The method of obtaining 16-methyl steroid intermediates.

 

(57) Abstract:

Describes how to obtain 16-methyl steroid of formula I, wherein spend processing the compounds of General formula II, in which the cycles a and b represent the surplus, which represents an oxo radical or a protective group of the oxo radical of the formula, n = 2 or 3, dehydrating substance to obtain compounds of General formula III, in which a and b have the above meanings, and when It represents an oxo-radical is exposed to the appropriate blocking reagent for oxo radical to obtain the compounds of formula III, where K has a value other than oxo and defined above, the compound of formula III is exposed to organometallics meteorologi reagent to obtain, after hydrolysis of the intermediate imine of the ketone of General formula (IV), where a and b have the above values, which is processed in an alkaline environment epoxidised substance to obtain compounds of General formula V, where a and b have the above values, which protects 20-ketogroup to obtain compounds of General formula VI, in which K' represents a protective group of 20-ketogroup formula; And, In and n have VIIa 16-methyl derivative of General formula (VII), where K', a and b have the above meanings, and then make unlock ketogroup in positions 3 and 20 to obtain the desired product of formula I. also Describes new intermediate products. The technical result is simplification. 2 S. and 6 C.p. f-crystals.

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The present invention relates to a method of obtaining 16 - methyl steroids and intermediate products.

Thus, the object of the present invention is a method of obtaining compounds of formula (I):

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characterized in that processed the compounds of formula (II):

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(II) in which the cycles A and B represent the balance:

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or

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in which K represents an oxo radical or a protective group of the oxo radical of the formula:

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n has a value of 2 or 3, a R1is an essential or difficult-volatile residue, drying agent, to obtain the compounds of formula (III):

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in which A and B have the above meaning, which, when It represents an oxo radical, is exposed to the appropriate blocking reagent specified oxo-for oxo radical and defined above, the compound of formula (III) is exposed to organometallics meteorologi reagent to obtain, after hydrolysis of the intermediate imine, ketone of formula (IV):

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which is subjected to treatment in an alkaline environment using epoxidised substances to obtain the compounds of formula (V):

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which protects 20-keto functional group to obtain the compounds of formula (VI):

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in which A' represents a protective group of the ketone functional groups, identical or different from It, of the formula:

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in this case n has the above meaning, which is processed organometallics meteorous reagent, to obtain 16 - methyl derivative of the formula (VII):

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which produce the unlocking of the ketone functional group in position 3 and 20 to obtain the desired product of formula (I).

When R1is an essential residue, we can talk about balance, well-known specialists, to lock the position 3 in this form, and, in particular, we can talk about an alkyl radical comprising from 1 to 6 carbon atoms, about alkoxylalkyl radical comprising from 3 to 8 carbon atoms, about ailnoth.

When R1represents an alkyl radical, it is, for example, about such radicals as methyl, ethyl, sawn, ISO-propyl, n-boutigny, second-boutigny, tert-boutigny, pentelenyi or sexily.

When R1represents alkoxylalkyl radical, it is, for example, about methoxyethoxymethyl radical.

When R1represents Uralkaliy radical, it is, for example, benzyl or penicilina radical.

When R1represents an aryl radical, it is, for example, phenyl radical or phenyl radical, substituted, in particular by one or more alkyl radicals.

When R1is an essential residue, it can also go on sicilianos group, for example, about trialkylsilyl group, such as trimethylsilyl, tert-butyldimethylsilyl or, for example, about three-Arielle group, such as triphenylethylene, or about varilly-silyl group, such as diphenyl tert-butylstyrene.

When R1represents an ester residue, we can talk about any residue, known to specialists, to lock the position 3 in this form, Uralkali radical, as specified above.

