DE1300943B - Process for the preparation of 3-deoxygonane compounds - Google Patents

Description

This invention relates to methods of making gonans which do not have an oxygen substituent in the 3 position.

The process according to the invention consists in the preparation of 3-deoxygonane compounds general formula (I)

Some particularly valuable products of the invention Procedures are the following:

13jS-ethylgone-4-en-17-one,
13 | 8-Αίην ^ οη-4-εη-17 | 8-ο1,

13/9-n-Propylgon-4-en-17-one,
17/5-n-Propylgon-4-en-17) 3-ol,
Da-ethynyl-IS / Sn-propylgon- ^ en-n / S-ol,

wherein R ^{1 is} an n-alkyl group of 2 to 4 carbon atoms, Y keto oxygen, ketalized keto oxygen, (H, / S-OH), («-alkyl, alkenyl or alkynyl, / 3-OH), (H, / 3-O -Acyl) or («-alkyl, alkenyl or alkynyl, / 9-O-acyl) and Q is a methylene or ethylene group, the substituents on the tertiary carbon atoms in the C ring are in the transantitrans configuration and ring A is either is saturated or contains an ethylenic bond in the 4 (5) position, a gon-4-ene compound of the general formula being used in the process in a manner known per se

αϊ)

where R ¹ , Y, Q and the configuration of the C ring have the above meaning and X keto oxygen, thioketalized keto oxygen, (H, OH), (H, O-acyl), (H, alkoxy), (H, Cl) or (H, Br) is hydrogenolyzed and, if necessary, hydrogenated to saturate the 4 (5) double bond, a 17 / J-hydroxy compound obtained is oxidized to a 17-ketone and / or a 17-ketone obtained is converted into a 17a -Alkyl, alkenyl or alkynyl-17 / S-hydroxy compound transferred.

R ¹ is preferably an ethyl or n-propyl group. Where Y is («-alkyl, alkenyl or alkynyl, / 5-OH), the alkyl group preferably contains fewer than 5 carbon atoms and can, for example, be methyl, ethyl, ethynyl, vinyl, n-propyl, propynyl or Be allyl group. Where Y is ketalized keto oxygen, it is preferably an alkylenedioxymethylene group, especially an ethylenedioxymethylene group. Where Y is (H, jS-O-acyl), the acyl portion is preferably a higher acyl group which has at least 6 carbon atoms. Particularly suitable groups are n-decanoyl, n-undecenoyl, / S-cyclopentylpropionyl and / S-phenylpropionyl groups.

_1S lS / S-ethyl-nÄ-vinylgonan-n / S-ol.

In the process of the invention, the hydrogenolysis agent used is of the nature of Group X depend. Where X is keto oxygen, ao is a mixture of lithium aluminum hydride and Aluminum chloride is a suitable reagent that converts the gon-4-en-3-one to the gon-4-en. Where X is thioketalized keto oxygen, especially an alkylenedithio group, such as an ethylenedithio- »5 group, the reductive cleavage is more suitable Way, using a deactivated Raney nickel or an alkali metal or alkaline earth metal carried out in liquid ammonia. Where X (H, OH), (H, O-acyl), (e.g. acetoxy), (H, alkoxy), (e.g. methoxy), (H, Cl) or (H, Br) can be an alkali metal or alkaline earth metal in liquid ammonia or in an aliphatic, primary amine. Suitable aliphatic amines are ethylamine, n-propylamine, n-butylamine and other lower primary Alkylamines. The use of lithium metal with such amines is particularly effective. Where X is (H, OH), hydrogenolysis can also be caused by the action of lithium aluminum hydride in Presence of aluminum chloride can be effected, and lithium aluminum anhydride can lead to cleavage a compound where X is (H, Cl) or (H, Br).

When performing an inventive method

As a rule, the starting material is preferably mixed with the hydrogenolysis agent in a solvent brought in contact. Liquid ammonia or an amine itself can be used as a suitable solvent act where this is part of the hydrogenolysis

So means is used, and such solvents,

such as ether, dioxane or tetrahydrofuran can also be used.

