The method of obtaining catala steroid derivative, and methods of making compounds

 

(57) Abstract:

The invention relates to a method for producing intermediate products in the synthesis of steroids with progestogenic activity, namely: Catala steroid derivative of the General formula I

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where R1is CH3or C2C5; R2is HE; R3is N, CH3or CH2CN, or R2and R3together are O; R4is (2-5C) alkylene consists in the fact that the compound of formula II

< / BR>
where R1and R2and R3have the previously given meanings, is treated in the presence of artefiera formula III

< / BR>
where R4is (2-5C) alkylene, or orthoevra formula IV

< / BR>
where R4has previously specified value, or a mixture of the alcohol corresponding to the General formula HOR4OH, where R4has the previously given significance. The method allows to obtain products with a minimum of impurities. 3 S. and 3 C.p. f-crystals.

The invention relates to a method for producing cyclic ketals steroid derivative.

A method of obtaining ketals steroid derivative (patent DD-296931 Germany). In accordance with this method is derived ganadian obtain methyl, ethyl-, propylketone derivatives of 3-keto-5(10), 9 (11) - Canadiana. However, cyclic ketals steroid derived in this way is not received. The above method is an improvement over previously known way, as dialkylamines used by way of, for example, the reaction of the derived 3-Cetagandan with alcohol in the presence of acid leads to the product, which is used in the environment is unstable and which was partially destroyed in the allocation or drying. To get keto in a stable form, it is necessary, first, to neutralize the alkali, which has the disadvantage that the next stage it is necessary again to remove the lye.

There is a need for a good method of obtaining ketals and, in particular, cyclic ketals of certain steroid derivatives as intermediates in the synthesis of steroids, having a progestogenic activity, in particular for use in contraception and hormonal maintenance therapy for women in peri - and postmenopausal women. However, it was found that this method, as described in 00-296931, not suitable for affordable get ketals.

The outputs obtained is between 50 and 65%, in exceptional cases, up to about 75%. Moreover, in this case formed of a significant amount (50%) unwanted 3,17-diketal.

There is a need for a method of producing ketals, in particular, cyclic ketals of derivatives of 3-keto-5(10), 9(11)-steroiden, which can be characterized and which gives a high yield of stable ketals and does not lead to the formation of digitala if 3,17-dietotherapy derivatives.

The method according to the present invention obtain Catala steroid derivative corresponding to General formula I:

< / BR>
where R1is CH3or C2H5;

R2is IT;

R3is H, CH3or CH2CN; or

R2and R3together are O;

R4is (2-5C) alkylene;

namely, the compound of formula II:

< / BR>
where R1, R2and R3have the previously given meanings, is treated in the presence of artefiera formula III:

< / BR>
where R4is (2-5C) alkylene, or orthoevra formula IV:

< / BR>
where R4has previously specified value,

or mixtures thereof

alcohol corresponding to the General formula HOR4OH, where R4the ima is4is 1.2-etandiola, 1,3-propandiol or 2,2-dimethyl-1,3-propandiol.

The alcohol corresponding to the General formula HOR4OH, can also be obtained in situ, on the basis of the initial substance, which gives free alcohol under the reaction conditions. Acetalization in General carried out in a conventional acidic conditions.

The method may specifically be used to obtain Catala formula I, where R1is CH3, R2and R3both are O and R4is-CH2-CH2-.

This product is extremely suitable as an intermediate product in obtaining progestogenic dienoguesta.

The term (2-5C) alkylene means alkylenes group containing from 2 to 5 carbon atoms, such as ethylene, propylene, 2,2-dimethylpropylene and the like.

The term Hal means halogen, such as chlorine, bromine, or iodine. Chlorine is preferred.

Areavery add a sink of water. Suitable areafile are 2,21-[1,2-ethandiyl-bis(oxy)] bis-1,3-dioxolane, 2,21-[1,3-propandiol(oxy)] bis-1,3-dioxane and 2.21-[2,2-dimethyl-1,3 - propanediyl)bis(oxy)] bis-5,5-dimethyl)-1,3-dioxane or a mixture thereof. These areavery easily poluchatel or triethylorthoformate, with diatomic alcohol, such as ethylene glycol. The use of the above orthoepical leads to the fact that the reaction proceeds at a constant rate, leading to fewer polluting products.

