DE2030056B - Process for the ethynylation of 17-keto steroids - Google Patents

Description

wherein R ₁ represents a lower alkyl radical, by ethynylation of 17-ketosteroids of the general ^'5 NEN partial formula II

(JD

in which R _{1 has} the same meaning as in partial formula I, with acetylene in the presence of alkali metal alcoholates of tertiary alcohols, characterized in that the ethynylation is carried out in the usual solvents which are free of tertiary alcohols.

35

The invention relates to a process for the preparation of 17a-ethynyl-17 /? - hydroxysteroids of the general Sub-formula I

OH

c C == CH

(D

UI)

40

45

where R _{1 is} a lower alkyl radical, by ethynylation of 17-ketosteroids of the general sub-formula II

O

55

in which R _{1 has} the same meaning as in partial formula I, with acetylene in the presence of alkali metal alcoholates, preferably potassium alcoholates, tertiary alcohols, characterized in that the ethynylation is carried out in the usual solvents, but with the exclusion of tertiary alcohols.

A lower alkyl radical (P.) is to be understood as meaning alkyl radicals with 1 to 6 carbon atoms. These alkyl radicals can be straight-chain or branched, saturated or unsaturated. Examples of substituents R ₁ which are particularly suitable for the process according to the invention are the methyl, ethyl and propylene radicals

Suitable starting compounds for the process according to the invention are 17-ketosteroids Estran and androstane series, which can be substituted in the usual way, for example by free, esterified or etherified hydroxyl groups in the 1-, 3-, 6- or 1-position, free or functionally modified oxo groups in the 3- or 11-position, methyl groups in the 1-, 2- or 6-position or methylene groups in the 1, 2-, 5,10- or 6,7-position. Further For example, the 17-ketosteroids can have an aromatic A or B ring or double bonds

! · ■ U ·. · T-, S-, - "-, Sf"), S (IO), Ο (ί>), β (ϊ - «>« J- 9 (11) position. The starting compounds can of course also contain several of the substituents and / or double bonds mentioned.

The ethynylation of 17-keto steroids with acetylene in the presence of alcoholates of tertiary alcohols and of tertiary alcohol is known (German patents 1 013 649, 016 707, German Ausiegeschrift 1 264 441 and R i η g ο 1 d et al., J. Amer. Chem. Soc., 78 1956, pp. 2477 to 2479). This is done using the 17-ketosteroid dissolved in a suitable solvent, with a solution of the alkali alcoholate in excess tertiary alcohol is added and acetylene is introduced into the reaction mixture. This ethynylation process but has the disadvantage that in the ethynylation of 17-ketosteroids, their 13-position angular Methyl group is alkyl-substituted, only low yields of the desired I7a-ethynyl-17 / miydroxysteroid (H. S m i t h et al., Chem. Soc. [London], 1964, pp. 4472 to 4492, in particular 4475). Therefore this process is only suitable for the synthesis of 17a-ethynyl-17 / * - hydroxysteroids, their 13-position angular methyl group is unsubstituted. Since this procedure is easy to perform, it is preferably used for the technical production of these steroids, although the reaction for Achieving good yields requires reaction times of more than 15 hours.

The invention was based on the object of creating an ethynylation process that does not work only for the production of na-ethynyl-n / mydroxysteroids with an unsubstituted 13-position methyl group, but just as well for the synthesis of 17u-ethyny [-17 / i-hydroxysteroids with an alkyl-substituted 13-position methyl group is suitable. The process to be created should not be technically more complex than the ethynylation method mentioned above, but it should be about the more universal applicability In addition, compared to this also have the advantage that the reaction also occurs in the Synthesis of compounds with an unsubstituted 13-position methyl group within a shorter reaction time can be carried out than in the known method.

This object was achieved according to the invention by the ethynylation of the 17-ketosteroids with Acetylene in the presence of alkali alcoholates of tertiary alcohols in the usual solvents, but below Exclusion of tertiary alcohols.

Suitable alkali alcoholates are the alcoholates of the tertiary alcohols, which are usually used in ethynylation reactions be used. Potassium alcoholates, for example potassium tert-butoxide, are particularly suitable and potassium tert-amylate.