Protection of the ketone functional group in 3 is made by methods well known in the art. So you can use, in particular, diol, dithiol or a mixed thiol of the formula HO-(CH2)n-OH, HS-(CH2)n-SH or HO-(CH2)n-SH, in an acidic medium, for example, in the presence of concentrated hydrochloric acid or concentrated hydrogen bromide, in a catalytic amount of P-toluenesulfonic acid, or in the presence of a Lewis acid such as zinc chloride, titanium tetrachloride or boron TRIFLUORIDE, preferably in the form of ether extract.

You can also use methylethylketoxime in the presence of acid, for example, any of the above acids. You can also use the alkyl halide, alkoxylalkyl, aralkyl or aryl in the presence of a base, forming in the intermediate stage enolate, for example, alkali hydride, alcoholate or gidrookisi.

You can use also the halide trialkyl, Triaryl or diarylethylene in alkaline medium, as described above.

You can also use the appropriate acid chloride, acting in the presence of a base, which can be isocost is particularly alkaline hydride, alcoholate or gidrookisi.

As the dehydrating agent is, in particular, phosphorus oxychloride, which is preferably used in the presence of a tertiary amine such as pyridine. You can use also a Lewis acid such as iron chloride, boron TRIFLUORIDE and its complex compounds, for example, ether extract, titanium tetrachloride, aluminum chloride or tin chloride, an inorganic acid, such as sulfuric acid, the acid, such as paratoluenesulfonyl or chlorine-acid, or derivative, such as chloride methanesulfonyl.

Organometallics meteorous reagent, leading to receipt of a ketone, for example, is magyarkanizsa, organolithium, caddyorganist connection, or a derivative of copper, such as CH3Cu, (CH3)2CuMg, (CH3)2CuLi. Preference in this case is given magnetogenesis compounds, such as methylaniline or methylethylamine.

Should act in the environment of the solvent in the first place - ester, such as a simple ethyl ether, tetrahydrofuran or dioxane, but you can use and aromatic SS="ptx2">

The hydrolysis of the imine obtained in the intermediate stage, is performed using an aqueous acid, for example acetic or formic or inorganic acid, such as hydrochloric acid.

As epoxidised substances can be used nagkalat, such as metaglidasen, albenzaalbenza, nadolinny, or hydrogen peroxide, used alone or in the presence of hexachloroacetone or HEXAFLUOROACETONE.

As epoxidised substances may also be used Gidropress, such as hydropeaking tert - butyl, which is used in the presence of vanadium acetylacetonate or other metals, such as molybdenum, in catalytic amount. Preference in this case is given hydrogen peroxide.

The operation is performed in a weak alkaline medium or in the presence of a base, for example sodium hydroxide, or in buffered medium, for example, using sodium acetate, secondary sodium phosphate, or sodium bicarbonate, or a mixture of tertiary sodium phosphate and phosphoric acid.

The operation is performed in the environment of an organic solvent, such as methylene chloride, carbon tetrachloride, trichloramine, in the presence of water.

Protection of the 20-ketone functional group is in the form of ketala, mixed Catala or dithioketal, by conventional methods, well known to specialists. Thus used diol, a dithiol, or a mixed thiol of the formula HO-(CH2)n-OH, HS-(CH2)n-SH or HO-(CH2)n- SH in an acidic medium, for example, in the presence of concentrated hydrochloric or Hydrobromic acid in a catalytic amount of para-toluenesulfonic acid, or in the presence of a Lewis acid such as zinc chloride, titanium tetrachloride or boron TRIFLUORIDE, preferably in the form of ether extract.

As organometallics meteorologi reagent, which is injected into the reaction with the epoxide of formula (VI), use one of the above reagents, with preference being given to those described above as such.

The release of the ketone functional group in position 3 and 20 is made by methods appropriate to the type of the protective group. Used sour agent in the presence of water or, in the case of ketala, a mixture of water and limit alcohol fatty series. We are talking about, for example, inorganic or organic acid, Isleta, paratoluenesulfonyl, or mixture of acids or acidic resin, for example, sulfonic resin. In the case of tickets or mixed Catala, removing the protection is carried out by exposure to iodine in the presence of a base, for example, alkali bicarbonate, or by exposure to iodine in catalytic amounts in the presence of oxidizing agent, particularly hydrogen peroxide, by exposure to iodine stands, Glyoxylic acid or salts of metals such as mercury, cadmium, copper or silver. In General, the operation can be performed in a solvent such as a lower limit fatty alcohol series, for example, methanol or ethanol, mixed with halogenated solvent, e.g. methylene chloride, in the presence of water. In the case of a mixed Catala, removing protection can also be carried out, for example, with salts containing divalent mercury, such as chloride of mercury, in the presence of a buffer mixture of acetic acid and potassium acetate at a temperature of about +100oC, using Raney Nickel, in the same conditions as described above, or using a mixture of hydrochloric and acetic acids at an elevated temperature.

In the case when R1is an ether or ester ostate the ptx2">

The object of the present invention is, in particular, the method described above, characterized in that at the initial stage of the connection of the formula (II), in which the cycles A and B represent the balance:

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moreover, n has the same meaning as above, in particular it equals 2.

The object of the present invention, in particular, is the above method, characterized in that the 20-keto functional group to protect the same Cetelem that and in position 3, in particular, ethylendiamine group.

In addition, the subject of the present invention as new industrial products and, in particular, as intermediates, which can be useful when implementing the method of the present invention, is the product of the formula (III) in which To have the above values, except for one oxo radical, and also the products of formula (IV), (V), (VI) and (VII) as described above.

The products of formula (II) used at the initial stage of the method, the known or can be prepared from the product of 3-keto described in the patent EEC N 263569, using conventional methods, well known to specialists. Among the developments that can espesaly (I) represents an important intermediate product for the synthesis of betamethasone as described, for example, in the patent EEC 54810.

The following examples illustrate the application of the invention, however, limiting it.

Example 1: a 16-methyl-17 - hydroxy-pregna 4,9 (11)-diene 3,20-dione

Step A: cyclic 3-(1,2-ethandiyl)-acetal 17-cyano-androst-5,9 (11), 16 (17)-triene-3-one

Inert gas mixed 30 g of cyclic 3-(1,2-ethandiyl)-acetal 17-hydroxy-17 - cyanoandrosta-5,9 (11) Dien-3-one and 240 cm3anhydrous pyridine, then add 30 cm3oxychloride of phosphorus. Then incubated for 2 h with shaking in an oil bath at a temperature of +40oC, and then for 18 hours at a temperature of +45oC. then the mixture is poured into a mixture of 450 g of ice, 240 cm3chloride-hydrogen acid at the 22oB and 100 cm3water. After that make stirring at room temperature, centrifuged, and the obtained crystals are washed with water and dried. The crude product suspension in a simple mixture of isopropyl ether and isopropanol (2: 1), and then centrifuged and dried crystals. The result 24,27 g of the desired product (tPL205-208oC).

IR spectrum (CHCl3)

The absorption at 2217 cm-1(CN), 1660, 1630 and 159/SUB>; 1,23 (s): 19-CH3; 3, 96: ketal; 5,44 (m) - the 5.45 (m): H6and H11; 6,65: H16.

Step B: cyclic 3-(1,2-ethandiyl) acetal of pregna-5,9 (11), 16 (17)-triene-3,20-dione

Inert gas mixing 9 g of the product obtained at Stage A, and 27 cm3toluene, then enter the 27 cm33 M solution of methylmagnesium in tetrahydrofuran. Then for 3 h 30 min, heated to a temperature of +60/65oC, cooled in a bath of ice - methanol and add 36 cm3of tetrahydrofuran, and then pour in under a nitrogen pressure at a temperature not higher than +10oC, in a mixture of 81 cm3ice, 27 cm3water and 135 cm3acetic acid, cooled with a bath of ice - methanol. The temperature is allowed to rise to approximately +20oC, the mixture is concentrated under reduced pressure, slightly warming in a water bath at a temperature of +45oC, and then poured into 20 volumes of a mixture of water and ice. Temperatures give again to rise with shaking, and then centrifuged crystals, washed with water and dried. So get 9,03 g crude product, which is thickened in a mixture of 45 cm3methanol, 5 cm3water and 0.5 cm3of triethylamine. Then heated at boiling temperature for 1 h 30 min and cooled at room get the result for 7.12 g of the desired product (tPL217-219oC).