Further, the invention relates to a method for obtaining compounds of formula I, where R1, R2, R3and R4have the above values, characterized in that:

a) compound of General formula V:

< / BR>
where R1, R2and R3have the previously given meanings, condensed with the compound of the formula CH-C(OR4O)-(CH2)3-XHal, where R4and Hal have the previously given meaning, and X is a metal atom, in particular, magnesium;

b) a hydroxy-group of the resulting product is oxidized in the usual way;

in) cyclist under alkaline conditions;

d) ketal otscheplaut in acidic conditions;

d) then, in alkaline conditions cyclist with obtaining the compounds of formula II, where R1, R2and R3have the above values,

e) after which the resulting product is treated in accordance with the above method of icecapital.

The advantage of this method is that use inexpensive raw products and that ctitle in the case of obtaining the appropriate intermediates for obtaining dienoguesta. In this case, proceed from compounds of General formula IV, where R1is CH3but as R2and R3is O.

Conventional methods of oxidation of the hydroxy-group are the methods described in the references, which are clear and professional. Examples of suitable methods of oxidation is the treatment of the chromium oxide/pyridine, chloride/pyridine, dichromate calcium, pyridiniomethyl and N-bromosuccinimide and the oxidation Oppenauer.

Circuit cycle from stage d) reaction under alkaline conditions, and conditions may be achieved using any reagent. Particularly suitable is the treatment of tert-butyl potassium.

Further, the invention relates to a method for obtaining compounds of formula II, where R1is CH3, R2is OH and R3is CH2CN, which consists in the fact that the 17-ketogroup katalevich steroid derivatives of formula I is transformed into a 17 - spirooxazines group, then oxiana group is revealed by treatment with cyanide, then Cataluna group of the obtained reaction product is cleaved under acidic conditions.

The conversion of 17-spirometry can be carried out in the usual way from gaining Livonia and tert-butyl potassium. As the base can also be used sodium hydride, lithium amide or sodium methoxide, in solvents such as dimethylformamide, tetrahydrofuran and dimethylsulfoxide.

Disclosure oxiranes ring is performed with the use of cyanide. Preferably as cyanide use cyanide of potassium or sodium.

Cleavage of ketala can be carried out in the usual way using acids in suitable solvents. Examples are hydrochloric acid, sulfuric acid and the like in alcohols, ketones (e.g. acetone), ethyl acetate, and the like, possibly mixed with water.

In conclusion, the invention relates to the synthesis of compounds of formula II, where R1is CH3, R2is OH and R3is CH2CN, characterized in that, on the basis of the compounds of formula V, by use of the method described above, through acetalization the compounds of formula II to the compound of formula I, which is converted in accordance with the above method, the compound of formula II, where R1is CH3, R2is OH and R3is CH2CN.

The invention is illustrated further by the following examples.

Example 1< 1.2 Dibromethane (3.2 g) is added to a mixture of 19.6 g of magnesium shavings and 105 ml of dry ethyl ether at 22oC. After the start of the reaction, the temperature rises to approximately 32oC and results in the release of gas. The mixture is stirred for a further 30 minutes the Mixture of 17.5 g of 5-chloro-2-partenariats and 3.2 g of 1,2 - dibromethane added to the reaction mixture for about 30 minutes with slow stirring. The temperature is brought to a boil (approximately 36oC). The mixture is stirred for a further 15 minutes the Mixture 132,7 g of 5-chloro-2-pentanone - pentalateral and 105 ml of tetrahydrofuran is added in the reaction mixture for about 2 hours so that the reaction mixture continues to boil. The reaction mixture was stirred without heating up until the temperature drops again. 400 ml of tetrahydrofuran is added in the reaction mixture for about 1 hour, a Mixture of Grignard heated for another 3 h to a boil and cooled to 20oC. the Excess magnesium is removed and define both molarity of a solution of the Grignard reagent.