For example, the gon-4-en-17 /? -Ol-3-on starting compounds from the corresponding 3-A1-koxygonan-1,3,5, (10) -trienes or 1,3,5, (10) 8, - or 9 (II) -tetraenen by Birch reduction to the Gona-2,5 (10) -dienes, which under strongly acidic conditions can be hydrolyzed to the desired gon-4-en-3-ones. The 17 «-alkyl, -Alkenyl- or -alkynyl-gon ^ -en-nß-ol-S-one starting compounds can by hydrolysis of the corresponding 3-alkoxy-gona-2,5 (10) -dienes under strong acidic conditions. Corresponding compounds in which X (H, OH), (H, O-acyl) or (H, alkoxy) can be obtained by reducing the 3-ketones with sodium borohydride, lithium aluminum hydride or a Meerwein-Ponndorf reagent, subsequently, where necessary, by esterification or

3 4

Etherification can be obtained. Starting materials, steroid hormone properties or as intermediate

where X is a thioketalized keto oxygen, materials for the conversion into such therapeutic

from the 3-ketones by a suitable thioketalipeutic agent. So is (±) -13 / i, 17 «-diethyl-

sierungsverfahren, for example by ketlasing gon-4-en-17/3-ol an anabolic agent, which a

with a thiol or dithiol in the presence of 5 higher effectiveness and a more favorable separation

Zinc chloride or boron trifluoride etherate is obtained and has anabolic and androgenic properties

the. Starting materials where X is (H, Cl) or (H, Br) as the corresponding 13/3 methyl compound and

the commercially available anabolic agent can be obtained from the corresponding 3-hydroxy compounds

bonds by treatment with thionyl chloride, (+) - 17a-ethyl-oestr-4-en-17j5-ol, and which also

Thionyl bromide or phosphorus oxychloride obtained io has strong progestational effects. (±) -13 / 3-

will. Ethyl-17 «-äthinylgon-4-en-17/3-ol is an effective one

Where in the starting material Y is keto oxygen, progestin and anti-estrogen, which do not

is, in some cases the reductive cleavage will tend to have estrogenic properties, and (±) -17 «-Allyl-

accompanied by the reduction of Y to (H, /? - OH) 13 / J-ethylgon-4-en-17/3-ol is also an effective one

be. Similarly, where Y is in the off »5 progestin.

Starting material (H, / 3-O-acyl) or («-alkyl, alkenyl The invention is illustrated by the following by or alkynyl, /? - O-acyl) is, the deacylation in games, in which the temperatures take place in some cases , and other "Celsius" values can be specified.
Changes in group Y during hydrogenolysis of group X under special conditions

be effected. If the group Y in example
a reduction product is not the desired one,

It can generally be carried out by one or more To prepare the starting material was to

subsequent reduction stages, namely oxidation (±) -18-homo-19-nortestosterone (0.47 g) in methanol

(for example with chromic acid), or alkylation 35 (5 ecm) and ethanedithiol (0.25 ecm) boron trifluoride

to introduce the alkyl, alkenyl or alkynyl etherate (0.25 ecm) added and the mixture

proportionately (for example by reacting with a 15 minutes at room temperature,

Grignard reagent such as ethyl or allyl magnesium then cooled to 0 °, filtered, the residue with

bromide or with an alkali metal acetylide) washed in methanol and dried. It happened

be guided. 30 (±) -13/5 - ethyl - 3,3 - ethylenedithiogone - 4 - en-17 / S-ol

Accordingly, in the compound according to the invention (0.39 g), melting point 167 to 169 °.

drive a gonan of structure (I), as above - this dithio compound (0.39 g) in ether (5 ecm)

where Y is a keto oxygen, or and tetrahydrofuran (2 ecm) was added with stirring

(«-Alkyl, alkenyl, or alkynyl, β · ΟΉ) is added by liquid ammonia (50 ecm), after which

Oxidation or alkylation of the corresponding 35 the addition of sodium (0.5 g) was carried out in pieces.

