HRP20210594T1 - Postupak za proizvodnju vardenafila i njegovih soli - Google Patents
Postupak za proizvodnju vardenafila i njegovih soli Download PDFInfo
- Publication number
- HRP20210594T1 HRP20210594T1 HRP20210594TT HRP20210594T HRP20210594T1 HR P20210594 T1 HRP20210594 T1 HR P20210594T1 HR P20210594T T HRP20210594T T HR P20210594TT HR P20210594 T HRP20210594 T HR P20210594T HR P20210594 T1 HRP20210594 T1 HR P20210594T1
- Authority
- HR
- Croatia
- Prior art keywords
- vardenafil
- monohydrochloride
- production
- water
- anhydrous
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims 16
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 title claims 14
- 229960002381 vardenafil Drugs 0.000 title claims 14
- 238000004519 manufacturing process Methods 0.000 title claims 10
- 150000003839 salts Chemical class 0.000 title claims 5
- XCMULUAPJXCOHI-UHFFFAOYSA-N 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-4-one;hydrochloride Chemical compound Cl.CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 XCMULUAPJXCOHI-UHFFFAOYSA-N 0.000 claims 7
- FBCDRHDULQYRTB-UHFFFAOYSA-N 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-4-one;trihydrate;hydrochloride Chemical compound O.O.O.Cl.CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 FBCDRHDULQYRTB-UHFFFAOYSA-N 0.000 claims 6
- 230000004048 modification Effects 0.000 claims 6
- 238000012986 modification Methods 0.000 claims 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 4
- 150000007529 inorganic bases Chemical class 0.000 claims 3
- 239000003960 organic solvent Substances 0.000 claims 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims 2
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims 2
- YRRWQMBIMZMVDB-UHFFFAOYSA-N 2-(2-ethoxyphenyl)-5-methyl-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-4-one Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C1=CC=CC=C1OCC YRRWQMBIMZMVDB-UHFFFAOYSA-N 0.000 claims 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 2
- 239000000010 aprotic solvent Substances 0.000 claims 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims 2
- 238000010992 reflux Methods 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 239000000725 suspension Substances 0.000 claims 2
- KGPAJYBNGXYRKS-UHFFFAOYSA-N 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonic acid hydrochloride Chemical compound Cl.CCCc1nc(C)c2n1[nH]c(nc2=O)-c1cc(ccc1OCC)S(O)(=O)=O KGPAJYBNGXYRKS-UHFFFAOYSA-N 0.000 claims 1
- MMVUIQGJLMGFBG-UHFFFAOYSA-N C(C)OC1=C(C=CC=C1)C=1NN2C(C(N1)=O)C(N=C2CCC)C Chemical compound C(C)OC1=C(C=CC=C1)C=1NN2C(C(N1)=O)C(N=C2CCC)C MMVUIQGJLMGFBG-UHFFFAOYSA-N 0.000 claims 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 1
- 238000007112 amidation reaction Methods 0.000 claims 1
- 238000009835 boiling Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- 230000008018 melting Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 229960001540 vardenafil hydrochloride Drugs 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Claims (17)
1. Postupak za proizvodnju vardenafila i/ili njegovih soli, naznačen time što se sulfokloriranje 2-(2-etoksi-fenil)-5-metil-7-propil-3H-imidazo[5,1-f][1,2,4]triazin-4-ona provodi u smjesi tionil klorida i klorsulfonske kiseline pod refluksom na točki vrenja otapala, sintetizirani klorid 4-etoksi-3-(5-metil-4-okso-7-propil-3,4-dihidroimidazo[5,1-f][1,2,4]triazin-2-il)benzen-sulfonske kiseline izoliran je iz reakcijske smjese u bezvodnim uvjetima i reagira s N-etilpiperazinom u aprotičnom otapalu u prisutnosti anorganske baze i nakon završetka reakcije pripremljena baza vardenafila izolira se poznatim postupcima i po želji transformira u sol.
2. Postupak za proizvodnju vardenafila prema zahtjevu 1, naznačen time što molarni omjer 2-(2-etoksi-fenil)-5-metil-7-propil-3H-imidazo[5,1-f][1,2,4]triazin-4-ona prema klorsulfonskoj kiselini i tionil kloridu iznosi 1:2.7:11.
3. Postupak za proizvodnju vardenafila prema zahtjevu 1 ili 2, naznačen time što je anorganska baza bezvodni natrijev karbonat.
4. Postupak za proizvodnju vardenafila prema bilo kojem od prethodnih zahtjeva, naznačen time što je aprotično otapalo toluen.
