AU666167B2 - Halogenation using halo-vilsmeier reagent - Google Patents

Description

OPI DATE 03/08/93 APPLN. ID AOJP DATE 14/10/93 PCT NUMBER 34348/93 I1111 II II PCT/US93/00079 ll llllll1 1 11111111IIII AU9334348 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 93/14106 C07J 43/00, 41/00 Al (43) International Publication Date: 22 July 1993 (22.07.93) (21) International Application Number: PCT/US93/00079 (72) Inventors; and Inventors/Applicants (for US only): BAINE, Neil, Howard (22) International Filing Date: 6 January 1993 (06.01.93) [US/US]; 216 Edgehill Road, Merion, PA 19066 (US).

KLINE, Donald, Nathaniel [US/US]; 912 Mill Grove Priority data: Drive, Audubon, PA 19403 MEWSHAW, Ri- 07/817,179 6 January 1992 (06.01.92) US chard, Eric [US/US]; 8511 Drumwood Road, Towson, 07/941,348 4 September 1992 (04.09.92) US MD 21204 OWINGS. Franklin [USiUS]; 5030 Copley Road, Philadelphia, PA 19144 (US).

Parent Applications or Grants (63) Related by Continuation (74)Agents: DUSTMAN, Wayne, J. et al.; SmithKline Bee- US 07/817,179 (CIP) cham Corporation, Corporate Patents-U.S., UW2220, Filed on 6 January 1992 (06.01.92) 709 Swedeland Road, P.O. Box 1538, King of Prussia, US 07/941,348 (CIP) PA 19406-0939 (US).

Filed on 4 September 1992 (04.09.92) (81) Designated States: AT, AU, BB, BG, BR, CA, CH, CZ, (71) Applicant (for all designated States except US): SMITH- DE, DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, MG, KLINE BEECHAM CORPORATION [US/US]; One MN, MW, NL, NO, NZ, PL, RO, RU, SD, SE, SK, US, Franklin Plaza, P.O. Box 7929, Philadelphia, PA 19101 European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN, TD, TG), Published With international search report.

(54)Title: HALOGENATION USING HALO-VILSMEIER REAGENT (57) Abstract The invention provides an improved process for the preparation of a halogenated steroidal diene. The process involves the simultaneous transformation of the steroidal 3-one to 3-halo and 17-carboxylic acid to 17-carboxamide in a single reaction without the isolation of an intermediate. The process takes place by reacting the steroidal starting material with a halogen-Vilsmeier reagent.

WO 93/14106 PCr/~US93/00079 1 "HALOGENATION USING HALO-VILSMEIER REAGENT".

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 Nc.

5,017,568, issued on May 21, 1991 to Holt et al., as being useful in inhibiting steroid 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-bromointermediates (in 40% yield) followed by catalytic or alkyllithium mediated carboxylation (in 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 and is not readily available in the bulk amounts needed for an industrial process.

The use of oxalyl chloride to halogenate steroidal a,3-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,P-unsaturated ketones to halo- 1,3-dienes. Preferably, said method will brominate cr iodinate steroidal a,p-unsaturated ketones to their corresponding halo-1,3-dienes.

SUMMARY OF 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,f3-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-one-4-ene-17carboxylic acid steroidal compounds.

This invention specifically relates to an improved process for the preparation of 17f-carboxamide-3-carboxylic acid.

According to one aspect of the present invention there is provided a process for the preparation of a compound of formula (I) i* 30 0 II R, *l ^-R

(I)

951 127,pAopcr\dab,34348.spc,2 2a in which:

R

1 is NR 3

R

4 where R 3 and R 4 are each independently selected from hydrogen, C 1 8 alkyl, C 3 -6 cycloalkyl, phenyl; or R 3 and R 4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturateC ring containing up to one other heteroatom selected from oxygen and nitrogen; and

R

2 is an acid or ester; or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting, at a reduced temperature (as hereinbefore defined), a compound of formula (II)

O

-OH

(II)

C

in the presence of a halogen-Vilsmeier reagent and a solvent then quenching with excess H-R 1 where R 1 is as defined above, to form a compound of formula (III)

O

II 1

C,R

30

(III)

halogen in which: halogen is bromine or iodine; and

R

1 is as defined above and 35 subsequently, in an appropriate solvent and at a reduced temperature (as hereinbefore defined), adding an lkyllithium reagent followed by a coupling reagent to form F4t! 951127,p:\oper\dab,34348.spe,2 2b a compound of formula provided that when R 3 and/or R 4 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, hydrate or solvate.

