Title of Invention

A PROCESS FOR THE PREPARATION OF A 3-OXO-4-AZASTEROID FROM A CORRESPONDING 4-AZA-ANDROSTEN-3-ONE.

Abstract An improved process for preparing steroids, such as 3-oxo-4-azasteroids, is described. Compounds of this type are known to be useful in the preparation of compounds having 5a-reductase inhibitor activity. The process comprises the hydrogenation of the corresponding steroid alkene in the presence of ammonium acetate, ammonium formate, and/or ammonium propionate and an appropriate catalyst.
Full Text
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"A PROCESS FOR THE PREPARATION OF A 3-0X0-4-AZASTER0ID FROM A CORRESPONDS
4-AZA-AHDR0STEN-3-0NE"
Field of the Invention
The present invention relates to an improvement in a process for the preparation of steroids. More particularly, the invention is concerned with improvements in a process tor preparing steroids, such.as 3-oxo-4-azasteroids, by hydrogenation of the corresponding steroid alkene. Compounds of this type are known to be useful in the preparation of compounds having 5a-reductase inhibitor activity.
Background of the Invention
Steroid 5 -reductases catalyze conversion of testosterone to DHT in an NADPH dependent fashion as shown in Scheme A.

The inhibition of the conversion of testosterone to DHT is anticipated to be useful in the treatment of a variety of androgen responsive diseases, e.g., benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness and hirsutism. Hence, 5 -reductase inhibitors have been the subject of active research worldwide. For example, see: Hsia, S. and Voight, W., J, Invest Derm., 62, 224 (1973); Robaire, B. et a/. J. Steroid Biochem,, 8, 307 (1977); Petrow, V, et al, Steroids, 38, 121 (1981); Liang, T". et a/., J. Steroid Biochem., 19, 385 (1983); Holt, D, et a/., J. Med. Chem., 33, 937 (1990); U.S. Patent No. 4,377,584, U.S. Patent-No. 4,760,071 and U.S. Patent No. 5,017,568. One

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particularly promising 5 -reductase inhibitor is MK-906 (Merck), known by the generic name, finasteride, and marketed under the trademark, Proscar, is an inhibitor of type 2 5 -reductase. In addition, dual inhibitors of type 1 and 2 human 5 -reductase are disciosed in WO 95/07926 and WO 95/07927. the contents of which are incorporated herein by reference.
Processes for the preparation of the 5 -reductase inhibitors are described in WO 95/07926, WO 95/07927, US 4,760,071, US 4,377,584, US 4,179,453, US 5,670,643 and Bhattacharya, A. et a/., J. Am. Chem. Soc, 110, 3318 (1988). Important intermediates in the preparation of 5 -reductase inhibitors are 4-aza-5a-androstan-3-ones, e.g. 3oxo-4-azaandrost-17P-carboxy]ic_acid,..which can be prepared by hydrogenation of the corresponding 4-aza-androst-5-en-3-one, e.g. l3-bxo-4-azaandrost-5-en-17p-carboxylic acid. WO 95/07926 and WO95/0792/Udescribe a process by which.a.17p-substituted 4-aza-androst-5-en-3-one is converted to the corresponding 17p-substituted 4-aza-5 -androstan-3-one-by hydrogenation. For example, the hydrogenation may be carried out in acetic acid at 60_to 70°C and 276-414 kPa (40-60 psi) hydrogen pressure in the presence of catalytic platinum oxide.
The problem to be solved by the present invention is the provision of a superior, and more selective process for the hvdroqenation of steroid alkenes.
Summary of the Invention
Scheme 1 shows the hydrogenation of a steroid, 3-oxo-4-azaandrost-5-en-17p-carboxylic acid, to the corresponding 5 -androstane and 5 -androstane isomers. 5a-androstane isomer produced using the reaction can be used in the preparation or 5 -reductase inhibrtors. For large scaie manufacture, a hydrogenation process which could be carried out at atmospheric pressure was desired. However, as demonstrated by the experiments below, considerable problems relating to


