SI9300067A - Process for the preparation of substituted steroidal dienes - Google Patents

Abstract

Invented is an improved process for the preparation of substituted steroidal dienes.

Description

Process for the preparation of substituted steroid dienes

The present invention relates to an improved process for the preparation of substituted steroid dienes. Such compounds are described in U.S. Pat. No. 5,017,568, issued May 21, 1991 by Holt et al., For their utility in inhibiting steroid 5-areductase.

Methods for the preparation of substituted steroidal diene derivatives have already been described. In particular, the use of oxalyl bromide for the conversion of steroidal α, 3-unsaturated-3-ketones into 3-bromo-3,5-diene intermediates (at 40% yield), followed by carboxylation, which is catalytic or. with alkyllithium mediator (15% yield using N-butyllithium) to form steroid 3,5-diene-3-carboxylic acid derivatives is set forth in U.S. Pat. No. 5,017,568.

In addition to the low overall yield, another disadvantage of this finding is that oxalyl bromide is a toxic, expensive liquid that is difficult to store and is not commercially available in the large quantities required for the industrial process.

The use of oxalyl chloride for halogenation of steroidal α, / 3-unsaturated ketones into chlorosteroidal dienes occurs with marginal results. Furthermore, the relatively low reactivity of the resulting chlorosubstituent causes problems in subsequent transformations. Therefore, there is a need in the art for a safe, economical and reliable process for the conversion of steroidal unsaturated ketones into their corresponding 1,3-diene carboxylic acid derivatives.

The present invention relates to a process for the fluorosulfonylation of multifunctional groups on the same molecule.

The present invention particularly relates to a process for the simultaneous fluorosulfonylation and amidation of 3-on-4-en-17-carboxylic acid steroid compounds.

The present invention particularly relates to an improved process for the preparation of N-t-butylandrost-3,5-diene-17/3-carboxamide-3-carboxylic acid.

From a further aspect of the present invention there are provided new intermediates useful in the process of the present invention.

By the term simultaneously used herein, it is intended that the conversion of sterodine 3-one to 3-fluorosulfonyl and 17-carboxylic acids into 17-carboxamide is carried out in a single reaction without isolation of the intermediate.

Throughout the description and claims, the carbon atoms of the steroid core are numbered and the rings are denoted as follows:

The pharmaceutically acceptable salts, hydrates and solvates of the compounds of formula (I) are formed, where appropriate, by a process well known to those skilled in the art.

The present invention provides a process for the manufacture of a compound of formula (I)

in which:

R ¹ is NR ³ R ^4, wherein R ³ and R ⁴ are each independently selected from hydrogen, C _lg alkyl, _C3 ^ -cycloalkyl, phenyl; or R ³ and R ⁴ together with the nitrogen to which they are attached represent

A 5-6 membered saturated ring comprising at most one different heteroatom selected from oxygen and nitrogen; and is

R ^{2 is an} acid or ester;

or a pharmaceutically acceptable salt, hydrate or solvate thereof comprising (a) the reaction of a compound of formula (II)

(II) with fluorosulfonic anhydride and solvent base;

(b) quenching the reaction with excess HR ¹ , wherein R ^{1 is} as described above to form a compound of formula (III)

in which it is

R ¹ as defined above; and (c) a subsequent reaction of said compound of formula (III) in a metal-catalyzed coupling reaction in the presence of coupling reagent, followed, optionally, if appropriate, by a hydrolysis reaction to form a compound of formula (I) and thereafter the formation of a pharmaceutically acceptable salt, hydrate or solvate thereof.

A preferred reaction for the conversion of compounds of formula (II) to a compound of formula (III) is carried out at a temperature of -78 ° C to 20 ° C; especially preferably in the temperature range from -10 ° C to 10 ° C.

A preferred reaction for the conversion of compounds of formula (III) to compounds of formula (I) is carried out at a temperature of from 25 ° C to 100 ° C; in particular, the temperature range is from 50 ° C to 90 ° C.

As such, compounds of formula III are particularly useful as intermediates in the preparation of compounds of formula I.

As used herein and in the claims, unless otherwise stated, C _{4 n-} alkyl means a straight or branched hydrocarbon chain having 1-n carbon atoms.

By the term acid as used herein and in the claims, we mean any group capable of acting as a proton donor, including but not limited to -COOH, -P (O) (OH) ₂ , -PH (O) OH, -SO ₃ H and - (0¾ ₃ -COOH.

By the term ester as used herein and in the claims, we mean a group consisting of an acid as defined above in which the proton (s) of the donor is replaced by alkyl substituents.

By the term solvent as used herein and in the claims, we mean an organic solvent such as e.g. methylene chloride, ethylene chloride, chlorofor ±, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, dimethyl sulfoxide, methanol or dimethylformamide.

