BG98887A - Halogeation by using willsmeyer halogen reagent - Google Patents

Abstract

The process involves a halogenated steroid dione. It involves simultaneous transformation of steroidal 3-one to 3-halo and 17-carboxylic acid to 17-carboxamide in a single reaction without isolating the intermediate. The process is carried out by reacting a steroidal starting material with a valsmiere halogen reagent.

Description

Technical field

The present invention relates to an improved process for the preparation of substituted steroid dienes. No. 5,017,568, issued May 21, 1991 to Holt et al., As useful for inhibiting steroid 5 - </ - - reduction.

BACKGROUND OF THE INVENTION

Methods for the preparation of substituted steroidal diene derivatives are described. In particular, the use of oxalyl bromide for the conversion of steroidal &lt; RTI ID = 0.0 &gt; L, 3-unsubstituted-3-ketones &lt; / RTI &gt; to 3-bromo 3,5,5-diene intermediates from catalytic or alkyllithium carboxylation (in 15% yield) (when 11-butyllithium is used) to obtain steroid-3,5-diene-3-carboxylic acid derivatives is disclosed in U.S. Patent 5,017,568.

In addition to the low overall yield, another drawback of the prior art is that oxalyl bromide is a toxic, expensive liquid that is difficult to store and is not readily available in the bulk quantities required for an industrial process.

The use of oxalyl chloride for the halogenation of steroid οΐ, β-unsaturated ketones to chloro-steroid dienes only results in marginal results. In addition, the relatively low reactivity of the chlorine substituent obtained poses non-trivial considerations for synthesis in subsequent transformations. there is a need for a safe, economical and applicable method for halogenating steroid od, β-unsaturated ketones to halo-1,3-dienes.3a preferably, said method will

-2 excludes the bromination or iodination of steroid axis-unsaturated ketones to their corresponding halo-1,3-dienes.

SUMMARY OF THE INVENTION

The present invention relates to a method of halogenating a compound having multifunctional groups on the same molecule.

This invention relates to an improved method of converting steroidal 7., / 3-unsaturated ketones to their corresponding halo -1,3 diene derivatives.

This invention relates to an improved process for the preparation of an acid halide from a steroid carboxylic acid substitute, followed by nucleophilic substitution of said halide.

In particular, this invention relates to an improved method for the in vitro conversion of steroidal carbonic acids to steroidal carboxamides.

In particular, this invention relates to a method for simultaneously brominating and amidating the 3-one-4-en-17-carboxylic acid ether-ester compound.

This invention specifically relates to an improved process for the preparation of N, N -butyl-androst-3,5-diene-17/ ³ -carboxamide-3carboxylic acid.

The term 'simultaneous' as used herein means that the transformation of the steroid 3-one to 3-halo and 17-carboxylic acid to 17-carboxamide takes place in a single reaction without isolating the intermediates.

As used lio-rope, and further in the description and claims, the carbon atoms of the steroid nucleus are numbered! and the rings are indicated by the letters as follows:

-ϋ—

The term reduced temperature as used herein means a temperature below 25 ° C, preferably between -15 and 15 ° C. with a temperature between 0 and 10 ° C being most preferred.

The term coupling reagent as used herein means a compound and / or conditions that are capable of + + interactions. For example, a metal-substituted moiety is formed to form an acid, ester, alkylcarbonyl or alkyl moiety. Preferably, said metal-substituted moiety is substituted by a lithium moiety prepared by reacting the corresponding halogenated moiety with an alkyllyl reagent. Compounds used as coupling reagents are chloroformates, alkyl bromides and acid chlorides. Preferably said coupling reagent will use carbon dioxide as a reactive compound.

The term acid as used herein means any group capable of acting as a proton donor, including, but not limited to: -COOH, -P / O // OH / ₂ »pH / O / it, - ^ about ₃ n and - / CH ₂ / _1v3 -COOH.

