AP370A

AP370A - Process for the preparation of substituted steroidal dienes.

Info

Publication number: AP370A
Application number: APAP/P/1993/000473A
Authority: AP
Inventors: Neil Howard Baine; Donald Nathaniel Kline; Richard Eric Mewshaw; Franklin Owings
Original assignee: Smithkline Beecham Corp
Priority date: 1992-01-06
Filing date: 1993-01-05
Publication date: 1994-11-10
Also published as: JPH07505138A; KR940703849A; AU3434893A; OA09961A; AP9300473A0; SK80094A3; WO1993014106A1; BG98887A; BR9305786A; MX9300025A; MA22761A1; TW300226B; HUT68273A; EP0643723A1; HU9402030D0; FI943214A0; NZ246788A; AU666167B2; CA2127272A1; EP0643723A4

Abstract

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

Description

Field of the Invention

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.

Background of the Invention

Processes for the preparation of substituted steroidal diene derivatives, have previously been described. In particular the use of oxalyl bromide to convert steroidal a,P~unsaturated-3-ketones to 3-bromo3.5- diene intermediates (in 40% yield) followed by catalytic or alkyllithium mediated carboxylation (in 15% yield when N-butyl lithium was used) to yield steroidal3.5- 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 and is not readily available in the bulk amounts needed for an industrial process.

The use of oxalyl chloride to halogenate steroidal a,β-unsaturated ketones to chloro-steroidal dienes proceeds with only marginal results. Furthermore, the relatively low reactivity 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 halogenate steroidal a,β-unsaturated ketones to halo1, 3-dienes. Preferably, said method will brominate or iodinate steroidal a,β-unsaturated ketones to their

ΖΓ.

f r

( ²5

SUMMARY QF THE INVENTION

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

This invention relates to an improved process for converting steroidal a, β-unsaturated ketones to their corresponding halo-1,3 diene derivatives.

This invention relates to an improved process for the formation of acid-halide from a steroidal carboxylic acid substituent followed by nucleophilic displacement of said halide.

This invention specifically relates to an improved process for the in situ conversion of steroidal carboxylic acids to steroidal carboxamides.

This invention specifically relates to a process for the simultaneous bromination and amidation of 3-one4-ene-17-carboxylic acid steroidal compounds.

This invention specifically relates to an improved process for the preparation of N-t-butyl-androst-3,5diene-1 7β -carboxamide-3-carboxylic acid.

Detailed Description .of the Invention

By the term simultaneous as used herein is meant that the transformation of the steroidal 3-one to 3-halo and 17-carboxylic acid to 17-carboxamide is performed in a single reaction without the isolation of an intermediate .

As used above and throughout the remainder of the specification and claims the carbons of the steroid

i.

nucleus are numbered and the rings are lettered as follows:

6

By the term reduced temperature as used herein is meant below 25°C, preferably between -15 and 15°C, most preferably between 0 and 10°C.

By the term coupling reagent as used herein is 10 meant a compound and/or conditions which are capable of reacting with a metalated moiety to form an acid, ester, Cx_galkylcarbonyl or Ci_20^alkyl moiety. Preferably said metalated moiety is a lithium metalated moiety prepared by reacting the corresponding halogenated moiety with an alkyllithium reagent. Compounds useful as coupling reagents include chloro formates, alkyl bromides and acid chlorides. Preferably said coupling reagent will utilize carbon dioxide as the reacting compound.

(

By the term acid as used herein is meant any group which is capable of acting as a proton donor including but not limited to; -COOH, -P(0)(OH)2,

PH(O)OH, -SO3H and - (CH2)1-3-COOH.

By the term ester as used herein 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 or appropriate solvent as used herein is meant an organic solvent such as

a.

carbon tetrachloride, tetrahydrofuran (THF), ethyl ether carbon, toluene or ethyl acetate.

