Title of Invention

PROCESS FOR THE SYNTHESIS OF HIGH PURITY D-(17 ALPHA)-13-ETHYL-17HYDROXY-18, 19-DINORPRE:GN-4-ENE-20-YNE-3-ONE-OXIME

Abstract The invention relates to a process for the synthesis of high purity d-( 17α)-13-ethyI-17hydroxy-18,19-dinorpregn-4- ene-20-yne-3-one-oxime (further on norelgestromine) via acetylation of d-norgeslrel at position 17, oximation of the oxo group at position 3 of the obtained 17-acetoxy derivative, and finally hydrolyzing the acetoxy group at position 17 of the obtained 3-oxime derivative. The process according to our invention is as follows: the starting material, d-(17α-17-hydroxy-13-ethyl-18,19-dinor- pregn-4-ene-20-yne-3one (d-norgestrel) - purity 93-94 % - is acerylated with acetic anhydride in acetic acid, in the presence of zinc chloride and hydrogen chloride, or 70 % perchloric acid in an inert gas atmosphere, and after completion of the reaction the excess of acetic anhydride and the "enol acetate" by-product are decomposed with aqueous hydrochloric acid then the formed d-(17α)-17-acetoxy-13-ethy]-18,19-dinoipregn-4-ene-20-yne-3-one is isolated from the reaction mixture by addition of ice-water, the precipitated product is filtered off, washed with water, dried, dissolved in dichloromethane or acetone and clarified with silica gel or aluminum oxideand charcoal, after filtration of the clarifier the resulted solution is concentrated and the residue is recrystallized, the obtained d-(17α)-17-acetoxy-13-eyhyal-18,l9-dinorpregn-4-ene-20-yne-3-one is reacted either with hydroxylammonium acetate or with hydroxylammonium chloride in the presence of sodium acetate, in acetic acid in nitrogen atmosphere under vigorous stirring for about 1 hour, aftercompletion of the reaction water is added, the precipitated product is filtered off, washed with water, dried and recrystallized, the obtained d-(17α-17'acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oximeis hydrolyzed with an equiv- alent amount of an alkali metal hydroxide in a C1 -C4 alkanol solution, in nitrogen atmosphere between a temperature of about 5-38 °C, under vigorous stirring, after completion of the reaction the mixture is diluted with water and the pH of the resulted suspension is adjusted to 7,5-9 with acetic acid, the precipitated product is filtered off, washed with water, dried, the crude product is dissolved in ethanol, clarified with charcoal, and after filtration of the clarifier water is added to the obtained solution, the precipitated high pu- rity d-(17α)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oxime is filtered off, washed with water and in given case recrystallized from ethanol.
Full Text WO 2005/000868 PCT/HU2004/000031
Process for the synthesis of high purity d-(17α)-13-ethyI-17-hydroxy-18,19-dinor-pregn-4-
ene-20-yne-3-one-oxime
The invention relates to a process for the synthesis of high purity d-(17α)-13-ethyl-17-
hydroxy-18,19-dmorpregn-4-ene-20-yne-3-one-oxime (further on norelgestromine) via acetyla-
tion of d-norgestrel at position 17, oximation of the oxo group at position 3 of the obtained 17-
acetoxy derivative, and finally hydrolyzing the acetoxy group at position 17 of the obtained 3-
oxime derivative.
The term "high purity" - as used in this specification - means prod-
ucts/materials/compounds, in which the content of the specified compound is at least 99.5 mass
percent and the overall amount of other steroid impurities is not more, than 0.1 mass percent
The investigation of the metabolism of norgestimate is described in the following pub-
lication: AmJ.Obstet Gynecol. 16^ 2127-31. (1990). The authors discovered, that after oral ap-
plication the metabolites of d-norgestimate are the norelgestromine, d-{17a)-13-ethyl-17-
acetoxy-18,19-dinorpregn-4-ene-20-yne-3-one (norgestrel acetate), as well as the d-(17α)-13-
ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yne-3-one (d-norgestrel), which are first of all re-
sponsible for the biological activity.
The efficacy and safety of norgestimate/ethynyl-oestradiol used as third generation con-
traceptive are described in the following publication: AmJ.Obstet Gynecol., 166. 1969-77.
(1992). They also determined, that the main metabolite of norgestimate is norelgestromine,
which has a similar pharmacological profile, than norgestimate and after oral administration it is
detectable in the blood serum already after a short period of time.
In the U.S. patent Number of 5,876,746 the authors suggested the use of norel-
gestromine as such or in combination with an oestrogen component hi transdermal plaster for
inhibition of fertility.
In the Hungarian patent Number of 165356 the synthesis of dl- as well as d-norgestrel
is disclosed. The starting material of the synthesis is the racemic or the optically active 3-
methoxy-gona-2,5(10)-diene-17P-ol, which is reacted with hydroxylammonium chloride in pyri-
dine at 100 °C, then the obtained l3-e1nyl-[3-(>ydroxy-irniiio)]-gon-4-ene-l7p-ol is oxidized at
position 17, followed by ethynylation of the oxo group at position 17 to give the dl-(17α)-13-
ethyl-17-hy the synthesis of the intermediates, the dl-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-