The term ester as used herein means a group comprising an acid, as mentioned above, in which the proton or proton donor is replaced by alkyl substituents.

The term solvent or suitable solvent as used herein means an organic solvent such as methylene chloride, ethylene chloride, chloroform, tetrachloromethane, tetrahydrofuran (THF), ethyl ether, toluene or ethyl acetate.

The term Bilsmeier halogen reagent as used herein means a halogenated, disubstituted formamide reagent having the structure:

β where B and B are each independently selected from an alkyl, aryl or arylalkyl group; and X is Br or I; and Y denotes an oppositely charged ion, which is obtained by:

a / reaction, preferably at reduced temperature, of a chloride source, such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substituted formamide reagent, preferably dimethylformamide, in a suitable solvent, preferably solvent, Wismayer reagent, said Wissmeier chromium reagent reacting in situ. preferably at reduced temperatures, with a bromine source / or with an iodine source, preferably hydrobromic gas; or b) reaction, preferably at reduced temperatures, of bromine '*', a source or iodide source, preferably oxalyl bromide, with a substituted formamide reagent, such as a dialkyl-substituted formamide reagent, preferably dimethylformamide in a suitable solvent, preferably methylene chloride.

This invention also relates to the in vitro preparation and use of a Wilsmeier bromine reagent or a Wilsmeier iodine reagent, said reagents being prepared safely and economically by known and readily available reagents, preferably the corresponding Wilsmeier chlorine reagent. application to all reactions using bromine Wilaymeier reagents or Wilmsmeier iodine reagents

-5—

Preferred alkyl lithium reagents for use herein include n-butyllithium, sec, butyllithium and tert-butyllithium2.

Unless otherwise stated, the term "halogen" as used herein means bromine or iodine.

Where necessary, pharmaceutically acceptable salts, hydrates and solvates of the compounds of formula (I) are prepared by methods known in the art.

The present invention provides a process for preparing a compound of formula (I):

alkyl cycloalkyl, phenyl of hydrogen, 3-4 or E and E taken together with the nitrogen to which they are attached represent

A 5-6 membered saturated ring containing at least one other heteroatom selected from oxygen and nitrogen; and

E represents acid, ester, C 1-6 alkylcarbonyl or C 1-6 alkyl; or a pharmacologically tolerated salt, hydrate or tear of this compound, which involves a lower temperature reaction of a compound of formula (II):

(Ii) a Wilsmeier reagent and solvent, in the presence of halogen, and then cooled sharply with an isolate of HE ^L where the above meanings to give the compound is formula / II

(III) where the above meanings are followed, then an alkyl lithium reagent is added to the presence of a suitable solvent and, at reduced temperature, a coupling reagent is added and a compound of formula (I) is obtained, provided that when x and / or E ^ is H, the compound of formula (III) is subjected to an alkaline medium suitable for the selective deprotination of the amide before the alkyl lithium reagent is added and then a pharmaceutically acceptable salt, hydrate or solvate is optionally formed.

Preferably said Wilsmeier halogen reagent is prepared by reaction, preferably at reduced temperatures, of a chloride source, such as oxalyl chloride or thionyl chloride, with a substituted formamide reagent such as a dialkyl substituted formamide reagent, preferably a formamide reagent, methylene chloride to form the Wilsmeier chlorine reagent, with said Wils-Layer chlorine reagent reacting in eit. preferably at reduced temperatures, with a bromide source or with an iodide source, preferably hydrogen bromide gas.

As used herein, unless otherwise indicated, alkyl means a straight or branched hydrocarbon chain having C. carbon.

J. ^e H here, unless otherwise stated,

-7 When used, the term alkyl means straight or branched chain hydrocarbon.

As used herein, unless otherwise indicated, the term aryl means an aromatic carbocyclic or heterocyclic ring which is unsubstituted or substituted with non-reactive substituents.

Preferably, the Wilsmeier halogen reagents used in the dihalogenation of the compounds of formula (II) are prepared and used in situ.