3

The present inventors have found a process for hvdroaenating steroid alkenes which can be performed at atmospheric pressure. The problem of low : ratios was solved by carrying out the hydrogenation in the presence of ammonium acetate, ammonium formate or ammonium propionate.
Accordingly, the present invention provides a process for hvdroqenatinq steroid alkenes comprising the step of hydrogenating one or more double bonds in.the presence of ammonium acetate, ammonium formate, ammonium propionate, or mixtures thereof and an appropriate catalyst.
A further aspect of the invention is the use of the process of the invention in the preparation of a 5 -reductase inhibitor.
Detailed Description of the Invention
The hydrogenation process provided by the present invention may be used in place of previous hydrogenation processes in the. preparation of 5 -reductase inhibitors, for example, in the preparation of 5a-reductase inhibitors as described in WO 95/07926, WO95/07.927..US 4,37.7,584,-US4,7.60,071_JUS^179,453I US 5,670,643,and Bhattacharya, A. et al., J. Am. Chem. Soc, 110, 3318 (1988).
In one embodiment, the invention provides a process for the- preparation of a steroid which comprises the hydrogenation of the corresponding steroid alkene in the presence of ammonium acetate, ammonium formate and/or ammonium

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propionate and an appropriate catalyst. Preferably the steroid is a 3-oxo-4-azasteroid. Preferably, the steroid alkene is a 4~aza-androsten-3-one.
In a preferred aspect of the invention, the 3-oxo-4-azasteroid is a compound of formula (I)

wherein:
R1 represents hydrogen, OH, C1-6alkyl, aryl or a heteroaromatic group;
R2 represents hydrogen, C1-6alkyl, aryl or a heteroaromatic group;
R3 represents hydrogen, OH, C1-6 straight or branched chain alkyl, C1-6 straight or.
branched chain alkoxy, aryl, heteroatomic group, or NHQ wherein Q represents
hydrogen, OH, C1-6 straight or branched chain alkyl, C1-6 straight or branched
chain alkoxy, (A)

wherein R4 and R5 are independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, halogen, phenyl (optionally substituted with one or more halogens), or when R4 and R5 are on adjacent carbons, taken together form a fused 5, 6 or 7 member ring optionally containing one or more oxygen or sulfur atoms;

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W and Z are methylene groups which taken together with the carbon to which they are attached form a saturated, 3 to 12 member ring system optionally:
1) substituted independently with one or more lower alkyl groups,
2) containing an oxygen or sulfur atom,
3) two said methylene groups of said 3 to 12 member ring are joined with a (C1-6)
alkylene group to form a bicyclic ring system; and

wherein R6 is trifluoromethyl, phenyt optionally substituted with one or more halogens or branched (C4-7) alkyl groups, or branched (C4-7) alkyl; either of R7 or R8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens or branched (C4-7)alkyl groups, or branched (C4-7) alkyl, while the other is hydrogen or halogen; and
X is hydrogen or halogen.
wherein the R groups are as defined above.
Preferably the 4-aza-androsten-3-one is 4-aza-androst-5-en-3-oneOMore preferably the 4-aza-androst-5-en-3~one is a compound of formula (II):


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As used herein the term 'lower" in relation to alkyl and alkoxy means 1 to 6 carbons, especially 1 to 4, straight or branched. As used herein the term "branched (C4-7) alkyl" means 3-6 carbons attached via a quaternary carbon, e.g., t-butyl, t-amyl, etc,
As used herein, the tdlrm "heteroaromatlc group" means rings containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms. Examples of 5-membered groups include thiophene, thiazole, pyrrole, pyrazole, imidazole and furan, whilst 6-membered groups include pyridyl, pyrazyl and pyrimidyl.
As used herein, the term "halogen" means fluorine, chlorine, bromine and iodine.
As used herein, the term "steroid" means a tetracyclic cyclopenta[a]phenanthrene.
As used herein, the term "steroid alkene" means a steroid having one or more double bonds.
Preferably, R1 is hydrogen. Preferably R2 is hydrogen.
Preferably R3 is hydrogen, OH, C4-7 alky!, C4-7 alkoxy or NHQ. More preferably R3 is hydrogen.
Preferably Q is hydrogen, OH, C1-6 straight or branched chain alkyl, C1-6 straight or branched chain alkoxy, or (B)

wherein R6 is trifluoromethyl or branched (C4-7) alky!; either of R7 or R8 is trifluoromethyi while the other is hydrogen; and X is hydrogen. More preferably Q is hydrogen, C4-7 straight or branched chain alkyl or 2,5-

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bis(trifluoromethyl))phenyl. Most preferably Q is tert-butyl or 2,5-bis(trifluoromethyi))phenyl.
It is to be understood that the present invention covers all combinations of suitable, convenient and preferred groups described hereinabove.
The hydrogenation process is suitably carried out in the presence of ammonium acetate, ammonium formate and/or or ammonium propionate. Ammonium acetate, ammonium formate, ammonium propionate or a mixture thereof are suitably present in the range 1-25% w/w compared to substrate, preferably 2-10%, more preferably 2.5-5%, most preferably approximately 2.5%. The hydrogenation process is preferably carried out in the presence of ammonium acetate. Preferably the ammonium acetate, ammonium formate and/or ammonium propionate is added to the reaction mixture at the start of the reaction.
Suitable catalysts for the hydrogenation reaction are: Pt2O,Pt/Ct Pd/C, Pd(OH)2 and Ni catalysts. Preferably the catalyst is Pt2O, Pt/C, Pd/C or Pd(OH)2, more preferably Pt2O.
The process of the invention is suitably carried out at a pressure range 103-3447 kPa (15-500 psi). Preferably the pressure range is 103-414 kPa (15-60psi).
The process of the invention is suitably carried out at temperature 50-75°C. Preferably at approximately 55°C.
4-aza-androsten-3-ones may be prepared by any method known in the art for the preparation of compounds of analogous structure. For example, a suitable method for the preparation of compounds of formula (II) is disclosed in WO 95/07926.
Those skilled in the art will appreciate that in the preparation of the compound of formula (I) or a solvate thereof it may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. The protecting groups used in the preparation of the compound of

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formula (I) may be used in a conventional manner. See for example Protective Groups in Organic Chemistry, Ed. J.F.W. McOmie, Plenum Press, London (1973) or Protective Groups in Organic Synthesis, Theodora Green, John Wiley and Sons, New York (1981).
The process of the invention -can be used in the Dreoaration of 5 -reductase
inhibitors by any method known in the art, for example as described in WO
95/07926, WO95/O7027, :US 4,37-7,584,. US 4.760,071, US 4,179,453, US
5,670,643, Bhattacharya, A. et al., J. Am. Chem. Soc, 110, 3318 (1988), and as
shownnn the Examples. A further.aspect,of the invention is therefore the use of
the process of-the-invention in the preparation of a 5a-reductase inhibitor, such
as, 17 -(N-t-butylcarbamoyl)-4-aza-5a-androst-1 -en-3-one or 17 -N-(2,5-
bis(trifluoromethyl))phenylcarbamoyl-4-aza-5a-androst-1-en-3-one. In other
words, a 5 -reductase inhibitor, such as 17p-(N-t-butylcarbamoyI)-4-aza-5a-
androst-1-en-3-one or 17 -N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-4-aza-
5 -androst-1-en-3-one, may be prepared using a process comprising, the
process of the invention. In the preparation of 5 -reductase inhibitors it will be
understood that the process of the invention may be used either for the
elimination of a double bond at an intermediate stage in the preparation of the
5 -reductase inhibitor, or as the last main step in a preparative sequence. For
example, in the preparation of 17p-N-(2,5-bis(trifiuoromethyl))phenylcarbamoyl-
4-aza-5 -androst-1-en-3-one the hydrogenation process may be used for the
elimination of a double bond at an intermediate stage in preparation, see for
example Scheme 2 below. Preferably, 17p-N-(2,5-
bis(trifluoromethyl))phenylcarbamoyI-4-aza-5a-androst-1-en-3-one is prepared by a method comprising the process of the invention, e.g. hydrogenating a compound of formula (II) to a compound of formula (I), followed by: (i) dehydrogenation, e.g. of a compound of formula (I) such as 4-aza-5 -
androstan-3~one-17p-carboxylic acid, to insert a double bond between
carbons 1 and 2; (ii) reaction with the compound of formula (111)

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;and
(iii) if necessary and/or desired, subjecting the compound thus obtained to one or more further reactions comprising;
(a) removing any protecting group or groups; and/or
(b) converting the compound or a solvate thereof into a pharmaceutically
acceptable solvate thereof.
The following examples illustrate aspects of this invention but should not be construed as limiting the scope of the invention in any way.

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Examples:
EXAMPLE 1: Preparation of 17 -N-f2,5-bis(trifluoromethvl))phenvlcarbamoyl-4-aza-5 -androst-1-en-3-one

Stage 1:17p-carboxy-5-oxo-A-nor-3,5-secoandrostan-3-oic acid (1)
Typical scale 34.0 kg
A solution of sodium periodate (183 kg, 7.9 eq.) and potassium permanganate (1.4 kg, catalytic.) in water (410 I) was heated at 75-80°C with stirring to effect solution. A mixture of 3-oxo-4-androstene-17(5carboxylic acid (CCI4837, 17-ADCA) (34.0 kg, 1 eq.), Na2CO3 (29 kg, 2.5 eq.), tert-butanol (580 I) and water (60 I) was heated at reflux (75-80°C) under a nitrogen atmosphere. The aqueous solution of sodium periodate / potassium permanganate was added to the refluxing CCI4837/ f-butanol/ water slurry, allowing for evolution of carbon dioxide at a controlled rate. Water (25 S) was used as a line wash following the addition. The mixture was heated at reflux (75-80°C) for about 1 hour. The

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mixture was cooled, and acetic acid (135 I) added while the contents were further cooled. The mixture was filtered, and the filter cake washed with tert-butanol (130 I) and acetic acid (135 I). The filtrate/ wash was transferred back into the reaction vessel through a filter, and vacuum distilled at Stage 2: 3-oxo-4-aza-5-androstene-17p-carboxylic acid (2)
Typical scale 54.0 kg
A mixture of the Seco-Acid 1 (54.0 kg, 1 eq.), NH4Oac (47 kg, 4.1 equiv.) and HOAc (190 I) were stirred at reflux for at least three hours. The mixture was cooled and water (190 I) was added. The mixture was stirred for at least 2 hours. The product was isolated by filtration, washed with water and dried at up to 55°C under vacuum with a nitrogen purge. Weight range: 45-51 kg (85-95% theory, 83-93% w/w).
Stage 3: 4-aza-5a-androstan-3-one-17p-carboxyHc acid (3).
Typical scale 33.5 kg
The hydrogenation vessel was charged with acetic acid (530 I), 3-oxo-4-aza-5-androstene-17p-carboxylic acid 2 (33.5 kg.), and ammonium acetate (1.0 kg, 0.1 eq.)- After purging at 20-25°C with nitrogen, the platinum oxide catalyst (3.0 kg.) was charged, the stirrer started and the temperature adjusted to 20-25°C. After purging with hydrogen, the stirring batch was allowed to take up hydrogen. After 30 minutes at
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Stage 4: 4-aza-5a-androst-1-ene-3-one-17p-carboxylic (4). Typical scale 20.0 kg
The reaction vessel was charged with dioxane (180 I), 4-aza-5a-androstan-3-
one-17 -carboxylic acid 3 (20.0 kg, 1 eq.) and 2,3-dichIoro-5,6-
dicyanobenzoquinone (DDQ) (15.6 kg, 1.1 eq.).
Bis(trimethylsily!)trifluoroacetamide (BSTFA) (78 I, 4.7 eq.) was added. The reaction mixture was heated to reflux and maintained at reflux for 2-4 hours. The mixture was cooled to Stage 5: (5a,17p)-N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide (5).
Typical scale 18.0 kg
A mixture of 4-aza-5a-androst-1-ene-3~one-17p-carboxylic acid 4 (18.0 kg, 1 eq.), toluene (540 I), pyridine (11.2 kg, 2.5 eq.) and dimethylformamide (0.2 kg, cat.) was stirred and cooled to
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solids were removed by filtration and washed with ethyl acetate (270 I). The combined filtrate/wash was extracted four times with 10% potassium hydroxide (57 I each). The organic solution was washed with 1N hydrochloric acid (57 I) and water (57 I). The resulting solution was concentrated in vacuo at

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EXAMPLE 2: Influence of ammonium acetate on the hydrogenation of 3-oxo-4azaandrost-5-ene-17 -carboxvlic acid
The hydrogenation vessel was charged with HOAc (16 vol.), 3-oxo-4-
azaandrost-5-ene-17 -carboxylic acid (1 wt), and NH4OAc (0.025 wt), while
maintaining the temperature at 20-25°C. The system was purged three times
with N2. The PtO2 (0.12 wt) was charged, stirring was initiated and the
temperature was adjusted to 20-25°C. The vessel was again purged three times
with N2; following the third purge, stirring was stopped and the vessel purged
three times with H2- Stirring was resumed and the batch allowed to take up
hydrogen. The temperature was maintained at 20-25°C for the first 30 minutes,
adjusted to 60-65°C over 30 minutes, and maintained until the reaction was
complete. Following reaction completion, stirring was stopped and the vessel
was purged three times with N2. Solka Floe (0.05 wt) was charged and stirring
was resumed. The hot reaction mixture was recirculated through a GAF filter
until the solution was clear and the hot reaction filtrate was then transferred to a
clean vessel. The reaction vessel was charged with HOAc (3 vol.), heated to 60-
65°C and stirred for at least 5 minutes. The hot rinse was filtered through the
GAF filter and combined with the reaction filtrate. Volume was reduced in vacuo
to 3.6 volumes and the resulting slurry was cooled to 20-25°C. Methanol (4 vol)
was added to the slurry and the mixture was "aged" to obtain a more filterable
particle for 2-24 hours at 20-25°C. The product was isolated by filtration and