Gonans, where Y (H, / 3-OH) or keto oxygen, ethanol was then added dropwise until

is made. the blue color was gone; below

A Gonan of structure (I) above with one was added ammonium chloride and water,

saturated Α ring can be produced by a process and the mixture was extracted with ether. Of the

be placed, in which a corresponding residue from the washed, dried and

Gon-4-en is hydrogenated, for example by means of kata- evaporated extracts was made from light petroleum

Lytic hydrogenation to saturation of the 4,5-ethyl (boiling point 60 to 80 °) recrystallized and resulted

niche binding. In such a case, the (±) -13 / 3-ethylgon-4-en-17/3-ol (0.29 g); Melting point

Reduction also to the state of the unsaturated - 118 to 120 °.
of a Y group when the same («-alkenyl 45

or alkynyl, β-ΟΉ) , and it may be preferable Example 2
be the procedure by saturating the appropriate

Compound where Y is keto oxygen, and by Zu (±) -13 / 3-Äthylgon-4-en-17/3-ol (0.29 g) (prepared

subsequent alkylation of the saturated compound, as described in Example 1) in acetone (40 ecm)

as described above. 50 became 8N chromic acid dropwise with stirring

A process in which the group Y is added to the until the solution has become permanently orange,

desired after carrying out the invention. Then isopropyl alcohol (3 ecm) was added,

according to the hydrogenolysis process and a saturation the solution to a volume of about 5 ecm

supply of the required 4,5-ethylenic bond steams, water added and the product with

is converted is chemically equivalent to the 55 ether extracted. Evaporation of the washed and

direct preparation of the compound with the for-dried extracts gave a residue which

Similar group Y, recrystallized from methanol using the hydro- (±) «13/3-ethylgon-4-en-

genolyzing stage and saturation of the required 17-one (0.24 g), melting point 102.5 to 103.5 °,

borrowed 4,5-ethylenic bond and lies as such (found: 83.55% C, 10.7% H; the gross formula

within the scope of the invention. 60 C ₁₉ H ₂₈ O requires 83.8% C, 10.4% H.)

The compounds that can be prepared according to the invention
can be used as racemates of the 13/3 and 13 "enantiomers

can be obtained when the starting materials are totally syn- Example 3
were prepared thetically and no separation of the enantiomers was carried out beforehand. The 85 (±) -13 / 3-Äthylgon-4-en-17-one (2.1 g) (prepared by the method according to the invention as described in Example 2) was used with lithium compounds as therapeutic agents because of acetylid ( 4.5 g) in dimethylacetamide (60 ecm), by its anabolic, progestational or other which a slow acetylene flow for 60 hours

5 6

was passed, stirred. Water was added (4.5 g) (prepared as described in Example 5) and the product was separated off by means of ether and added from acetone (100 ecm) until the solution was recrystallized from methanol and became continuously orange by chromatography. Isopropylin benzene solution was then purified on neutral aluminum oxide (35 g), alcohol (10 ecm) and solid potassium carbonate (5 g) and again recrystallized from methanol; 5 was added and the mixture was filtered and the methanol solvate of (±) -13β-ethyl- evaporated. The product was chromatographed over neutral AIu-17 <x-äthinylgon-4-en-17 / i-ol (0.99 g), melting point, and through a Ge-107 to 108 °. (Found: 80.3% C, 10.1% H; the mixture of equal volumes of benzene and ether, gross formula C ₂₁ H ₃₀ O · CH ₃ OH, requires 79.95 ° / ₀ C. The eluate was eluted on a residue ver-10.4% H.) This methanolate (0.5 g) was evaporated from io, which was recrystallized from methanol, a mixture of ether and hexane recrystallized (±) -13 ^ -n-Propylgon-4-en-17- on (3.2 g), melting point, gave the unsolvated compound (0.25 g), 86-89 °. With further recrystallization from melting point 109 to 110 °. (Found: 84.4% C, a mixture of ether and hexane increased this 9.9% H; the gross formula C ₂₁ H ₃₀ O requires 84.5% to 89 to 90 °. (Found: 83.9% C, 10.5% H; C, 10.1% H.) 15 the gross formula C ₂₀ H ₃₀ O requires 83.9% C,