Suitable solvents are those for these ethynyl

Method of application of common solvents. Suitable solvents are, for example, aromatic Hydrocarbons such as benzene, toluene or xylenes, ethers such as diethyl ether, glycol dimethyl ether, Dioxane or tetrahydrofuran or polar apr «- tonic solvents such as dimethylformamide, N-methylacetamide or dimethyl sulfoxide.

The process according to the invention is preferably carried out at a reaction temperature below 60.degree. C., reaction temperatures between +20 and -20.degree. C. are particularly preferred

The inventive method can both

ha normal pressure as well as under increased pressure, preferably DIS to J / \ imuspiiareii, uurtiigciunri wcrurn.

The reaction mixtures are worked up by the customary working methods, for example by concentrating the mixture in vacuo or by precipitating the reaction products with water or diluted mineral acids. Ketal groups present in the process product can occur during processing. Enol groups or enamine groups - optionally with additional isomerization of existing double bonds - are split off. The crude products obtained can be processed in a customary manner, for example by chromatography and / or crystallization.

The following table shows the superiority of the method according to the invention over that known ethynylation method jm the example of the ethynylation of 3-methoxy-18-methyl-2,5 (10) -estradien-17-one. These experiments were carried out by adding tertiary butanol to 5.5 g of potassium tertiary butoxide, diluting the mixture to 110 ml with tetrahydrofuran and cooling it to -10 ° C, Introduced acetylene for 1 hour, then admixed with 10 g of substance, introduced further acetylene and gradually The reaction mixture was analyzed at the end of the reaction time.

Percentage of sales

3-methoxy-18-methyl-2,5 (10) -estradien-17-one

with different tertiary butanol content in the

Reaction mixture

testosterone or noAthmyHS-inethyl-lS-nor-testosterone. In addition, the compounds which can be set up with the aid of the process according to the invention are valuable intermediates for the synthesis of pharmacological

gically effective pregnane derivatives, such as 17 »-hydroxyprogesterone capronate, ntt-hydroxy-IS-nor-progesterone-capronate, hydrocortisone or prednisolone, because it is possible to add the n * AthinyI side chain to the To convert progesterone side chain (J. N. G a r d-

ner et al. J. Org. Chent, 33, 1968, 3294). Suitable The starting compounds are therefore those 17-ketosteroids which are converted into n ^ ethynyl-17 / f-hydroxysteroids by using the ertmdungsgema-Ben process

IUIUCIl, UIc μΙιαΐϋΐα1ι. ^ Ιν, ₆ ^ ~ Ι »" ^ I—- -i— * ~ ^ ~ - ™ «· h-

, «: Term intermediates for the synthesis of pregnane derivatives. Preferred starting compounds for the process according to the invention are 17-ketosteroids of the general formula III

20th

(HD

where R _{1 is} a lower alkyl radical and A is the groupings

reaction time ml - tert-butanol UmI in hours 0 ml 31.0% 1 82.3% 37.8% 2 93.3% - 3 98.8% 48.2% 4th 49.3% 5 -

45 and

As this table shows, the conversion of 17-ketosteroids with an alkyl-substituted 13-methyl group performed both a considerable amount Accelerated reaction as well as a significant increase in yield if the reaction is carried out in Performs in the absence of tertiary alcohols. When 17-keto steroids are reacted with an unsubstituted 13-methyl group, the reaction rate is also more than five-fold increased if the ethynylation is carried out in the absence of tertiary alcohols.

With the aid of the process according to the invention, pharmacologically active 17a-ethynyl-17/3-hydroxysteroids can be produced, for example the t effective steroids: 17a-ethynyl-19-nor- R ₂ O

in which R _{2 represents} a hydrogen atom, a lower alkyl or lower acrylic radical, R _{3 represents} a hydrogen atom or a methyl group, X represents a lower alkoxy radical, a lower acyloxy radical or a morpholino, piperidino or pyrrolidmo group, and Y each represents a lower alkoxy group or both Y together denote a keto group or an alkylenedioxy group.