Preferably, the base used to prepare the compounds of formula II is triethylamine or pyridine, most preferably pyridine. Preferably, the solvent used to prepare the compounds of formula II is methylene chloride. Preferably, the catalyst used in said metal-catalyzed coupling reaction of palladium (II) acetate. Preferably the acids used to define R ² in formula (I) include: -COOH, -P (O) (OH) ₂ , -PH (O) OH, -SO ₃ Hin (CH 2 -COOH).

Particularly preferred among the above acids is -COOH.

By the term metal-catalyzed coupling reaction as used herein and the claims it is intended that the prepared fluorosulfonated compound reacts in a suitable organic solvent, preferably dimethylsulfoxide alkanol (C ₁ -C ₆ ) solution (if desired ester) or toluene, dimethylformamide, THF or C ₄ -C ₆ OH (if acid is desired) with a base, preferably a tertiary amine base, such as e.g. triethylamine, pyridine or tributylamine or aqueous KOH or aqueous NaOH; phosphine, such as e.g. bis (diphenylphosphino) alkane, preferably 1,3-bis (diphenylphosphino) propane or tri-otolylphosphine and metal catalysts, preferably palladium catalysts, such as e.g. palladium (II) acetate, palladium (II) chloride, and bis (triphenylphosphine) palladium (II) acetate to form a metallized complex with subsequent addition of coupling reagent.

By the term coupling reagent as used herein and in the claims, we mean a compound capable of being incorporated into said metal complex with subsequent elimination to give the corresponding ester or acid. Preferred coupling reagents which, when added to the metal-catalyzed coupling reaction as described herein, preferably give the acid and ester groups as shown herein, are carbon monoxide (obtain -COOC ^), formic acid (obtain -COOH), ethylributyl stannyl acetate (obtain -CH ₂ COOH), dimethyl phosphite (obtain -ΡζΟχΟΗ) ^ and crystals of hypophosphoric acid (obtain -PH (O) OH).

Using the methods of the present invention for the preparation of preferred compounds of formula (I), new intermediates of the following formula (IV) are synthesized

(IV) in which

R ¹ CONR ³ R ⁴ where R ³ and R ^{4 are} each independently selected from hydrogen, C 1-6 alkyl, C _3-4 cycloalkyl, phenyl; or R ³ and R ⁴ together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising at most one different heteroatom selected from oxygen and nitrogen.

Preferably, therefore, the process of the present invention is particularly useful for the preparation of compounds of structure IIA

(HA) and converting it in one or two steps to the next compound of structure (IA)

N-H (IA)

Ί or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Without further improvement, it is believed that the present invention will be able to take full advantage of the present invention by using the foregoing description. The following examples are therefore drawn up for illustration only and in no way to limit the scope of the present invention.

1,3-bis (diphenylphosphino) propane, bis (triphenylphosphine) palladium acetate and palladium acetate are generally available. Androst-4-en-3-one-17/3-carboxylic acid is available from Berlichem, Inc. (Wayne, NJ).

Fluorosulfonic anhydride was prepared as described by S. Kongprich, et. al., Inorg. Syn. 1968, XI, 151.

Example 1

N-t-butyl-androst-3,5-diene-17 ' 3-carboxamide-3-carboxylic acid (i) N-t-butyl-androst-3,5-diene-3-fluorosulfonyl-17 g-carboxamide

A mixed mixture of androst-4-en-3-one-17,9-carboxylic acid (1 mol eq) and pyridine (3 mol eq) in 1000 ml of methylene chloride was cooled to 0-5 ° C and treated with fluorosulfonic anhydride (2 , 5 mol eq.) While maintaining the temperature between 0-10 ° C. After stirring for 1 hour, the reaction was quenched in a solution of tert-butylamine (10 molar equiv) in methylene chloride while maintaining the temperature between 0-10 ° C. The mixture was stirred for 30 minutes. Add about 100 ml of water. Separate the organic phase and reduce its volume to about half by distillation. The solution is restored to its original volume with acetone. Repeat this concentration / filling process twice more. The resulting acetone solution (about 300 ml) is heated to about 50 ° C and treated with about 100 ml of water to precipitate the product. The suspension was cooled and N-t-butyl-androst-3,5-diene-3-fluorosulfonyl-17 S-carboxamide was isolated by filtration and dried.

(ii) Methyl 17g- (N-tert-butylcarboxamide) -androst-3,5-diene-3-carboxylate

The vessel was filled with dimethyl sulfoxide (1350 ml), methanol (75 ml, 5.4 mol eq), Nt-butyl-androst-3,5-diene-3-flurosulfonyl-17/3-carboxamide (150 g, 1 mol eq), triethylamine (76.3 g, 2.2 mol eq) and 1,3-bis (diphenylphosphino) propane (1.4 g, 0.01 mol eq). The mixture was stirred until a solution was obtained. Palladium acetate (0.768 g, 0.01 mol eq.) Was added and the flask was filled and evacuated with carbon monoxide three times. The vessel was placed under a carbon monoxide atmosphere at a pressure of 4.83.10 ⁴ Pa and the reaction mixture was stirred vigorously. The reaction solution was heated to 75 ° C. The uptake of carbon monoxide is completed in approximately 1.5 hours. The reaction was cooled to 15 ° C and stirred for 2 hours. The solid product was isolated by suction and the mother liquors were used to rinse the inside of the reacto. The solid was washed thoroughly with water (1.5 L) and dried in vacuo at 95 ° C to give pure methyl 17 / 3- (N-tert-butylcarboxamide) -androst-3,5-diene-3-carboxylate.