10.6% H.) Example. 4

Example 7

Magnesium (0.36 g) and allyl bromide (0.15 ecm)

in dry ether (10 ecm) was 15 minutes 20 (±) -13 /? - n-Propylgon-4-en-17-one (1.5 g) (refluxed, and (±) -13 / S -Ethylgon-4-en- as described in Example 6) in dimethylacetamid 17-one (0.9 g) (prepared as described in Example 2- (50 ecm) was a stirred suspension of ben) in a mixture of ether (40 ecm) and lithium acetylide (40 ecm of a 15% solution in allyl bromide (2.9 ecm) were then added. The refluxing of a mixture of dioxane and triethylamine was continued for 3 hours, a slow one Acetylene stream is then passed through the aqueous ammonium chloride and the cooled mixture and stirring is added for 40 hours in the case of solution. The product was continued using room temperature ether. The mixture was separated and recrystallized from methanol, and then poured into ice water and the product gave (±) - 17 "- allyl -13/3 - äthylgon -A- / S-ol ether separated en-17th The residue obtained after evaporation of the ether (0.97 g), melting point 88.5 to 91 °, crystallized after recrystallization recrystallization from a mixture of ether from methanol and gave (±) -17a-ethynyl and hexane improved to 92 to 94 °. (Found: lSjß-n-propylgon ^ -en-n / S-ol (0.95 g), melting point 84.4% C, 10.9% H; the gross formula C ₂₂ H ₃₄ O 88 to 98 °; after Recrystallization from methanol requires 84.0% C, 10.9% H.). and again from hexane 118 to 119 °. (Found:

35 84.8% C, 10.4% H; the gross formula C ₂₂ H ₃₂ O requires 84.55% C, 10.3% H.)

Example 5

For the preparation of the starting compound, see Example 8

(±) -13 / 3-n-Propylgon-4-en-17jS-ol-3-one (6.0 g) in vinegar- 40

acid (15 ecm) ethanedithiol (1.75 ecm) added, magnesium (0.36 g) and allyl bromide (0.15 ecm)

This was followed by the addition of boron trifluoride etherate, the mixture was refluxed for 15 minutes and (1.75 ecm). The mixture was poured into a mixture for 15 minutes at (±) -13 / 3-n-propylgon-4-en-3-one (0.90 g) (prepared at room temperature and poured into water as described in Example 6). The product was filtered off and recrystallized from dry ether (10 ecm) and allyl bromide methanol; (±) -3,3-Ethy- (2.9 ecm) was then added. The refluxing len-dithio-13 / In-propylgon-4-en-17 / S-ol (6.05 g), holding was continued for 3 hours and an aqueous melting point 165 to 166.5 °, which with further ammonium chloride then the added cooled solution to recrystallization from methanol at 167 to 168.5 °. The separation by means of ether and change. Crystallization from methanol gave (±) -17 «-Allyl-This dithio compound (5.8 g) in tetrahydro-13 / In-propylgon-4-en-17 /? -Ol (0.92 g), melting point furan (40 ecm) and ether (20 ecm) was at 88 to 90 °; after recrystallization from hexane 90 ° stirring of a solution of sodium (3 g) in liquid up to 92 °. (Found: 84.15% C, 11.1% H; the gross ammonia (250 ecm) added. Additional sodium formula C ₂₃ H ₃₆ O requires 84.1% C, 11.1% H.) (3 g ) was added in small portions for 30 minutes, 55
after which ethanol was added dropwise,

until the blue color was gone. Water example 9

was then added carefully and the product

separated by means of ether and from a mixture for the preparation of the starting compound was

recrystallized from ether and hexane. The result was 60 (±) -13 / 3.17 "-Diethylgon-4-en-17/9-ol-3-one (10.0 g) in (±) - 13/5 - η - Propylgon - 4 - en - 17/3 - oil (4.5 g), tetrahydrofuran (100 ecm) and ether (100 ecm) Melting point 115 to 119 °. while stirring a suspension of lithium-aluminum

Minium hydride (5.0 g) in ether (1000 ecm) was added.