The following examples are intended to explain the process according to the invention.

example 1

In an on - 10 ⁰ C cooled mixture of 11 g potassium tert-butylate and 200 ml of tetrahydrofuran one hour acetylene is tqng stirring initiated

tet. Then sets one 20 g of racemic 3-methoxy-18-methyl-2 ^ (10-Ö3tradien- 17-one and passes under stirring at -. 10 ⁰ C for additional 3 hours acetylene one After completion of the reaction decomposing the mixture by Addition of 100 ml of methanol and 18% concentrated hydrochloric acid, the solvent is distilled off in vacuo at 45 to SS ^° C. and during the distillation it is replaced by 320 ml of water. washes it neutral with water, dries it in a vacuum and recrystallizes it from acetone .

17.6 g of H / i-hydroxy-IS-methyl-iyrt-ether are obtained

nyl-4-estrene-3-one (= 85% of theory) of melting point 207 to 209 ⁰ C.

Example 2

In a chilled to +15 ⁰ C mixture of 5.5 g of potassium tert-butoxide and 52.5 ml of tetrahydrofuran long passes with stirring for 1 hour, an acetylene. Then 10 g of 3-methoxy-2,5 (10-estradien-17-one) are added and acetylene is passed in for a further 90 minutes with stirring at + 15 ° C. After the reaction mixture has been worked up as described in Example 1 and recrystallized of the crude product from methylene chloride, 8.6 g of 17 / <- hydroxy-17a-ethinyl-4-estren-3-one (= 82.5% of theory) with a melting point of 206 to 207.5 ° C. are obtained.

[α]? = -24.1 ° (chloroform, c = 1%).

Example 3

10g3-methoxy-18-ethyl-2,5 (10) -estradien-17-one werdeii in a suspension of 5.3 g of potassium tertiary butoxide in 110 ml of tetrahydrofuran, into which acetylene was previously passed for 1 hour at -15 ° C , registered. Acetylene is passed in for a further 3 hours and the reaction mixture is worked up as described in Example 1. The crude product is recrystallized from cyclohexane diisopropyl ether and gives 8.35 g of β- hydroxy-18-ethyl-17α-ethinyl-4-estren-3-one (= 80.5% of theory) with a melting point of 182 to 184 ° C .

[«]? = - 26.3 ° (chloroform).

Example 4

10 g of 3-methoxy-18-methyl-1,3,5 (1O) -ostratrie.j-17-one are in a suspension of 5.5 g of potassium tert-butoxide in 100 ml of tetrahydrofuran, in which acetylene was previously passed in at -5 ° C. for 1 hour, entered. One passes more at -5 ° C Acetylene is used for 3 hours, then the reaction mixture is decomposed by adding 27 ml of 20% strength Sulfuric acid and 14 ml of water, the tetrahydrofuran is distilled off in vacuo and replaced with water. The precipitated substance is then extracted with methylene chloride and the methylene chloride phase is washed neutral and concentrates them to dryness. The residue is recrystallized from methylene chloride and gives 8.41 g of S-methoxy-IS-methyl-na-ethinyl, 3,5 (10) -estratriene-17y? -ol (= 77% of theory) from melting point 98 His 99 ° C.

["]" = -17.8 ° (chloroform).

Example 5

Under the conditions described in Example 4, 10 g of racemic 3-methoxy-18-ethyl-1,3,5 (10) -estatriene-17-one are ethinylated. After the reaction mixture has been worked up, as in Example 5, and the crude product has been recrystallized from ethyl acetate, 8.24 g of 3-methoxy-18-ethyl-l 7'-ethinyl-U, 5 (10) -östratrien- 17 /? - ol are obtained (= 76% of theory) from melting point 128 to 130 ° C.

Example 6

10 g of 3-methoxyl, 3,5 (10) -östratrien- 17-one are in a suspension of 6.0 g of potassium tertiary butoxide in 100 ml of tetrahydrofuran, in the previous 1 hour ίο long at -10 ⁰ C acetylene was initiated, entered. One passes into the mixture under tubes a further 2 hours of acetylene at -10 ° C, works

the reaction mixture, as in ocispicit ucsutu itotn, and the crude product recrystallizes from ethyl acetate. 9.68 g of methoxy-17 “-ethinyl-1,3,5 (10) -estratriene-17 / i-oil (= 89% of theory) with a melting point of 151 to 152.5 ° C. are obtained.
O]? = +4.5 (dioxane).

