RU2321592C2 - Method for insertion of 1,2-double bond into 3-oxo-4-azasteroid compounds - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes an improved method for synthesis of 17β-substituted 4-azaandrost-1-en-3-one of the general formula (I):

wherein R means -OH, (C₁-C₄)-alkyl, (C₁-C₄)-alkenyl, phenyl, benzyl and others, or their pharmaceutically acceptable salts. Method involves insertion protective groups into 3-keto-4-aza (lactam) form of compound of the general formula (II):

wherein R has indicated values to form compound of the general formula (III):

wherein R₃ means trialkylsilyl, or in common with R₄ residue -C(O)-C(O)- or -C(O)-Y-C(O)- wherein R₄ means tert.-butyloxycarbonyl preferably; Y means -(CH₂)_n wherein n = 1-4, or ortho-phenylene. Then a synthesized compound is converted in the presence of a dehydrogenation catalyst of in the presence of benzoquinone, allylmethylcarbonate, allylethylcarbonate and/or allylpropylcarbonate, and △¹-double bond is introduced in 1,2-position followed by removal of protective groups and, if necessary, (when R means -OH) conversion to salts. Method provides the high yield and purity degree of synthesized compounds.

EFFECT: improved method of synthesis.

21 cl, 9 ex

Description

The present invention relates to a method for introducing a 1,2-double bond into 3-oxo-4-azasteroids by dehydrogenation of 3-oxo-4-azasteroids saturated at the 1,2-position, in particular by dehydrogenation of 17β-substituted 3-oxo- 4-azasteroids, to obtain the corresponding 17β-substituted 3-oxo-4-azasteroids, which in the 1,2-position have one double bond.

From patent EP 0 155 096 it is known to produce 17β-substituted 4-aza-5-alpha-androstanes with a 1,2-double bond by oxidizing the corresponding 1,2-dihydro compound with a mixture of benzene and selenic acid anhydride. Other methods of introducing a 1,2-double bond into 17β-substituted 4-aza-5-alpha-androstanes are described, for example, also in patents EP 0298652, EP 0428366 and EP 0473225. 17β-substituted 4-aza-5-alpha-androstanes with a 1,2-double bond are pharmaceutically important compounds with a wide spectrum of action. Of particular importance is, for example, the compound 17β- (N-tert-butylcarbamoyl) -4-aza-androst-1-en-3-one (finasteride), which is used, for example, as an inhibitor of 5-alpha reductase for the treatment of benign hyperplasia prostate gland or androgenetic alopecia. Of great importance, for example, is also 17β- {N- [2,5-bis (trifluoromethyl) phenyl]} - 4-aza-androst-1-en-3-one (dutasteride). Known methods for producing these compounds have their particular disadvantages, so there is a need for an improved alternative method.

The present invention relates to such an alternative production method.

The present invention is disclosed in the claims. The present invention relates to a method for producing 17β-substituted 4-aza-androst-1-en-3-ones of the general formula (I):

in which mean:

R hydroxyl, possibly substituted, linear or branched (C ₁ -C ₁₂ ) -alkyl or (C ₁ -C ₁₂ ) alkenyl; phenyl or benzyl; balance

—OR ₁ or the residue —NHR ₁ or the residue —NR ₁ R ₂ ;

R ₁ hydrogen, possibly substituted, linear or branched (C ₁ -C ₁₂ ) -alkyl or (C ₁ -C ₁₂ ) alkenyl, or phenyl, optionally substituted;

R _{2 is} hydrogen, methyl, ethyl or propyl; or

—NR ₁ R _{2 a} 5- or 6-membered heterocycle, and for R = hydroxyl also a pharmaceutically acceptable salt thereof,

characterized in that

(A) to a 3-keto-4-aza group (lactam group) of a compound of general formula (II):

protective groups are introduced, so that a compound of the general formula (III) is formed:

in which mean:

R _{3 is} trialkylsilyl, or together with R _{4 the} residue —C (O) —C (O) - or

-C (O) -Y-C (O) -;

R ₄ alkyloxycarbonyl or phenyloxycarbonyl, preferably Boc (= tert-butyloxycarbonyl); or trialkylsilyl, or together with R _{3 the} residue —C (O) —C (O) - or —C (O) —YC (O) -;

Y is [C (R ₅ ) (R ₆ )] _n -, or —CH (R ₅ ) = CH (R ₆ ) - or orthophenylene;

R ₅ and R ₆ are independently hydrogen, linear or branched (C ₁ -C ₈ ) -alkyl or -alkenyl, phenyl, possibly substituted, or benzyl; and

n is an integer from 1 to 4;

and in case R is hydroxyl, it may have reacted with a protecting group;

(B) the compound obtained [according to step (A)] reacts (i) in the presence of a dehydrogenation catalyst and (ii) in the presence of, possibly substituted, benzoquinone, allyl methyl carbonate, allyl ethyl carbonate and / or allyl propyl carbonate, with Δ ¹ being introduced at the 1/2 position double connection, and

(C) the protective groups R ₃ and R ₄ are removed, and at R = hydroxyl the resulting compound is possibly converted to a salt.

R preferably means linear or branched (C ₁ -C ₆ ) -alkyl, preferably methyl, ethyl, propyl or n-butyl, sec-butyl or tert-butyl, preferably tert-butyl; or balance

—OR ₁ , or the residue —NHR ₁ , or the residue —NR ₁ R ₂ . Preferably, the residue is —NHR ₁ .

If R is hydroxyl (or the residue —C (O) R is carboxyl), a pharmaceutically acceptable salt of a compound of formula (I) can also be prepared according to the invention, preferably an alkali metal salt, alkaline earth metal salt or ammonium salt, preferably sodium salt, potassium or ammonium, preferably a sodium or potassium salt.

R ₁ is preferably linear or branched (C ₁ -C ₆ ) -alkyl, or phenyl optionally substituted. R ₁ as (C ₁ -C ₆ ) -alkyl means preferably methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl, preferably tert-butyl. R ₁ as phenyl, possibly substituted, means preferably mono (trifluoromethyl) phenyl or bis (trifluoromethyl) phenyl, preferably 2,5-bis (trifluoromethyl) phenyl.

In the residue —NR ₁ R ₂ R ₂ preferably means methyl.

The substituent —NR ₁ R ₂ as a 5- or 6-membered heterocycle preferably means a piperidine or pyrrolidine residue.

Preferably, the substituent is —NHR ₁ , wherein R ₁ is tert-butyl or 2,5-bis (trifluoromethyl) phenyl.

R ₃ preferably means trimethylsilyl or together with R _{4 the} residue —C (O) —C (O) - or —C (O) —YC (O) -.

R ₄ preferably means BOC, trimethylsilyl, or together with R _{3 the} residue —C (O) —C (O) - or —C (O) —YC (O) -. Preferably, R ₄ is Boc or, together with R _{3, the} residue —C (O) —C (O) - or —C (O) —YC (O) -.

R ₄ as alkyloxycarbonyl means preferably isobutyloxycarbonyl, tert-butyloxycarbonyl, tert-amyloxycarbonyl, cyclobutyloxycarbonyl, 1-methylcyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, 1-methylcyclohexyl, preferably tert-butyloxycarbonyl.

R ₅ and R _6, independently of one another, are preferably hydrogen, linear or branched (C ₁ -C ₄ ) -alkyl, or phenyl, preferably hydrogen, methyl, ethyl or propyl or phenyl.

n means preferably 1 or 2, preferably 1.

Preferably, Y is the residue —CH (R ₅ ) - or orthophenylene, preferably methylene.

For the introduction of a protective trialkylsilyl group, i.e. to silylate an NH group and / or an oxygen atom or an OH group [according to step (A)], (alkyl) ₃ Si (halogen), for example, (CH ₃ ) ₃ SiCl, or bistrimethylsilyl trihaloacetamide, bistrimethylsilylacetamide, hexamethyldisilazane and / or bistrimethylurea, preferably bistrimethylsilyl trifluoroacetamide, or trialkylsilyl trifluoromethanesulfonate, preferably trimethylsilyl trifluoromethanesulfonate. The conditions for the silylation reaction are known from EP 0473226.

For the introduction of a protective group, when R ₃ together with R ₄ are the residue —C (O) —C (O) - or —C (O) —YC (O) -, a compound of the general formula (II) or a lactam group [according to the step (A)] is reacted with oxalyl chloride (oxalic acid chloride) or malonyl chloride (malonic acid chloride), with oxalyl chloride being preferred. The reaction conditions with oxalyl chloride are known from EP 0428366, and with malonyl chloride or similarly reactive compounds should be used in a similar manner.

To introduce a protecting group when R ₄ is alkyloxycarbonyl, for example tert-butyloxycarbonyl (Boc), a known method is used in which the compound of general formula (II) is reacted, for example, with Boc anhydride (Boc-O-Boc) { [(CH ₃ ) ₃ C — O — C (O)] ₂ —O} or with Boc carbamate [(CH ₃ ) ₃ COC (O) —N (C _1-4 alkyl) ₂ ]. In this case, Boc may also mean other similarly reacting compounds, that is, compounds in which the tert-butyl residue is replaced by another similarly reacting residue, such as, for example, the named residues tert-amyl, cyclobutyl, cyclopentyl or cyclohexyl. Such similar reactions are described in large numbers in the literature. If R ₃ is trialkylsilyl and R ₄ is Boc, then a protective Boc group is introduced first and then silylated.

In step (B), the compound obtained in step (A) is converted in the presence of (i) a dehydrogenation catalyst and in the presence of (ii) benzoquinone, optionally substituted, allyl methyl carbonate, allyl ethyl carbonate and / or allyl propyl carbonate, in the 1- / 2-position Δ ¹ double bond is introduced. The dehydrogenation catalyst is preferably selected from compounds (salts and complexes) of the transition metal group of the periodic system of elements, in particular, selected from metal compounds of group VIII of the periodic system, in particular from iron (Fe), ruthenium (Ru) and osmium (Os); cobalt (Co), rhodium (Rh), and iridium (Ir); nickel (Ni), palladium (Pd) and platinum (Pt), as well as group IB, i.e. copper (Cu), silver (Ag) and gold (Au). Preferred compounds of metals of group VIII of the periodic system. Particularly preferred are rhodium (Rh), palladium (Pd) and platinum (Pt) dehydrogenation compounds or catalysts. Palladium compounds are preferred. Examples of such palladium compounds are: Pd (0) compounds, such as the Tris (dibenzylideneacetone) dipalladium chloroform complex and Pd (II) compounds, such as PdCl ₂ , Pd (dppe) ₂ , [dppe = bis (1,2- diphenylphosphine) ethane], Pd (dppe) Cl ₂ , Pd (OAc) ₂ , Pd (dppe) (OAc) ₂ , p-allyl-Pd complexes, preferably p-allyl-Pd-chloride dimer. Pd (0) compounds are preferred, in particular the tris (dibenzylideneacetone) dipalladium chloroform complex. These compounds, as well as salts and complexes, are known and described in the literature.

For thermal stabilization of the palladium complex, an additional complexing agent such as 2,2'-dipyridyl or 1,10-phenanthroline, preferably 2,2'-dipyridyl, can be used.

To explain the mechanism of catalysis, we can indicate that the Pd element is attached to the C-atom in the 2-position with the removal of the oxygen-protecting group [for example, the group-Si (CH ₃ ) ₃ ]. Subsequent cleavage of beta hydrogen at the C atom at the 1 position results in the formation of the desired Δ ¹ double bond at the 1- / 2 position, and another palladium element is released, which returns to the catalytic cycle. Indications of this reaction mechanism are given in Tetrahydron Letters, p. 4783 (1984). However, the present invention is not associated with this explanation.

As quinone, substituted quinone can also be used, for example quinone substituted with C _1-4 alkyl, halogen, cyano or nitro. Such quinones are known.

In step (C), the resulting compound is converted to a compound of formula (I) by removal of the introduced protecting groups. This preferably takes place by treatment with a suitable acid, for example formic acid, acetic acid and / or trifluoroacetic acid, preferably formic acid. Then, the obtained compound can, if necessary, be converted into a pharmaceutically acceptable salt (for R = hydroxyl) in a known manner.

Preferably, the resulting compound is recrystallized. This recrystallization can be carried out in non-polar solvents such as gasoline, heptane, hexane and toluene, preferably in toluene. By the compound of formula (I) is meant, in particular, the compound 17β- (N-tert-butylcarbamoyl) -4-aza-androst-1-en-3-one (finasteride) mentioned above, which occurs in two polymorphic forms, namely, polymorphic form I and polymorphic form II, wherein form I is preferred. Form I is formed, for example, by recrystallization of the crude finasteride obtained according to the invention from a saturated toluene solution (about one part of the crude finasteride in six parts of toluene) when cooled to about 25 ° C . Polymorphic form II is formed, for example, by recrystallization of the crude finasteride obtained according to the invention from a toluene solution (about one part of the crude finasteride to about six parts of toluene) when cooled to about 0 ° C.

The properties of 17β- {N- [2,5-bis (trifluoromethyl) phenyl]} - 4-aza-androst-1-en-3-one (dutasteride) are known from the literature.

Numerous organic anhydrous compounds, such as, for example, toluene, gasoline, hexane, heptane, tert-butyl alcohol, diethyl ether, acetone, benzene, dioxane, tetrahydrofuran, can be used as the solvent for the described process with steps (A) to (C). , chloroform, dimethylformamide or pyridine. The following examples illustrate the invention.

Example 1 (Substitution of dihydrofinasteride with a Boc group at the nitrogen atom of a 3-keto-4-aza group)

10 g (26.7 mmol) of dihydrofinasteride are placed in tetrahydrofuran (THF) and cooled to -78 ° C. To the resulting suspension was added 15 ml (30 mmol) of lithium diisopropylamide solution (Li-DA solution), and the clear solution was stirred for about 30 minutes. Then a solution of 6.7 g (30 mmol) of Boc-anhydride in THF is added. The solution was allowed to warm to room temperature. After the usual processing, a wet yellow powder is obtained, which is kept in an oven overnight and used directly in Example 2.

Example 2 (Silylation of the compound obtained in example 1)

1 g (2.1 mmol) of 4-Boc-dihydrofinasteride is dissolved in THF. Under cooling with a mixture of ice and methanol, 2.3 ml (4.6 mmol) of a Li-DA solution are added to a clear yellow solution. The suspension was stirred for about 45 minutes, after which 0.46 g (4.2 mmol) of trimethylchlorosilane (TMSCl) was added dropwise at 18-20 ° C. The clear solution was concentrated and the residue combined with heptane. After filtration, the filtrate is concentrated as much as possible and the resulting honey-brown oil is used in the following steps (Example 3 and Example 5).

Example 3 (Introduction Δ ¹ double bond in 4-benzyloxycarbonylfinasteride)

0.145 g (0.65 mmol) of palladium acetate is dissolved with 0.07 g (0.65 mmol) of benzoquinone in acetonitrile and left. 0.8 g (1.5 mmol) of the silyl compound obtained according to Example 3 are combined with acetonitrile and added dropwise at an internal temperature (BT) of 20-25 ° C. The reaction mixture was stirred for 8 hours and purified by silica gel. A slightly colored clear solution was concentrated at ambient temperature of 55-60 ° C. The obtained solid is used in example 4.

Example 4 (Deprotection and Crystallization)

a) 0.5 g of the solid from Example 3 was mixed with 20 g (0.175 mol) of trifluoroacetic acid and heated under reflux for about 15 hours. In this case, trifluoroacetic acid is used both as a reagent and as a solvent. After cooling, the reaction mixture was poured onto a mixture of 300 g of a saturated solution of sodium bicarbonate and 50 g of ice and extracted with 20 g of ethyl acetate;

b) the brown intermediate obtained in the previous step a) is dissolved in toluene at 90 ° C (mass ratio of toluene: feed = 6: 1), cooled to 20-25 ° C. The grayish-white mass precipitated is filtered off at 20-25 ° C and dried. Get finasteride polymorph I.

Example 5 (Introduction of Δ ¹ double bond into 4-benzyloxycarbonylfinasteride)

2.0 g (3.7 mmol) of the compound of Example 2 are mixed with 1.29 g (11.1 mmol) of allyl methyl carbonate in acetonitrile. The mixture was added dropwise to a solution of 166 mg (0.74 mmol) of palladium-II acetate in acetonitrile heated to 60-70 ° C. After 1-2 hours of heating under reflux, it is treated as described in Example 3. 3 g of a solid are obtained.

Example 6 (Introduction of Δ ¹ double bond)

A) 20 g (0.047 mol) of dihydrofinasteride oxalylene tin ester [compound IIIa, with R = —NH-tert-butyl, R ₃ and R ₄ = —C (O) —C (O) -] are heated together with 16.3 g (0.140 mol) allyl methyl carbonate and 76 g of anhydrous acetonitrile to a reflux temperature. Alternately 5 portions of the mixture are added, each containing 18 g of xylene and 0.049 g of the complex Tris (dibenzylideneacetone) dipalladium-chloroform (total molar amount of catalyst 0.284 mmol). Each time you add significant gas formation is observed. After 12 hours of heating under reflux, the reaction is resumed by adding a second portion of a hot mixture containing 3 g of xylene and 0.024 g of a dehydrogenation catalyst (the mixture is slowly heated), if necessary, subsequent portions are added. After filtration, the reaction mixture is concentrated to the extent possible, after which 24.5 g of a yellow, honey-like mass remains.

B) The honey paste is combined with 105 g of methanol and cooled to 0-5 ° C. Slowly add 11.3 g (0.0403 mol) of a 25% potassium methoxide solution and mix for about 1 hour at an internal temperature of 0-5 ° C. Then add 20 g of water and remove the cooling bath, the internal temperature is raised to 15-20 ° C. The mixture was concentrated to dryness, 50 g of water was added to the solid residue, 90 g of toluene and 12 g of methanol were heated at reflux temperature for 1 hour. After stopping the stirrer, the organic and aqueous phases are separated without problems; the organic phase is isolated hot. Cooling within 2-4 hours to 25 ° C leads to finasteride in polymorphic form I to crystallize. After drying, 8.1 g of white powder are obtained.

Example 7

A method similar to that described in Examples 1 to 6 is carried out when a Δ ¹ double bond is introduced into the dihydrodutasteride, i.e. to the corresponding dihydro compound of formula (I) in which R is the radical —NHR ₁ and R ₁ is 2,5-bis (trifluoromethyl) phenyl, and dutasteride is formed by introducing the Δ ¹ double bond.

Example 8 (Preparation of 3-oxo-4-aza-5α-androst-1-en-17β-carboxylic acid methyl ester)

Step 1 (Preparation of Compound IIIb, i.e., Compound of Formula (III), where R = —OMe, R ₃ and R ₄ = —C (O) —C (O) -)

2 g (0.005 mol, content> 95%) of 3-oxo-4-aza-5α-androst-1-ene-17β-carboxylic acid methyl ester are mixed with 30 g of toluene and 2.6 g (0.019 mol) are slowly added while cooling ) oxalyl chloride. Gradually, constant gas formation begins. The turbid mixture was stirred overnight. Excess oxalyl chloride and toluene are removed from the clear reaction solution at room temperature and under reduced pressure by distillation to half the original volume. In this case, a white solid precipitates, which is filtered and washed intensively three times with heptane 15 g each time. After drying by suction, 1.6 g of crude methyl ester remains. It is combined with approximately 20 g of dichloromethane, the turbid solution is washed extensively with 33 g of a 5% potassium carbonate solution, the mixture is filtered and the organic phase is washed three times, using 10 g of water each time. The clear, colorless organic phase was concentrated as much as possible and 0.9 g of compound III was obtained.

¹ H-NMR (200 MHz, CDCl ₃ , δ): 4.95 (1H, t); 3.68 (3H, s); 3.62-3.5 (1H, m); 3.22-3.06 (1H, m); 2.41-0.80 (17H, m); 0.97 (3H, s); 0.68 (3H, s)

Stage 2 (Introduction Δ ¹ double bond)

0.2 g (0.5 mmol) of compound IIIb obtained in step 1 is heated together with 8 g of absolute acetonitrile, 1.5 g of chloroform, 0.18 g (1.5 mmol) of allyl methyl carbonate and 0.05 g (0.05 mmol) of palladium catalyst at reflux temperature (70-80 ° C). Already upon heating, gas formation is observed. After about 30 minutes of heating under reflux, the reaction mixture was concentrated as much as possible, the residue was combined with a mixture of 15 g of methanol and 5 g of toluene and heated until a clear solution was formed. After cooling to 0-5 ° C, a solution containing 0.18 g (1 mmol) of a 30% solution of sodium methoxide in 2 g of methanol is slowly added, the clear solution is stirred for 1 hour. After removal of the cooling bath, 3 g of water was added thereto, and the cloudy mixture was stirred at room temperature for another 1 hour. It is then concentrated as much as possible and 10 g of toluene and 3 g of water are added to the residue. As soon as the mixture is divided into two transparent phases during heating, the organic phase is separated and cooled. Adding 2-4 g of heptane leads to crystallization of the product. After filtration, repeated washing with approximately 5 g of heptane and suction drying, 34 mg of 3-oxo-4-aza-5α-androst-1-ene-17β-carboxylic acid methyl ester remains.

¹ H-NMR (200 MHz, CDCl ₃ , δ): 6.81 (1H, d); 5.82 (1H, d); 5.48 (1H, s, broad); 3.69 (3H, s); 3.4-3.35 (1H, m); 2.45-1.0 (17H, m); 0.97 (3H, s); 0.66 (3H, s)

Example 9 (Preparation of Dutasteride)

Stage 1 (obtaining 3-oxo-4-aza-5α-androstane-17β-carboxylic acid)

A suspension of 100 g (0.26 mol) of dihydrofinasteride, 480 g of a 20% HCl solution (2.63 mol) and 120 g of methanol is heated to reflux and is boiled vigorously for 8-12 hours. When heated, the educt passes into the solution, after 8 hours a suspension is obtained, which can be easily filtered. The precipitate is washed three times intensively on a suction filter, using 100 g of water each time, about 15 minutes are dried by suction and then dried overnight. Yield: 60 g.

¹ H-NMR (200 MHz, DMSO, δ): 11.95 (1H, s); 7.32 (1H, s); 2.95 (1H, m); 2.2 (2H, m); 2.0-0.85 (17H, m); 0.81 (3H, s); 0.62 (3H, s)

Stage 2 (Preparation of compound IIIc, i.e., compounds of formula (III), where R = Cl, R ₃ and R ₄ = —C (O) —C (O) -

To a suspension of 40 g (0.12 mol) of the compound from step 1 in 633 g of benzene, 159 g (1.2 mol) of oxalyl chloride are added dropwise with cooling dropwise within 20-30 minutes, the suspension is stirred for 12 hours (gas formation unnoticed). Under reduced pressure and room temperature, benzene and excess oxalyl chloride are separated by distillation until the volume of the initial solution is reduced by half. In this case, a grayish-white solid precipitates, which, after filtration, is washed three times with heptane, using 150 g each time, and dried for about 15 minutes by suction. Yield: 37.1 g of compound IIIc.

¹ H-NMR (200 MHz, CDCl ₃ , δ): 4.93 (1H, t); 3.58 (1H, m); 3.12 (1H, m); 2.88 (1H, m); 2.31-0.72 (18H, m); 0.97 (3H, s); 0.80 (3H, s)

Step 3 (Preparation of Compound IIId (R = —NH— (2,5- (CF ₃ ) ₂ —C ₆ H ₃ ), R ₃ and R ₄ = —C (O) —C (O) -

A suspension of 1.48 g (6 mmol) of bis-2,5-trifluoromethylaniline, 2.35 g (5.3 mmol) of compound IIIc from step 2 and 50 g of toluene is heated at reflux temperature (100-110 ° C for about 8 hours) ) and then cool. Under reduced pressure and room temperature, toluene and aniline are separated by distillation until the volume of the initial solution is reduced by half. 30 g of heptane was added to the suspension and heated to 60-70 ° C. After one hour of vigorous stirring, it was filtered on suction, the residue on the suction filter was washed four times intensively, each time 10 g of heptane, and dried for about 30-45 minutes by suction. Yield: 1.7 g of compound III.

¹ H-NMR (200 MHz, CDCl ₃ , δ): 8.79 (1H, s, broad); 7.72 (1H, d); 7.49 (2H, m); 4.93 (1H, t); 3.59 (1H, m); 3.17 (1H, m); 2.38-1.0 (17H, m); 0.97 (3H, s); 0.81 (3H, s)

Stage 4 (Preparation of Dutasteride)

1 g (1.6 mmol) of compound IIId from step 3 is heated together with 8 g of absolute acetonitrile, 2 g of chloroform, 0.55 g (4.8 mmol) of allyl methyl carbonate and 0.17 g (0.16 mmol) of a palladium catalyst to reflux temperature (70-80 ° C). Already upon heating, gas formation is observed. After about 30 minutes of heating under reflux (gas formation is no longer visible), the reaction mixture is concentrated to the extent possible and the residue is combined with 5 g of methanol. After cooling to 0-5 ° C, a solution consisting of 0.6 g (3.2 mmol) of a 30% solution of sodium methylate in 4 g of methanol is slowly added, and the clear solution is stirred for 1 hour at an internal temperature of 0-5 ° C. After removing the cooling bath, 3 g of water are added to this, again stirred for 1 hour at room temperature, the turbid mixture is concentrated as much as possible and 20 g of toluene and 6 g of water are added to the residue. The mixture is heated to reflux. After 30 minutes, the clear organic phase was separated hot and cooled to room temperature. The addition of 5-10 g of heptane leads to the crystallization of dutasteride. After filtering, washing three times with heptane, 4 g each time, and drying by suction, 0.3 g of dutasteride is isolated.

¹ H-NMR (200 MHz, CDCl ₃ , δ): 8.80 (1H, s, broad); 7.75 (1H, d); 7.49 (2H, m); 6.80 (1H, d); 5.82 (1H, d); 8.80 (1H, s, broad); 5.46 (1H, broad); 3.35 (1H, m); 2.38-1.0 (17H, m); 0.97 (3H, s); 0.81 (3H, s).

Claims (24)

1. The method of obtaining 17β-substituted 4-aza-androst-1-en-3-ones of the General formula (I)

where R is hydroxyl, linear or branched (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) alkenyl; phenyl or benzyl; the residue —OR ₁ , or the residue —NHR ₁ , or the residue —NR ₁ R ₂ ; R _{1 is} hydrogen, linear or branched (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) alkenyl, or phenyl optionally substituted; R _{2 is} hydrogen, methyl, ethyl or propyl; or —NR ₁ R ₂ is a 5- or 6-membered heterocycle, and in the case where R is hydroxyl, also their pharmaceutically acceptable salts, characterized in that (A) to a 3-keto-4-aza group (lactam group) of a compound of general formula (II)

protecting groups are introduced so that a compound of general formula (III) is formed

in which R _{3 is} trialkylsilyl, or together with R _{4 the} residue —C (O) —C (O) - or —C (O) —YC (O) -; R ₄ alkyloxycarbonyl or phenyloxycarbonyl, preferably Boc (= tert-butyloxycarbonyl); or trialkylsilyl, or together with R ₃ residue —C (O) —C (O) - or —C (O) —YC (O) -; Y- [C (R ₅ ) (R ₆ )] n- or orthophenylene; R ₅ and R _{6 are} independently hydrogen, methyl or ethyl; and n is an integer from 1 to 4; and in case R is hydroxyl, possibly reacts with a protecting group; (B) the compound obtained [according to stage (A)] is converted in the presence of (i) a dehydrogenation catalyst selected from compounds of metals of group VIII of the periodic system of elements, and in the presence of (ii) benzoquinone, optionally substituted, allyl methyl carbonate, allyl ethyl carbonate and / or allyl propyl carbonate, while in the 1- / 2-position is introduced Δ ¹ -double bond, and (C) the protective groups R ₃ and R ₄ are removed, and at R = hydroxyl the obtained compound is converted into a salt, if necessary. 2. The method according to claim 1, characterized in that R means methyl, ethyl, propyl or n-butyl, sec-butyl or tert-butyl, preferably tert-butyl; or the remainder —OR ₁ , or the remainder —NHR ₁ , or the remainder —NR ₁ R ₂ , preferably the remainder —NHR ₁ , preferably —NH-tert-butyl, or phenyl, optionally substituted. 3. The method according to claim 1 or 2, characterized in that R ₁ means methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl, preferably tert-butyl. 4. The method according to claim 1 or 2, characterized in that R means the remainder of —NHR ₁ , where R ₁ means 2,5-bis (trifluoromethyl) phenyl. 5. The method according to claim 1 or 2, characterized in that in the remainder of —NR ₁ R _{2, the} substituent R ₂ is methyl. 6. The method according to claim 1 or 2, characterized in that the substituent -NR ₁ R ₂ as a 5- or 6-membered heterocycle means a piperidine or pyrrolidine residue. 7. The method according to one of claims 1 to 6, characterized in that R ₃ means trimethylsilyl, or together with R _{4 the} residue —C (O) —C (O) - or —C (O) —YC (O) - . 8. The method according to one of claims 1 to 6, characterized in that R ₄ means alkyloxycarbonyl, preferably isobutyloxycarbonyl, tert-butyloxycarbonyl, tert-amyloxycarbonyl, cyclobutyloxycarbonyl, 1-methylcyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, 1-methylcycloxyloxycarbonyloxycarbonyl, 1-methyl . 9. The method according to one of claims 1 to 8, characterized in that R ₄ means Boc, trimethylsilyl, or together with R _{3 the} residue is -C (O) -C (O) -or -C (O) -YC (O ) -, preferably Boc, or together with R ₃ means the residue —C (O) —C (O) - or —C (O) —YC (O) -. 10. The method according to claim 9, characterized in that R ₅ and R ₆ mean independently hydrogen, methyl, ethyl or propyl or ortho-phenylene, preferably the residue —CH (R ₅ ) - or ortho-phenylene, preferably methylene , and n is 1 or 2, preferably 1. 11. The method according to one of claims 1 to 9, characterized in that for the introduction of the Boc protecting group, a compound of the general formula (II) Boc-anhydride or Boc-carbamate or a similar compound in which the tert-butyl residue is replaced by tert- amyl, cyclobutyl, cyclopentyl or cyclohexyl. 12. The method according to one of claims 1 to 11, characterized in that the dehydrogenation catalyst [in step (B)] is selected from compounds of iron, ruthenium and osmium; cobalt, rhodium and iridium; nickel, palladium and platinum; copper, silver and gold; preferably from compounds based on rhodium, palladium and platinum. 13. The method according to p. 12, characterized in that the dehydrogenation catalyst [at the stage (B)] is selected from compounds Pd (0), and preferably is a complex of Tris (dibenzylideneacetone) dipalladium-chloroform. 14. The method according to p. 12, characterized in that the dehydrogenation catalyst [in step (B)] is selected from Pd (II) compounds, preferably from PdCl ₂ , Pd (dppe) ₂ , dppe = bis- (1,2-diphenylphosphine ) ethane], Pd (dppe) Cl ₂ , Pd (OAc) ₂ , Pd (dppe) (OAc) ₂ and / or from π-allyl-Pd complexes, preferably π-allyl-Pd-chloride dimer. 15. The method according to one of claims 1 to 14, characterized in that for thermal stabilization of the dehydrogenation catalyst, preferably a palladium salt or a palladium complex, there is an additional complexing agent, preferably 2,2′-bipyridyl or 1,10-phenanthroline, preferably 2, 2′-bipyridyl. 16. The method according to one of claims 1 to 15, characterized in that as the quinone [in step (B)], substituted quinone is used, preferably quinone substituted with C _1-4 alkyl, halogen, cyano or nitro. 17. The method according to one of claims 1 to 16, characterized in that the protective groups introduced in [step (C)] are removed by treatment with a suitable acid, preferably treatment with formic acid, acetic acid and / or trifluoroacetic acid, preferably formic acid. 18. The method according to one of claims 1 to 17, characterized in that the compound obtained in [step (C)] in which R is hydroxyl is converted to an alkali metal salt, an alkaline earth metal salt or an ammonium salt, preferably a sodium salt, potassium or ammonium, preferably in a sodium or potassium salt. 19. The method according to one of claims 1 to 17, characterized in that the obtained compound of formula (I) is crystallized from a non-polar solvent, preferably from gasoline, heptane, hexane and / or toluene, preferably from toluene. 20. The method according to claim 19, characterized in that the obtained compound of formula (I), which is 17β- (N-tert-butylcarbamoyl) -4-aza-androst-1-en-3-one, is crystallized from a saturated toluene solution at a temperature of about 25 ° C in polymorphic form I. 21. The method according to claim 19, characterized in that the obtained compound of formula (I), which is 17β- (N-tert-butylcarbamoyl) -4-aza-androst-1-en-3-one, is crystallized from a saturated toluene solution at a temperature of about 0 ° C in polymorphic form II. Priorities for items: July 16, 2002 according to claims 1-21; 08.08.2002 according to claims 1-21; 01/08/2003 according to claims 1-21.