Preferably said Wilsmeier halogen reagent; is Wilsmeyer's bromine reagent.

Preferably, said Wilsmeier bromine reagent is / bromomethylene / dimethylammonium bromide.

Preferred organic acids used to describe $ 2 in formula (I) include: -COOH, -P / O // OHg, -PH / O // OH /. - and - (CH2 +) COOH. Especially preferred among them is e-COOI

The preferred bases used to prepare the alkaline medium used to selectively deprotonate the amide of the compounds of formula (III) are metal hydrides, alkyl lithium reagents: Grignard reagents and metal alkoxides. Preferred among the above bases are ethyl butyldimethylbutylamide mercury and ethylmagnesium chloride. Particularly preferred among the bases described is ethylmagnesium chloride. Preferably, the selective deponization of said amide is carried out at a temperature above 25 ° (most preferably temperature ura between 30 and 50 ° C.

Preferably, the alkyl lithium reagent used to initiate halogen-metal exchange with respect to the compounds of formula (III) is sec-butyllithium.

One preferred aspect of the invention is semi

The formation of steroidal halo-1,3-diene systems of steroxy, unsaturated ketones, ^ν ? .Το uses the Wilsmeier halogen reagent obtained and used in situ.

One preferred aspect of the invention is the formation of an hourly acid-halide reagent by a part of steroid carboxylic acid with the Wilsmeier halogen reagent, wherein said acid halide substituent is displaced by a nucleophilic reagent. Preferred nucleophilic reagents include 1 HS, where ® has the above meanings. Particularly preferred among the above nucleophilic reagent! is tert-butylamine.

Preferably, the method of the present invention is particularly useful for preparing a compound of the structure: (SHA):

and converting this compound to the next compound with a jet! rounds / TAs /:

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Without further elaboration, it will be appreciated that any person skilled in the art may use the foregoing to apply the present invention to its full extent. The following examples should therefore be regarded as non illustrative, rather than limiting the scope of the present invention.

I, Synthetic Examples

Dimethylformamide, oxalyl chloride, oxalyl bromide, tert.-butylachine, 0.2M ethylchagnesium chloride in tetrahydrofuran (THF), 1.2 'and sec-butyllithium in cyclohexane and / -; - / - 4-cholesten-3-one are supplied by Xldrick Co.Aevn / MilWamcee, VVT /. Ferrous gas and carbon dioxide gas are supplied from Mat is op / E. Vi? Er ^ ogs /, MJ /. Androst-4-en-3-one-17-carbic acid is supplied by Peril c4x, Inc. / Wayne, TsT </ /. 3-Bromandrosta-3,5-diene-17-carbonic acid was prepared as described in U.S. Patent 5,017,568 (Example 25B / II).

Example 1 Dimethylethyl / aminocarbonyl / androst-3,5-diene-3 -

-carboxylic acid

1/3-Bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17,4-carboxamide

Fill a flask under a nitrogen atmosphere with 100 ml. methylene chloride and 6.12 ml. / 2.5 molar equivalent / dimethylformamide. The solution was cooled to 0-5 ° C and treated with 6.9 ml. / 2.5 molar equivalent / oxalyl chloride while maintaining the temperature between 0 -10 ° C. A white precipitate forms. After shaking for one hour, the solution is bubbled

50.1 grams / 19.6 molar equivalent / hydrogen bromide, keeping the temperature between 0 ° C. The suspension is in the form of a clear colorless solution. methylene chloride was added. This concentration / refill procedure was repeated. Androst-4-en-3-one was added to the resulting white suspension. -carbon

. -10acid 10.9 grams? ^f 1 molar equivalent /,., the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled sharply with a vessel containing 100 ml. methylene chloride and 23.1 grams / 10 molar equivalent / tert-butylamine, while maintaining the temperature between 0-10 ° C, The mixture was stirred for 39 minutes. I get around 190 ml. water and the two-phase mixture are filtered through a celite sealer. The organic phase is separated and the volume is reduced to about half by vacuum distillation. The solution is restored to its original volume with acetone. acetone solution (about 300 ml.) was warmed to about 50 ° C and treated with ambient <100 ml. water to precipitate the product. The suspension is cooled and the product 3-bromo-N- (1,1-dimethylethyl) -androsta-3,5-diene-17/3 carboxamide is isolated by filtration and dried. 89%, mp 181-183 ° C.