B e i s ρ i e 1 7

2: 0 g of 3-hydroxy -1,3.5 (10) -estratrien-17-one become in a suspension of 25.2 g of potassium tert-butoxide in 400 ml of tetrahydrofuran, in the previous 1 hour acetylene was introduced for a long time at + 15 ° C,

carry. Acetylene is passed into the mixture for a further 3 hours at +15 ° C. with stirring, the reaction mixture is worked up as described in Example 4, the crude product is recrystallized from acetone and 18.7 g of 17a-1,3-ethynyl are obtained 5 (10) - estatria- 3.17 / i-dio! (= 85% of theory) from melting point 182.5 to 183.5 C.
[α]? = + 2.6 ° (dioxane).

Example 8

5 g of 4-oestrene-3,17-dione are added to a suspension of 5.5 g of potassium tertiary butoxide in 55 ml of tetrahydrofuran, into which acetylene had previously been introduced for 1 hour at -10 ° C. One leads into the Mix for a further 2 hours with stirring

at -10 ^c C acetylene, the reaction mixture works as described in Example 4, the crude product crystallizes from methylene chloride u * n and receives 4.4 g of 17 / i - hydroxy - 17α - ethinyl - 4 - estrogen - 3 - on (= 80.4% of theory) from melting point 205 to 206 ⁰ C.

[a]? = -23.8 (chloroform).

Example 9

Analogously to the examples, 10 g of 18-methyl-4-oestrene-3,17-dione are ethinylated at -10 ° C. in the presence of 11 g of potassium tertiary butoxide ir 110 ml of tetrahydrofuran by passing in acetylene for two hours. After the reaction mixture has been worked up as described in Example 4 and the crude product has been recrystallized from methylene chloride, 8.28 g of 17 /? -Hydroxy-18-methyl-na-äthinyl-4-estren-? - one (= 76% of theory) are obtained ) from melting point 235 to 237 ⁰ C.
[α]? = -32.8 ° (chloroform).

Example 10

5 g of 3 /? - hydroxy-5-androstene-17-one are in a suspension of 2.75 g of potassium tert-butoxide in 50 ml of tetrahydrofuran, in the 1 hour long introduced with stirring at +15 ⁰ C above acetylene , registered. Acetylene is passed into the mixture for a further 2 hours at + 15 ° C., and the reaction mixture is worked up as described in Example 4.,

The crude product crystallizes from methylene chloride and receives 5.15 g of 17a-ethynyl-5-androstene-3 / f, 17 /? - diol (= 94% of theory) with a melting point of 234 to 238 ° C.
[α] »= _127 ° (dioxane). S.

Example 11

a) 17 / i - acetoxy -18 - methyl - 5 (10) - oestrene - 3 - one (m.p. 145 to 146 ° C) becomes 170-acetoxy-18-methyl-5 (10) - with Raney nickel Oestren-3 / <- ol (F. 100 to 101.5 ⁰ C) hydrogenated, which with methylene iodide in the presence of zinc-copper to 170-acetoxy-18-methyl5.10 / J-methylen-5 / i-estran-30-ol (mp. 127.5 to 128.5 ° C) is implemented. After oxidation with chromic acid to the corresponding 3-Keton (mp 140 to 141.5 "C) the 5,10 / J-methylene ring is cleaved under acidic conditions and 1 l-acetoxy-18-methyl-4-androsten-3 is obtained - on (mp 113 to 114 ° C.) To form the ketal, the 3-keto group is treated with ethylene glycol in the presence of p-toluenesulfonic acid with separation of water (F. 200.5 to 203 ⁰ C) is saponified with potassium carbonate in water and methanol to the 17 / i-hydroxy compound (M. 161.5 to 163 ° C), which with CrO ₃ / pyridine at room temperature to 3.3- Ethylenedioxy- »5 18-methyl-5-androsten-17-one (mp 194.5 ° to 198 ° C.) is oxidized. The 3,3-ethylenedioxy-18-methyl-5-androsten-17-one becomes ketal cleavage The 18-methyl-4-androstene-3,17-dione obtained in this way (temperature 141 to 142 ° C.) is isomerized with potassium tert-butoxide in tert-butanol at low temperatures and then with lithium aluminum - tri - tert - butoxyhydri d to 3ß - hydroxy -18 - methyl - 5 - androstene -17 - one (F. 166 to 168 ⁰ C) reduced.