The mixture was held for 2 hours under reflux example, "6 ⁶ 5, cooled and the excess hydride

decomposed by careful addition of water. the

8N chromic acid was added dropwise with stirring. The ether phase was separated off and the aqueous phase a solution of (±) -13 / S-n-Propylgon-4-en-17 /? - ol extracted with ether and the combined ether

solutions washed, dried and evaporated. They gave the residue (±) -13 / 3,17a-diethylgon-4-ene-3,17 / 3-diol (10.0 g), melting point 110 to 122 °. This diol (3.0 g) was dissolved in pyridine (30 ecm) and Acetic anhydride (3 ecm) dissolved and the mixture left to stand overnight at 0 °. The mixture was then evaporated under reduced pressure while maintaining the temperature below 50 ° and the residue is recrystallized from a mixture of ether and hexane; (±) -3-Acetoxy-13jö, 17 «-diäthylgon-4-en-17/3-ol resulted (2.43 g), melting point 85-100 °.

This acetoxy compound (1.35 g) in ether (50 cm) was added to a stirred solution of lithium (0.5 g) in redistilled ethylamine (10 cm); the mixture was stirred for 15 minutes and the excess lithium was decomposed with sodium nitrite. The ethylamine was evaporated and anhydrous sodium sulfate (10 g) and ether (200 ecm) were added. Evaporation of the filtered ether solution and Aus ao crystallization of the residue from a mixture of ether and hexane gave (±) -13j3.17 «-Diethylgon-4-en-17ß-ol (0.52 g); Melting point 96 to 112 °. A sample was dissolved in benzene and the solution chromatographed on neutral aluminum oxide, eluting with benzene containing a small amount of ether; subsequently the evaporated eluate was recrystallized from ether and gave the pure compound, melting point 117.5 to 118.5 °. (Found: 83.5% C, 11.3% H; the gross formula C _2x H ₃₄ O requires 84.3% C, 11.3% H.)

Example 10

(±) - 13j8 - ethyl - 17a - äthinylgon - 4 - en - 17/3 - oil (0.175 g) (prepared as described in example 3) in pyridine (2 ecm) and benzene (2 ecm) was in a hydrogen atmosphere with Lindlar catalyst (0.01 g, prepared according to the Lindlar process, HeIv. Chim. Acta, 1952, 35, 446) shaken until absorption was complete (31.4 ecm). The catalyst was filtered, the solvent evaporated and the residue (0.15 g) from methanol, which contained some ether, recrystallized and then at 60 ° and 0.005 mm. Hg dried for 3 hours; The result was (±) -13/3 - ethyl - 17 * - vinylgonane - Πβ - oil (0.15 g), melting point 101.5 to 103 °, whose infrared absorption maxima ^{at wavelengths of 3600, 3440 and 1635 cm -1} Indicates the presence of the vinyl group and the absence of 4,5 unsaturation.

Claims (2)

Patent claims: 1. Process for the preparation of 3-deoxygonane compounds of the general formula wherein R ^{1 is} an n-alkyl group of 2 to 4 carbon atoms, Y keto oxygen, ketalized keto oxygen (H, / 3-OH), (a-alkyl-, alkenyl or alkynyl,, 3-OH), (H, / 3-O -Acyl) or («-alkyl, alkenyl or alkynyl, j8-O-acyl) and Q is a methylene or ethylene group, the substituents on the tertiary carbon atoms in the C ring are in the trans-antitrans configuration and the ring A is is either saturated or contains an ethylenic bond in the 4 (5) position, characterized in that a gon-4-ene compound of the general formula is used in a manner known per se where R ¹ , Y, Q and the configuration of the C ring have the above meaning and X keto oxygen, thioketalized keto oxygen, (H, OH), (H, O-acyl), (H, alkoxy), (H, Cl) or (H, Br) denotes hydrogenolyzed and, if necessary, hydrogenated to saturate the 4 (5) double bond, a 17 /? - hydroxy compound obtained is oxidized to a 17-ketone and / or a 17-ketone obtained is converted into a 17 «-Alkyl, alkenyl or alkynyl-17 / S-hydroxy compound transferred. 2. The method according to claim 1, characterized in that a 13-Äthylgon-4-en as Starting material is used. 909533/317