PROCESS FOR THE SYNTHESIS OF (1 1 BETA.17ALPHA)-17-ACETOXY-1 1 -METHYL-19-NORPREGN-4-EN-3.20-DIONE

The invention relates to a process for the synthesis of (1 l p, 17a)-17-acetoxy-l 1- methyl-19-norpregn-4-en-3,20-dione of formula (I), also known as Norgestomet.

(I)

Norgestomet belongs to the family of progestins, which is used in veterinary medicine alone or in combination with estradiol monobenzoate to synchronize reproductive cycles.

In stock-farming it is very important, that the period of birth of mammalian female domestic animals preferably should be synchronized and the fertilization of animals should happen in a maximal proportion. Moreover it is essential, that the body- weight gain of the animals should be acceptable.

The maturation of mammalian domestic animals (goat, cow, etc.) can be promoted with a 6-21 day treatment with of an ear implant containing Norgestomet. As an effect of administration of Syncromate-B to 4-5 month old heifers 3 month after a prolonged (185 day) treatment the animals gained on one hand higher weight, and on the other hand the fertilization rate increased too after synchronization of their reproductive cycles.

The aim of the so far known processes for the synthesis of (11β, 17α)-17- acetoxy-l l-methyl-19-norpregn-4-en-3,20-dione of formula (I) was to provide suitable amount of the compound or compounds for the pharmacological investigations, as well as to support the patent applications in accordance with the promising biological data. However during industrial scale syntheses further development was necessary to fulfill the purity requirements of the active ingredient suitable for therapeutic application. Up till now the target compound of formula (I) was synthesized in a 26-step chemical process starting from 11 -keto-tigogenin acetate. During the chemical synthesis starting from the 1 -keto-tigogenin acetate first the l l-methylene-5a-androstan-3,17- dione was synthesized in 9 steps according to the processes described in patents British Drug Houses GB912035, GB912036, GB912037. The synthesis is the following: the oxo group in position 1 of 1 1 -keto-tigogenin acetate (3 -acetoxy-5a,25D-spirostan- 11-one) is reacted with methyl magnesium iodide, then the hydroxy! group in position 3 of the obtained Ι ΐβ-hydroxy-l la-methyl derivative is acetyl ated and the 11 -methyl en- spirostan derivative is obtained via elimination of water in the presence of formic acid. Then the 3P-acetoxy-l l-methylen-5a-pregn-16-en-20-one is obtained in two steps (ring opening of spirostan and oxidation of the appropriate furost-2Q(22)-ene), this is transformed into 3P-acetoxy-l l -methylen-5a-androstan-17-one via side-chain degradation using known methods (oxime formation, elimination reaction with phosphorus oxychloride) and after hydrolysis and Jones oxidation of the latter the 1 1- methylen-5a-androstan-3, 17-dione is obtained (Scheme 1.).

Scheme 1.

The title compound of formula (I) is synthesized according to the US patent No. 3,527,778 disclosed by researchers of Searle in 17 further steps starting from 11- methylen-5 -androstan-3,17-dione as follows: first the oxo groups in positions 3 and 17 of the compound are reduced with lithium tri-tert-butoxyaluminum hydride, then the methylene group in position 1 1 is hydrogenated in the presence of Pt0 ₂ catalyst to yield the appropriate Πβ-methyl derivative and the two hydroxy! group is re-oxidized to obtain the l l -methyl-3,17-dioxo derivative. Next hromination is carried out in positions 2 and 4, then 1 ip-methyl-androsta-l,4-dien-3, 17-dione is obtained via elimination reaction with MgO/dimethyl formamide, which was protected with ketal group in position 17 in ethylene glycol in the presence of para-toluenesulfonic acid, then ring A is aromatized in the presence of biphenyl and diphenylmethane, followed by methylation of the hydroxy! group in position 3 with methyl iodide in the presence of potassium carbonate and the ketal protective group is removed to yield the 3-methoxy- 11 β-methyl-estra- 1 ,3 ,5 -trien- 17-one.

The formation of the 17oc-hydroxy-pregnane side-chain is carried out next.

The 17-oxo derivative is reacted with ethyl triphenylphosphonium iodide in the presence of potassium tert-butylate to yield (1 1 β, 17α)-11 -methyl- 9-norpregna- 1,3,5( 0), 17(20)-tetraen-3 -ol-3 -methyl ether.

The alternative synthesis of this intermediate is that the 17-oxo derivative is ethynylated and the 17β-hydroxy-17α-ethynyl derivative is hydrogenated in the presence of 5% Pd/C, finally the obtained 17-hydroxy- 17-ethyl derivative is dehydrated with thionyl chloride.

The next step is the oxidation of the 17(20) double bond with osmium tetroxide to furnish 1 7,20-diol, this way (11β, 17α)-1 l-methyl-^-norpregna-l^ _j S O^trien- S^^O-triol-S-methylether is obtained.

In the further part of the synthesis the aromatic ring A is reduced with lithium metal in liquid ammonia to yield 3-methoxy-2,5(10)-diene system, which is transformed into the appropriate 3-oxo-4-ene derivative with acid treatment. The hydroxy! group in position 20 of the obtained (l ^,17a)-17,20-dihydroxy-l l-methyl-19-norpregn-4-en-3- one is oxidized with Jones reagent in the presence of manganese di chloride and finally the 17a hydroxy! group is acetyl ated with acetyl chloride in 1, 1 ,2-trichloro- trifluoroethane in the presence of antimony pentachloride to obtain the target compound (Scheme 2,).

Scheme 2.

An alternative route is when the hydroxy! group in position 20 is oxidized with Jones oxidation prior to the Birch reduction and the keto group in position 20 is protected with ketal group in the presence of ethylene glycol. After the Birch reduction the acetvlation and the acid hydrolysis are carried out simultaneously, this way the ethylene ketal protective group is also removed (Scheme 3.),

Scheme 3, The intermediates are characterized by NMR, infrared spectroscopy and melting points. The above synthesis is a multistep process, the descriptions do not give yields of the individual reaction steps, moreover some of the applied reagents (for example osmium tetroxide, Jones reagent) are environmentally harmful.

The synthesis of the individual structural elements of the target compound is rather complicated. For example the compound containing Ι ΐβ-methyl substituent is obtained in 4 steps: synthesis of 11-oxo derivative, reaction with methyl magnesium i odi de, elimination of water from the obtained 1 1 -hydroxy- 1 1 -methyl group to yield 11~ methylene group, and finally hydrogen ati on.

The formation of the structure of ring A is carried out in 6 steps: first the (5a,l i p)-l l-methyl-androstan-3,17-dione is converted into 2,4-dibromo derivative with bromination, then into 3~oxo-l ,4-diene with elimination reaction, followed by aromatization, then methylation of the hydroxy! group in position 3, formation of di en ol ether by Birch reduction, finally reaction with acid.

During the formation of the 17oc-hydroxy-norpregnan-20-one side-chain the oxidation of the double bond in positions 17,20 is carried out with almost equivalent amount of osmium tetroxide in pyridine.

The US patent application No. 2006002436 describes the formation of Γΐβ- methyl-3-oxo-4-ene structure in the compound family of 17-hydroxy-19-nor derivatives, in which first the 3,3-ethylenedioxy-17p-hydroxy-5(10)9(l l.)-diene is epoxidated, then the 4: 1 mixture of the obtained epoxides 5α,10α,-5β, 1.0β is reacted without further purification with methyl magnesium bromide in the presence of copper(I) chloride. The next step is the removal of the ethylene ketal group in position 3 in the presence of hydrochloric acid, then after purification steps the 1 1 β-ηιεΛν!-4,9- dien-3-one derivative is obtained in 47% yield. The Birch reduction of the double bond in positions 9(10) is carried out in liquid ammonia, in a mixture of tetrahydrofuran and tert-butanol as solvent, at a temperature of -78°C, then the isomerization of the obtained double bond in positions 5(10) is carried out in methanol containing 10% of hydrochloric acid at reflux temperature. The crude product of the reaction is purified by crystallization and this way the (l l β,17β)-l l-methyl-17-hydroxy-estr-4-en-3one is obtained in 35% yield (Scheme 4.).

Scheme 4.

In the case of nor-compounds the formation of the 17a-hydroxy-pregnan-20-one side-chain has been carried out via the ethynylation of 17-oxo group, when the target compound was the 17a-hydroxy-norpregn-4-en~3 ,20-dione. According to the process described in the US patent No. 3,381,003 the position 17 of the estron-3-alkyl ether is ethynylated, the 17-hydroxyl group of the obtained compound is acylated, then the ethynyl group is brominated with N-bromo-acetamide in a mixture of tert-butanol and water to obtain 3 -alkoxy- 17oc-dibromo-acetyl-gona- 1,3,5(10)-trien- 17 -hydroxy acetate. This product is dehydrobrominated with zinc in acetic acid to yield 3-alkoxy- 17a-acetyl-gona-l,3,5(10)-trien-17[j~hydroxy acetate, which is reduced in the next step with calcium metal in liquid ammonia. The iso-pregnane side-chain of the obtained compound is isomerized in acetic acid in the presence of zinc at reflux temperature for 24 h. This is followed by the formation of the hydroxyl group in position 17, in which the keto group in position 20 is transformed into enol-acetate with acetic anhydride in the presence of p-toluenesulfonic acid as catalyst and the formed Δ ^{17"20 "} double bond is oxidized with perbenzoic acid. Finally the keto group in position 20 is protected as ethyl ene-ketal with ethylene glycol in the presence of p-toluenesulfonic acid as catalyst. In the next two reaction steps the 3-methoxy-17a-hydroxy-17a-acetyl-l,3-5(10)-estra- triene derivative protected in position 20 with ethyl ene-ketal is reduced with lithium metal in liquid ammonia, then the target compound is synthesized from the obtained 3- methoxy-2,5-diene derivative with acid hydrolysis. The whole reaction sequence is 11 steps, yields are not given. The side-chain synthesis described in the patent is very long, the applied reaction steps (reduction with zinc and acetic acid, isomerization with zinc and acetic acid at reflux temperature) have safety and explosion risks, as well as they damage the enamel layer of the applied equipment (Scheme 5.).

Beyond the above mentioned processes there are known syntheses in the literature based on cyanohydrine formation in which first the 17-oxo derivative is reacted with potassium cyanide or acetone cyanohydrine in acetic acid, then the 17β- cyano-17a-hydroxy derivative, which crystallizes more easily, is obtained after the equilibrium reaction.

According to the Chinese article published in the Journal of Central South University of Technology (English Edition) (2004), 1 1(3), 300-303 the 17a-hydroxy- pregnane side-chain is formed the following way: the tertian,' hydroxy! group in position 17 of the 3,3-ethylenedioxy-17 -cyano-17a-hydroxy-estr-5(10)-ene is protected with butyl vinyl ether and the obtained compound is reacted with methyl lithium in diethyl ether as solvent. The protective groups are removed with hydrochloric acid hydrolysis to furnish the crude 17a-hydroxy-norpregn-4-en-3,20-dione in 67% yield. The diethyl ether and the butyl vinyl ether used in the process are extremely flammable.

A further method for the synthesis of 17 -hydroxy-pregnan-20-one side-chain is described the US patent No. 6,020,328. The hydroxy! group in position 17 is protected with trimethylsilyl chloride in the presence of pyridine, then the protected cyanohydrine is reacted with methyl magnesium bromide in a mixture of tetrahydrofuran:toluene= l :3 at reflux temperature. After removal of the trimethylsilyl protective group and purification by column chromatography the desired 3-ethylenedioxy-17a-hydroxy-19- norpregna-5(10)9(l l)-dien-20-one is obtained in 46% yield.

According to the article published in Steroids 65 (2000), 395-400 by Rao et al. starting from 3-ethylenedioxy-17 -cyano-17a-chloromethyl-dimethylsilyloxy-estra- 5(10),9(l l)-dien-dione, a mixture of 17oc-hydroxy-pregna-dien-3,20-dione derivatives is obtained, in which the ratio of 4,9-diene and the 8(10),9(l l)-diene is 4: 1 , by reacting the cyanohydrine derivative protected with chlorom ethyl dimethyl silyl group with lithium ditert-butyl-biphenyl at a temperature below -70°C under very rigorous reaction conditions and subsequent acid treatment. Chemically pure compound is obtained from the mixture after formation of ethyl ene-ketal. The overall yield of the two steps is 60%.

The aim of the process described in the international patent application No. WO2009/001148 is to synthesize 17a-acetoxy-l i -[4-(dimethyl-amino)-phenyl]-21- methoxy-19-norpregna-4,9-dien-3,20-dione, in which the formation of 17oc-acetoxy-21- methoxymethyl-pregnan-20-one side-chain is also carried out. First the 11β-[4- (dimethylamino-phenyl)-3,3-ethylenedioxy-5a, 17a-bis(trimethylsilyloxy)]-5 -estr- 9(l l)-en-17p-carbonitrile is reduced with diisobutyl aluminum hydride to furnish the appropriate carbaidehyde, which is reacted with methoxymethyl magnesium chloride in the presence of HgCl ₂ , finally the protective groups are removed with aqueous KHS0 ₄ solution to obtain ^,20-dihydroxy-l i -[4-(dimethylamino-phenyl)]-21-methoxy-19- norpregna-4,9-dien-3-one, and the latter is transformed into the appropriate 3,20-dione with trifluoroacetic acid and dimethyl sulfoxide as oxidizing agent in the presence of dicyclohexylcarbodiimide. According to the new process elaborated by us the synthesis of the target compound, the (1 ip,17oc)-17-acetoxy-l 1 -methyl- 19-norpregn-4-en-3,20-di one of formula (I), is simple, rapid and realizable on industrial scale.

Except the above mentioned patents, which describe the synthesis of Norgestomet of formula (I), there are no other synthetic examples in the family of 19- nor derivatives for the introduction of Π β-methyl group, for the formation of 17a- hydroxy-pregnan-20-one side-chain and the 3-oxo-4-ene system.

The synthesis of our invention can be carried out on industrial scale, safe and the purity of the obtained active ingredient fulfills the requirements of the pharmacopeia.

According to the invention the synthesis of the compound of formula ( !) is carried out the following way: the 3 ,3 -ethylendioxy-5a, 1 Oa-epoxy- 17a- (trimethylsilyloxy)-estr-9(l l)-en-17 -carbonitril of formula (II) obtained according to method described in international patent application No. WO20009/001148

is reacted with methyl magnesium chloride in the presence of copper(I) chloride in an ether type solvent at a temperature not more than 15°C,

the obtained 3,3-ethylendioxy-l 1 p-methyl-5oc-hydroxy- 17a-(trimethylsilyloxy)- estr-9-en-17 -carbonitrile of formula (III)

is reacted with trim ethyl si lyl chloride in the presence of a tertiary amine in an ether type or haiogenated solvent at a temperature not more than 40°C,

the obtained 3,3-ethylendioxy-l i -methyl-5 , 17a-bis(trimethylsilyloxy)-estr-9- en-17 -carbonitrile of formula (IV)

is reduced with an excess amount of diisobutylaluminum hydride in an ether type solvent at a temperature not more than 0°C,

the obtained 3,3-ethylendioxy-l ip-methyl-5a, 17a-bis(trimethylsilyloxy)-estr-9- en- 1 Τβ-carbaldehyde of formula (V)

is reacted without further purification with methyl magnesium chloride to furnish the 20-hydroxy-pregnane derivative, then the protective groups are removed by addition of aqueous K! ISO , while keeping the temperature below 30°C,

the obtained (11 β,17α,20ξ)-1 l-methyl-norpregna-4,9-dien-17,20-diol of formula is reduced with lithium in liquid ammonia in a mixture of THF and an apolar solvent at a temperature not more than -30°C,

the hydroxy! group in position 20 of the obtained (1 1β, 17α,20ξ)-11 -methyl - norpregn-5(10)-en-17,20-diol-3-one of formula (VII)

is oxidized with at least three equivalent of dimethyl sulfoxide/oxalyl chloride reagent mixture in dichioromethane while keeping the temperature below -40°C, then after adding not more than three equivalent of trialkyl amine the oxidation is continued at a temperature not more than 0°C,

the obtained (Ι Ιβ,17α)- 17-hydroxy- 11 -methyl -norpregn-5( 10)-en-3 ,20-dione of formula (VIII)

is acetylated with acetic anhydride in dichioromethane in the presence of perchloric acid at a temperature not more than 0°C,

finally the obtained (l lβ,17 )-17-acetoxy-l l-methyl-noφregn-5(10)-en-3,20- dione of formula (IX) is isomenzed with hydrochloric acid in methanol at reflux temperature to furnish the title compound of formula (I).

According to an alternative method the double bond in position 5(10) of (11β,17α,20ξ)-1 l -methyl-norpregn-5(10)-en-17,20-diol-3-one of formula (VII) obtained as described above is isomenzed with hydrochloric acid in methanol at reflux temperature, then the hydroxy! group in position 20 of the obtained (1 1β,17α,20ξ)-11- methyl-norpregn-4-en-17,20-diol-3-one of formula (Villa)

is oxidized with at least three equivalent of dimethyl sulfoxide/oxaiyl chloride reagent mixture in dichloromethane while keeping the temperature below -40°C, then after adding not more than three equivalent of trial kyl amine the oxidation is continued at a temperature not more than 0°C,

finally the obtained (l. ^, 17a)-17-hydroxy-l l -methyl-norpregn-4-en-3,20-dione of formula (IXa)

is acetyiated with acetic anhydride in a halogenated solvent in the presence of perchloric acid at a temperature not more than 0°C to furnish the title compound of formula (I).

The short draft of the process of our invention is shown on Scheme 6.

Scheme 6.

According to one preferred embodiment of our invention in the first step of the synthesis the 3,3-ethylendioxy-5a, 10a-epoxy-17 -(trimethylsilyloxy)-estr-9(l l)-en- 17 -carbonitril of formula (II) is reacted with methyl magnesium chloride in tetrahydrofuran in the presence of copper(I) chloride at a temperature below 10°C. After completion of the reaction followed by extraction work-up and concentration the crude product is purified by treatment with diisopropyl ether.

Then the 3,3-ethylendioxy-l ip-methyl-5a-hydroxy- 17a-(trimethylsilyloxy)- estr-9-en-17P-carbonitrile of formula (III) is reacted with trimethylsilyl chloride in tetrahydrofuran in the presence of imidazole as base at a temperature of 20-25°C. After completion of the reaction the solid by-product is filtered off, and after extraction workup and concentration the product is crystallized from methanol.

The reduction of the obtained 3,3-ethylendioxy-l i -methyl-5a, 17a- bis(trimethylsilyloxy)-estr-9-en-17P-carbonitrile of formula (IV) with diisobutylaluminum hydride is preferably carried out in methyl tert-butyl ether containing 5-10% of tetrahydrofuran at a temperature of -15-(~20)°C, After completion of the reaction the excess of the reagent is decomposed with addition of 50% aqueous acetic acid and after work-up and concentration the crude product is used as an oil in the next step without further purification.

The obtained 3,3-ethylendioxy-l i -methyl-5a, 17a-bis(trimethylsilyloxy)-estr- 9~en~17 -carbaldehyde of formula (V) is reacted with methyl magnesium chloride in tetrahydrofuran at a temperature of -15-(-10)°C to furnish the 20-hydroxy-pregnane derivative, then the protective groups are removed with aqueous KHS0 ₄ solution at a temperature of 20-25°C. The reaction is quenched by addition of aqueous sodium carbonate solution, and after extraction work-up and concentration the product is crystallized by treatment with a mixture of ethyl acetate and n-heptane.

Then the (11β,17α,20ξ)-1 l-methyl-norpregna-4,9-dien-17,20-diol of formula ( VI) is reduced with lithium metal in a mixture of tetrahydrofuran and toluene in the presence of liquid ammonia at a temperature below -30°C, after completion of the reaction the excess of the reagent is decomposed with water under vigorous nitrogen flow and after removal of large amount of the ammonia the reaction mixture is acidified. After extraction work-up and concentration the product is obtained as an oil, which is used in the next step without further purification.

On the one hand the hydroxy! group in position 20 of (! 1 β, 17α,20ξ)-11 -methyl - norpregn-5( 10)-en- 17,20-diol -3 -one of formula (VII) is oxidized by Swern oxidation (oxalyl chloride-dimethyl sulfoxide), when the reaction of oxalyl chloride and dimethyl sulfoxide is carried out in dry dichloromethane at -60°C for about 10 min. Then the solution of the steroid in dichloromethane is added at -60°C and after 60 min dry triethylamine is added and the reaction is continued at 0°C. After acidification of the reaction mixture, extraction work-up and concentration the product is crystallized from a mixture of ethyl acetate and diisopropyl ether.

The 17a hydroxyl group of the obtained (1 1 ,1.7a)-17-hydroxy-l 1 -methyl- norpregn-5(10)-en-3,20-dione of formula (VIII) is acetylated in dichlorom ethane at - 20°C, when the acetic anhydride and the 70% perchloric acid are added to the reaction mixture.

Finally the double bond in positions 5(10) of the obtained (11β,17α)-17- acetoxy-l l-methyl-norpregn-5(10)-en-3,20-dione of formula (IX) is preferably isomerized with 10% aqueous hydrochloric acid in methanol solution at reflux temperature, after completion of the reaction the mixture is neutralized and after workup the crude product is purified by column chromatography and crystallization from methanol.

On the other hand the double bond in position 5(10) of (1 1 β, 17α,20ξ)-11- methyl-norpregn-5(10)-en-17,20-diol-3-one of formula (VII) is preferably isomerized with 10% aqueous hydrochloric acid in methanol at reflux temperature, after completion of the reaction the mixture is neutralized and after work-up the crude product is purified by column chromatography.

The hydroxyl group in position 20 of the obtained (1 1β,17α,20ξ)-11 -methyl - norpregn-4-en-17,20-diol-3-one of formula (Villa) is oxidized by Swern oxidation. After acidification of the reaction mixture, extraction work-up and concentration the product is crystallized from a mixture of ethyl acetate and diisopropyl ether.

Finally the 17a. hydroxyl group of the obtained (1 ^,17a)-17-hydroxy-l l- methyl-norpregn-4-en-3,20-dione of formula (IXa) is acetylated in dichlorom ethane at

-20°C, when the acetic anhydride and the 70% perchloric acid are added to the reaction mixture. After completion of the reaction the mixture is neutralized and after work-up the crude final product is purified by column chromatography and crystallization from methanol.

The intermediates of the important steps of the synthesis are new, these are the following:

3,3 -ethyl endioxy- 11 β-methy 1 -5oc-hydroxy- 17a-(tri m ethylsilyl oxy)-estr-9-en-

17p~earbonitril (III) 3,3-ethylendioxy-l 1 -methyl-5a, 17a-bis(trimethylsilyloxy)-estr-9-en-17p- carbonitril (IV)

3,3-ethylendioxy-l ip-methyl-5a, l 7a-bis(trimethylsilyloxy)-estr-9-en-17p- carb aldehyde (V)

(1 1 β,17α,20ξ)-1 l-methyl-norpregna-4,9-dien-17,20-diol-3-one (VI)

(11β,17α,20ξ)-1 1 -methyl-norpregn-5(10)-en-17,20-diol-3-one (VII)

(1 l^,17a)-17-hydroxy-l l -methyl-norpregn-5(10)-en-3,20-dione (VIII)

(11β, 17α,20ξ) 17,20-dihydroxy-l l-methyl-norpregn-4-en-3,20-dione (Villa)

(1 l^,17a)-17-aeetoxy-l l-methyl-norpregn-5(10)-en-3,20-dione (IX).

Using the process according to our invention the purity of several intermediates was suitable for the use in the next steps of the synthesis.

The process of our invention offers considerable benefits in many respects.

In the process of our invention environmentally harmful and flammable agents are not used.

An important step of the synthesis is the Birch reduction of the 4,9-diene structure to the appropriate 3-oxo-5(10)-ene derivative. This step can only be carried out if the 20-oxo group of the " 17 -hydroxy-pregnane" side-chain of the steroid is protected as ketal or the 20-hydroxy derivative is used instead of it.

During the formation of the side-chain the cyanohydrine (IV) protected as trim ethyl silyl derivative can not be reacted with methyl magnesium halogenide. Prior to the Grignard reaction carried out with methyl magnesium chloride it is necessary to reduce the cyanohydrine (IV) to carbaidehyde derivative (V).

The reduction of compound (IV) is carried out in methyl tert-butyl ether containing 5-10% of tetrahydrofuran, this way the increase of the amount of 17a-H byproduct could be avoided and the "crude" carbaidehyde derivative (V) could be used in the next chemical reaction without further purification.

After the Grignard reaction the removal of the protective groups is carried out with aqueous KHS0 ₄ solution, this way the amount of the by-products was decreased, the 4,9-diene derivative of formula (VI) was purified by a simple crystallization step. The oxidation of the hydroxy! group in position 20 of the compound of formula (VIII) was carried out with oxalyl chloride-DMSO system instead of chromium salt, this way after work-up the compound of formula (IX) could be isolated in crystalline form.

After the final isomerization step followed by purification by column chromatography and crystallization the final product was suitable for therapeutic purposes. On the other hand the product (Villa) obtained after Swern oxidation of compound of formula (VII) after work-up can be purified by simple crystallization.

Unless otherwise stated in the examples and in the claims the given % values are weight/weight percentages.

The invention is illustrated by the following not limiting examples.

Examples

Example 1

3,3-ethylendiox -l Iβ-meth l-5α-h drox -17α-(triIneth lsil lox )-estr-9-en-17β- carbonitril (HI)

Under nitrogen, to a solution of 223 cm ³ of 3M methyl magnesium chloride in tetrahydrofuran (0.67 mol) 21.6 g of copper(I) chloride was added at 20°C, then the mixture was diluted with 400 cm ^J of tetrahydrofuran. After stirring for 15 min the reaction mixture was cooled to 10°C and a solution of 72 g (0, 168 mol) of 3,3- ethylendioxy-5a, 10a-epoxy-17 -(trimethylsilyloxy)-estr-9(l l)-en-17p-carbonitril in 720 cm ³ of tetrahydrofuran was added over about 15 min at this temperature, the reaction time is about 60 min after the addition. After completion of the reaction 720 cm ³ of saturated ammonium chloride solution was carefully added to the reaction mixture with cooling, followed by addition of 720 cm ³ of water and the phases were separated. The organic phase was extracted with 720 cm ¹ of saturated ammonium chloride solution. The separated organic phase was concentrated, the residue was dissolved in 1080 cm ³ of dichlorom ethane and the solution was washed with 2x270 cm ³ of water, dri ed and concentrated. The product was crystallized from diisopropyl ether to yield 67.43 g (90.26%) of the title compound.

Melting point: 174-176°C 1H NMR (CDCI ₃ ): 4,34 (s, I H), 3.88-4.11 (m, 4H), 3.19 (t, .) 7.8 Hz, 1 H), 2.69 (dt, j 1 4.7, 3.6 Hz, 1H), 2.30-2.49 (m, 2H), 1.86-2.11 (m, 6H), 1.75-1.86 (m, H i), 1.60- 1.70 (rn, 4H), 1.55 (ddd, j 1 2, 12.9, 4,4 Hz, IH), 1.31-1.48 (m, 4H), 1.13 (d, j 7 8 Hz, 3H), 1.05-1.10 (m, 3H), 0.13-0.33 (m, 9H)

1 ³ C NMR (CDCI ₃ ) : 138,5, 130.7, 121 , 1 , 108.8, 78.7, 70,0, 64.7, 64. 1, 49,7, 47.4, 47.3,

38.6, 38.0, 36.8, 35.8, 35.3, 30.0, 25.5, 24.5, 24.3, 22.8, 18.2, 1.1

Example 2

3,3-ethylendioxy-ll3-methyl-5ot,17a-bis(trimethylsilyloxy)-e str-9-en-17p- carbonitril (IV)

To a solution of 67 g (0. 1 5 mol) of 3,3-ethylendioxy-l ip-methyl-5a-hydroxy-l 7a- (trimethylsilyloxy)-estr-9-en-17p-carbonitril in 335 cm ³ of tetrahydrofuran 18.28 g (0.27 mol) of imidazole was added. Then 28.18 cm ³ (0.222 mol) of trimethylchlorosilane was added dropwise while keeping the temperature at room temperature with ice cooling and the reaction mixture was stirred at this temperature for 1 h. The precipitated solid by-product was filtered off, washed with 3x100 cm ^J of dichloromethane and the combined filtrates were washed with 3x150 cm ³ of water, dried and concentrated. 100 cm ³ of methanol was distilled off from the residue, then it was crystallized from methanol to yield 66.8 g (85.8%) of the title compound.

Melting point: 100-101°C.

1H NMR (CDCI ₃ ) : 3.94-4.04 (m, 2H), 3.84-3.93 (m, 2H), 3.18 (t, J=7.8 Hz, IH), 2.31- 2.61 (m, 3H), 2.15 (dd, J=14.2, 2.5 Hz, IH), 1.90-2.10 (m, 5H), 1.75-1.89 (m, IH), 1.65 (id, .1 12 1. 7.6 Hz, IH), 1.46-1.62 ( rn. 4H), 1.32-1.45 (rn, 4H), 1 .12 (d, j 7 8 Hz, 3H), 1.08 (s, 3H), 0.23 (s, 9H), 0.15 (s, 9H)

i C NMR (CDCI ₃ ) : 137,3, 132.4, 121 , 1 , 108.5, 78.7, 73 ,6, 64.6, 63.5, 49,8, 49.0, 47.0,

38.7, 38.6, 36.7, 36.1 , 35.3, 29.9, 25.1, 24.6, 24.2, 23.0, 18.2, 2.5, 1.1

Example 3

3,3-ethylendioxy-ll3-methyl-5ot,17a-bis(trimethylsilyloxy)-e str-9-en-173- carbaldehyde (V) 66.7 g (128 mmol) of 3,3-ethylendioxy-l. ip-methyl-5a,l 7a-bis(trimethylsilyloxy)-estr- 9-en-17p-carbonitril was dissolved in a mixture of 420 cm ^" ' of methyl tert-butyl ether and 33 cm ³ of tetrahydrofuran. The solution was stirred under nitrogen and cooled to -15-(-20)°C. 310 cm ³ (310 mmol) of 1M DIBAL-H in toluene was placed under nitrogen to a dropping funnel and added drop wise to the solution of steroid while keeping the temperature below -15°C. The reaction mixture was stirred at this temperature until completion of the reaction, controlled by TLC. The reaction time was 50 min. Just prior to the work-up the reaction mixture was poured into a separation funnel and added dropwise to 840 cm ³ of 50% acetic acid cooled to -5°C. After quenching the reaction the mixture was stirred under nitrogen at 20-25 ^c 'C for 15 min, then the phases were separated. The organic phase was washed with 450 cm ^" ' of water, 2x450 cm ^J of 0.3M NaHC0 ₃ solution and 2x450 cm ³ of water. The organic phase was dried over Na ₂ S()4, filtered and the filtrate was concentrated under diminished pressure at 40°C. The residue (66.7 g oil) was used in the next step without further purification. The product can be crystallized from methanol.

Melting point: 96-97°C.

1H NMR. (800 MHz, CD ₂ C1 ₂ ): 9,59 (s, IH), 3 ,90-3 ,98 (m, 2H), 3.80-3.86 (m, 2H), 3 ,09- 3.15 (m, IH), 2.53 (ddd, J=15.1, 1 1.6, 3.5 Hz, 1H), 2.47 (dt, J=14.0, 4.3 Hz, IH), 2.36- 2.41 (m, IH), 2.30 (dd, J 13.4, 7.9 Hz, IH), 2.06-2.12 (m, 2H), 1.87-1.92 (m, 2H), 1.78-1.83 (m, H), 1.73-1.78 (m, I H), 1.53-1.61 (m, 2H), 1.51 (d, j 14 3 Hz, I H), 1 .41- 1.48 (m, 2H), 1.31-1.40 (m, 2H), 1.21 (d, J=14.5 Hz, IH), 1.06 (d, J=7.7 Hz, 3H), 0.85 (s, 3H), 0.14 (s, 9H), 0.10 (s, 9H)

i ³ C NMR (201 MHz, CD ₂ C1 ₂ ) : 203.9, 138.3, 132.6, 109.0, 91.8, 74.2, 65.2, 64.0, 50.3, 49.5, 49.5, 39.2, 37.2, 36.6, 36.5, 31.2, 30.6, 25.5, 25.0, 24,9, 23,5, 17.3, 2,8, 1.9

Example 4

(l iP 7a,20 )-ll-meihyl-norpregiia--4,9-dksi-i7,20-dioI-3-O8ie (VI)

66.7 g ( 128 mmol) of 3,3-ethylendioxy-l -methyl-5a,17a-bis(trimethyisiiyloxy)-estr- 9-en-17p-carbaldehyde obtained in the previous step was dissolved in 490 cm ³ of dry tetrahydrofuran. The solution was stirred under nitrogen and cooled to -10°C, then 225 cm" (50.6 g, 676 mmol) of 3M MeMgCl in tetrahydrofuran was added dropwise while keeping the temperature below -1 G°C. Stirring was continued at -10°C for 1 h.

Then the reaction mixture was added to 1380 cm ^J of 5% Na ₂ C0 ₃ solution, followed by addition of 690 cm ³ of ethyl acetate. The mixture was stirred for 10 min, then the phases were separated, the water phase was extracted with 2x690 cm ^J of ethyl acetate, the combined organic phases were washed with 2x450 cm ¹ of 20% NaCi solution, dried over Na?S0 ₄ , filtered and the filtrate was concentrated under diminished pressure at 40°C. The residue was treated with 69 cm ³ of ethyl acetate and when the crystallization started 23 cm ³ of diisopropyl ether was added and the mixture was cooled to 0°C. After stirring for 30 min the crystals were filtered off, washed with 23 cm" of diisopropyl ether cooled to 0°C and dried at 40°C in vacuum to yield 17.11 g (40%) of the title compound.

Column chromatography (360g of silica gel, eluent: cyclohex an e: ethyl acetate=4: l) of the mother liquor (17.94 g) yielded 2.76 g of pure product.

Overall yield: 19.87 g (47%)

Melting point: 184-186°C

1H MR (CDCh) : 5.67 (s, I I I ), 4.05-4.10 (m, 1H), 3.24 (t, .! 7.7 Hz, 1 H), 2,88 (dt, J 14 7, 5.2 Hz, 1H), 2.52-2.64 (m, IH), 2.42-2.50 (m, 3H), 2.35-2.41 (m, 2H), 2.11 (s, I I I ). 2.05-2.08 (m, IH), 2,05 (s, IH), 1 ,93 (dq, .1 12.8, 4,2 Hz, H i ). 1 .85 (td, .) 12.3 , 7.3 Hz, IH), 1.75-1.80 (m, IH), 1.71-1.75 (m, 1H), 1.67 (d, J=13.4 Hz, IH), 1.64 (d, J=5.1 Hz, I H), 1.49 (ddd, .) 14.9. 9,2, 6. 1 Hz, I H), 1 ,32-1 ,40 (m, I H), 1 ,22-1 ,29 (m, 2H), 1.19 (d, 1=6 A Hz, 3H), 1.17 (d, J=8.1 Hz, 3H), 1.03 (s, 3H)

¹³ C NMR (CDCI ₃ ) : 199.8, 158.0, 151.4, 125.3, 121 ,9, 85.3, 70.1, 49.8, 47.0, 38.0, 37.1, 36.5, 33.6, 31.4, 31. 1 , 27.7, 25.4, 23.8, 23.4, 18.8, 17.7

Example 5

(lip,17a,204)-ll-methyl-norpregn-5(10)-en-17,20-diol-3-one (VII)

19.58 g (59.4 mmol) of (1 1β, 17α,20ξ)-1 l-rnethyi~norpregna-4,9-dien-17,20-dioi~3-one was dissolved in a mixture of 347 cm ³ of tetrahydrofuran and 1025 cm ³ of toluene and the mixture was cooled to -40°C. Then 1100 cm ³ of liquid ammonia was added and the cooling bath was removed. Addition of the ammonia caused colloid type precipitation. Then 1.31 g (0, 186 mol) of granulated lithium metal was added to the reaction mixture, after addition of the lithium the color of the mixture changed to deep blue. The reaction mixture was stirred at -35°C for 50-60 min, then 9 cm ³ of water was added and the blue color disappeared. The ammonia was distilled off until +15°C was reached, then 540 cm ³ of 10% hydrochloric acid was added while stirring was continued. The phases were separated, the organic phase was washed with 675 cm ³ of water and concentrated to yield about 22.5 g product as an oil, which was crystallized from diisopropyl ether. Yield: 16.70 g (85,3 %)

Melting point: 141-143.5°C

ΐ NMR ( DM SO-./,, ) : 4.02 (d, J=6.9 Hz, 1H, OH), 3.73-3.80 (m~qui, 1 H), 3.45 (s, 1H, OH), 2.66 + 2.77 (AB, J=20.6 Hz, 2xlH), 2.39-2.47 (m, 1H), 2.22-2.39 (m, 4H), 1.98- 2. 1 (m. 1 1 1 ). 1 ,75-1.92 (m, 4H), 1 ,42-1 ,70 (m, 5H), 1 ,22-1 ,33 (m, 1 H), 1 ,04-1 ,22 (m, 2H), 1.00 (d, J 6.2 Hz, 3H), 0.85 (d, j 8.0 Hz, 3H), 0.84 (s, 3H)

¹³ C NMR (DMSO-de) : 210.2, 130,0, 127.5, 84.7, 69.1 , 49.74, 49,72, 47.7, 44.5, 38.8, 38.4, 33.5, 32.7, 29.8, 29.2, 26.4, 25.8, 22.8, 18.7, 18.3, 17.4

Example 6

(llp,17 )~17~hyi!roxy~li~methyl~!iorpregsi~5(10)~eii~3,20~diosie (VIII)

Under nitrogen 13,36 cm ³ (188 mmol) of dry dimethyl sulfoxide was added to 1500 cm ³ of dry dichlorom ethane and the mixture was cooled to -60°C, Then 15 cm ³ (188 mmol) of oxalyi chloride was added to the mixture at this temperature and after 10 min stirring a solution of 16.70 g (50.17 mmol) of (11β, 17 ,20ξ)-1 l -methyl-norpregn-5(10)-en- 17,20-diol-3-one in 33 cm" of dichloromethane was added. The reaction mixture was stirred at this temperature for 1 h, then 167 cm ^J of tri ethyl amine was added while keeping the temperature below -60°C. After the addition the temperature was allowed to raise to 0°C and the mixture was stirred at this temperature for 30 min. After completion of the reaction (TLC: toluene:acetone=4: l) the reaction mixture was added to 1500 cm ³ of 10% hydrochloric acid, then the phases were separated. The water phase was extracted with 450 cm ³ of dichloromethane, the combined organic phases were washed with 1 500 cm ³ of 5% aqueous NaHC0 ₃ solution and 1000 cm ¹ of water, dried, filtered and concentrated. The product was crystallized from a mixture of ethyl acetate diisopropyl ether and filtered to yield 13.00 g (78%) of the title compound as white crystals.

Melting point: 153-157°C

^; il NMR (500 MHz, DMSO-d ₆ ) : 5.28 (s, IH), 2.62-2.82 (m, 2H), 2.53-2.61 (m, IH), 2.39-2.47 (m, HI), 2.25-2.39 (m, 411)..2.22 (dd, J 13.1, 6.0 Hz, 111), 2.09 (s, 3H), 1,99- 2.08 (m, 111), 1.85-1.94 (m, 2H), 1.77-1.85 (m, 1H), 1.63-1.70 (m, 1H), 1.55-1.63 (m, IH), 1,45-1,54 (m, 111), 1.40 (dd, .1 1 1.1,8 Hz, Hi), 1,29-1,37 (m, HI), 1.08-1.25 (m, 2H), 0.84 (d, J 7.3 Hz, 311).0.61 (s, 311)

i ³ C NMR (125 MHz, DMSO-d ₆ ) : 210.2, 210.0, 129.8, 127.8, 89.0, 50.5, 49.6, 47.0, 44,5, 38,5, 37,5, 32,6, 32,1, 29,8, 29.2, 26.7, 26.4, 25.9, 22.5, 18.1, 17.3

Example 7

(Ii ,17a)-17-acetoxy-ll-methyl-siorpreg8i-5(10)-e8i-3,20-dioiie (IX)

To a solution of 12.9 g (39.09 mmol) of (lip,17a)-17-hydroxy-ll-methyl-norpregn- 5(10)-en-3,20-dione in 130 cm ³ of dichloromethane 25.8 cm ³ (273 mmol) of acetic anhydride was added, then the mixture was cooled to -20°C and 6.81 cm ³ of 70% perchloric acid in 30 cm ³ of dichloromethane was added dropwise while keeping the temperature at ~20°C (very exothermic reaction). After completion of the reaction (60 min reaction time) the reaction mixture was diluted with 185 cm ³ of dichloromethane and 185 cm ³ of ion-exchanged water was added to the stirred mixture (the temperature raised to 0°C). Then the temperature was allowed to raise to room temperature and the mixture was stirred for 15 min. The phases were separated, the organic phase was washed with 3x45 cm ³ of water, dried, filtered and concentrated. The residue (13.37 g oil) was purified by column chromatography, 400 g of silica gel, toluene as eiuent. When the product started to elute, the eiuent was changed: first 2 v/v%, then 5 v/v% of acetone was added. The fractions containing the product were concentrated to yield 8 g the title compound as an oil, which was used in the next step without further purification. The oily product can be crystallized from diisopropyl ether.

Melting point: 202-205°C

1H NMR (500MHz, CDC1 ₃ ) : 2.90-3.01 (m, IH), 2.71-2.85 (m, 2H), 2.39-2.53 (m, 4H), 2.28-2.38 (m, 2H), 2,12 (s, 3H), 2.07-2.18 (m, IH), 2.05 (s, 3H), 1,95-2,03 (m, IH), 1 .82-1 .92 (rn, 2H), 1.66-1.80 (m, 3H), 1 ,53-1 ,64 (m, I H), 1 .49 (dd, .M 3.1 , 1.9 Hz, I H), 1 .24- 1 .40 (m, 21 1 ), 0.90 (d, ,1=7.5 Hz, 3H), 0.76 (s, 3H)

i ³ C NMR (125MHz, CDC1 ₃ ) : 211.4, 203.9, 170,6, 129.9, 128,5, 96.5, 51.9, 49.9, 47.5, 44.9, 39.0, 38.2, 33.1, 30.4, 30.4, 29.8, 26.5, 26.3, 26.3, 23.2, 21.3, 17.9, 17.5

Example 8

(lip,17a)- ^' 17-acetoxy-ll-methyl-19-norpregn-4-en-3,20-dione (I) (Norgestomet)

8.00 g of (l i ,17a)-17-acetoxy-l l-methyl-noq)regn-5(10)-en-3,20-dione obtained in the previous step was dissolved in 480 cm ¹ of methanol, 29.3 cm ³ of 10% hydrochloric acid was added and the mixture was refluxed for 1 h under nitrogen. The reaction mixture was cooled, a solution of 16 a of sodium acetate in 160 cm ³ of water was added and the methanol was distilled off. The aqueous residue was extracted with 2x250 cm of dichloromethane, the phases were separated and the combined organic phases were concentrated. 1x30 cm ³ of methanol was distilled off from the obtained oily product (8.2 g) and the residue was recrystallized from methanol twice to yield 5.6 g (70%) of the title compound.

Melting point: 190-191°C

HPLC: total amount of impurities: 0.37% (240 nm), 1.41% (210 nm)

1H NMR (CDCI ₃ ): 5.86 (s, H), 2.94 (dd, j 13.8, 1 1.0 Hz, IH), 2.47 (dt, J 14 2, 3.3 Hz, IH), 2.42 (dt, J=16.2, 4.5 Hz, IH), 2.23-2.33 (m, 5H), 2.16-2.23 (m, IH), 2.10-2.13 (m, 3H), 2.05 (s, 3H), 1.94 (ddt, J=13.0, 4.9, 3.2 Hz, IH), 1.66-1.75 (m, 3H), 1.55-1.63 (rn, 2H), 1 .52 (d, .) 1 1 .6 Hz, I H), 1 .28-1 ,36 (m, IH), 1 , 13-1 ,23 (m, 2H), 1.08 (d, J 7 5 Hz, 3H), 0,76 (s, 3H)

i C NMR (CDC! 3) : 203.8, 199.8, 170.6, 167.1 , 124,5, 96.4, 52.3, 52.0, 46.8, 38.4, 36.3, 35.3, 34.6, 31.5, 30.1 , 28.8, 26.3, 26.1, 23.5, 21.3, 17.4, 17.3

Example 9

{llp,17 ₅ 20 )-ll~ffleihyl-norpregii-4-en~r7,20~diol-3-O8ie (Villa)

22.5 g of (1 1 β, 17α,20ξ)-11-ηΐ6Λν1-ηοί·ρι^ι -5(10)-εη-17,20^ϊο1-3-οη6 obtained in example 5 was dissolved in 1350 cm ³ of methanol, 83 cm ^J of 10% hydrochloric acid was added and the mixture was reflux ed for 1 h. The reaction mixture was cooled, a solution of 45 g of sodium acetate in 450 cm ¹ of water was added and the methanol was distilled off. The aqueous residue was extracted with 2x450 cm ^J of dichloromethane, the phases were separated and the combined organic phases were concentrated. The obtained oily residue (24.16 g) was purified by column chromatography, 300 g of silica gel, first toluene, then a mixture of toluene and acetone as eluent (1, 2 then 5 v/v% of acetone). The obtained oily product (16.7 g, 74%) was used in the next step without further purification.

! MR (DMSO-d6) : 5.73 (s, 1 1 1 ). 4.03 (d, j 7.0 Hz, 1 1 1 ). 3.76 (t, J=6.5 Hz, 1H), 3.44 (s. 1 1 1 ). 2,39 (d, i S 4. 1 Hz, 1H), 2.18-2.28 (m, 4H), 2,04-2, 14 (m, 3H), 1.82 (dd, J=13.7, 6.1 Hz, 3H), 1.66 (d, J=13.4 Hz, 1H), 1.42-1.64 (m, 7H), 1.27 (dd, 1=9.3, 6.0 Hz, 3H), 1.06-1.14 (m, 3H), 1.03 (d, J 7 5 Hz, 3H), 0,99 (d, .1 6.8 Hz, 31 1 ), 0.96-1 .01 (m, 51 1 ), 0.84-0.86 (m, 3H)

¹³ C NMR (DMSO-de): 198.5, 168,0, 123.5, 84.7, 69. 1, 52,5, 50.2, 46.9, 39.2, 38,0, 36.1 , 34.7, 34.2, 33.4, 31.5, 28.4, 25.8, 23.2, 18.8, 17.9, 17.3

Example 10

(li ,l'7a)-17-hydroxy-ll-methyl-norpregn-4-en-3,20-dione (IXa)

Under nitrogen 12,42 cm ³ (175 mmol) of dry dimethyl sulfoxide was added to 1125 cm ³ of dry dichloromethane and the mixture was cooled to -60°C. Then 14.90 cm ³ (175 mmol) of oxalyl chloride was added to the mixture at this temperature and after 10 min stirring a solution of 16.70 g (50.17 mmol) of (1 1 β,17α,20ξ)-11-Γη6ίΗν1-ηοΓρΓβ η-4-βη- 17,20-diol-3-one in 153 cm ³ of dichloromethane was added. The reaction mixture was stirred at this temperature for 1 h, then 15.3 cm ³ of tri ethyl amine was added while keeping the temperature below -60°C. After the addition the temperature was allowed to raise to 0°C and the mixture was stirred at this temperature for 30 min. After completion of the reaction the mixture was added to 2250 cm ³ of 10% hydrochloric acid, then the phases were separated. The water phase was extracted with 450 cm ³ of dichloromethane, the combined organic phases were washed with 360 cm ³ of water, dried, filtered and concentrated. The product was ciystallized from ether and filtered to yield 10.00 g of the title compound as ochre crystals (overall yield of two steps: 51%). Melting point: 193-195°C

1H MR (CDCls) : 5.85 (s, H), 2.73 (s, IH), 2.69-2.73 (m, 1H), 2.46 (dt, .1=14.2, 3.3 Hz, IH), 2,41 (dt, .) 16.3. 4.5 Hz, H I ), 2.20-2.31 (rn, 8H), 2. 15-2.20 (rn, IH), 2.04 (dd, J=13.3, 6.3 Hz, IH), 2.01 -2.08 (m, IH), 1.89-1.99 (m, 2H), 1 .80 (dd, .1 9.7. 2.4 Hz, 1 1 1 ), 1.70-1.77 (m, IH), 1.50-1.63 (m, 4H), 1.41 (dd, j 13.2, 1 ,7 Hz, IH), 1.37 (dd, j H .6, 6.5 Hz, 2H), 1.12-1.20 (m, 3H), 1.06 (d, .1 7.7 Hz, 4H), 0.84-0.86 (m, 3H)

i ³ C NMR (CDCI ₃ ) : 21 1.3, 199,9, 167.4, 124.5, 89.7, 52.5, 51 ,0, 48.2, 38.5, 37,5, 36.4, 35.3, 34.5, 33.4, 31.5, 28.7, 27.8, 26.1, 25.6, 23.5, 18.5, 17.3 Example 1 1

(l i ,17a)-17-acetoxy-ll-methyl-19-norpregii-4-eii-3,20-dione (I) (Norgestomet) To a solution of 9.9 g (30 mmol) of (1 ip, 17oc)-17-hydroxy-l 1 -methyl -norpregn-4-en-

3,20-dione in 100 cm ³ of dichloromethane 18.9 cm ³ (200 mmol) of acetic anhydride was added, then the mixture was cooled to -20°C and 5.13 cm" of 70% perchloric acid in 22.5 cm ³ of dichloromethane was added dropwise while keeping the temperature at -20°C (very exothermic reaction). After completion of the reaction (40 min reaction time) the reaction mixture was diluted with 45 cm ³ of dichloromethane, 45 cm ³ of ion- exchanged water (the temperature raised to 0°C) and 45 cm ^J of 25% ammonia solution (over a period of 10 min) were added to the stirred mixture (pH=7-8). Then the temperature was allowed to raise to 25°C and the mixture was stirred for 15 min. The phases were separated, the water phase was extracted with 2x45 cm ¹ of dichloromethane, the combined organic phases were washed with 3x45 cm ³ of water, dried, filtered and concentrated. The oily residue (13 ,37 g) was purified by column chromatography, 135 g of silica gel, toluene as eiuent. When the product started to elute, the eiuent was changed: first 2 v/v%, then 5 v/v% of acetone was added. The fractions containing the product were concentrated, the residue was dissolved in methanol, decolorized, filtered and the filtrate was concentrated to a smaller volume. The product (7.52 g) obtained after filtration and drying was recrystallized again from methanol to yield 6,61 g (59.3%) of the title compound.

Melting point: 190- 191 °C \ W ! R (CDCI ₃ ): 5.86 (s, IH), 2.94 (dd, i S .8. 11.0 Hz, I H), 2.47 (dt, i 14 2, 3.3 Hz, IH), 2.42 (dt, J=16.2, 4.5 Hz, IH), 2.23-2.33 (m, 5H), 2.16-2.23 (m, IH), 2.10-2.13 (m, 3H), 2.05 (s, 3H), 1.94 (ddt j 13.0, 4.9, 3 ,2 Hz, IH), 1.66-1.75 (m, 3H), 1.55-1.63 (m, 2H), 1 .52 (d, J=11.6 Hz, IH), 1.28-1.36 (m, IH), 1. 13-1.23 (m, 2H), 1.08 (d, J 7.5 Hz, 3H), 0,76 (s, 3H)

°C NMR (CDC1 ₃ ) : 203.8, 199.8, 170.6, 167.1 , 124.5, 96.4, 52.3, 52.0, 46.8, 38.4, 36.3, 35.3, 34.6, 31.5, 30.1, 28.8, 26.3, 26.1, 23.5, 21.3, 17,4, 17,3.