IR spectrum (CHCl3)

The absorption at 1664, 1590, 1361 cm-1: unsaturated ketone ,.

Range Yarm: (CDCl3+ C5D5N - 300 MHz - million-1)

0,87 (s): 18-CH3; 1,22 (s): 19-CH3; and 2.26 (s): ketone; 3,94 (m): ketal; 5,44 - of 5.45 (m): -CH= at position 11 and 5; of 6.71 (t): -CH= in position 16.

Step A: cyclic 3-(1,2-ethandiyl)-acetal 16,17 - epoxy-pregna-5,9 (11)-diene - 3,20-dione

Inert gas mixing 7 g of the product obtained at Stage B, 70 cm3of tetrahydrofuran and 35 cm3of methanol. Then enter 7 cm3concentrated caustic soda and 7 cm3hydrogen peroxide at 200 volumes. Then heated for 17 hours at a temperature of 40/45oC, cooled at room temperature, and poured into a mixture of 70 cm3water and 70 g of ice. Then aged with stirring, allowing the temperature to rise, then centrifuged, washed with water until disappearance of oxidizing ability and dried. So get 7,08 g of the desired product which is used without further processing in the next step.

IR spectrum (CHCl3)

The absorption at 1704 (C = O), 901-855 cm-1(epoxide).

Range Yarm: (CDCl< -CH= at position 16; 3,94 (m): ketal; 5,40 (m) 5,51 (t): -CH= at position 11 and 5.

Step G: cyclic 3,20 bis-(1,2-ethandiyl)-acetal 16,17 - epoxy-pregna-5,9 (11)-diene-3,20-dione

Inert gas is mixed with 4 g of the product obtained at Stage B, 40 cm3of methylene chloride, 40 cm3of ethylene glycol, 20 cm3utilitiarian and 0.3 g of dehydrated paratoluenesulfonyl. After 7 h, concentrated under reduced pressure to 1 mbar at room temperature, and then incubated with shaking for 30 minutes then pour in under 300 cm3a 10% aqueous solution of sodium bicarbonate and Tegaserod for 30 minutes Then centrifuged, washed with water and dried resulting crystals. The product was then purified by chromatography on silica (eluant : toluene - ethyl acetate (8: 2)) with 0.05% triethylamine. Then the obtained product absorb cyclohexane, centrifuged and dried under reduced pressure. Thus obtain 3.28 g of the desired product (tPL176-177oC).

IR spectrum (CHCl3). The absence of C = O. the Presence of ketala.

Range Yarm: (CDCl3+ C5D5N - 300 MHz - million-1)

0,94 (s): 18-CH3; 1,20 (s): 19-CH3; 1,42 (s): CH3-; 3,41 (s): H in position 16; 3,85 the eh 16-methyl,17 - hydroxy-pregna-5,9 (11)-diene-3,20-dione

Inert gas freeze 24 cm33 M solution methylacrylamide in the air. The solvent is evaporated under reduced pressure, while stirring in a bath at a temperature of +60/65oC. Then injected 21 cm3of tetrahydrofuran and 3 g of the product obtained in Stage G, then shaken for 16 h, bringing the temperature up to +70oC. Then add 4 cm3the ether solution of the above magyarkanizsa connection and 10 cm3tetrahydrofuran (THF) and shaken for 7 hours then again add 10 cm3of tetrahydrofuran, kept at boiling temperature for 16 h, cooled to approximately +40oC and poured into a mixture of 16 g of dehydrated secondary phosphate and 900 cm3water, maintained at a temperature of 0oC. the Temperature is allowed to rise, after which the product is centrifuged, washed with water and dried. Then the product is distilled thickening 15 volume mixture of methylene chloride and ethyl acetate (9:1) with 0.05% triethylamine, and then by chromatography on silica, elwira the same mixture. The result 2,42 g of the desired product (tPL180-181oC).