b) 4g3 /? - Hydroxy-18-methyl-5-androsten-17-one are in a suspension of 2.15 g of potassium tertiary butoxide and 44 ml of tetrahydrofuran, in the previously Introduced acetylene for 1 hour with stirring at -15 ° C was added. The mixture is passed into the mixture for a further 2 hours with stirring

- 15 ^C C acetylene, the reaction mixture works up as described in Example 4, the crude product recrystallizes from methylene chloride and receives 3.9 g of 18-methyl-17a-ethinyl-5-androstene-3 / ?, 170-diol (= 90% of theory) from a melting point of 220 to 222 "C

Example 12

In a rolling autoclave containing 20 ml of Tetra hydrofuran and Ig Kalhtrn tertiary butoxide In each case nitrogen and acetylene are injected under 2 atmospheres overpressure.

After a stand, the autoclave is carburized

- 10 ⁰ C decompresses the autoclave, adds 500 mg of racetniscfaes 18-methyl-4-oestrene-3,17-dione to the mixture and then presses in nitrogen and acetylene again. After a reaction time of one hour, the mixture is prepared as described in Example 8, and 400 mg of 17 /? - hydroxy-18-methyl-17o-ethinyl-4-estren-3-one (= 70% of theory) melting point are obtained 208 to 211 ⁰ C.

Example 13

a) 6g of 18-methyl-4-androstene-3,17-dione are dissolved in 60 ml of methanol, the solution with 3.5 ml Added pyrrolidine and left to stand at room temperature. The precipitated 3-pyrrolidino-1K-methyl-3,5-androstadien-17-one is filtered off with suction, washed and dried in vacuo (yield 6.3 g).

bSSlidiihlSd

17-one is an on - 10 ⁰ C cooled suspension of 6.6 g of potassium tert-butylate in 120 ml of tetrahydrofuran - 1 hour in the above "* long acetylene was initiated - is added. Acetylene is passed into the reaction mixture at -10 ° C. for a further 3 hours.

The reaction mixture is poured into water, the tetrahydrofuran is stripped off in vacuo and the aqueous phase is extracted with methylene chloride. Concentration of the methylene chloride phase and recrystallization of the crude product from acetone, 3.8 g of n / j-hydroxy-lS-methyl-na-äthinyM-androsten-3-one of melting point 233-236 ⁰ C.

[α]? = + 13.8 ° (chloroform).

Example 14

10 g of 3-methoxy-2,5 (10) -estradien-17-one are, as described in Example 2, ethinylated for 90 minutes at 15 ° C. The reaction mixture is then mixed with water, the tetrahydrofuran is distilled off in vacuo and the precipitated crude product is filtered off. The crude product is recrystallized from methanol-methylene chloride with the addition of pyridine, and 8.72 g of 3-methoxy-12a-ethinyl-2,5 (10) -estradiene-170 oil (= 80% of theory) with a melting point of 192 are obtained up to 194 ° C.

[α]? = + 65.2 ° (chloroform).

Example 15

Acetylene is passed under tubes for 1 stand into a ^{suspension, cooled to 10 °} C., of 5.5 g of potassium tertiary butoxide and 60 ml of tetrahydrofuran. 10 g of 33> 5 (10> ö3tren-17-one zn are then added and acetylene is passed in for a further period at 10 ° C. The reaction mixture is then prepared as described in Example 1 and the crude product obtained is recrystallized from methylene chloride obtained 7.71 g 17 /> - hydroxy-I7a-äthi · Nym dstren-3-one (= 82% of theory) of melting point 206-207 ⁰ C.

fa] 7-23.5 "(chloroform),

Claims (1)

Claim: Process for the preparation of 17a-ethynyl 170-hydroxysteroids of the general sub-formula I OH R | / \ r C 3 = CH (D 10