CA2129347A1 - Process of preparing 3-acylandrostadienes - Google Patents

Abstract

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

Description

WO93/1609X PCT/USg3/01071 2~29;~

TooSho~:Pr ~ ssofPTepaing3-Acyl~dros~dienes The present invention relates to an improved process for the preparation of substituted steroidal dienes. Such compounds are described in US Patent No.
5,017,568, issued on May 21, 1991 to Holt et~ al., as being useful in inhibiting steroid 5 a-reductase.

~
Processes for the preparatio~ of substituted steroidal diene derivatives, have previously been described. In particular the use of oxalyl bromide to convert steroidal ~-unsaturated-3-ketones to 3-bromo-3,5-diene intermediates (in 40% yield) followed by catalytic or alkyllithium mediated caI-boxylation (in 15-~yield when N-butyl lithium was used) to yield steroidal--3,5-diene-3-carboxylic acid derivatives is reported in US Patent No. 5,017,568.
In addition to a low overall yield, another shortcoming of this disclosure is that oxalyl bromide is a toxic, expensive liquid which is difficult to store Z~2g347 - -and is not commercially available in the bulk amounts needed for an industrial process.

The use of oxalyl chloride to halogenate steroidal ~,~-unsaturated ketones to chloro-steroidal dienes proceeds with only marginal results. Furthermore, the xelatively low reacti~ity of the resultant chloro substituent poses non-trivial synthetic considerations in subsequent transformations. Thus, there is a need in the art for a safe, economical and reliable method to convert steroidal a,~-unsa~urated ketones to their corresponding carboxylic acid-1,3-dienes derivatives.

SUM~ARY OF THF. INVENTION

This invention relates to a process for the fluorosulphonylation of multiple functional groups on the same molecule.

This invention specifically relates to a process for the simultaneous fluorosulphonylation and amidation of 3-one-4-ene-17-carboxylic acid steroidal compounds.

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

In a further aspect of the invention there are provi.ded novel intermediates useful in the presen~ly invented process.
n9~ u~s~ s~~ he Il~v~ntiQ~

By the term "simultaneous" as used here~n is meant that the transformation of the steroidal 3-one to 3-fluorosulphonyl and 17-carboxylic acid to 17-carbcxamide is performed in a single reaction without the isolation of an intermediate.

W093/16098 3 PCTiUS93/01071 '~1293~7 As used above and throughout the remainder of the specification and claims the carbons of the steroid nucleus are numbered and the rings are lettered as follows:
~12~ ~7 11 C '3D
~1~ ~14--/
I A 1 ~ I
3~7 Pharma~eutically acceptable salts, hydrates and solvates of Formula ~I) compounds are formed where appropriate ~y methods well known to those of skill in the art.

The present invention provides a process for the production of a compound of formula ~I) ~ R1 2 (I) --in which:
Rl is NR3R4, where R3 and ~4 are each independently selec~ed from hydrogen, Cl_~alkyl, ~3_6cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5~6 membered saturated ring comprising up to one other he~eroatom selected from oxygen and nitrogen; and R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises (a) reacting a compound of Formula (II) WO 93/16098 PCI`/US93/01071 .,~, ~ ;, Z~1293~7 , ~

~ (II) with fluorosulfonic anhydride and a base in a solvent;
(b) quenching the reaction with excess H-R1, where R1 is as described above, to form a compound of Formula, (III) O ~ R' F ~ ~ ~III) in which 10R1 is as defined above; and ~ c) subsequently re~cting said compound of formula III in a metal-catalyzed coupling reaction in the presence of coupling reagent, followed by an optional, if applicable, hydrolysis reaction to form a compound of 15 Formula (I), and thereafter optioncllly forming à~
pharmaceutically acceptable salt, hydrate or solvate thereof.
Prefera~)ly the reaction to convert Formula II
compounds to formula III is performed at a temperature from -78C to 20C; A particularly preferred temperature range is from -10G to 10C.

Preferably the reaction to convert Formula I~I
compounds to Formula I compounds is performed at a temperature of 25C to 100C; a particularly preferred temperature ran~e is from S0 to 90C.

'~X9347 As such, compounds of the Formula III are particularly useful as intermediates in the preparation of Formula I compounds.

As used herein and in the claims, unless otherwise specified, Cl_n alkyl means a straight or branched hydrocarbon chain having l-n carbons.

By the term "acid" as used herein and in the claims is meant any group which is capable of acting as a pxoton donor including but not limited to; -COOH, -P(O)(OH)2, -PH(O)OH, -S03H and -(CH2)l_3-COOH.