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washed with methanol (1.5 vol). The resulting solid was dried on the filter for at least 30 minutes, then dried in vacuo at 50-60 °C for 12-18 hours.
Results
Following successful campaigns using 276-345 kPa (40-50 psi) H2 pressure, where a:p ratios had been >9:1, manufacturing constraints necessitated additional investigations at atmospheric H2 pressure. Unfortunately, atmospheric hydrogenation resulted in a:p ratios of 10:1 (Table 1). Contrary to literature precedent, ammonium chloride was not effective. Also ineffective were ammonium dihydrogen phosphate, and sodium acetate. Tetramethylethylenediammonium (TMEDA) acetate, was effective at improving the : ratio, but significantly retarded the hydrogenation.
The results of a pilot study at 0%, 2.5% and 10% NH4OAc loads are shown in Table 2. Atmospheric hydrogenation at 2.5 w/w% NH4OAc load was successfully applied to batches of >30 kg input each (Table 3), supplying 83-85% isolated yields of 3-oxo-4-aza-5aandrostane (2) of >99% purity.



nd = not detected

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WE CLAIM:
1. A process for the preparation of a 3-oxo-4-azasteroid from a corresponding 4-aza-
androsten-3-one comprising the step of hydrogenating one or more double bonds in the
presence of ammonium acetate, ammonium formate or ammonium propionate or
mixtures thereof and an appropriate catalyst.
2. A process as claimed in claim 1 wherein the 3-oxo-4-azasteroid is a compound of
formula (I):

wherein:
R1 represents hydrogen, OH, C1-6 alkyl, aryl or a heteroaromatic group;
R2 represents hydrogen, C1-6 alkyl, aryl or a heteroaromatic group;
R3 represents hydrogen, OH, C1-6 straight or branched chain alkyl, C1-6 straight or branched
chain alkoxy, aryl, heteroaromatic group, or NHQ wherein Q represents hydrogen, OH,
C1-6 straight or branched chain alkyl, C1-6 straight or branched chain alkoxy, (A)


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wherein R4 and R5 are independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, halogen, phenyl (optionally substituted with one or more halogens), or when R4 and R5 are on adjacent carbons, taken together form a fused 5, 6 or 7 member ring optionally containing one or more oxygen or sulfur atoms;
W and Z are methylene groups which taken together with the carbon to which they are attached form a saturated, 3 to 12 member ring system optionally:
1) substituted independently with one or more lower alkyl groups,
2) containing an oxygen or sulfur atom,
3) two said methylene groups of said 3 to 12 member ring are joined with a (C1-6)
alkylene group to form a bicyclic ring system; and
X is hydrogen or halogen or(B)

wherein R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens or branched (C4-7) alkyl groups, or branched (C4-7) alkyl;
either of R7 or R8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens or branched (C4-7)alkyl groups, or branched (C4-7) alkyl, while the other is hydrogen or halogen; and
X is hydrogen or halogen.
3. A process as claimed in claim 1 or 2 wherein the 4-aza-androsten-3-one is a 4-aza-androst-5-en-3-one of formula (II)


wherein:
R1 represents hydrogen, OH, C1-6 alkyl, aryl or a heteroaromatic group;
R2 represents hydrogen,C1-6 alkyl, aryl or a heteroaromatic group;
R3 represents hydrogen, OH, C1-6 straight or branched chain alkyl, C1-6 straight or branched
chain alkoxy, aryl, heteroaromatic group, or NHQ wherein Q represents hydrogen, OH,
C1-6 straight or branched chain alkyl, C1-6 straight or branched chain alkoxy, (A)

wherein R4 and R5 are independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, halogen, phenyl (optionally substituted with one or more halogens), or when R4 and R5 are on adjacent carbons, taken together form a fused 5, 6 or 7 member ring optionally containing one or more oxygen or sulfur atoms;
W and Z are methylene groups which taken together with the carbon to which they are attached form a saturated, 3 to 12 member ring system optionally:
1) substituted independently with one or more lower alkyl groups,
2) containing an oxygen or sulfur atom,

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3) two said methylene groups of said 3 to 12 member ring are joined with a (C1-6) alkylene group to form a bicyclic ring system; and
X is hydrogen or halogen or(B)

wherein R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens or branched (C4-7) alkyl groups, or branched (C4-7) alkyl;
either of R7 or R8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens or branched (C4-7)alkyl groups, or branched (C4-7) alkyl, while the other is hydrogen or halogen; and
X is hydrogen or halogen.
4. A process as claimed in claim 2 or 3 wherein R1 is hydrogen; R2 is hydrogen; and
R3 is hydrogen, OH, C1-4 alkyl, C1-4alkoxy or NHQ.
5. A process as claimed in any one of claims 2-4 wherein Q is hydrogen, OH, C1-6
straight or branched chain alkyl, C1-6 straight or branched chain alkoxy, or (B)


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wherein R6 is trifluoromethyl or branched (C4-7) alkyl; either of R7 or R8 is trifluoromethyl while the other is hydrogen; and X is hydrogen.
6. A process as claimed in any one of claims 2-5 wherein Q is hydrogen,
C1-4straight or branched chain alkyl or 2,5-bis(lrifluoromethyl)phenyI.
7. The process as claimed in any one of claims 1-6 wherein the process is carried
out in the presence of ammonium acetate.
8. The process as claimed in any one of claims 1-7 wherein the ammonium acetate
is present in the range 1-25% w/w.
9. The process as claimed in any one of claims 1-8 wherein the ammonium acetate
is present in the range 2.0-10% w/w.
10. The process as claimed in any one of claims 1-9 wherein the catalyst is selected
from Pt2O, Pt/C, Pd/C, Pd(OH)2 and Ni catalysts.
11. The process as claimed in any one of claims 1-10 wherein the catalyst is selected
from Pt2O, Pt/C, Pd/C or Pd(OH)2.
12. The process as claimed in any one of claims 1-11 wherein the catalyst is Pt2O.
13. The process as claimed in any one of claims 1-12 wherein the process is carried
out within the pressure range 103-3447 kPa.
14. The process as claimed in any one of claims 1-13 wherein the pressure range is
103-414 kPa.
15. The process as claimed in any one of claims 1-14 wherein the process is carried
out within the temperature range 50-70°C.

16. A process as claimed in claims 1 or 2 wherein the 4-aza-androsten-3-one is a 4-
aza-androst-5-en-3-one.
17. The process as claimed in any one of claims 1-15, comprising the steps of:
(i) dehydrogenation to insert a double bond between carbons 1 and 2; and
(ii) reaction with the compound of formula (III)

and (iii) if necessary and/or desired, subjecting the compound thus obtained to one or more further reactions comprising:
(a) removing any protecting group or groups; and/or
(b) converting the compound or a solvate thereof into a pharmaceutically
acceptable solvate thereof,
to obtain the compound 17p-N-(2,5-bis(trifluoromethyl)phenylcarbamoyl-4-aza-5 -androst-1 -en-3-one.
An improved process for preparing steroids, such as 3-oxo-4-azasteroids, is described. Compounds of this type are known to be useful in the preparation of compounds having 5a-reductase inhibitor activity. The process comprises the hydrogenation of the corresponding steroid alkene in the presence of ammonium acetate, ammonium formate, and/or ammonium propionate and an appropriate catalyst.

Documents:


Patent Number 207384
Indian Patent Application Number 00470/KOLNP/2003
PG Journal Number 23/2007
Publication Date 08-Jun-2007
Grant Date 08-Jun-2007
Date of Filing 16-Apr-2003
Name of Patentee GLAXO GROUP LIMITED
Applicant Address GLAXO WELLCOME HOUSE, BERKELEY AVENUE, GREENFORD, MIDDLESEX UB6 0NN,
Inventors:
# Inventor's Name Inventor's Address
1 DAVIS ROMAN GLAXOSMITHKLINE, FIVE MOORE DRIVE, P.O.BOX 13398, RESEARCH TRIANGLE PARK, NORTH CAROMINA 27709,
2 MILLAR ALAN GLAXOSMITHKLINE, FIVE MOORE DRIVE, P.O.BOX 13398, RESEARCH TRIANGLE PARK, NORTH CAROMINA 27709,
3 STERBENZ JEFFREY THOMAS GLAXOSMITHKLINE, FIVE MOORE DRIVE, P.O.BOX 13398, RESEARCH TRIANGLE PARK, NORTH CAROMINA 27709,
PCT International Classification Number C07J 5/00
PCT International Application Number PCT/US01/48173
PCT International Filing date 2001-11-02
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0026876.3 2000-11-03 U.K.