WO2014162230A1 - Process for the purification of norethindrone and norethindrone acetate - Google Patents
Process for the purification of norethindrone and norethindrone acetate Download PDFInfo
- Publication number
- WO2014162230A1 WO2014162230A1 PCT/IB2014/059994 IB2014059994W WO2014162230A1 WO 2014162230 A1 WO2014162230 A1 WO 2014162230A1 IB 2014059994 W IB2014059994 W IB 2014059994W WO 2014162230 A1 WO2014162230 A1 WO 2014162230A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- norethindrone
- purification
- water
- volume
- acetate
- Prior art date
Links
- IMONTRJLAWHYGT-ZCPXKWAGSA-N Norethindrone Acetate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 IMONTRJLAWHYGT-ZCPXKWAGSA-N 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 32
- 229960001652 norethindrone acetate Drugs 0.000 title claims abstract description 28
- 238000000746 purification Methods 0.000 title claims abstract description 23
- 229940053934 norethindrone Drugs 0.000 title claims abstract description 19
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 title claims abstract description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 238000002955 isolation Methods 0.000 claims description 6
- IIJREXIVDSIOFR-UHFFFAOYSA-N dichloromethane;heptane Chemical compound ClCCl.CCCCCCC IIJREXIVDSIOFR-UHFFFAOYSA-N 0.000 claims description 4
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002002 slurry Substances 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
Classifications
-
- 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 present invention relates to process for the purification of norethindrone and norethindroneacetate.
- Norethindrone (I) and norethindrone acetate (Il) are first-generation progestin, chemically known as 17-hydroxy-19-nor-17a-pregn-4-en-20-yn-3-one and 17-hydroxy-19-nor-17a- pregn-4-en-20-yn-3-one acetaterespectively. These are used alone or in combination with ethinylestradiolasoral contraceptives.
- the patent US 3,409,643 describes purification of norethindrone acetate from methanol containing a drop of pyridine.
- the present invention provides a process forthe purification of norethindrone (I) from mixture of dimethyl formamide-water.
- the present invention further provides two processes for purification of norethindrone acetate (II):
- Process A It involves purification from mixture of dichloromethane- n-heptane and
- Process B It involves purification from mixture of methanol-water.
- a process for the purification of norethindrone comprising; i) dissolution of norethindrone in dimethyl formamide by heating, ii) addition of water, iii) cooling, and iv) isolation.
- Norethindrone is dissolved in dimethyl formamide by heating at reflux temperature, preferably 55-60 °C.
- the ratio of dimethyl formamide-water isl: 100 to 100: 1, preferably 20: 1 to 1 :20, more preferably 10:1 to 5: 1 (volume/volume).
- the quantity of dimethyl formamide-water with respect to norethindrone (I) is 1-20 times (weight/volume) preferably 5-10 times (weight/volume).
- the purity of norethindrone (I) obtained by the present invention is greater than 99%.
- Process A Process for the purification of norethindrone acetate (II) comprising a) stirring of norethindrone acetate in dichloromethane, b) addition of n-heptane, c) cooling, and d) isolation.
- the ratio of dichloromethane and n-heptane is 1 : 10 to 10: 1, preferably 1:5 to 5:1 (volume/volume) .
- Process B Process for the purification of norethindrone acetate (II) comprising: a) stirring of norethindrone acetate in mixture of ethanol-water and b) isolation.
- Stirring of norethindrone acetate in mixture of ethanol-water mixture is carried out in the temperature range of 10-70 °C, preferably 20-50 °C, more preferably 30-35 °C.
- Norethindrone acetate in ethanol-water mixture is stirred for 30 minutes to 10 hours, preferably 1-5 hours, more preferably 1-2 hours.
- the ratio of ethanol-water is 1 : 10 to 10: 1, preferably 1: 1 to 1 :4 (volume/volume).
- the purity of norethindrone acetate (II) obtained by the purification process of present invention is greater than 99%.
- the pure compounds according to the present invention can be isolated by methods known in the literature such as filtration, concentration and evaporation etc.
- Norethindrone (4.5 g) was added to dimethyl formamide (27 ml) at 25-30 °C.
- the slurry was heated to 55-60 °C.
- To the solution water (23.5 ml) was added and stirred for 45 minutes at 55-60°C.
- the slurry cooled to 20-25°C and stirred for 3 hrs. Filtered, washed with water and dried under vacuum.
- HPLC Purity 99.01
- Norethindrone 50 g was added to toluene (1.55 litres) containing acetic anhydride (400 ml) at 20-30 °C.
- 4-dimethylamino pyridine 4 g was added,heated to 80-90°C then stirred for 3 hours and cooled to 10-25 °C then water (1.25 litres) was added.
- the reaction mass further cooled to 10-15°C then pH adjusted to 5.5 to 6.5 using 5% NaOH.
- the organic layer was separated and cyclohexane (500 ml) was added to it.
- Second crop (8.5 g) was obtained from filtrate by cooling to 0-5 °C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1313/MUM/2013 | 2013-04-04 | ||
| IN1313MU2013 IN2013MU01313A (enrdf_load_stackoverflow) | 2013-04-04 | 2014-03-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014162230A1 true WO2014162230A1 (en) | 2014-10-09 |
Family
ID=50390155
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2014/059994 WO2014162230A1 (en) | 2013-04-04 | 2014-03-20 | Process for the purification of norethindrone and norethindrone acetate |
Country Status (2)
| Country | Link |
|---|---|
| IN (1) | IN2013MU01313A (enrdf_load_stackoverflow) |
| WO (1) | WO2014162230A1 (enrdf_load_stackoverflow) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875656A (zh) * | 2020-06-23 | 2020-11-03 | 浙江神洲药业有限公司 | 一种炔诺酮醋酸酯的制备方法 |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2744122A (en) | 1951-11-22 | 1956-05-01 | Syntex Sa | delta 4-19-nor-17alpha-ethinylandrosten-17beta-ol-3-one and process |
| US2964537A (en) | 1956-06-16 | 1960-12-13 | Schering Ag | Therapeutically valuable carboxylic acid esters of 17-alkyl-19-nor-testosterone |
| US3408371A (en) | 1966-06-16 | 1968-10-29 | Syntex Corp | Esterification of 17alpha-ethinyl-17beta-hydroxy steroids |
| US3409643A (en) | 1966-03-11 | 1968-11-05 | Schering Corp | Process for the preparation of 17alpha-alkynl-17beta-alkanoyloxy steroids of the androstane and estrane series |
| US3759961A (en) | 1970-06-13 | 1973-09-18 | Schering Ag | Process for ethinylating 17-ketosteroids |
| US3813418A (en) * | 1972-06-29 | 1974-05-28 | Schering Ag | Process for the preparation of 6-keto-delta1,3,5(10)steroids |
| US4029779A (en) * | 1974-10-18 | 1977-06-14 | Schering Aktiengesellschaft | 1α-Hydroxy steroids |
| US4244949A (en) * | 1978-04-06 | 1981-01-13 | The Population Council, Inc. | Manufacture of long term contraceptive implant |
| US4826689A (en) * | 1984-05-21 | 1989-05-02 | University Of Rochester | Method for making uniformly sized particles from water-insoluble organic compounds |
| DD295637A5 (de) * | 1981-09-07 | 1991-11-07 | Jenapharm Gmbh Jena,De | Verfahren zur reinigung von steroiden |
-
2014
- 2014-03-20 IN IN1313MU2013 patent/IN2013MU01313A/en unknown
- 2014-03-20 WO PCT/IB2014/059994 patent/WO2014162230A1/en active Application Filing
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2744122A (en) | 1951-11-22 | 1956-05-01 | Syntex Sa | delta 4-19-nor-17alpha-ethinylandrosten-17beta-ol-3-one and process |
| US2964537A (en) | 1956-06-16 | 1960-12-13 | Schering Ag | Therapeutically valuable carboxylic acid esters of 17-alkyl-19-nor-testosterone |
| US3409643A (en) | 1966-03-11 | 1968-11-05 | Schering Corp | Process for the preparation of 17alpha-alkynl-17beta-alkanoyloxy steroids of the androstane and estrane series |
| US3408371A (en) | 1966-06-16 | 1968-10-29 | Syntex Corp | Esterification of 17alpha-ethinyl-17beta-hydroxy steroids |
| US3759961A (en) | 1970-06-13 | 1973-09-18 | Schering Ag | Process for ethinylating 17-ketosteroids |
| US3813418A (en) * | 1972-06-29 | 1974-05-28 | Schering Ag | Process for the preparation of 6-keto-delta1,3,5(10)steroids |
| US4029779A (en) * | 1974-10-18 | 1977-06-14 | Schering Aktiengesellschaft | 1α-Hydroxy steroids |
| US4244949A (en) * | 1978-04-06 | 1981-01-13 | The Population Council, Inc. | Manufacture of long term contraceptive implant |
| DD295637A5 (de) * | 1981-09-07 | 1991-11-07 | Jenapharm Gmbh Jena,De | Verfahren zur reinigung von steroiden |
| US4826689A (en) * | 1984-05-21 | 1989-05-02 | University Of Rochester | Method for making uniformly sized particles from water-insoluble organic compounds |
Non-Patent Citations (1)
| Title |
|---|
| ALARY, JOSETTE ET AL: "Study of pregn-4-ene-3,20-dione and related molecules by pulse polarography. Determination of progesterone and certain synthetic progestogens", BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE , (7-8, PT. 1), 649-52 CODEN: BSCFAS; ISSN: 0037-8968, 1977, XP008169640 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875656A (zh) * | 2020-06-23 | 2020-11-03 | 浙江神洲药业有限公司 | 一种炔诺酮醋酸酯的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| IN2013MU01313A (enrdf_load_stackoverflow) | 2015-04-10 |
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