By the term 'tester" as used herein and in the claims is meant a group consisting of an acid, as defined above, in which the donatable proton or protons are replaced by alkyl substituents.

By the term "solvent" as used herein and in the claims is meant an organic solve~t such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, tolue.ne, ethyl acetate, dimethylsufloxide, methanol or dimethylforamide.
2~
Preferably the ~ase utili~ed to prepare compounds of Formula II is triethylamine or pyridine, most preferably pyridine. Preferably the solvent utilized to prepare compounds of Formula II is methylene chloride.
Preferably the catalyst utilize~ in said metal catalyze~
coupling reaction is palladium (II) acetate. Preferred acids used to describe ~2 in ~ormula (I) include; -CVOH, -P(O)[OH)2, -PH(O)OH, -SO3H, and (CH2)l-CGOH.
Particularly pxeferred among the above acids is -COOH.
By the term "metal-catalyzed coupling reaction" as used herein and in the claims is meant that the prepared X~Z9;~
fluorosulfonated compound is reacted in a suitable organic solvent; preferably a dimethylsulfoxide-alkanol~Cl-C6) solution (when an ester is desired) or toluene, dimethylformamide, THF or C4-C6OH (when an acid is desired) with a base, preferably a tertiary amine base such as triethylamine, pyridine or tributylamine or aqueous KOH or aqueous NaOH; a phosphine such as bis(diphenylphosphino)alkane, preferably l,3 bis(diphenylphosphino)propane or tri-o-tolylphosphine, and a metal catalyst, preferably a palladium catalyst such as palladium ~II) acetate, palladium (II) chloride and bis(triphenylphosphine) palladium II acetate, thereby forming a metalated complex with subsequent addition of a coupling reagent.
By the term "coupling reagent" as used herein and in the claims is meant a compound which is capable of inserting into said metalated complex with subsequent elimination to yield the correspondin~ ester or acid.
Preferred coupling reagents, which when added to the metal-catalyzed coupling reaction, as described herein, yield preferred acid and ester groups, as disclosed herein, are carbon monoxide (to yield -COOCl_6), formic , acid (to yield -COOH), ethyltributylstannyl acetate ~to yield -CH2COOH), dimethyl phosphite (to yield -P~O)(OH)2) a~d hypophosphorous acid ~rystals ~to yield -PH(O)OH).

In utilizing the presently invented process to prepare the preferred compounds of Formula ~I), novel intermediates of the following Formula (IV) are synthesized WO~3/16Q98 PCT/US93/01071 ~7~ Z1293j4~
~

F ~ O ~IV~

in which Rl is CoNR3R4/ whe~e R3 ~nd R4 are each indeper.dently selected from hydrogen, Cl_8alkyl, C3_6cycloalky1, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen.
Preferably, therefore the process of the present invention is particularly useful for preparing a compound of Structure IIA

0~ N-H
~ i ~ S~
2 (IIA) and converting the same in one or two steps into the following compound of structure (IA) N-H

0~/~
Il 23 HO-C ( IA) WO93/160g8 8 PCT/US93/01071 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

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

Fluorosufonic anhydride was prepared as described by S. Kongpricha, et~ al., Inorg. Syn. 1968, XI, 151.