By the term halogen-Vilsmeier reagent as used herein is meant a halogenated disubstituted formamide reagent of the structure:

^eZ

N:

z b

\ Y©

X©Y wherein R$ and are independently selected from an alkyl, aryl or arylalkyl group; and X is Br or I; and y is a counter ion, which is prepared by

a) reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodine source, preferably hydrogen bromide gas or

b) reacting, preferably at reduced temperatures, a bromide source or an iodide source, preferably oxalyl bromide, with a disubstituted formamide reagent, such as a dialkyl substituted formamide reagent preferably dimethylformamide in an appropriate solvent, preferably methylene chloride.

This invention, therefore, relates to the jji situ prepartation and use of a bromo-Vilsmeier reagent or an iodo-Vilsmeier reagent, said reagents being prepared safely and economically from known and readily available

reagents preferably the corresponding chloro-Vilsmeier reagent. As such, this invention will have utility in all reactions wherein bromo-Vilsmeier reagents or iodoVilsmeier reagents are utilized.

Preferred alkyllithium reagents for use herein include n-butyllithium, sec-butvllithium and tertbutyllithium.

Unless otherwise specified the term halogen and its derivatives as used herein means bromine or iodine.

Pharmaceutically acceptable salts, hydrates and solvates of Formula (I) compounds are formed where appropriate by 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)

in which:

R¹ is NR^r⁴, where R^ and R⁴ are each independently 25 selected from hydrogen, Ci_galkyl, Cg-gcycloalkyl, phenyl; or R^ and R⁴ taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; and

R^ is an acid, ester, Ci_galkylcarbonyl or Ci_20 alkyl;

or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting, at a reduced temperature, a compound of formula (II)

OH (II) in the presence of a halogen-Vilsmeier reagent and a solvent then quenching with excess H-R¹, where R¹ is as described above, to form a compound of formula (III)

(III) in which R¹ is as defined above and subsequently, in an appropriate solvent and at a reduced temperature, adding an alkyllithium reagent followed by a coupling reagent to form a compound of formula (I), provided that when R³and/or R⁴ is H the compound of formula (III) is subjected to a basic medium suitable for the selective deprotination of the amide prior to the addition of the alkyllithium reagent, and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferably said halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide

reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloroVilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas.

As used herein, unless otherwise specified, Ci__nalkyl means a straight or branched hydrocarbon chain having Ci__n carbons.

As used herein, unless otherwise specified, alkyl means a straight or branched hydrocarbon chain.

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

Preferably the halogen-vilsmeier reagents used in the dihalogenation of formula (II) compounds are prepared and utilized in situ.

Preferably said halogen-Vilsmeiei; reagent is a bromo-Vilsmeier reagent.

Preferably said bromo-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.

Preferred organic acids used to describe R² in formula (I) include; -COOH, -P(O)(OH)₂, -PH(O)(OH), -SO3H and -(CH₂)1-3COOH. Particularly preferred among the above acids is -COOH.

Preferred bases utilized in preparing the basic medium used to selectively deprotonate the amide of (

f' 25 (

f' 25 formula (III) compounds include metal hydrides, alkyllithium reagents, Grignard reagents and metal alkoxides. Preferred amori*g the above disclosed bases are ethylmagnesium bromide, butyllithium and ethylmagnesium chloride. Particularly preferred among the above disclosed bases is ethylmagensium chloride. Preferably the selective deprotonation of said amide is conducted at a temperature above 25°C, most preferably between 30 and 50°C.

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

A preferred aspect of the invention is the preparation of steroidal halo-1,3-diene systems from steroidal α,β-unsaturated ketones utilizing a halogenvilsmeier reagent prepared and utilized in situ.

A preferred aspect of the invention is the halogenVilsmeier induced formation of an acid halide moiety from a steroidal carboxylic acid moiety, said acidhalide substituent being subject to displacement by a nucleophilic reagent. Preferred nucleophilic reagents as used herein include H-R¹ where R¹ is as defined above. Especially preferred among the above nucleophilic reagents is tert-butylamine.