According to another aspect of the present invention there is provided a process for the preparation of a steroidal carboxamide substituent which comprises halogenation of the corresponding carboxylic acid with a halogen-Vilsmeier reagent followed by quenching with excess

H-R

1 in which R 1 is NR 3

R

4 where R 3 and R 4 are each independently selected from hydrogen, C 1 8 alkyl, C 3 -6 cycloalkyl, phenyl; or R 3 and R 4 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.

The present invention also provides a process for the preparation of a steroidal halo-1,3-dienes which comprises halogenation of the corresponding a, -unsaturated ketone with a halogen-Vilsmeier reagent.

The present invention further provides 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.

30 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 17carboxylic 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 ecification and claims the carbons of the steroid /7 951127,p:oper\dab,34348.spe,2 04 WO 93/14106 PCT/US93/00079 3 nucleus are numbered and the rings are lettered as follows: /12\ 17 11 C 13D I /16 2 8 1 I A I B I 3 7 4 6 By the term "reduced temperature" as used herein is meant below 25 0 C, preferably between -15 and 15 0 C, most preferably between 0 and 10 0

C.

By the term "coupling reagent" as used herein is meant a compound and/or conditions which are capable of reacting with a metalated moiety to form an acid, ester, Cl-6alkylcarbonyl or C 1 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(O)(OH) 2 PH(O)OH, -S0 3 H and -(CH 2 )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 methylene chloride, ethylene chloride, chloroform, 'WO 93/14106 PCT/US93/00079 4 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: Rs /H R \X©Y wherein R 5 and R 6 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 sitj, 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 in 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 WO 93/14106 PCT/US93/00079 reagents preferably the corresponding chloro-Vilsmeier reagent. As such, this invention will have utility in all reactions wherein bromo-Vilsmeier reagents or iodo- Vilsmeier reagents are utilized.

Preferred alkyllithium reagents for use herein include n-butyllithium, aj-butyllithium 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 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) 0 IIxR

C

R (i) in which:

R

1 is NR 3

R

4 where R 3 and R 4 are each independently selected from hydrogen, C-g 8 alkyl, C 3 6 cycloalkyl, phenyl; or R 3 and R 4 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

2 is an acid, ester, C-g 6 alkylcarbonyl or C1-20 alkyl; or a pharmaceutically acceptable salt, hydrate or WO 93/14106 PCr/US93/00079 6 solvate thereof, which comprises reacting, at a reduced temperature, a compound of formula (II) 0 11KOH

C

(II)

in che presence of a halogen-Vilsmeier reagent and a solvent then quenching with excess H-R 1 where R 1 is as described above, to form a compound of formula (III) 0 II R

C

(III)

in which R 1 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 provided that when R 3 and/or R 4 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 WO 93/14106 PCr/US93/0079 7 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.

As used herein, unless otherwise specified, C1-n alkyl means a straight or branched hydrocarbon chain having C1-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-Vilsmeier reagent is a bromo-Vilsmeier reagent.

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

Preferred organic acids used to describe R 2 in formula include; -COOH, (OH) 2 -PH(O) (OH), -S0 3 H and -(CH 2 )1_3COOH. Particularly preferred among the above acids is -COOH.

Preferred bases utilized in preparing the basic medium used to selectively deprotonate th- amide of WO 93114106 PCTIUS93/00079 8 formula (III) compounds include metal hydrides, alkyllithium reagents, Grignard reagents and metal alkoxides. Preferred among the above disclosed ba3es 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 0 C, most preferably between 30 and 50 0

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 a,p-unsaturated ketones utilizing a halogen- Vilsmeier reagent prepared and utilized in situ.

A preferred aspect of the invention is the halogen- Vilsmeier 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-R 1 where R 1 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) WO 93/14106 PCT/US93/00079 II N(H)C(CH 3 3

C

(IIIA)

and converting the same into the following compound of structure (IA) 0

HO-C'

(IA)

or a pharmaceutically acceptable salt, hydrate or -rlvate 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. SYNTHETIC EXAMPLES Dimethylformamide, oxalyl chloride, oxalyl bromide, tert-butylamine, 2.0M ethylmagnesium chloride in THF, 1.2M sec-butyllithium in cyclohexane, and cholesten-3-one are available from Aldrich Chemical Co.