WO 2005/000868 PCT/HU2004/000031
yne-3-one-oxime and norelgestromine, are described in recipes, the identification and the purity
(the quality requirements) as well as the biological activity of these compounds are not given in
the patent.
In the U.S. patent Number of 4,027,019 mainly the synthesis of the 17-acetoxy and the
ester derivatives of norelgestromine in general, as well as the biological examinations thereof are
described.
Considering, that to meet the more and more demanding requirements of pharmaco-
poeia is a basic requirement for every active ingredient applied in therapy, especially for steroids
having high biological activity, we made an effort to elaborate an economical process for pro-
ducing such high purity product, which meets even the most demanding requirements as well.
The purity of the desired compound is also determined by the purity of the starting ma-
terials . This is especially important, if the purification of the final product can b e carried out only
with large loss of material, because in this case the economical realization of the process can be a
limit of the accessible purity. However in many cases providing the sufficiently pure starting
material can also be carried out with large loss of material. In this case, it can be tried to take
advantage of the more advantageous physical property of the last or any of the previous interme-
diates for producing the pure final product
Surprisingly it was found, that an order of magnitude more pure, than the purity limit
(maximum amount of impurity is less than 1 %) usually given in pharmacopoeias, noieT-
gestromine can be prepared according to our invention as follows:
the starting material, d-(17α)-17-hydroxy-13-ethyl-18,l9-dinorpregn-4-ene-20-yne-3-
one (d-norgestrel) - purity 93-94 % - is acetylated with acetic anhydride in acetic acid, in the
presence of zinc chloride and hydrogen chloride, or 70 % perchloric acid in an inert gas atmos-
phere, and after completion of the reaction the excess of acetic anhydride and the "enol acetate"
by-product are decomposed with aqueous hydrochloric acid,
then the formed d-(17α)-17-acetoxy-13-ethyl-18,19-dmorpregn-4-ene-20-yne-3-one is
isolated from the reaction mixture by addition of ice-water, the precipitated product is filtered
oif, washed with water, dried, dissolved in dichloromethane or acetone and clarified with silica
gel or aluminum oxide and charcoal, after filtration of the clarifier the resulted solution is con-
centrated and the residue is preferably recrystallized from a 9:1 mixture of diisopropyl
ether/acetonitrile or diisopropyl ether/ethanol,

WWO 2005/000868 PCT/HU2004/000031
- 3 -
the obtained d-(17α)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one is re-
acted either with hydroxylammonium acetate or with hydroxylammonium chloride in the pres-
ence of sodium acetate, in acetic acid in nitrogen atmosphere under vigorous stirring for about 1
hour, after completion of the reaction water is added, the precipitated product is filtered off,
washed with water, dried and recrystallized preferably from ethanol,
the obtained d^l7a)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene--20-yne-3-one-oxime
is hydrolyzed with an equivalent amount of an alkali metal hydroxide in a Ci-C4 alkanol solu-
tion, in nitrogen atmosphere between a temperature of about 5-38 °C, under vigorous stiiring,
after completion of the reaction the mixture is diluted with water and the pH of the resulted
suspension is adjusted to 7,5-9 with acetic acid, the precipitated product is filtered off, washed
with water, dried, the crude product is dissolved in ethanol, clarified with charcoal, and after
filtration of the clarifler water is added to the obtained solution, the precipitated high purity d-
(17a>17-acetoxy-13^myl-18J9-diriorpregn-4-ene-20-yne-3-one-oxime is filtered off, washed
with water and in given case recrystallized from ethanol.
The above mentioned "enol acetate" is a labile compound having a 3-acetoxy-3,5-diene
structure. This structure is formed in small amounts as product of an equilibrium by-reaction
under the circumstances of the first acetylation step and is decomposed under forming d-(17α)-
17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one with aqueous hydrochloric acid
According to our invention it is also possible, that the geometrical isomers are sepa-
rated from the anti/syn isomeric mixture formed in the oximation step before the hydrolysis by
known methods, for example by chromatography, and the so obtained compounds are hydro-
lyzed. Therefor, as the hydrolysis according to our invention does not influence the geometry of
the nitrogen atom of the oxjme, after the hydrolysis the appropriate, pure anti and syn isomers of
norelgestromine are obtained.
The invention is illustrated by the following not limiting examples.

WO 2005/000868 PCT/HU2004/000031
-4-
Example 1
d-(17α)-13-Ethyl-17-hydroxy-18,19-dinorpregn -4-ene-20-yne-3-one (Norgestimate)
Under nitrogen, to a vigorously stirred suspension of 150 g (about 045 mol) of d-
norgestrel (purity 94 %) and 1500 ml of acetic acid 135 ml (1.428 mol) of acetic anhydride and 3
ml of 70 % aqueous perchloric acid are added. The suspension becomes clear in a few minutes.
Stirring is continued for 20 min, then 135 ml of water and 75 ml of 10 % aqueous hydrochloric
acid is added to the reaction mixture. After stirring for 1 h the reaction mixture is poured into 14
1 of ice-water. The precipitated product is filtered off, washed with water and dried. The obtained
crude product is dissolved in 1500 ml of dichloromethane and stirred with 150 g of silica gel for
30 min for clarifying. The silica gel is filtered off and the solvent is evaporated. The residue is
refluxed with a 9:1 mixture of isopropyl ether/acetonitrile for 15 min, then the solution is cooled
to 0 °C. the precipitated product is filtered off and dried to yield 137 g of the p\u:e title com-
pound. A further 19 g of the title compound can he obtained from the mother liquor by repeating
the above purification process. Overall yield: 152 g (89.3 %). Mp.: 204-205 °C. [OJD= -25°
(c=l% chloroform)
According to thin layer chromatography the product contains less than 1 % of impurity
(calculated for levonorgestrel acetate). (For TLC 25 DC-Alufolien Kieselgel 60 F254 plates and a
4:1 mixture of toluene-acetone, as eluent were used. Detection was carried out by spraying the
plates with a mixture of ethanol-sulfuric acid.)
Example 2
d-(17α)-13-Ethyl-17-hydroxy-18,19-dinorpregn -4-ene-20-yne-3-one (Norgestimate)
Under nitrogen, to a stirred suspension of 10 g (about 0.03 mol) of d-norgestrel (purity
93 %) and 100 ml of acetic acid 6 ml (0.063 mol) of acetic anhydride, 2 g of anhydrous zinc
chloride and 1.6 ml of 6.7 % hydrogen chloride solution in acetic acid are added. The suspension
becomes clear in a few minutes. Stirring is continued for 20 min, then 5 ml of -water and after a
further 15 min of stirring 3 ml of 18 % aqueous hydrochloric acid are added to the reaction mix-
ture, which is stirred for a further 45 min. Then the reaction mixture is poured into 600 ml of ice-
water, the precipitated product is filtered off, washed with water and dried. The crude title com-
pound is purified according to the method described in example 1.
Yield: 15.4 g (90.47 %). Mp.: 204-205 °C. [a]D= -25° (c=l % chloroform). Maximum
impurity is 1 % according to the analysis described in example 1.

WO 2005/000868 PCT/HU2004/000031
-5-
Example 3
d-(17α)-13-Ethyl-17-hydroxy-18,19-dinorpregn -4-ene-20-yne-3-one-oxime(Norgestimate)
Under nitrogen, to a stirred solution of 12 g (0.033 mol) of d-norgestrel acetate, ob-
tained according to example 1 or 2, and 120 ml of acetic acid 9.44 g (0.1 mol> of hydroxylam-
monimn acetate is added. The reaction mixture is stirred at room temperature for 45 min, then it
is poured into 11 of water. The precipitated crystals are filtered off, washed with water and dried
below 40 °C in vacuum. The obtained 12.2 g of crude product is dissolved in 250 ml of boiling
ethanol, clarified with 1.2 g of charcoal, and after filtration of charcoal the solution is concen-
trated to a volume of about 20 % of the original one. The so obtained solution containing the
crystalline product is cooled to 0 °C and kept at this temperature for 12 h. the precipitated crys-
tals are filtered off, washed with ethanol and dried below 40 °C to yield 11.0 g C88 %) of the title
compound. Mp.: 224-226 °C.
According to Test 1 and Test 2 described in USP 26th Pharmacopoeia on page 1335 the
impurity of the product is less, man 0.5 %.
Example 4
d-(17α)-13-Ethyl-17-hydroxy-18,19-dinorpregn -4-ene-20-yne-3-one-oxime(Norgestimate)
Under nitrogen, to a vigorously stirred solution of 120 g (0.33 mol) of norgestrel ace-
tate, obtained according to example 1 or 2, and 1259 g (1200 ml) of acetic acid 90.2 g (1.1 mol)
of anhydrous sodium acetate and 76 g (1.93 mol) of hydroxylammonium hydrochloride. are
added. The temperature of the reaction mixture should be below 30 °C. The reaction is com-
pleted in 1 h. Then the obtained white suspension is poured into 10 1 of water and the obtained
mixture is stirred for 30 min. The precipitated product is filtered off, washed with water and
dried at 40 °C.
The obtained crude product (122 g) is dissolved in 197.3 g (2500 ml) of boiling etha-
nol, clarified with 12 g of charcoal, filtered and the filtrate is concentrated under reduced pres-
sure below 40 °C to a volume of 400 ml, then cooled to 0-5 °C and kept on this temperature for 3
h. The precipitated white crystalline product is filtered off, washed with 197 g (250 ml) of etha-
nol in two portions and dried below 40 °C to yield 102 g (81.6 %) of the title compound. Mp.:
224-226 °C.
According to Test 1 and Test 2 described in USP 26th Pharmacopoeia on page 1335 the
impurity of the product is less, than 0.5 %.

WO 2005/000868 PCT/HU2004/000031
-6-
Example 5
d-(17α)-13-Ethyl-17-hydroxy-18,19-dinorpregn -4-ene-20-yne-3-one-oxime(Norel-
gestromine)
Under nitrogen, to a stirred suspension of 50.0 g (135.3 mmol) of norgestimate, ob-
tained according to example 3 or 4, and 500 ml of methanol 17.04 g (0.406 mol) of lithium hy-
droxide monohydrate is added at 20-28 °C. After stirring for about 30 min a homogeneous solu-
tion is obtained, and the temperature rises 10 °C. The reaction mixture is stirred at 25-35 °Cfor 3
h and the completion of the reaction is checked by thin layer chromatography. Then the reaction
mixture is poured into 51 of water at 10-25 °C (the pH of the suspension is about 13), and the pH
of the suspension is adjusted to 7.5-9 with 14.7 ml (0.25 mol) of acetic acid. The so obtained
suspension is stirred for 20 min, then the crystalline product is filtered off and washed with 2 x
200 ml of water. The pH of the filtrate is checked and washing is repeated until the pH of the
filtrate is 1-75. The filtered crude product is dried at 50 °C. The obtained 45 g of crude product
is dissolved in 440 ml of ethanol at 25-30 °C, then 2.2 g of charcoal is added. After 20 mis stir-
ring the clarifier is filtered off and washed with ethanol. Then the filtrate is poured into 4.4 I of
water at 10-25 °C under vigorous stirring. The obtained product is filtered off, washed with wa-
ter and dried at 50 °C to yield 42.0 g (94.8 %) of the title compound. Mp.: 110-130 °C.
Water content: 0.4 %.
Example 6
d-(17α)-13-Ethyl-17-hydroxy-18,19-dinorpregn -4-ene-20-yne-3-one-oxime(Norel-
gestromine)
Under nitrogen, to a stirred suspension of 10.0 g (0.027 mol) of norgestimate
(levonorgestrel-acetate-oxime), obtained according to example 3 or 4, and 100 ml of methanol
3.25 g (0.081 mol) of sodium hydroxide is added at 22 °C. After stirring for about 10 min a ho-
mogeneous solution is obtained, and the temperature rises to 32 °C. Then the reaction mixture is
stirred at 25 °C for 3 h and the completion of the reaction is checked by thin layer chromatogra-
phy. The reaction mixture is poured into 1000 ml of water at 10-20 °C under stirring and the pH
of the suspension is adjusted to 7-7.5 with 3 ml of acetic acid. Then the obtained suspension is
stirred for 20 min, the precipitated product is filtered off, washed with water and dried in vacuum
at 40 °C over phosphorous pentoxide to yield 8.4 g (94.8 %) of the title compound as a mixture

WO 2005/000868 PCT/HU2004/000031
-7-
of 3E and 3Z isomers. Mp.: 110-130 °C. According to HPLC the amount of all the impurities is
0.09 %.
Example 7
d-(17α)-13-Ethyl-17-hydroxy-18,19-dinorpregn -4-ene-20-yne-3-one-oxime(Norel-
gestromine)
Under nitrogen, to a stirred suspension of 10.0 g (0.027 mol) of norgestimate
(levonorgestrel-acetate-oxime), obtained according to example 3 or 4, and 100 ml of methanol
4.56 g (0.081 mol) of potassium hydroxide is added at 22 °C. After stirring for about 10 min a
homogeneous solution is obtained, and the temperature rises to 32 °C. Then the reaction mixture
is stirred at 25 °C for 3 h and the completion of the reaction is checked by thin layer cbromatog-
raphy. The reaction mixture is poured into 1000 ml of water at 10-20 °C under stirring and the
pH of the suspension is adjusted to 7-7.5 with 2.7 mi of acetic acid. Then the obtained suspen-
sion is stirred for 20 min, the precipitated product is filtered off, washed with water and dried in
vacuum at 40 °C over phosphorous pentoxide to yield 8.6 g (96.9 %) of the title compound as a
mixture of 3E and 3Z isomers. Mp.: 110-130 °C. According to HPLC the amount of all the im-
purities is 0.1 %.
The purity of the obtained norelgestromine samples was determined by HPLC using
Shimadzu instrument, UV detection and Shimadzu integrator. Detection was performed at 244
nm. 150 x 4.6 mm column was used, filled with 5 urn size Supelcosil LC-18-DB packing mate-
rial. A 7:25:68 mixture of acetonitrile:tetrahydrofuran:water was used as eluent. The determina-
tion was carried out at room temperature, with a flow rate of 1 cm3/min.
The sample solution was prepared as follows: 25 mg of the compound was measured
into a 50 ml volumetric flask, 5 ml of methanol was added and the sample was dissolved, then
the flask was filled with the eluent until the calibration line. The standard solution (STD) was
prepared the same way from analytical purity norelgestromine, containing the E/Z isomers in a
ratio between 1.3-1.6.
The amount of impurity in % (S%) was calculated by the following formula:

In the formula:
A = area under the curve for the component in the subscript
CSTD = concentration of the standard solution [mg/ml]



WO 2005/000868 PCT/HU2004/000031
-9-
What we claim is:
1. Process for the synthesis of high purity d-(17a>13-ethyl-l7-hydroxy-18,l9-
dinorpregn-4-ene-20-yne-3-one-oxime via acetylation of d-norgestrel at position 17, oximation
of the oxo group at position 3 of the obtained 17-acetoxy derivative, and finally hydrolyzing the
acetoxy group at position 17 of the obtained 3-oxime derivative, characterized by
carrying out the acetylation of the starting material, d~(17α)-17-3iydroxy-13-e£hyl-
18,19-dinorpregn-4-ene-20-yne-3-one (d-norgestrel) - purity at least 93-94 % -, with acetic an-
hydride hi acetic acid, in the presence of zinc chloride and hydrogen chloride, or 70 % perchloric
acid in an inert gas atmosphere, and after completion of the reaction decomposing the excess of
acetic anhydride and the "enol acetate" by-product with aqueous hydrochloric acid,
then isolating the formed d-(17α)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-
3-one from the reaction mixture by addition of ice-water, filtering off the precipitated product,
washing with water, drying, dissolving in dichloromeuiane or acetone and clarifying with silica
gel or aluminum oxide and charcoal, concentrating the resulted solution after filtration of the
clarifier and recrystallizing the residue,
reacting the obtained d-(17α)-17-acetoxy-13-ethyl-18,19-dmorpregn-4-ene-20-yne-3-
one either with hydroxylammonium acetate or with hydroxylammonium chloride in the presence
of sodium acetate, in acetic acid in nitrogen atmosphere under vigorous stirring for about 1 hour,
addition of water after completion of the reaction; filtering off the precipitated product, washing
with water, drying and recrystallizing,
hydrolyzing the obtained d-(17a>17-acetoxy-13-ethyl-18,19-dmorpregn-4-ene-2{>-yne-
3-one-oxime with an equivalent amount of an alkali metal hydroxide in a C1-C4 alkanol solution,
in nitrogen atmosphere between a temperature of about 5-38 °C, under vigorous stirring, diluting
the reaction mixture with water after completion of the reaction and adjusting the pH of the re-
sulted suspension to 7,5-9 with acetic acid, filtering orYthe precipitated product, washing with
water, drying, dissolving the crude product in ethanol, clarifying with charcoal, and addition of
water after filtration of the clarifier to the obtained solution, filtering off the precipitated high
purity d-(17a>17-acetoxy-13-ethyl-18,19-dinorprega-4-ene-20-yne-3-one-oxiiue, washing with
water and in given case recrystallizing from ethanol.

WO 2005/000868 PCT/HU2004/000031
-10-
2. The process according to claim 1, characterized by hydrolyzing the d-
(17α)-17'acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oxirae in methanol with lith-
ium hydroxide monohydrate.
3. The process according to claim 1, characterized by recrystallizing the
obtained d-(17α)-17-acetoxy-13-etiiyl-18,19-dinorpregn-4-ene-20-yne-3-one from a 9:1 mixture
of diisopropyl ether/acetonitrile or diisopropyl ether/ethanol.
4. The process according to claim 1, characterized by recrystallizing the
obtained d-(17α)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oxime from etha-
nol.


The invention relates to a process for the synthesis of high purity d-( 17α)-13-ethyI-17hydroxy-18,19-dinorpregn-4-
ene-20-yne-3-one-oxime (further on norelgestromine) via acetylation of d-norgeslrel at position 17, oximation of the oxo group at
position 3 of the obtained 17-acetoxy derivative, and finally hydrolyzing the acetoxy group at position 17 of the obtained 3-oxime
derivative. The process according to our invention is as follows: the starting material, d-(17α-17-hydroxy-13-ethyl-18,19-dinor-
pregn-4-ene-20-yne-3one (d-norgestrel) - purity 93-94 % - is acerylated with acetic anhydride in acetic acid, in the presence of
zinc chloride and hydrogen chloride, or 70 % perchloric acid in an inert gas atmosphere, and after completion of the reaction the
excess of acetic anhydride and the "enol acetate" by-product are decomposed with aqueous hydrochloric acid then the formed
d-(17α)-17-acetoxy-13-ethy]-18,19-dinoipregn-4-ene-20-yne-3-one is isolated from the reaction mixture by addition of ice-water,
the precipitated product is filtered off, washed with water, dried, dissolved in dichloromethane or acetone and clarified with silica gel
or aluminum oxideand charcoal, after filtration of the clarifier the resulted solution is concentrated and the residue is recrystallized,
the obtained d-(17α)-17-acetoxy-13-eyhyal-18,l9-dinorpregn-4-ene-20-yne-3-one is reacted either with hydroxylammonium acetate
or with hydroxylammonium chloride in the presence of sodium acetate, in acetic acid in nitrogen atmosphere under vigorous stirring
for about 1 hour, aftercompletion of the reaction water is added, the precipitated product is filtered off, washed with water, dried and
recrystallized, the obtained d-(17α-17'acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oximeis hydrolyzed with an equiv-
alent amount of an alkali metal hydroxide in a C1 -C4 alkanol solution, in nitrogen atmosphere between a temperature of about 5-38
°C, under vigorous stirring, after completion of the reaction the mixture is diluted with water and the pH of the resulted suspension
is adjusted to 7,5-9 with acetic acid, the precipitated product is filtered off, washed with water, dried, the crude product is dissolved
in ethanol, clarified with charcoal, and after filtration of the clarifier water is added to the obtained solution, the precipitated high pu-
rity d-(17α)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oxime is filtered off, washed with water and in given case
recrystallized from ethanol.

Documents:

02614-kolnp-2005-abstract.pdf

02614-kolnp-2005-claims.pdf

02614-kolnp-2005-description complete.pdf

02614-kolnp-2005-form 1.pdf

02614-kolnp-2005-form 3.pdf

02614-kolnp-2005-form 5.pdf

02614-kolnp-2005-international publication.pdf

2614-kolnp-2005-granted-abstract.pdf

2614-kolnp-2005-granted-assignment.pdf

2614-kolnp-2005-granted-claims.pdf

2614-kolnp-2005-granted-correspondence.pdf

2614-kolnp-2005-granted-description (complete).pdf

2614-kolnp-2005-granted-examination report.pdf

2614-kolnp-2005-granted-form 1.pdf

2614-kolnp-2005-granted-form 13.pdf

2614-kolnp-2005-granted-form 18.pdf

2614-kolnp-2005-granted-form 3.pdf

2614-kolnp-2005-granted-form 5.pdf

2614-kolnp-2005-granted-gpa.pdf

2614-kolnp-2005-granted-reply to examination report.pdf

2614-kolnp-2005-granted-specification.pdf


Patent Number 238264
Indian Patent Application Number 2614/KOLNP/2005
PG Journal Number 05/2010
Publication Date 29-Jan-2010
Grant Date 28-Jan-2010
Date of Filing 16-Dec-2005
Name of Patentee RICHTER GEDEON VEGYESZETI GYAR R.T.
Applicant Address GYOMROI UT 19-21, H-1103 BUDAPEST
Inventors:
# Inventor's Name Inventor's Address
1 MAHO SANDOR RIM U.20., H-1183 BUDAPEST
2 TUBA ZOLTAN BOGAR U. 20/B, H-1022 BUDAPEST
3 KISS JANOS SZOVETSEG U, 9/B, H-1074 BUDAPEST
4 MAGYARI ENDRENE IL KERULET HOMOKRESZ 27, H-2730 ALBERTIRSA
5 TERDY LASZLO KAPISZTRAN U. 11., BUDAPEST
PCT International Classification Number C07J 41/00
PCT International Application Number PCT/HU2004/000031
PCT International Filing date 2004-04-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 P 301982 2003-06-30 Hungary