Preferably, therefore, the process of the present invention is particularly useful for preparing a compound of structure (IIIA)

and converting the same into the following compound of structure (IA)

II

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.

I.......SINTiiElIC EXAMPLES

Dimethylformamide, oxalyl chloride, oxalyl bromide, tert-butylamine, 2.0M ethylmagnesium chloride in THF, 1.2M sec-butyllithium in cyclohexane, and (+)-4cholesten-3-one are available from Aldrich Chemical Co. (Milwaukee, WI). Hydrogen bromide gas and carbon dioxide gas are available from Matheson (E. Rutherford, NJ,.

Androst-4-en-3-one-17p-carboxylic acid is available from Berlichem, Inc. (Wayne, NJ). 3-Bromo-androsta-3,5-diene17p-carboxylic acid was prepared as described in U.S. Patent 5,017,568 (Example 25B(ii)).

Example 1

17p-r f (1.1-dimethyletbvJ.l aminol carbonyl 1 androsta-3. 5diene-3-carboxylic acid ( 25 (i) 3-Bromo-N- (1,1-dimethylethyl)-androsta-3, 5-diene17p-carboxamide

A flask under nitrogen atmosphere was charged with 100 mL of methylene chloride and 6.12 mL (2.5 molar equivalents) of dimethylformamide. The solution was cooled to 0-5°C, and was treated with 6.9 mL (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0-10°C. A white precipitate formed. After stirring for one hour, 50.1 grams (19.6 molar equivalents) of hydrogen bromide gas were bubbled through the solution while maintaining the temperature between 0-10°C. The suspension became a clear colorless solution. The solution was degassed by reducing the solution volume by about one-half by vacuum distillation and restoring to its original volume with methylene chloride. This concentration/refill procedure was repeated. Androst-4-en-3-one-17p-carboxylic acid, 10.0 grams (1 molar equivalent), was added to the resulting white suspension and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched into a vessel containing 100 mL of methylene chloride and 23.1 grams (10 molar equivalents) of tert-butylamine while maintaining the temperature between 0-10°C. The mixture was stirred for 30 minutes. About 100 mL of water were added and the biphase mixture was filtered through a pad of Celite. The organic phase was separated and reduced to about half its volume by

original volume with acetone. This concentration/fill procedure was repeated twice more. The resulting acetone solution (about 300 mL) was warmed to about 50°C and was treated with about 100 mL of water to precipitate the product. The suspension was cooled, and the product, 3bromo-N-(1,1-dimethylethyl)-androsta-3,5-diene-17pcarboxamide, was isolated by filtration and dried. Yield 89%, mp 181-183°C.

(ii) 17β-[[(1,1-dimethylethyl)amino]carbonyl]androsta3,5-diene-3-carboxylic acid

A solution of 10.0 g (1 molar equivalent) of 3bromo-N- (1,1-dimethylethyl)-androsta-3, 5-diene-173~ carboxamide in 250 mL of dry THF was warmed to 30°C under a nitrogen atmosphere. The solution was treated with 29 mL of 2.0M ethylmagnesium chloride (2.5 molar *

equivalents) in THF, and the temperature was allowed to rise to about 40-50°C. After stirring for 20 minutes, the reaction was cooled to 0-5°C and treated with 82.5 mL of 1.2M sec-butyllithium in cyclohexane (2.5 molar equivalents). After stirring for 5 minutes, excess dry carbon dioxide was bubbled through the solution. The gassing was continued as the solution was allowed to warm to room temperature. The resulting suspension was then washed with 100 mL of 3.3M aq. hydrochloric acid and the aqueous phase was removed. The organic phase was washed twice with about 150 mL of water. About 85 mL of water was added to the organic phase, and the organic phase was then removed by distillation under reduced pressure. The resulting aqueous suspension of product was extracted into 100 mL of methyl ethyl ketone. The aqueous phase was separated and the organic phase was washed with 100 mL of water. The organic phase was treated with 0.6 g of decolorizing carbon and was filtered through celite. Evaporation of the filtrate followed by trituration in ethyl acetate to afford 6.4 g

£..

of 17β-[[(1,1-dimethylethyl) amino]-carbonyl]androsta3,5-diene-3-carboxylic acid. Yield 63%, mp 248-249°C.