2/17 β-I // 11,1.-Dimethyl ethyl / amino / carbonyl / androsta-3,5-diene-3-carboxylic acid.

A solution of 10.0 grams (1 molar equivalent) of 3-bromo + N- (1,1-dimethylethyl) -androst-3,5-diene-17/9-carboxamide in 250 ml. the dry tetrahydrofuran was warmed to 30 ° C under a nitrogen atmosphere. The solution was treated with 29 ml. 2. OM ethyl magnesium chloride (2.5 molar equivalent) in tetrahydrofuran and the temperature allowed to rise to about 40-50 ° C. After stirring for 20 minutes, the reaction mixture was cooled to 0-5 ° C and treated with 82.5 ml. 1.2 L sec-butyllithium in cyclohexane (2.5 molar equivalent). After stirring for 5 minutes, dry carbon dioxide is bubbled into excess. Saturation with gas is continued and the solution is allowed to warm to room temperature. is washed

-11with 100 ml. 3.3 M aqueous hydrochloric acid and the aqueous phase is separated. The organic phase is washed twice with about 150 ml. water. About 35 ml were added to the organic phase. water and then the organic phase is removed by distillation under reduced pressure. The resulting aqueous suspension of the product is extracted into 100 ml. The aqueous phase was separated and the organic phase was washed with 100 ml. water. The organic phase is treated with 0.6 ml grams of decolourising carbon and filtered through celite. The filtrate was evaporated and washed with ethyl acetate, yielding 6.4 grams of N, N-dimethylethyl (amino) -carbonyl / androsta-3,5-diene-3-carboxylic acid. mp 248-249 ° C.

Example 2

3-bromo-B1- (1,1-dimethylethyl) -androsta-3,5-diene-17/2-carboxamide 10 ml solution. methylene chloride containing 5 mg. p-quinone and 0.328 grams (1.8 molar equivalent) of dimethylformamide were cooled to 0 ° C and treated with 0.85 grams (1.6 molar equivalent m / oxalyl bromide). The reaction mixture was warmed to room temperature and stirred for 30 minutes. The solution was cooled to about 5 ° C and 0.95 grams (1 molar equivalent) of 3-bromo-hydrosta-3,5-diene-17β-carboxylic acid in 20 ml was added to the white suspension. methylene chloride. The solution was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was cooled sharply with 2.2 ml. /8.4 molar equivalent, t-butylamine and stirred for 5 minutes. The mixture was poured into 100 m. Ethyl acetate and the organic phase was washed with 59 ml. 10% aqueous sodium hydroxide solution, the aqueous phase was separated and extracted with 50 ml. ethyl acetate. The combined organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated by evaporation. suction until a crude solid is obtained which is

-12 blurs with 24 ml. (50/50 t-Butyl? Tetylether / hexane, The solid was isolated by filtration and dried under vacuum to give 0.5 grams of 3-bromo-T < 1- (1,1-dimethylethyl) -androst &quot; 3,5-Diene-17β-carboxamide. The filtrate was concentrated and washed as above to give an additional 0.25 grams of product. The total product yield is 69 mp 181-183 ° C.