750 ml of a 0.8 M solution of chloride of 2-pentagonmaterial-5-magnesium in tetrahydrofuran is added to the suspension to a 126.7 g of the lactone (+)-5-hydroxy-7a-methyl-2,3,3 and,4,5,6,7,7 and octahydro-1H-inden - 1-one-4 -(3-propionic acid) (USP 4784953 included as a reference) at -30oC for about 2 hours Paramashiva 0oC for 1 h To this mixture is added 550 ml of water. The tetrahydrofuran is distilled off under vacuum, adding water, whereby the pH increases to 7.7. At the 50oC add 840 ml of toluene and after 30 min of stirring, the layers separated. The toluene layer is washed with 50oC water and 0.1% of pyridine and a layer of toluene, stirred for 30 min at 20oC, add 20 g of sodium sulfate. The suspension is filtered and to the filtrate add 0.1% (by volume) of pyridine. After drying the residue to determine the net weight solution in toluene.

Example 2

(+)-3,3-(Dimethylpropylene)-4,5-semestr-9-EN-5.17-dione

72 g of gaseous chlorine is introduced into a solution of 236 g (+)-5-hydroxy-7a-methyl-4 -[7,7-(dimethylpropylene)-3 - oxo-octyl]-2,3,3 a 4,5,6,7,7-octahydro-1H-inden-1-it in 1500 ml of toluene and 285 ml of pyridine at 0oC for 7 to 8 hours the Reaction mixture is stirred for a further one hour at 0oC. the Reaction mixture was poured into a solution of 274 g of sodium sulfite and 228 g of sodium carbonate in 2500 ml of water. The layers are separated and the toluene layer washed with water. A solution of 246 g of potassium hydroxide in 345 ml of water and 810 ml of methanol are added to a solution in toluene. The reaction mixture is stirred for another 2 h at 65oC. After cooling to 50- water. To a solution in toluene add 375 ml of pyridine and the solution is evaporated to dryness. To the dried residue add 1100 ml of ethanol and 4 ml of pyridine and the mixture is boiled for 50 minutes After cooling to 40oC the solution is treated with activated carbon (Norit). After filtering the solution in ethanol is used as such.

Example 3

Östra-4,9-diene-3,17-diene-dione

A solution of 100 g of (+)-3,3-dimethylpropionic-4,5-semestr-9-ene-5,17-dione and 18.7 ml 2H hydrochloric acid in 500 ml of acetone is stirred under nitrogen atmosphere for 2.5 h at 23oC. a Solution of 4.5 g of sodium acetate in 1120 ml of water is added to the reaction mixture. The acetone is distilled off, whereby the amount of support the same when you add water. 5% sodium chloride (by volume) and 200 ml of toluene was added when 50oC. the Layers are separated and the aqueous layer was extracted with addition of toluene. Selected extracts of toluene, washed with 5% sodium chloride solution and evaporated to a volume of 500 ml. of This solution was used in the next stage.

A solution of (+)-4,5-semestr-9-EN-3,5,17-trione in toluene is added to a suspension of 8 g of potassium tert-butylate in 240 ml of toluene and 77 ml of tert-butanol in an atmosphere of nitrogen for 18oC. To the reaction mixture is added 8 ml of acetic acid with posleduyuschuyu is evaporated to a volume of 175 ml and added to 440 ml of hexane. The suspension is boiled for 30 minutes After cooling, it is stirred for 2 h at 0oC. After filtration and drying obtain 66 g of the crude östra-4,9-diene-3,17-dione, after purification through column with silica gel and crystallization from a mixture of ethyl acetate and hexane get 40 grams of pure östra-4,9-diene-3,17-dione.

Example 4

3,3-Atlantal östra-5(10), 9(11)-the diene-3,17 - dione

A mixture of 500 ml of cyclohexane,183 ml triethylorthoformate, 92 ml of ethylene glycol and 0.9 g of p-toluenesulfonic acid is stirred for 30 min at room temperature and then heated to boiling. The resulting ethanol is distilled off together with cyclohexane, while the volume of support by continuous addition of cyclohexane. After 4.5 hours the rest of the cyclohexane is distilled off and 1 EQ. balance add itself as an absorber of water in the atmosphere of nitrogen to 1 g östra-4,9-diene-3,17-dione, 0.1 EQ. hydrogen chloride in dioxane and 1.5 EQ. ethylene glycol 15 ml dimethoxyethane at -10oC. After 75 min, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. The crystal mass is filtered off after 15 minutes of drying, washed with water and dried under vacuum, after which obtain 1.1 g of 3,3-atelectasia , the eat 97%.