(Milwaukee, WI). Hydrogen bromide gas and carbon dioxide gas are available from Matheson Rutherford, NJ).

WO 93/14106 PC/US93/00079 Androst-4-en-3-one-17p-carboxylic acid ,s available from Berlichem, Inc. (Wayne, NJ). 3-Bromo-androsta-3,5-diene- 17p-carboxylic acid was prepared as described in U.S.

Patent 5,017,568 (Example Example 1 17p-rr(1,1-dimethylethyllaminolcarbony11androsta-3.5diene-3-carboxylic acid 3-Bromo-N-(1, 1-dimethylethyl)-androsta-3,5-diene- 17p-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 0 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 0-100C. 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-cafboxylic 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 0 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 vacuum distillation. The solution was restored to its WO 93/14106 PCT/US93/00079 11 original volume with acetone. This concentration/fill procedure was repeated twice more. The resulting acetone solution (about 300 mL) was warmed to about 500C 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 0

C.

(ii) 17p-[[(1,1-dimethylethyl)amino]carbopyl]androsta- 3,5-diene-3-carboxylic acid A solution of 10.0 g (1 molar equivalent) of 3bromo-N-(1,1-dimethylethyl)-androsta-3,5-diene-17pcarboxamide in 250 mL of dry THF was warmed to 30 0

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 40-500C. After stirring for 20 minutes, the reaction was cooled to 0-5 0 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 WO 93/14106 PCT/US93/00079 12 of 17p-[[(1,1-dimethylethyl)amino]-carbonyl]androsta- 3,5-diene-3-carboxylic acid. Yield 63%, mp 248-2490C.

Example 2 3-Bromo-N-(1.1-dimethylethyl- androsta-3. 5-diene-17pcarboxamide 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 0 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 0

C.

WO 93/14106 PCT/US93/00079 13 Example 3 3-Bromocholesta-3.5-diene A solution of 10 mL of methylene chloride 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 wau stirred at -5 0 C for minutes, and 1.0 gram (1 molar equivalent) of cholesten-3-one in 6 mL of methylene chloride was added to the white suspension. The solution was allowed to 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 64-670C.

Example 4 3-Bromo-N-(l.l-dimethylethyl)-androsta-3.5-diene- 175-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 0 C, and treated with oxalyl bromide 1.71 g (2.5 molar equivalents) while maintaining the temperature between 0-10 0 C. A white precipitate formed. Androst-4-en-3one-178-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 minutes. The reaction was treated with tert-butylamine 2.2 ml (8 molar equivalents) in methylene chloride (2 WO 93/14106 PCT/US93/00079 14 ml) while maintaining the temperature between 0-10 0

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,l-diemthylethyl)-androsta-3,5-diene- 178-carboxamide. yield 58%. MP 177-179 0

C.

14a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "rcomprise", or variations such as "comprises"i or "cornprisingf, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

06 s* o 951 I 2 7,PAOPerab,34348sp, 14

Claims (21)

1. A process for the preparation of a compound of formula (I) O c-R R2 (I) R2 in which: R 1 is NR 3 R 4 where R 3 and R 4 are each independently selected from hydrogen, C 1 8 alkyl, C 3 -6 cycloalkyl, phenyl; or R 3 and R 4 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 2 is an acid or ester; or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting, at a reduced temperature (as hereinbefore defined), a compound of formula (II) o 0. o 0 S S S S. (II) in the presence of a halogen-Vilsmeier reagent and a solvent then quenching with excess H-R 1 where R 1 is as defined above, to form a compound of formula (III) 951 127,p:oper\dab,34348.spc,15

