hydrogen atom located on Kolüenstoffatom 21 is replaced in a known manner by a corresponding alkyl radical and the 17/9 hydroxyl group is regenerated in a known manner. 2. The method according to claim 1, characterized in that the 17/9 hydroxyl group by condensation with a vinyl ether, in particular with 2,3-dihydropyran, protects. 909 609/435 1.59