Example 5

3-Atlantal 17-Spiro-1',2'-oxiranes-5 (10), 9(11) - Dien-3-one

t-Butyl (32,7 g) are added to a solution of 30.0 g of 3-atelectasia östra-5(10), 9(11)-the diene-3,17-dione and 42.2 g of iodide trimethylsilane in 300 ml of dimethylformamide at a temperature of 35oC. the Mixture was stirred at about 30oC for 75 min, after which the reaction mixture is slowly poured in 2.7 l of water. The aqueous layer was extracted three times by adding 300 ml of ethyl acetate. The organic layer is washed with water, evaporated to dryness and dried under vacuum at 50oC, which gives to 29.8 g of 3-atelectasia 17 Spiro-1',2'-oxiranes-5(10),9(11)-Dien-3-one.

Example 6

3-Atlantal 17-cyanomethyl-17 hydroxyestra-5(10), 9(11)-Dien-3-one

A solution of 64.5 g of potassium cyanide in 120 ml of water are added to a solution of 25.8 g of 3-atelectasia 17-Spiro-1,2 oxiranes-5(10), 9(11)-Dien-3-one in 645 ml of ethanol. The mixture is stirred for 5 h at 25oC, then slowly add 650 ml of water. The mixture is left to stand for 15 h, after which a clear solution is decanted from the oily residue. The oily residue is dissolved in 150 ml of ethyl acetate, then the organic solution is washed with water and evaporated to dryness, giving a 20.2 g of 3-atelectasia 17 cyanomethyl-17 hydroc Hydrochloric acid (11,0 ml) are added to a solution of 17.0 g of 3-atelectasia 17 cyanomethyl-17-hydroxyestra-5 (10),9(11)-Dien-3-one in 362 ml of acetone. The mixture is stirred for 2 h at 25oC, after which the mixture is neutralized with the help of 20.8 ml of triethylamine and add 110 ml of water. Acetone (320 ml) is distilled off and after cooling to 20oC, the crystals are filtered and dried under vacuum at 50oC that gives 13,0 g of the crude l7-cyanomethyl-17-hydroxyestra-4,9-Dien-3-one. The crude product vykristallizovyvalas twice from acetone, giving 7,4 g 17-cyanomethyl - anometer-17 hydroxyestra-4,9-Dien-3-one having a purity of 98%.

1. The method of obtaining Catala steroid derivative of the General formula I

< / BR>
where R1is CH3or C2H5;

R2is OH;

R3is H, CH3or CH2CN, or R2and R3together are O;

R4is (2 - 5C) alkylene,

characterized in that the compound of formula II

< / BR>
where R1, R2and R3have the above values,

process in the presence of artefiera formula III

< / BR>
where R4is (2 - 5C) alkylene,

or orthoevra formula IV

< / BR>
where R4has previously specified value,

or a mixture of the alcohol corresponding to the General formula

HOR4OH,

where R4has previously in the 3 together are O and R4is-CH2-CH2-.

3. The method according to p. 1 or 2, characterized in that arteparon is 2,21-[1,2-atanderson(oxy)]bis-1,3-dioxolane.

4. The method of obtaining the compounds of formula I, where R1, R2, R3and R4have the above values, characterized in that: a) compound of General formula V

< / BR>
where R1, R2and R3have the above values,

condensed with the compound of the formula

CH3-C(OR4O)-(CH2)3-XHal,

where R4has the previously given meanings;

Hal is a chlorine atom, bromine or iodine;

X is a metal atom, in particular magnesium;

b) a hydroxy-group of the resulting product is oxidized in the usual way;) cyclist under alkaline conditions; d) ketal otscheplaut in acidic conditions; d) and then in alkaline conditions cyclist with obtaining the compounds of formula II, where1, R2and R3have the previously given meanings; (e) after which the resulting product is treated in accordance with the method described in paras.1 - 3.

5. The method according to p. 4, wherein R1is CH3and R2and R3together are O.

6. The method of obtaining CN, characterized in that on the basis of the compounds of formula V in which R1is CH3and R2together with R3are O, get the connection formula I on p. 5 with subsequent conversion of the specified compound I to compound of formula II by transformation 17-ketogroup product obtained by the method according to p. 2 or 3, in spirooxazines group, which is then revealed by treatment with cyanide, followed by removal of katalavei groups of the resulting reaction product under acidic conditions.

 

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