Example 2

3-Bromo-N-(1.1-dimethylethyl)-androsta-3.5-diene-17Bcarboxamlde

A solution of 10 mL of methylene chloride containing 5 mg of p-quinone, and 0.328 g (1.8 molar equivalents) of dimethylformamide was cooled to 0°C and treated with 0.85 g (1.6 molar equivalents) of oxalyl bromide. The reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The solution was cooled to about 5°C and 0.95 g (1 molar equivalent) of 3-bromo-androsta-3,5-diene-17p-carboxylic acid in 20 mL of methylene chloride was added to the white suspension. The solution was allowed to warm to room temperature and was stirred for 1.5 hours. The reaction mixture was quenched with 2.2 mL (8.4 molar equivalents) of t-butylamine and stirred for 5 minutes. The mixture was poured into 100 mL of ethyl acetate and the organic phase was washed with 50 mL of 10% aq sodium hydroxide. The aqueous phase was separated and extracted with 50 mL of ethyl acetate. The combined organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to afford a crude solid which was triturated with 24 mL of 50/50 tbutylmethyl ether/hexane. The solid product was isolated by filtration and dried under vacuum to afford 0.5 gram of 3-bromo-N-(1,1-dimethylethyl)-androsta-3,5-diene-17pcarboxamide. The filtrate was concentrated and triturated as above to yield another 0.25 g of product. The total yield of product was 69%. mp 181-183°C.

Example 3

3-Bx.omQChPlest.a-3,5-diene

A solution of 10 mL of methylene chloride 5 containing 0.24 mL (1.2 molar equivalents) of dimethylformamide was cooled to 0°C and treated with 0.62 gram (1.1 molar equivalents) of oxalyl bromide. The resulting white suspension was stirred at -5°C for 45 minutes, and 1.0 gram (1 molar equivalent) of (+)-410 cholesten-3-one in 6 mL of methylene chloride was added to the white suspension. The solution was allowed to

I warm to room temperature and was stirred for 30 minutes.

The reaction mixture was poured into a mixture of 100 mL of ethyl acetate and 40 mL of water. The organic phase was separated and extracted with 50 mL of ethyl acetate. The combined organic phases were washed with 10 mL of brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to afford a crude solid which was purified by silica gel chromatography using hexane to afford 1.1 g of 3-bromocholesta-3,5diene. Yield 93%. A sample was recrystallized from methanol-diethyl ether which had mp 64-67°C.

c ( 25

Example .4

3-Bromo-N-(1.1-dimethylethyl)-androsta-3.5-diene17fl-carboxamide

A flask under nitrogen atmosphere was charged with dimethylformamide 0.6 g (2.6 molar equivalents) in methylene chloride (20 ml). The solution was cooled to

0-5°C, and treated with oxalyl bromide 1.71 g (2.5 molar equivalents) while maintaining the temperature between 0-10°C. A white precipitate formed. Androst-4-en-3one-17fi-carboxylic acid 1 g (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 was treated with tert-butylamine

/Γ.

ml) while maintaining the temperature between 0-10°C.

The reaction was stirred for 10 minutes then poured into a mixture of ethyl acetate (150 ml) and 10% sodium hydroxide (50 ml) . The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated to afford a solid. The solid was triturated in a solution of t-Butyl methyl ether (4 ml)/hexanes (4 ml), isolated by filtration and dried to yield 3-Bromo-N- (1,1-diemthylethyl)-androsta-3,5-diene10 17fi-carboxamide. yield 58%. MP 177-179°C.