(iii) N-t-butyl-androst-3,5-diene-17H-carboxamide-3-carboxylic acid

Mixture of methanol (80 ml), water (80 ml), methyl 17 / 3- (N-tert-butylcarboxamide) -androst3,5-diene-3-carboxylate (15.9 g, 1 molar equiv.) And sodium hydroxide (4.80 g, 3 mol.

eq.), heated at reflux for 8-12 hours. The hot reaction solution was filtered through celite and the filter pad was washed with water (80 ml) at 60 ° C. The filtrate was diluted with water (80 ml). The methanol was removed by distillation to a temperature in the column head of 100 ° C. The mixture was cooled to 60 ° C and quenched by vigorous stirring in 1.5 N hydrochloric acid (160 ml). The resulting white suspension was stirred for 15 nlinut. The slurry was cooled to 0-5 ° C and stirred for 1 hour. The product was isolated by filtration, washed with deionized water and dried in vacuo at 100 ° C to give N-t-butyl-androst-3,5-diene-17 / 3carboxamide-3-carboxylic acid.

Example 2

N-t-Butyl-androst-3,5-diene-17/3-carboxamide-3-carboxylic acid

The container was filled with 5 volumes of dimethylformamide, Nt-butyl-androst-3,5-diene-3fluorosulfonyl-17/3-carboxamide (1 mol eq.), Prepared as described in Example 1 (i), tri-n- butylamine (4.5 molar equiv.), formic acid (2 molar equiv.) and bis (triphenylphosphine) palladium acetate (0.02 molar equiv.). Evacuate the flask and fill with carbon monoxide three times. The vessel was placed under a carbon monoxide atmosphere at a pressure of 4.83.10 ⁴ Pa and the reaction mixture was stirred vigorously. The reaction solution was heated to 75 ° C until the carbon monoxide uptake was complete. The reaction mixture was cooled to room temperature. Ethyl acetate was added and water was separated and the organic layer separated. The organic phase was washed with water and dried over magnesium sulfate. The organic phase was concentrated in vacuo to give Nt-butyl-androst-3,5diene-17β-carboxamide-3-carboxylic acid.

Claims (9)

A process for the preparation of a compound of formula (I) wherein: R ¹ is NR ³ R ^4, wherein R ³ and R ⁴ are each independently selected from hydrogen, C _lg alkyl, _C3 ^ -cycloalkyl, phenyl; or R ³ and R ⁴ together with the nitrogen to which they are attached represent A 5-6 membered saturated ring comprising at most one different heteroatom selected from oxygen and nitrogen; and is R ^{2 is an} acid or ester; or a pharmaceutically acceptable salt, hydrate or solvate, characterized in that it comprises (a) reaction of a compound of formula (II) (II) with a fluorosulfonic anhydride and a solvent base, followed by quenching with excess HR ¹ , wherein R ^{1 is} as described above to form a compound of formula (III) (III) in which R ¹ as defined above; and (b) the subsequent reaction of said compound of formula (III) in a metal-catalyzed coupling reaction in the presence of coupling reagent, followed, optionally, by a hydrolysis reaction, to form a compound of formula (I) and thereafter , forming a pharmaceutically acceptable salt, hydrate or solvate thereof. A process according to claim 1, wherein R ^{1 is} -N (H) C (CH ₃ ) ₃ . Process according to claim 1, characterized in that said base is selected from pyridine or triethylamine. Process according to claim 3, characterized in that the base is pyridine. Process according to claim 1, characterized in that the metal-catalyzed coupling reaction comprises 1,3-bis (diphenylphosphino) propane. Process according to claim 1, characterized in that the metal catalyzed coupling reaction comprises palladium acetate. A process according to claim 1, characterized in that the coupling reagent is formic acid. Process according to claim 3, characterized in that the compound prepared or a pharmaceutically acceptable salt, hydrate or solvate thereof. A compound having a structure comprising: R ¹ NR ³ R ⁴ wherein R ³ and R ^{4 are} each independently selected from hydrogen, C 1-6 alkyl, C _3-4 cycloalkyl, phenyl; or R ³ and R ⁴ together with the nitrogen to which they are attached represent A 5-6 membered saturated ring comprising at most one different heteroatom selected from oxygen and nitrogen.