~xamp~e 1 ~ , (i-. N-t-hutyl-andro~t-3.5-diene-3-fluor~sulphonyl-A stirred mixture of androst-4-en-3-one-17~
carboxylic acid (1 molar equivalent) and pyridine (3 molar equivalents) in 1000 mL of methylene chloride is cooled to 0~5C, and is treated with fluorosulfonic anhydride ~2.5 molar equivalents) while maintaining the temperature between 0-10C. After stirring for one hour, the reaction mixture is quenched into a solution of tert-butylamine (10 molar equivalents) in methylene chloride while maintaining the temperature between 0-10C. The mixture is stirred for 30 minutes. About 100 , ~129;~47 mL of water is added. The organic phase is separated and reduced to about half its volume by vacuum distillation.
The solution is restored to its original volume with acetone. This concentration/fill procedure is repeated twice more. The resulting acetone solution (about 300 mL) is warmed to about 50C and is treated with about 100 mL of water to precipitate the product. The suspension is cooled, and N-t-butyl-androst-3,5-diene-3-fluorosulphonyl-17~-carboxamide is isolated by filtration and dried.
(ii) Methyl 17~-(N-tert-hutylcar~oxamide)-androst-A vessel is charged with dimethylsulfoxide ~1350 mL), methanol (75 mL, 5.4 molar equivalents3, N-t-butyl-androst 3,5-diene-3-fluorosulphonyl-17~-carboxamide (150 g, 1 molar equivalent), triethylamine (76.3 g, 2.2 molar equivalents), and l,3-bis(diphenylphosphino)propane (1.4 g, 0.01 molar equivalent). The mixture is stirred until a solution is obtained. Palladium acetate (0.768 g, 0.01 molar equivalent) is added and the flask is filled and evacuated with carbon monoxide three timçs. The vessel is pressurized with 7 psi carbon monoxide and the reaction is stirred rapidly. The reaction solution is heated to 75C. The carbon monoxide uptake is finished 2S in about 1.5 hours. The reaction is cooled to 15~ and stirred for 2 hours. The solid product is isolated by suction filtration, and the mother liquors are used to rinse out the inside of the reactor. The solid product is thoroughly washed with water (1.5 L) and dried under vacuum at 95C ~o afford pure methyl 17~-(N-tert-butylcarboxamide)-androst-3,5-diene-3-carboxylate.
(iii). N-t-hutyl-androst-3,5-di~ne-17~-~C~
A mixture of methaI~ol (80 mL), water (80 mL), methyl 17~-(N-tert-butylcarboxamide)-androst-3,5-diene-3-car~oxylate (15.9 g, 1 molar equivalents) and sodium hydroxide (4.80 g, 3 molar equivalent), is heated to W093/16098 10 PCT/US93~01071 2i29;~

reflux for 8-12 hours. The hot reaction solution is filtered through celite and ~he filter pad i5 washed with 60C water (80 mL). The filtrate is diluted with water (80 mL). The methanol is removed by distillation to a head temperature of 100C. The mixture is cooled to 60C and is quenched with vigorous stirring into 1.5 N hydrochloric acid (160 mL). The resulting white suspension is stirred for 15 minutes. The slurry is cooled to 0-5C and stirred for 1 hour. The product is isolated by filtration, washed with deionized water, and dried under vacuum at 100C to afford N-t-butyl-androst-3,~-diene-17~-carboxamide-3-carboxylic acid.
F.xa~nple 2 ~-t-~utyl-androst-3,5-diene-l7~-carhoxamide-3-arhoxylic aci~
A vessel is charged with 5 volumes of dimethylformamide, N-t-~utyl-androst-3,5-diene-3-fluorosulphonyl-17~-carboxamide (1 molar equivalent, prepared as described in Example l(i)), tri-n~butylamine (4.5 molar equivalents), formic acid (2 molar equivalents) and bis(triphenylphosphine)palladium acetate (0~02 molar equivalents). The flask is evacuated and filled w~th carbon monoxide three times.
The vessel is pressurized with 7 psi carbon monoxide and the reaction is stirred rapidly. The reaction solution is heated to 75C until the uptake of carbon monoxide is complete. The reaction is cooled to room -temperature.
Ethyl acetate and water are added, and the organic layer is separated~ The organic phase is washed with water and dried over magnesium sulfate. The organic phase is concentrated under vacuum to yield N-t-butyl-androst-3,5-diene-17~-carboxamide-3-carboxylic acid.

Claims (9)

What is claimed is:

1. A process for the preparation of a compound of formula (I) (I) in which:
R1 is NR3R4, where R3 and R4 are each independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; and R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises (a) reacting a compound of Formula (II) (II) with fluorosulfonic anhydride and a base in a solvent then quenching with excess H-R1, where R1 is as defined above, to form a compound of Formula (III) (III) in which R1 is as defined above and (b) subsequently reacting said compound of Formula III in a metal-catalyzed coupling reaction in the presence of a coupling reagent, followed by an optional, if applicable, hydrolysis reaction to form a compound of Formula (I) and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate.

2. A process according to claim l in which R1 is -N(H)C(CH3)3

3. A process according to claim l in which said base is selected from pyridine or triethylamine.

4. A process according to claim 3 in which the base is pyridine.

5. A process according to claim l in which the metal-catalyzed coupling reaction comprises 1,3-bis(diphenylphosphino)propane.

6. A process according to claim l in which the metal-catalyzed coupling reaction comprises palladium acetate.

7. A process according to claim l in which the coupling reagent is formic acid.

8. A process according to claim 3 in which the compound prepared is or a pharmaceutically acceptable salt, hydrate or solvate thereof.

9. A compound of the structure in which;
R1 is NR3R4, where R3 and R9 are each independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen.