WO2005000868A1 - Process for the synthesis of high purity d-(17alpha)-13-ethyl-17­hydroxy-18,19-dinorpre:gn-4-ene-20-yne-3-one-oxime - Google Patents

Process for the synthesis of high purity d-(17alpha)-13-ethyl-17­hydroxy-18,19-dinorpre:gn-4-ene-20-yne-3-one-oxime Download PDF

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Publication number
WO2005000868A1
WO2005000868A1 PCT/HU2004/000031 HU2004000031W WO2005000868A1 WO 2005000868 A1 WO2005000868 A1 WO 2005000868A1 HU 2004000031 W HU2004000031 W HU 2004000031W WO 2005000868 A1 WO2005000868 A1 WO 2005000868A1
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WO
WIPO (PCT)
Prior art keywords
ene
yne
ethyl
water
acetoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/HU2004/000031
Other languages
English (en)
French (fr)
Inventor
Zoltán Tuba
Sándor MAHÓ
János KISS
Endréné MAGYARI
László TERDY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Vegyeszeti Gyar Nyrt
Original Assignee
Richter Gedeon Vegyeszeti Gyar RT
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to UAA200600812A priority Critical patent/UA80059C2/uk
Priority to CA002528952A priority patent/CA2528952A1/en
Priority to JP2006518378A priority patent/JP2007516946A/ja
Priority to MXPA05013948A priority patent/MXPA05013948A/es
Priority to DE602004026306T priority patent/DE602004026306D1/de
Priority to NZ544378A priority patent/NZ544378A/en
Priority to EP04730316A priority patent/EP1638988B1/en
Priority to YUP-2005/0897A priority patent/RS20050897A/sr
Priority to BRPI0412186-4A priority patent/BRPI0412186A/pt
Application filed by Richter Gedeon Vegyeszeti Gyar RT filed Critical Richter Gedeon Vegyeszeti Gyar RT
Priority to AT04730316T priority patent/ATE462712T1/de
Priority to AU2004251118A priority patent/AU2004251118A1/en
Priority to EA200600119A priority patent/EA008411B1/ru
Priority to HR20060038A priority patent/HRP20060038A2/xx
Publication of WO2005000868A1 publication Critical patent/WO2005000868A1/en
Anticipated expiration legal-status Critical
Priority to NO20060455A priority patent/NO20060455L/no
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0016—Oximes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives

Definitions

  • the invention relates to a process for the synthesis of high purity d-(17 ⁇ )-13-ethyl-17- hydroxy-18,19-dinorpregn-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.
  • high purity 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.
  • d-norgestimate the metabolites of d-norgestimate are the norelgestromine, d-(17 ⁇ )-13-ethyl-17- acetoxy-18,19-dinorpregn-4-ene-20-yne-3-one (norgestrel acetate), as well as the d-(17 ⁇ )-13- ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yne-3-one (d-norgestrel), which are first of all responsible for the biological activity.
  • norgestimate/ethynyl-oestradiol used as third generation contraceptive 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 norelgestromine as such or in combination with an oestrogen component in transdermal plaster for inhibition of fertility.
  • 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-17 ⁇ -ol, which is reacted with hydroxylammonium chloride in pyri- dine at 100 °C, then the obtained 13-ethyl-[3-(hydroxy-imino)]-gon-4-ene-17 ⁇ -ol is oxidized at position 17, followed by ethynylation of the oxo group at position 17 to give the dl-(17 ⁇ )-13- ethyl-17-hydroxy-18,19-dino regn-4-ene-20-yne-3-one-oxime, or norelgestromine.
  • the purity of the desired compound is also determined by the purity of the starting materials. This is especially important, if the purification of the final product can be 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 intermediates for producing the pure final product.
  • norel- gestromine can be prepared according to our invention as follows: the starting material, d-(17 )-17-hydroxy-13-ethyl-18,19-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 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-(17 )-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-y
  • 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-(17 ⁇ )- 17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one with aqueous hydrochloric acid.
  • 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 hydrolyzed.
  • Example 1 d-(17 ⁇ )-13-Ethyl-17-acetoxy-18,19-dinorpregn-4-ene-20-yne-3-one (NorgestreI acetate) Under nitrogen, to a vigorously stirred suspension of 150 g (about 0.45 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.
  • Example 2 d-(17 )-13-EthyI-17-acetoxy-18,19-dinorpregn-4-ene-20-vne-3-one (Norgestrel acetate) 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.
  • Example 3 d-(17 )-13-Ethyl-17-acetoxy-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, obtained according to example 1 or 2, and 120 ml of acetic acid 9.44 g (0.1 mol) of hydroxylam- monium acetate is added. The reaction mixture is stirred at room temperature for 45 min, then it is poured into 1 1 of water. The precipitated crystals are filtered off, washed with water and dried below 40 °C in vacuum.
  • Example 4 d-(17 )-13-Ethyl-17-acetoxy-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 acetate, 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 completed in 1 h.
  • 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 pressure 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 ethanol in two portions and dried below 40 °C to yield 102 g (81.6 %) of the title compound.
  • Example 5 d-(17 )-13-Ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yne-3-one-oxime (Norelgestromine) 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 hydroxide monohydrate is added at 20-28 °C.
  • Example 6 d-(17 )-13-Ethyl-17-hydro ⁇ y-18,19-dmorpregn-4-ene-20-yne-3-one-oxime (Norelgestromine) 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.
  • norgestimate levonorgestrel-acetate-oxime
  • reaction mixture is stirred at 25 °C for 3 h and the completion of the reaction is checked by thin layer chromatography.
  • 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 of 3E and 3Z isomers.
  • Example 7 d-(17 ⁇ )-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.
  • norgestimate levonorgestrel-acetate-oxime
  • reaction mixture is stirred at 25 °C for 3 h and the completion of the reaction is checked by thin layer chromatog- 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 2.1 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 8.6 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 impurities is 0.1 %.
  • norelgestromine samples were determined by HPLC using Shimadzu instrument, UN detection and Shimadzu integrator. Detection was performed at 244 nm. 150 x 4.6 mm column was used, filled with 5 ⁇ m size Supelcosil LC-18-DB packing mate- rial. A 7:25:68 mixture of acetonitrile:tetrahydrofuran:water was used as eluent. The determination was carried out at room temperature, with a flow rate of 1 cm 3 /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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)
PCT/HU2004/000031 2003-06-30 2004-04-29 Process for the synthesis of high purity d-(17alpha)-13-ethyl-17­hydroxy-18,19-dinorpre:gn-4-ene-20-yne-3-one-oxime Ceased WO2005000868A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
BRPI0412186-4A BRPI0412186A (pt) 2003-06-30 2004-04-29 processo para a sìntese de d-(17alfa)-13-etil-17-hidroxi-18,19-dinorpregn-4-eno-20-i no-3-ona-oxima de pureza elevada
JP2006518378A JP2007516946A (ja) 2003-06-30 2004-04-29 高純度ｄ−（１７α）−１３−エチル−１７−ヒドロキシ−１８，１９−ジノル−プレグ−４−エン−２０−イン−３−オン−オキシムの合成方法
MXPA05013948A MXPA05013948A (es) 2003-06-30 2004-04-29 Proceso para la sintesis de d-(17a)-13-etil-17-hidroxi-18 19-dinor-pregn-4-ene-20-ina-3-ona-oxima.
DE602004026306T DE602004026306D1 (de) 2003-06-30 2004-04-29 Verfahren zur herstellung von hochreinem d-(17alpha)-13-ethyl-17-hydroxy-18,19-dinor-pregn-4-ene-20-yne-3-one-oxim
NZ544378A NZ544378A (en) 2003-06-30 2004-04-29 Process for the synthesis of high purity norgestrel 3-one-oxime
EP04730316A EP1638988B1 (en) 2003-06-30 2004-04-29 Process for the synthesis of high purity d-(17alpha)-13-ethyl-17hydroxy-18,19-dinorpre:gn-4-ene-20-yne-3-one-oxime
YUP-2005/0897A RS20050897A (sr) 2003-06-30 2004-04-29 Postupak za sintezu d-(17-alfa)-13- etil-17-hidroksi-18,19- -dinor-pregn- 4-en-20-in-3-on-oksima visoke čistoće
UAA200600812A UA80059C2 (en) 2003-06-30 2004-04-29 Process for the synthesis of high purity d-(17alpha)-13-ethyl-17hydroxy-18,19-dinorpregn-4-ene-20-yne-3-one-oxime
AT04730316T ATE462712T1 (de) 2003-06-30 2004-04-29 Verfahren zur herstellung von hochreinem d- (17alpha)-13-ethyl-17-hydroxy-18,19-dinor-pregn 4-ene-20-yne-3-one-oxim
CA002528952A CA2528952A1 (en) 2003-06-30 2004-04-29 Process for the synthesis of high purity d-(17alpha)-13-ethyl-17­hydroxy-18,19-dinorpre:gn-4-ene-20-yne-3-one-oxime
AU2004251118A AU2004251118A1 (en) 2003-06-30 2004-04-29 Process for the synthesis of high purity d-(17alpha)-13-ethyl-17-hydroxy-18,19-dinorpre:gn-4-ene-20-yne-3-one-oxime
EA200600119A EA008411B1 (ru) 2003-06-30 2004-04-29 СПОСОБ СИНТЕЗА ВЫСОКОЧИСТОГО ОКСИМА D-(17α)-13-ЭТИЛ-17-ГИДРОКСИ-18,19-ДИНОРПРЕГН-4-ЕН-20-ИН-3-ОНА
HR20060038A HRP20060038A2 (en) 2003-06-30 2004-04-29 PROCESS FOR THE SYNTHESIS OF HIGH PURITY D-(17α)-13-ETHYL-17-HYDROXY-18,19-DINOPREGN-4-ENE-20-YNE-3-OXIME
NO20060455A NO20060455L (no) 2003-06-30 2006-01-27 Fremgangsmate for syntesen av hoyrent D-(17alfa)-13-etyl-17-hydroksy-18,19-dinor-pregn-4-en-20-yn-3-on-oksim.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP0301982 2003-06-30
HU0301982A HUP0301982A2 (hu) 2003-06-30 2003-06-30 Eljárás nagy tisztaságú d-(17alfa)-13-etil-17-hidroxi-18,19-dinor-pregn-4-én-20-in-3-on-oxim előállítására

Publications (1)

Publication Number Publication Date
WO2005000868A1 true WO2005000868A1 (en) 2005-01-06

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PCT/HU2004/000031 Ceased WO2005000868A1 (en) 2003-06-30 2004-04-29 Process for the synthesis of high purity d-(17alpha)-13-ethyl-17­hydroxy-18,19-dinorpre:gn-4-ene-20-yne-3-one-oxime

Country Status (17)

Country Link
EP (1) EP1638988B1 (https=)
JP (1) JP2007516946A (https=)
CN (1) CN100355771C (https=)
AT (1) ATE462712T1 (https=)
AU (1) AU2004251118A1 (https=)
BR (1) BRPI0412186A (https=)
CA (1) CA2528952A1 (https=)
DE (1) DE602004026306D1 (https=)
EA (1) EA008411B1 (https=)
HR (1) HRP20060038A2 (https=)
HU (1) HUP0301982A2 (https=)
MX (1) MXPA05013948A (https=)
NO (1) NO20060455L (https=)
NZ (1) NZ544378A (https=)
RS (1) RS20050897A (https=)
UA (1) UA80059C2 (https=)
WO (1) WO2005000868A1 (https=)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1818338A1 (en) * 2005-12-22 2007-08-15 S.N.I.F.F. Italia S.P.A. Process for the preparation of norelgestromin
US7576226B2 (en) 2003-06-30 2009-08-18 Richter Gedeon Vegyeszeti Gyar Rt. Process of making isomers of norelgestromin and methods using the same
CN108827950A (zh) * 2018-05-31 2018-11-16 成都市科隆化学品有限公司 乙酸中微量乙酸酐的检测方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4027019A (en) * 1975-07-24 1977-05-31 Ortho Pharmaceutical Corporation 3-Oximes of D-17α-ethynyl-19-nortestosterone esters and method
AT348151B (de) * 1972-05-26 1979-02-12 Richter Gedeon Vegyeszet Verfahren zur herstellung von razemischem oder von optisch aktivem 13beta-aethyl-17alfa-aethinyl-gon-4-en-3-on- 17beta-ol
US5876746A (en) * 1995-06-07 1999-03-02 Cygnus, Inc. Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT348151B (de) * 1972-05-26 1979-02-12 Richter Gedeon Vegyeszet Verfahren zur herstellung von razemischem oder von optisch aktivem 13beta-aethyl-17alfa-aethinyl-gon-4-en-3-on- 17beta-ol
US4027019A (en) * 1975-07-24 1977-05-31 Ortho Pharmaceutical Corporation 3-Oximes of D-17α-ethynyl-19-nortestosterone esters and method
US5876746A (en) * 1995-06-07 1999-03-02 Cygnus, Inc. Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RUFER C ET AL: "[Total synthesis of optically active 13-ethyl-gonane derivatives]", JUSTUS LIEBIGS ANNALEN DER CHEMIE. 1967, vol. 702, 1967, pages 141 - 148, XP002297402, ISSN: 0075-4617 *
SISENWINE, SAMUEL F. ET AL: "The conversion of d-norgestrel-3-oxime-17-acetate to d-norgestrel in female rhesus monkeys", CONTRACEPTION , 15(1), 25-37 CODEN: CCPTAY; ISSN: 0010-7824, 1977, XP008035682 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7576226B2 (en) 2003-06-30 2009-08-18 Richter Gedeon Vegyeszeti Gyar Rt. Process of making isomers of norelgestromin and methods using the same
US7816546B2 (en) 2003-06-30 2010-10-19 Richter Gedeon Vegyeszeti Gyar Rt. Process for the synthesis of high purity d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime
EP1818338A1 (en) * 2005-12-22 2007-08-15 S.N.I.F.F. Italia S.P.A. Process for the preparation of norelgestromin
US7393964B2 (en) 2005-12-22 2008-07-01 S.N.I.F.F. Italia S.P.A. Process for the preparation of norelgestromin
CN108827950A (zh) * 2018-05-31 2018-11-16 成都市科隆化学品有限公司 乙酸中微量乙酸酐的检测方法
CN108827950B (zh) * 2018-05-31 2020-08-21 成都市科隆化学品有限公司 乙酸中微量乙酸酐的检测方法

Also Published As

Publication number Publication date
HUP0301982D0 (en) 2003-09-29
HRP20060038A2 (en) 2006-11-30
EA200600119A1 (ru) 2006-06-30
ATE462712T1 (de) 2010-04-15
JP2007516946A (ja) 2007-06-28
NO20060455L (no) 2006-03-29
CN1805970A (zh) 2006-07-19
MXPA05013948A (es) 2006-03-09
HUP0301982A2 (hu) 2005-04-28
NZ544378A (en) 2008-02-29
CN100355771C (zh) 2007-12-19
AU2004251118A1 (en) 2005-01-06
CA2528952A1 (en) 2005-01-06
UA80059C2 (en) 2007-08-10
RS20050897A (sr) 2007-08-03
DE602004026306D1 (de) 2010-05-12
EP1638988B1 (en) 2010-03-31
EP1638988A1 (en) 2006-03-29
EA008411B1 (ru) 2007-04-27
BRPI0412186A (pt) 2006-08-22

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