16- (III) halogen in which: halogen is bromine or iodine; and R 1 is as defined above and subsequently, in an appropriate solvent and at a reduced temperature (as hereinbefore defined), adding an alkyllithium reagent followed by a coupling reagent to form a compound of formula provided that when R 3 and/or R 4 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, hydrate or solvate. 2. A process according to claim 1 in which the halogen-Vilsmeier reagent is prepared by reacting a chloride source with a disubstituted formamide reagent in an appropriate solvent to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ with a bromide source or an iodide source. 3. A process according to claim 2 in which the 30 reactions are performed at reduced temperatures (as hereinbefore defined). 4. A process according to claim 2 or claim 3 in which the chloride source is oxalyl chloride or thionyl chloride. 5. A process according to any one claims 2 to 4 in which the disubstituted formamide reagent is dialkyl S 951127,p p b,34348.s .9 0l 951127,p:\opci\dab,34348.spc,16

17- substituted formamide reagent. 6. A process according to claim 5 in which the dialkyl substituted formamide reagent is dimethyl formamide. 7. A process according to any one of claims 2 to 6 in which the appropriate solvent is methylene chloride. 8. A process according to any one of claims 2 to 7 in which the bromide source is hydrogen bromide gas. 9. A process according to any one of the preceding claims in which the halogen-Vilsmeier reagent is a bromo- Vilsmeier reagent. A process according to any one of claims 1 to 8 in which the halogen-Vilsmeier reagent is an iodo-Vilsmeier reagent. 11. A process according to claim 9 in which the bromo- Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide. 12. A process according to any one of the preceding claims in which R 2 is: -S03H, (OH) 2 -PH(O)OH or -(CH 2 )1_ 3 -COOH. 13. A process according to any one of claims 1 to 11 in which R 2 is -COOH. 14. A process according to any one of the preceding claims 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. 15. A process according to claim 14 in which the base is ethylmagnesium bromide or ethylmagnesium chloride. 951127p.op\dab3434 pe,17 *IA/ f 951127p:\opcrdab,34348.spe, 17 -18- 16. A process according to claim 14 or claim 15 in which the base is ethylmagnesium chloride. 17. A process according to any one claims in which the alkyllithium reagent is

18. A process according to any one claims in which R 1 is -N(H)C(CH 3 3 .0 19. A process according to any one claims in which the compound prepared is of the preceding sec-butyllithium. of the preceding of the preceding 3 3 (IA) or a pharmaceutically acceptable salt, hydrate or solvate thereof. A process for the preparation of a steroidal carboxamide substituent which comprises halogenation of the corresponding carboxylic acid with a halogen-Vilsmeier reagent followed by quenching with excess H-R 1 in which R 1 is NR 3 R 4 where R 3 and R 4 are each independently selected from hydrogen, C1-8 alkyl, C3_ 6 cycloalkyl, phenyl; or R 3 and R 4 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. S S 4

21. A process according to claim 20 in which the halogen-Vilsmeier reagent is prepared by reacting a chloride S 35 source with a disubstituted formamide reagent in an 4 appropriate solvent to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ with a bromide S951127,p\opr\dab34348sp 951127,p:\opc\dab,34348.spe,18 19- source or an iodide source.

22. A process according to claim 21 in which the reactions are performed at reduced temperatures (as hereinbefore defined).

23. A process according to claim 21 or claim 22 in which the chloride source is oxalyl chloride or thionyl chloride.

24. A process according to any one claims 21 to 23 in which the disubstituted formamide reagent is dialkyl substituted formamide reagent.

25. A process according to claim 24 in which the dialkyl substituted formamide reagent is dimethyl formamide.

26. A process according to any one of claims 21 to in which the appropriate solvent is methylene chloride.

27. A process according to any one of claims 21 to 26 in which the bromide source is hydrogen bromide gas.

28. A process according to any one of claims 20 to 27 in which the halogen is a bromine. S. 29. A process according to claim 28 in which the bromo- Vilsmeier reagent is prepared and utilized in situ. 06 01 30 30. A process of claim 29 in which the bromo-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.

31. A process for the preparation of a steroidal halo- 1,3-dienes which comprises halogenation of the corresponding 35 a,/-unsaturated ketone with a halogen-Vilsmeier reagent. .0 S32. A process according to claim 31 in which the S951127,p b,4348.s ,19 i "951 127,p:\opcdb,34348.spc,19 halogen-Vilsmeier reagent is prepared by reacting a chloride source with a disubstituted formamide reagent in an appropriate solvent to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ with a bromide source or an iodide source.

33. A process according to claim 32 in which the reactions are performed at reduced temperatures (as hereinbefore defined).