Claims

1. A process for the preparation of a compound of formula (I) in which:

I R¹ is NR^R^, where and are each independently selected from hydrogen, C^-g alkyl, C3_g cycloalkyl, phenyl; or r3 and R⁴ taken together with the nitrogen to

10 which they are attached represent a 5-6 membered saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; and r2 is an acid or ester;

or a pharmaceutically acceptable salt, hydrate or

15 solvate thereof, which comprises (a) reacting, at a reduced temperature, a compound of formula (II) c

in the presence of a halogen-Vilsmeier reagent and a solvent then quenching with excess H-R¹, where R¹ is as defined above, to form a compound of formula (III)

Π (III) in which halogen is bromine or iodine; and 5 R¹ is as defined above and (b) subsequently, in an appropriate solvent and at a reduced temperature, adding an alkyllithium reagent followed by a coupling reagent to form a compound of formula (I),

10 provided that when and/or R⁴ is H the compound of formula (III) is subjected to a basic medium suitable for the selective deprotonation of the amide, prior to addition of alkyllithium reagent, and thereafter optionally forming a pharmaceutically acceptable salt,

15 hydrate or solvate.

2. A process according to claim 1 in which the halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source

20 such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent,

25 said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas.

3. A process according to claim 2 in which the

4. A process according to claim 2 in which the halogen-Vilsmeier reagent is an iodo-Vilsmeier reagent.

5 5. A process according to claim 3 in which the bromo-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.

6. A process according to claim 2 in which r2 is:

10 -SO₃H, -P(O)(OH)₂, -PH(O)OH or -(CH₂) 1-3-COOH.

7. A process according to claim 2 in which is -COOH.

15

8. A process according to claim 2 in which the base used to prepare said basic medium is selected from a group consisting essentially of: hydrides, alkyl lithium, grignard reagents and metal alkoxides.

20

9. A process according to claim 8 in which the base is ethylmagnesium bromide or ethylmagnesium chloride.

f

10. A process according to claim 9 in which the ( 25 base is ethylmagnesium chloride.

11. A process according to claim 2 in which the alkyllithium reagent is sec-butyllithium.

30

12. A process according to claim 2 in which R^ is

-N(H)C(CH₃)_3>

13. A process according to claim 2 in which the compound prepared is /Γ.

C-N(H)C(CH₃)

HO-C (ΙΑ) ί

Γ' (

ί

Γ' (

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

14. A process for the preparation of a steroidal carboxamide substituent which comprises halogenation of the corresponding carboxylic acid with a halogenVilsmeier reagent followed by quenching with excess H-R¹in which R¹ is NR³R^, where R³ and are each independently selected from hydrogen, C^-g alkyl, C3--5 cycloalkyl, phenyl; or R³ and R^ taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one other heteroatom selected from oxygen and nitrogen.

15. A process according to claim 14 in which the halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas.

16. A process according to claim 15 in which the halogen is a bromine.

17. A process according to claim 16 in which the bromo-Vilsmeier reagent is prepared and utilized in situ5

18. A process of claim 17 in which the bromoVilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.

10 18. A process for the preparation of a steroidal halo-1,3-dienes which comprises halogenation of the corresponding α,β-unsaturated ketone with a halogenVilsmeier reagent.

15

19. A process according to claim 18 in which the halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl

20 substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide

25 source or an iodide source, preferably hydrogen bromide gas .

20. A process according to claim 19 in which the compound prepared is a steroidal bromo-1,3-diene.

21. A process according to claim 19 in which the compound prepared is a steroidal 3-bromo-3,5-diene.

22. A process of claim 21 in which the halogen35 Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.

I.- -4

23. A process for the halogenation of multiple functional groups on a single molecule which comprises halogenation of a molecule with multiple functional groups with a halogen-Vilsmeier reagent.

24. A process according to claim 23 in which the halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a

10 disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ,

15 preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas .