HRP20161282T1 - Postupak za proizvodnju estetrola - Google Patents
Postupak za proizvodnju estetrola Download PDFInfo
- Publication number
- HRP20161282T1 HRP20161282T1 HRP20161282TT HRP20161282T HRP20161282T1 HR P20161282 T1 HRP20161282 T1 HR P20161282T1 HR P20161282T T HRP20161282T T HR P20161282TT HR P20161282 T HRP20161282 T HR P20161282T HR P20161282 T1 HRP20161282 T1 HR P20161282T1
- Authority
- HR
- Croatia
- Prior art keywords
- compound
- formula
- group
- process according
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- Prior art date
Links
- 238000000034 method Methods 0.000 title claims 18
- AJIPIJNNOJSSQC-NYLIRDPKSA-N estetrol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)[C@@H]4O)O)[C@@H]4[C@@H]3CCC2=C1 AJIPIJNNOJSSQC-NYLIRDPKSA-N 0.000 title 1
- 229950009589 estetrol Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 29
- 239000003795 chemical substances by application Substances 0.000 claims 8
- -1 alkylsilyl chloride Chemical compound 0.000 claims 7
- 125000001424 substituent group Chemical group 0.000 claims 7
- 238000006243 chemical reaction Methods 0.000 claims 6
- 125000000217 alkyl group Chemical group 0.000 claims 5
- 125000001153 fluoro group Chemical group F* 0.000 claims 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 4
- 230000026030 halogenation Effects 0.000 claims 4
- 238000005658 halogenation reaction Methods 0.000 claims 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 3
- 239000003638 chemical reducing agent Substances 0.000 claims 3
- 125000006239 protecting group Chemical group 0.000 claims 3
- 238000006277 sulfonation reaction Methods 0.000 claims 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 229910052740 iodine Inorganic materials 0.000 claims 2
- 239000011630 iodine Substances 0.000 claims 2
- 239000007800 oxidant agent Substances 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000001263 acyl chlorides Chemical class 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000005695 dehalogenation reaction Methods 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 230000006326 desulfonation Effects 0.000 claims 1
- 238000005869 desulfonation reaction Methods 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 229910052987 metal hydride Inorganic materials 0.000 claims 1
- 229910000487 osmium oxide Inorganic materials 0.000 claims 1
- JIWAALDUIFCBLV-UHFFFAOYSA-N oxoosmium Chemical compound [Os]=O JIWAALDUIFCBLV-UHFFFAOYSA-N 0.000 claims 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims 1
- 239000012286 potassium permanganate Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims 1
- 229940071536 silver acetate Drugs 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 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
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (14)
1. Postupak za pripravu spoja formule (I), hidrata ili solvata iste;
[image]
(I)
pri čemu navedeni postupak obuhvaća sljedeće korake:
a) reakciju spoja formule (II), sa sililirajućim sredstvom kako bi se dobio spoj formule (III),
[image]
(II) (III)
pri čemu je P1 zaštitna skupina odabrana između R1CO-, ili R2Si(R3)(R4)-, P2 je zaštitna skupina odabrana između (R2)Si(R3)(R4)-, pri čemu je R1 skupina odabrana između C1-6alkila ili C3-6 cikloalkila, svaka skupina po izboru je supstituirana s jednim ili više supstituenata nezavisno odabranih između fluoro ili C1-4alkila; svaki od R2, R3 i R4 su nezavisna skupina odabrana između C1-6alkila ili fenila, a svaka skupina po izboru je supstituirana s jednim ili više supstituenata nezavisno odabranih između fluoro ili C1-4alkila;
b) reakciju spoja formule (III) u prisustvu najmanje jednog oksidacijskog sredstva odabranog iz permanganata soli, osmij oksida, hidrogen peroksida, ili jod i srebro-acetata kako bi se dobio spoj formule (IV); i
[image]
(IV)
c) uklanjanje zaštite spoja formule (IV) kako bi se dobio spoj formule (I).
2. Postupak prema zahtjevu 1, pri čemu P1 predstavlja R2Si(R3)(R4)-, a P2 predstavlja (R2)Si(R3)(R4)-.
3. Postupak prema zahtjevima 1 ili 2, u kome se sililirajuće sredstvo odabire iz skupine koju čine C1-6alkilsililklorid, C1-6alkilsililtriflat, C6arilsilil klorid, C6arilsililtriflat, C1-6 alkilC6arilsililklorid, C1-6alkilC6arilsililtriflat, svaka skupina po izboru je supstituirana s jednim ili više supstituenata nezavisno odabranih između fluoro ili C1-4alkila.
4. Postupak prema bilo kojem zahtjevu 1 do 3, u kome je u koraku (b) navedeno oksidacijsko sredstvo kalijev permanganat.
5. Postupak prema zahtjevu 4, u kome se korak (b) provodi u prisutnosti kiseline.
6. Postupak prema bilo kojem od zahtjeva 1 do 5, u kome se spoj formule (II) dobiva postupkom koji obuhvaća sljedeće korake:
i) reakciju spoja formule (V) sa acilirajućim ili sililirajućim sredstvom kako bi se dobio spoj formule (VI),
[image]
gdje je P3 zaštitna skupina odabrana između R9CO-, ili R10Si(R11)(R12)-, pri čemu je R9 skupina odabrana između C1-6alkila ili C3-6cikloalkila, svaka skupina po izboru je supstituirana s jednim ili više supstituenata nezavisno odabranih između fluoro ili C1-4alkila; svaki od R10, R11 i R12 su nezavisna skupina odabrana između C1-6alkila ili fenila, a svaka skupina po izboru je supstituirana sa jednim ili više supstituenata nezavisno odabranih između fluoro ili C1-4alkila;
ii) reakciju spoja formule (VI) u prisustvu paladij acetata ili njegovih derivata, ili vrsta joda (V), kako bi se dobio spoj formule (VII); i
[image]
(VII)
iii) reakciju spoja formule (VII) s redukcijskim sredstvom kako bi se dobio spoj formule (II).
7. Postupak prema zahtjevu 6, u kome P3 predstavlja R9CO-.
8. Postupak prema zahtjevu 7, u kome korak (i) obuhvaća korake (i1), zaštitu hidroksila spoja formule (V) sa sililirajućim sredstvom kako bi se dobio spoj formule (Va), pri čemu P1 ima isto značenje kao što je definirano u zahtjevu 1; i
[image]
(Va)
(i2) zaštitu ketona spoja formule (Va), u prisustvu acilirajućeg sredstva kako bi se dobio spoj formule (VI).
9. Postupak prema bilo kojem od zahtjeva 1 do 5, u kome se spoj formule (II) dobiva postupkom koji obuhvaća korake 1) reakciju spoja formule (V) sa sililirajućim ili acilirajućim sredstvom kako bi se dobio spoj formule (Va), pri čemu P1 ima isto značenje kao u zahtjevu 1;
[image]
(V) (Va)
2) halogeniranje ili sulfoniranje spoja formule (Va) kako bi se dobio spoj formule (Vb);
[image]
(Vb)
pri čemu je X halo, ili -SO-R20, a R20 je skupina odabrana između C6-10arila ili heteroarila, a svaka skupina po izboru je supstituirana sa jednim ili više supstituenata neovisno odabranih između kloro ili C1-4alkila;
3) dehalogeniranje ili desulfoniranje spoja formule (Vb) kako bi se dobio spoj formule (V); i
[image]
(VII)
4) reakciju spoja formule (VII) sa redukcijskim sredstvom kako bi se dobio spoj formule (II).
10. Postupak u skladu sa zahtjevom 9, u kome je korak (2) sulfoniranje a sulfoniranje se izvodi reakcijom spoja formule (Va) sa bazom i reagensom za sulfinilaciju.
11. Postupak u skladu sa zahtjevom 9, u kome je korak (2) halogeniranje a halogeniranje se izvodi reakcijom spoja formule (Va) sa reagensom za halogeniranje.
12. Postupak prema bilo kojem od zahtjeva 6 do 9, u kome se korak (iii) i korak (4) izvode upotrebom redukcijskog sredstva koje se odabire iz skupine koju čine metalni hidridni spojevi.
13. Postupak prema bilo kojem od zahtjeva 6 do 12, u kome se sredstvo za sililiranje odabire iz skupine koju čine C1-6alkilsililklorid, C1-6alkilsililtriflat, C6arilsililklorid, C6arilsililtriflat, C1-6alkil C6arilsililklorid, C1-6alkilC6arilsilil triflat, svaka skupina po izboru je supstituirana sa jednim ili više supstituenata nezavisno odabranih između fluora ili C1-4alkila.
14. Postupak prema bilo kojem od zahtjeva 6 do 12, u kome se acilirajuće sredstvo odabire iz skupine koju čine C2-6alkenilC1-6alkanoat, C2-6alkenilC3-6cikloalkanoat, acil kloridi i anhidridi.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161544591P | 2011-10-07 | 2011-10-07 | |
| EP11184278 | 2011-10-07 | ||
| EP12778664.8A EP2764008B1 (en) | 2011-10-07 | 2012-10-05 | Process for the production of estetrol |
| PCT/EP2012/069761 WO2013050553A1 (en) | 2011-10-07 | 2012-10-05 | Process for the production of estetrol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20161282T1 true HRP20161282T1 (hr) | 2016-11-18 |
Family
ID=48043195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20161282TT HRP20161282T1 (hr) | 2011-10-07 | 2016-10-05 | Postupak za proizvodnju estetrola |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US8987484B2 (hr) |
| EP (1) | EP2764008B1 (hr) |
| JP (1) | JP6196625B2 (hr) |
| KR (1) | KR102007874B1 (hr) |
| CN (1) | CN103890001B (hr) |
| AU (1) | AU2012320423C1 (hr) |
| BR (1) | BR112014008196B8 (hr) |
| CA (1) | CA2847813C (hr) |
| CL (1) | CL2014000802A1 (hr) |
| CY (1) | CY1118674T1 (hr) |
| DK (1) | DK2764008T3 (hr) |
| EA (1) | EA024003B1 (hr) |
| ES (1) | ES2593316T3 (hr) |
| HK (1) | HK1199882A1 (hr) |
| HR (1) | HRP20161282T1 (hr) |
| HU (1) | HUE028963T2 (hr) |
| IN (1) | IN2014MN00841A (hr) |
| LT (1) | LT2764008T (hr) |
| ME (1) | ME02527B (hr) |
| MX (1) | MX348917B (hr) |
| PL (1) | PL2764008T3 (hr) |
| PT (1) | PT2764008T (hr) |
| RS (1) | RS55231B1 (hr) |
| SG (1) | SG11201401282PA (hr) |
| SI (1) | SI2764008T1 (hr) |
| SM (1) | SMT201600375B (hr) |
| WO (1) | WO2013050553A1 (hr) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX342537B (es) | 2011-06-01 | 2016-10-04 | Estetra Sprl | Proceso para la produccion de intermediarios de estetrol. |
| MX341561B (es) | 2011-06-01 | 2016-08-25 | Estetra Sprl | Proceso para la produccion de intermediarios de estetrol. |
| EP2383279A1 (en) | 2011-07-19 | 2011-11-02 | Pantarhei Bioscience B.V. | Process for the preparation of estetrol |
| WO2013034780A2 (en) * | 2012-12-20 | 2013-03-14 | Crystal Pharma, S.A.U. | Process for the preparation of estetrol and related compounds |
| CA2924255C (en) | 2013-09-18 | 2022-11-22 | Crystal Pharma, S.A.U. | Process for the preparation of estetrol |
| NO3106148T3 (hr) | 2015-06-18 | 2018-08-11 | ||
| WO2016203009A1 (en) | 2015-06-18 | 2016-12-22 | Mithra Pharmaceuticals S.A. | Orodispersible tablet containing estetrol |
| GEP20217243B (en) | 2015-06-18 | 2021-04-26 | Sprl Estetra | Orodispersible dosage unit containing an estetrol component |
| HUE054551T2 (hu) | 2015-06-18 | 2021-09-28 | Estetra Sprl | Ösztetrolt tartalmazó, szájban diszpergálódó tabletta |
| KR20220144885A (ko) | 2016-08-05 | 2022-10-27 | 에스테트라, 소시에떼 아 레스폰서빌리떼 리미떼 | 월경통 및 생리통의 관리방법 |
| TWI801561B (zh) | 2018-04-19 | 2023-05-11 | 比利時商依思特拉私人有限責任公司 | 化合物及其用於緩解絕經相關症狀的用途 |
| JOP20200260A1 (ar) | 2018-04-19 | 2019-10-19 | Estetra Sprl | مركبات واستخداماتها للتخفيف من الأعراض المصاحبة لانقطاع الطمث |
| EP3647413A1 (en) * | 2018-10-31 | 2020-05-06 | Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas O.A., M.P. (CIEMAT) | Improvements for performing and facilitating the recovery after hematopoietic stem cell transplantation |
| HU231240B1 (hu) | 2019-09-03 | 2022-04-28 | Richter Gedeon Nyrt. | Ipari eljárás nagytisztaságú ösztetrol hatóanyag előállítására |
| IT201900021879A1 (it) | 2019-11-22 | 2021-05-22 | Ind Chimica Srl | PROCESSO PER LA PREPARAZIONE DI (15α,16α,17β)-ESTRA-1,3,5(10)-TRIENE-3,15,16,17-TETROLO (ESTETROLO) ED INTERMEDI DI DETTO PROCESSO |
| IT201900017414A1 (it) | 2019-09-27 | 2021-03-27 | Ind Chimica Srl | Processo per la preparazione di (15α,16α,17β)-estra-1,3,5(10)-triene-3,15,16,17-tetrolo (Estetrolo) ed intermedi di detto processo |
| MX2022003688A (es) | 2019-09-27 | 2022-04-26 | Ind Chimica Srl | Proceso para preparar (15alfa,16alfa,17beta)-estra-1,3,5(10)-trien o-3,15,16,17-tetrol (estetrol) e intermedios de dicho proceso. |
| IT202100019631A1 (it) | 2021-07-23 | 2023-01-23 | Newchem S P A | Metodo per produrre estetrolo e i suoi intermedi |
| WO2023021026A1 (en) * | 2021-08-17 | 2023-02-23 | Aspen Oss B.V. | A synthetic pathway to estra-1,3,5(10)-triene-3,15a,16a,17b-tetrol |
| CN118251402A (zh) | 2021-10-01 | 2024-06-25 | 工业化学有限公司 | 制备(15α,16α,17β)-雌甾-1,3,5(10)-三烯-3,15,16,17-四醇（雌四醇）一水合物的方法 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW548277B (en) * | 1999-07-16 | 2003-08-21 | Akzo Nobel Nv | Orally active androgens |
| PL202999B1 (pl) * | 1999-12-02 | 2009-08-31 | Organon Nv | Androgeny zawierające pierścień cyklopropanowy w pozycjach 14, 15 i zastosowanie takich androgenów |
| EP1562976B1 (en) * | 2002-11-08 | 2010-05-26 | Pantarhei Bioscience B.V. | Synthesis of estetrol via estrone derived steroids |
| UA89964C2 (ru) * | 2004-09-08 | 2010-03-25 | Н.В. Органон | 15β-ЗАМЕЩЕННЫЕ СТЕРОИДЫ, КОТОРЫЕ ИМЕЮТ СЕЛЕКТИВНУЮ ЭСТРОГЕННУЮ АКТИВНОСТЬ |
| MX341561B (es) | 2011-06-01 | 2016-08-25 | Estetra Sprl | Proceso para la produccion de intermediarios de estetrol. |
| MX342537B (es) | 2011-06-01 | 2016-10-04 | Estetra Sprl | Proceso para la produccion de intermediarios de estetrol. |
| EP2383279A1 (en) * | 2011-07-19 | 2011-11-02 | Pantarhei Bioscience B.V. | Process for the preparation of estetrol |
-
2012
- 2012-10-05 HU HUE12778664A patent/HUE028963T2/en unknown
- 2012-10-05 SI SI201230705A patent/SI2764008T1/sl unknown
- 2012-10-05 KR KR1020147007408A patent/KR102007874B1/ko active IP Right Grant
- 2012-10-05 CN CN201280049319.2A patent/CN103890001B/zh active Active
- 2012-10-05 MX MX2014003723A patent/MX348917B/es active IP Right Grant
- 2012-10-05 EP EP12778664.8A patent/EP2764008B1/en active Active
- 2012-10-05 EA EA201490713A patent/EA024003B1/ru unknown
- 2012-10-05 CA CA2847813A patent/CA2847813C/en active Active
- 2012-10-05 BR BR112014008196A patent/BR112014008196B8/pt active IP Right Grant
- 2012-10-05 ME MEP-2016-229A patent/ME02527B/me unknown
- 2012-10-05 ES ES12778664.8T patent/ES2593316T3/es active Active
- 2012-10-05 LT LTEP12778664.8T patent/LT2764008T/lt unknown
- 2012-10-05 DK DK12778664.8T patent/DK2764008T3/en active
- 2012-10-05 US US14/349,940 patent/US8987484B2/en active Active
- 2012-10-05 RS RS20160859A patent/RS55231B1/sr unknown
- 2012-10-05 WO PCT/EP2012/069761 patent/WO2013050553A1/en active Application Filing
- 2012-10-05 PT PT127786648T patent/PT2764008T/pt unknown
- 2012-10-05 JP JP2014533925A patent/JP6196625B2/ja active Active
- 2012-10-05 PL PL12778664T patent/PL2764008T3/pl unknown
- 2012-10-05 SG SG11201401282PA patent/SG11201401282PA/en unknown
- 2012-10-05 AU AU2012320423A patent/AU2012320423C1/en active Active
-
2014
- 2014-04-02 CL CL2014000802A patent/CL2014000802A1/es unknown
- 2014-05-05 IN IN841MUN2014 patent/IN2014MN00841A/en unknown
-
2015
- 2015-01-13 HK HK15100344.6A patent/HK1199882A1/zh unknown
-
2016
- 2016-10-05 HR HRP20161282TT patent/HRP20161282T1/hr unknown
- 2016-10-10 CY CY20161101001T patent/CY1118674T1/el unknown
- 2016-10-17 SM SM201600375T patent/SMT201600375B/it unknown
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