Example 3

3-bromolesterol-3,5-diene

10 ml solution. methylene chloride containing 0.24 ml. (1.2 molar equivalent) of dimethylformamide is cooled to 0 ° C and treated with 0.62 grams (1.1 molar equivalent) of oxalyl bromide. The resulting white suspension was stirred at -5 ° C for 45 minutes, and L.0 gram (1 molar equivalent) (+) -4-cholesterol-3-one in 6 ml was added to the white suspension. The solution was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was poured into a mixture of 100 ml. ethyl acetate and 40 ml. water. The organic phase was separated and extracted with 50 ml. ethyl acetate. The combined organic phases are washed with 10 ml. brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude solid which was purified by silica gel chromatography using hexane to give 1.1 g of 3-brocholest-3,5-diene. Yield 93%. The sample was recrystallized from methanol-diethyl ether and had a melting point of 64-67 ° C.

Example 4

3-6ροΜ-N- (1,1-dimethylethyl) -androst-3,5-diene-17β-carboxamide.

The flask under nitrogen atmosphere was charged with dimethylformamide 0.6 grams (2.6 molar equivalent) in methylene chloride (20 ml.).

The solution was cooled to 0-5 ° C and treated with oxalyl bromide 1.71 grams (2.5 molar equivalent) while maintaining the temperature between 0 -10 ° C. A white precipitate forms. Androst-4-en-3-one-17β-carboxylic acid 1 gram (1 molar equivalent) was added to the resulting white suspension and the mixture was warmed to near room temperature and stirred for 30 minutes. The reaction mixture was treated with tert-butylamine 2.2 ml = (3 molar equivalent) in methylene chloride (2 ml) while maintaining the temperature between 0-10 ° C. The reaction medium was stirred for 10 minutes. then poured into a mixture of ethyl acetate (150 ml) and 10% sodium hydroxide solution (50 ml). The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated to give a solid. The solid was triturated with t-butyl methyl ether (4 mL / hexane / 4 mL). it was isolated by filtration and dried to give 3-bromo-N- (1,1-dimethylethyl) -androst-3,5-diene-17-carboxamide. Doyiv 58%. Melting point 177-179 ° C.

Claims (16)