34. A process according to claim 32 or claim 33 in which the chloride source is oxalyl chloride or thionyl chloride.

35. A process according to any one claims 32 to 34 in which the disubstituted formamide reagent is dialkyl substituted formamide reagent.

36. A process according to claim 35 in which the dialkyl substituted formamiae reagent is dimethyl formamide.

37. A process according to any one o" claims 32 to 36 in which the appropriate solvent is methylene chloride. 25 38. A process according to any one of claims 32 to 37 in which the bromide source is hydrogen bromide gas. S39. A process according to any one of claims 31 to 38 in which the compound prepared is a steroidal bromo-1,3- diene.

40. A process according to any one of claims 32 to 38 in which the compound prepared is a steroidal 3-bromo-3,5- diene.

41. A process of claim 40 in which the halogen- Vilsmeier reagent is (bromomethylene) dimethyl ammonium

951127.p:\opcr\dab.34.348.spc,20 -21 bromide. 42. A process for the halogenation of multiple functional groups on a single molecule which ccmprises halogenation of a molecule with multiple functional groups with a halogen-Vilsmeier reagent. 43. A process according to claim 42 in which the halogen-Vilsmeier reagent is prepared by reacting a chloride source with a disubstituted formamide reagent in an appropriate solvent to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ with a bromide source or an iodide source. 44. A process according to claim 43 in which the reactions are performed at reduced temperatures (as hereinbefore defined). A process according to claim 43 or claim 44 in which the chloride sources is oxalyl chloride or thionyl chloride. 46. A process according to any one claims 43 to 45 in whi-h the disubstituted formamide reagent is dialkyl 25 sulbtituted formamide reagent. 47. A process according to claim 46 in which the dialkyl substituted formanide reagent is dimethyl formamide. 30 48. A process according to any one of claims 43 to 47 in which the appropriate solvent is methylene chloride. 49. A process according to any one of claims 43 to 48 in which the bromide source is hydrogen bromide gas. S 00e 7 l 951127,p:\operdab,34348.spc,21 -22- A process for the preparation of a compound of formula substantially as hereinbefore described with reference to the Examples. DATED this 27th day of November, 1995 SmithKline Beecham Corporation By Its Patent Attorneys DAVIES COLLISON CAVE I o r o if .SSJ -r 951 127,pAopctrdb,34348.spe,22 INTERNATIIONAL SEARCH REPORT International application No, PCTIUS93/00079 A. CLASSIFICATION OF SUBJECT MATITER :C071 43/00, 41/00 US CL -540/108,110; 5521610 According to in mational Patent Classification (lPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) STN-Reg Structure Search. Structure hits searched with Vilsmeier reagents. C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A USA 5,017,568 (HOLT, ET AL) 1-24 21 MAY 1991 See entire document Further documents are listed in the continuation of Box C. E: See patent family annex. Special categore of clited documnts:b W"lae document pub!limed after the rnentoa iling data or prority date and nom in conflict with the application but cited to understand the documnent deinins the general Vale of the art which is o oniee princilo or theory, underlying the itiveta to be pard of particular relevance *E erlir dcumet pblihedon o afer he Rt~ W documnent of portiuhar relevance the claimed invenitoc cannot be arler ocumnt ublshe on r aterthe ilig catecoosiered novel or cannot be conaidered to involve to inventive step LU docmn which may throw doubts n priority claim(s) or which is when the documentnis taken alone cited to establish the publicatiosi date of another citation or other Y special mama (as specified) Y documnnt of particular relevance; the claimed invention cannot be comidered to involve an inventive step when the document.i .0 documnent referring to an oral disclosure, ue. exhibition or other combined with ow or more otherihcocmel, sch cobiation MeINS being obvious to a person skiHLed in the ait .r documnent p~lisbed prior to the int::ratiosul filin te bu W" documient member of the sme~ patent Eamily the priority date Date of the actual completion of the international P.Arch 24 MARCH 1993 Date of mailing of the in etional search report APR~ 19 r) i Name and mailing address of the ISAJUS Commnissioner of Paet& and Trademarks Box PcI' Washington, D.C. 20231 Authorized officer /Al KIMBERLX-.KETLER Telephone No. (703) 308-1235 Fnrmp PrTqS d V11fl econ i sheeft~il t y 199)1