IR spectrum (CHCl3)

The absorption at 3580 cm-1: OH; 1670-1; 1,19 (d): CH3-CH-; 1,20 (s): 19-CH3; 1,39 (s): CH3-C; 3,85 on 4,05: ketals; the 5.45 and 5,48: H in position 6 and H in position 11.

Step E: 16-methyl,17 - hydroxy-pregna 4,9 (11)-diene-3,20-dione

Inert gas is mixed with 2 g of the product obtained in Stage D, 15 cm3acetone and 5 cm3water. Then enter 4 drops of concentrated sulfuric acid, heated for 4 h 30 min in a bath at a temperature of +60oC. Then add 20 cm3water, allow to cool, centrifuged crystals, washed with water and dried. Thus obtain 1.55 g of the target product (tPL173oC).

IR spectrum (CHCl3)

The absorption at 3610 cm-1: -OH; 1709-1353 cm-1: CO = CH3; 1663-1616 cm-1: Cato.

Range Yarm: (CDCl3- 300 MHz - million-1)

0,87 (s): 18-CH3; to 1.19 (d,J = 7): CH3-CH-; 1,34 (s): 19-CH3; 2,27 (s): CO-CH3; 3,01 (s): 1H mobile.; 5,52 (m): H in position 11; 5,75 (m): H in position 4.

1. The method of obtaining 16-methyl steroid of the formula I

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characterized in that conduct processing of compounds of General formula II

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in which cycles a and b represent the balance of

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which represents an oxo radical or a protective group of the oxo-radical fbsa formula III

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in which a and b have the above meanings, and when It represents an oxo radical, is exposed to the appropriate blocking reagent for oxo radical to obtain the compounds of formula III, where K has a value other than oxo and defined above, the compound of formula III is exposed to organometallics meteorologi reagent to obtain, after hydrolysis of the intermediate imine of the ketone of General formula IV

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where a and b have the above values,

which is subjected to treatment in an alkaline environment epoxidised substance to obtain compounds of General formula V

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where a and b have the above values,

which protects the 20th ketogroup to obtain compounds of General formula VI

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where K' represents a protective group of 20-ketogroup formula

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or

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A, B and n have the above values,

which processed organometallics meteorous reagent to obtain 16 - methyl derivative of General formula VII

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where K', A and B have the above values,

then make unlock ketogroup in positions 3 and 20 to obtain the target product is ignored phosphorus in the presence of a tertiary amine.

3. The method according to p. 1, characterized in that organometallics meteorous reagent is methylaniline.

4. The method according to p. 1, characterized in that as epoxidised substance use hydrogen peroxide.

5. The method according to p. 1, characterized in that as ORGANOMETALLIC reagent in the reaction with the epoxide of formula VI using the reagent under item 3.

6. The method according to any of paragraphs.1 to 5, characterized in that as the source is used as a compound of the formula II, in which the cycles a and b represent the balance of

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moreover, n has the same meaning as above, in particular n = 2.

7. The method according to any of paragraphs.1 - 6, characterized in that 20-metafunctional group protects the same Cetelem that at position 3 in particular ethylendiamine group.

8. The compounds of formula III, as described in paragraph 1, where K has the values specified in paragraph 1, except the oxo radical, and also compounds of formulas IV, V, VI, and VII as intermediate products.

 

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EFFECT: the invention ensures simplification of the method of the process, reduction of its duration and power input.

1 cl, 2 ex

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