Patent Claims 1, a method for the preparation of a compound of formula (I): where C 1-6 cycloalkyl, phenyl C 1-8 ^alkyl or l and k and taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing to each other a heteroatom selected from oxygen and nitrogen; and E is an acid or ester *, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that it comprises a (reduced temperature) reaction of a compound of formula (II) (II) in the presence of P-E in an excipient for halogen reagent of Wilsmaler abrupt cooling, where E also has a solvent as defined above, formula (III): to form compound with (III) -Ιοί where halogen means bromine or iodine; and 2 has the above meanings and b / is followed by the addition of an alkyllithiasis reagent to a suitable solvent and a reduced temperature, followed by the addition of a coupling reagent to form a compound of formula (I) 3 4 provided that when $ and / or 3? is And, the compound of rormula (III) is subjected to an alkaline medium suitable for selective deprotonation of the amide, before the addition of an alkyl lithium reagent and then optionally a pharmaceutically acceptable salt, hydrate or solvate is obtained, A method according to claim 1, characterized in that the halogen Wilsmeier reagent is prepared by reacting, preferably at reduced temperature, a chloride source, such as oxalyl chloride or thionyl chloride, with a substituted formamide reagent, such as a dialkyl substituent substituted preferably dimethylformamide, with suitable solutions! preferably methylene chloride to form Wilsmeier chlorine reagent, such as said Wilsmeier chlorine reagent in situ, preferably at reduced temperature, with a bromide source, preferably hydrogen bromide gas. 3. The method of claim 2, wherein the halogen Wilsmeier reagent is a Wilsmeier bromine reagent. 4. The method of claim 2, wherein the halogen Wilsmeier reagent is a Wilsmeier iodine reagent. 5. The method according to claim 3, characterized in that the Wilsmeier bromine reagent is (bromomethylene) dimethylammonium bromide. A method according to claim 2, characterized in that S ² is - $ O ₃ H, -P / O // 0H / ₂ , -PH / O / OH or - (CHg) - - COOH. A method according to claim 2, characterized in that ΙΑ 2 ² e -C00H. A method according to claim 2, characterized in that the base used to prepare said alkaline medium is selected from the group consisting of hydrides, alkyl lithium, Grignard reagents and metal alkoxides. A method according to claim 3, wherein the base is ethylmagnesium bromide or ethylmagnesium chloride A method according to claim 9, characterized by r> This base is ethyl magnesium chloride. 11. The method of claim 2, wherein the alkyl lithium reagent is sec-butyllithium Method according to claim 2, characterized in that it is - / V / H / C / CH _3/3 13. In a method according to claim 2, characterized in that the compound of formula (IA) is obtained: 0 n C - KE / H / C / CH ₃ / (IA) or a pharmaceutically acceptable salt, hydrate or solvate thereof. 14. A process for the preparation of a steroidal carboxamide substituent characterized in that it involves halogenation of the corresponding carboxylic acid with a Wilsmeier halogen reagent, followed by 1 13 4 by abrupt cooling with excess of H-®, since $ denotes NS 1 where ® and! are independently selected from hydrogen, alkyl, C ₃ _ ^ cycloalkyl, phenyl; or B and ® taken together with the nitrogen to which they are attached are a 5-6 membered saturated ring containing to each other a heteroatom selected from oxygen and nitrogen. A method according to claim 14, characterized in that -17- The Wilsmeyer halogen reagent is obtained by 3 Zaichs .-, e ^;, stzi < preferably at reduced temperature, a chloride source such as oxalyl chloride or thionyl chloride is a disubstituted formamide reagent, such as a dialkyl-over-substituted formamide reagent, preferably dimethylformamide, in a suitable solvent, preferably methylene reagent, methylene chloride, said Wilsmeier chlorine reagent reacts in situ, preferably at reduced temperature with a bromide source or is an iodide source, preferably a hydrocarbon gas. 15. The method of claim 15, wherein the halogen is bromine. The process of claim 16, wherein the bromine reagent is Wilsmeier receives it and uses an in situ A method according to claim 17, characterized in that the bromine reagent of Wilsmeier bromide 19. A method for the preparation of steroidal halo-1,3-dienes, characterized in that it involves halogenation of the corresponding unsaturated ketone with a Wilsmeier halogen reagent 20 ,. A method according to the Wilsmeier halogen reagent is obtained by a method of purification. preferably at reduced temperature, such as oxalyl chloride or thionyl chloride, with a mamide hahihxxxx ό <= γ®ητ, such as a dialkyl-substituted form; a copper reagent, preferably dimethylformamide, in a suitable solvent, preferably methylene chloride, to form a Wilsmeier chlorine reagent, said Wilsmeier chlorine reagent reacting in situ, preferably at reduced temperature, with a bromide source or with an iodide source, preferably bromozorodotrod gas. 21. 'etude according to claim 19, received compound is steroids d en 22. '' etude according to l retention 19, get it is toto co elin et ^tt 'e is steroids day 23. ^{, vol} according to claim 21, characterizing oh this, h is broio-1,3-diene. characterizing it is MS this, h is C-bromo-C, 5-diene. characterized , -h this, that the halogen reagent of Vilsiaier bromide. 24. A method for halogenating a (broiomethylene) dimethylammonium multifunctional group on one iolucule, characterized in that it is halogenated; of the molecule with multifunctional groups is a halogen reagent of Belspaner. 25. The method according to claim 24, wherein the halogenated Wilsmeier reagent is obtained by reaction, preferably at reduced temperature, of a chloride source, such as oxalyl chloride or thionyl chloride, with a dsubstription of rioramide reagent reagent, , preferably dimethylformamide, with a suitable solvent, preferably methylene chloride, to form a Wilsmeier chlorine reagent, such as said Wilspayer chlorine reagent _x in sieve, preferably at lower one temperature, with a bromide source or with an iodide source, preferably bromohydrogen gas