5. Postupak za proizvodnju vardenafila prema bilo kojem od prethodnih zahtjeva, naznačen time što molarni višak N-etilpiperazina i anorganske baze u odnosu na polazni 2-(2-etoksi-fenil)-5-metil-7-propil-5H-imidazo[5,1-f][1,2,4]triazin-4-on iznosi 1:2.5:5.7.
6. Postupak za proizvodnju vardenafila prema bilo kojem od prethodnih zahtjeva, naznačen time što se reakcije sulfokloriranja i amidiranja provode pod refluksom.
7. Postupak za proizvodnju vardenafila prema bilo kojem od prethodnih zahtjeva, naznačen time što je sol u koju se vardenafil pretvara vardenafil hidroklorid.
8. Postupak za proizvodnju vardenafila prema bilo kojem od prethodnih zahtjeva, naznačen time što je sol u koju se vardenafil pretvara vardenafil monohidroklorid trihidrat.
9. Postupak za proizvodnju vardenafil monohidroklorid trihidrata naznačen time što:
a/ baza vardenafila otapa se u organskom otapalu;
b/ dodana je količina koncentrirane solne kiseline;
c/ bezvodna modifikacija V vardenafil monohidroklorida se taloži;
d/ suspenzija bezvodne modifikacije V vardenafila monohidroklorida dovodi se u kontakt s vodom,
e/ suspenzija vardenafil monohidroklorid trihidrata se filtrira, ispire i suši.
10. Postupak prema zahtjevu 9 naznačen time što baza vardenafila sadrži manje od 1.0% vode.
11. Postupak prema zahtjevu 9 ili 10 naznačen time što je organsko otapalo otapalo koje se miješa s vodom sa sadržajem vode manjim od 0.4%.
12. Postupak prema zahtjevu 11 naznačen time što je organsko otapalo koje se miješa s vodom aceton.
13. Postupak prema bilo kojem od zahtjeva 9 do 12, naznačen time što molarni omjer vardenafila monohidroklorida i dodane vode iznosi 1:5.55 i vrijeme kontakta bezvodne modifikacije V vardenafil monohidroklorida i vode je najmanje 4 sata.
14. Postupak prema bilo kojem od zahtjeva 9 do 13, naznačen time što se vardenafil monohidroklorid trihidrat suši u vakuumu na 30-35 °C.
15. Bezvodna modifikacija V vardenafil monohidroklorida u kristalnom obliku naznačena time što ima difraktogram praha sa slijedećim nizom položaja vrhova, opisanih međuplanarnim udaljenostima d (Å) i kutovima difrakcije 2Θ (°):
d(Å) 2Θ (°)
9.444 9.37
8.527 10.37
7.386 11.98
6.756 13.11
5.554 15.96
5.185 17.10
4.895 18.12
4.498 19.74
4.263 20.84
4.079 21.79
3.367 26.45
3.237 27.54
3.148 28.61
16. Bezvodna modifikacija V vardenafil monohidroklorida u kristalnom obliku prema zahtjevu 15, naznačena time što njegova točka topljenja iznosi 234 °C.
17. Upotreba bezvodne modifikacije V vardenafil monohidroklorida prema zahtjevu 15 ili 16 naznačena time što se koristi za pripravu vardenafil monohidroklorid trihidrata.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL406524A PL223869B1 (pl) | 2013-12-16 | 2013-12-16 | Sposób otrzymywania wardenafilu i jego soli |
| PCT/PL2014/000135 WO2015093994A1 (en) | 2013-12-16 | 2014-12-08 | The method for manufacturing of vardenafil and its salts |
| EP14827879.9A EP3083629B1 (en) | 2013-12-16 | 2014-12-08 | The method for manufacturing of vardenafil and its salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20210594T1 true HRP20210594T1 (hr) | 2021-06-11 |
Family
ID=52355157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20210594TT HRP20210594T1 (hr) | 2013-12-16 | 2021-04-14 | Postupak za proizvodnju vardenafila i njegovih soli |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US9845328B2 (hr) |
| EP (1) | EP3083629B1 (hr) |
| CY (1) | CY1124259T1 (hr) |
| EA (1) | EA032040B1 (hr) |
| ES (1) | ES2866627T3 (hr) |
| HR (1) | HRP20210594T1 (hr) |
| HU (1) | HUE055214T2 (hr) |
| PL (1) | PL223869B1 (hr) |
| WO (1) | WO2015093994A1 (hr) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU230154B1 (hu) * | 1997-11-12 | 2015-09-28 | Bayer Intellectual Property Gmbh | Eljárás 2-es helyzetben fenil-szubszituenst hordozó imidazo-triazinon-származékok előállítására |
| DE10063108A1 (de) * | 2000-12-18 | 2002-06-20 | Bayer Ag | Verfahren zur Herstellung von Sulfonamid-substituierten Imidazotriazinonen |
| DE10232113A1 (de) | 2002-07-16 | 2004-01-29 | Bayer Ag | Vardenafil Hydrochlorid Trihydrat enthaltende Arzneimittel |
| CN100360531C (zh) | 2003-12-18 | 2008-01-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 用于预防或治疗阳萎和性冷淡的新吡唑并嘧啶类化合物 |
| US7977478B2 (en) * | 2006-03-13 | 2011-07-12 | Dr. Reddy's Laboratories Limited | Polymorphic forms of vardenafil |
| CZ2011767A3 (cs) | 2011-11-24 | 2013-06-05 | Zentiva, K.S. | Zpusob prípravy a izolace solí vardenafilu s kyselinami |
-
2013
- 2013-12-16 PL PL406524A patent/PL223869B1/pl unknown
-
2014
- 2014-12-08 WO PCT/PL2014/000135 patent/WO2015093994A1/en active Application Filing
- 2014-12-08 EA EA201600466A patent/EA032040B1/ru not_active IP Right Cessation
- 2014-12-08 HU HUE14827879A patent/HUE055214T2/hu unknown
- 2014-12-08 US US15/104,285 patent/US9845328B2/en not_active Expired - Fee Related
- 2014-12-08 EP EP14827879.9A patent/EP3083629B1/en active Active
- 2014-12-08 ES ES14827879T patent/ES2866627T3/es active Active
-
2021
- 2021-04-14 HR HRP20210594TT patent/HRP20210594T1/hr unknown
- 2021-06-14 CY CY20211100531T patent/CY1124259T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015093994A1 (en) | 2015-06-25 |
| PL406524A1 (pl) | 2015-06-22 |
| PL223869B1 (pl) | 2016-11-30 |
| US20160311827A1 (en) | 2016-10-27 |
| EP3083629B1 (en) | 2021-03-31 |
| CY1124259T1 (el) | 2022-07-22 |
| EA032040B1 (ru) | 2019-03-29 |
| EP3083629A1 (en) | 2016-10-26 |
| HUE055214T2 (hu) | 2021-11-29 |
| ES2866627T3 (es) | 2021-10-19 |
| US9845328B2 (en) | 2017-12-19 |
| EA201600466A1 (ru) | 2017-03-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2014110400A (ru) | Способ и промежуточные соединения для получения макролактамов | |
| CA3013134C (en) | Process for preparing lithium sulphate | |
| CA2634149A1 (en) | Novel hydrogen sulfate salt for use in the treatment of hyperproliferative diseases | |
| KR101975468B1 (ko) | 수산화리튬의 제조 방법 | |
| HRP20231424T1 (hr) | Postupak proizvodnje kalijevog acesulfama | |
| RU2016151208A (ru) | Радиоактивно меченные производные 2-амино-6-фтор-n-[5-фтор-пиридин-3-ил]-пиразоло[1, 5-а]пиримидин-3-карбоксамида, используемые в качестве ингибитора atr киназы, препараты на основе этого соединения и его различные твердые формы | |
| JPH03115259A (ja) | 有機チオスルフエート類 | |
| RU2015142819A (ru) | Натриевая соль (2s, 5r)-6-бензилокси-7-оксо-1,6-диаза-бицикло[3.2.1]октан-2-карбоновой кислоты и ее получение | |
| JP2017505280A5 (hr) | ||
| BR112015024255B1 (pt) | Método de preparação de azoxistrobina | |
| MX2018003311A (es) | Ácido nucleico artificial puenteado a guanidina, entrelazado, método para la producción del mismo, y compuesto intermediario. | |
| HRP20170023T1 (hr) | Kristalni oblik pemirolasta | |
| HRP20210594T1 (hr) | Postupak za proizvodnju vardenafila i njegovih soli | |
| TN2016000269A1 (en) | Water soluble crystallin salts of certain harringtonines unambiguously protonated on their alkaloid nitrogen and their use as chemotherapeutic drugs. | |
| WO2011104637A3 (en) | Crystalline forms of the tri-mesylate salt of perphenazine-gaba and process of producing the same | |
| KR101985962B1 (ko) | 염화리튬의 제조 방법 | |
| JP2014510043A5 (hr) | ||
| BRPI0808570B8 (pt) | processo para a preparação de inibidores de glyt-1 | |
| Zvarych et al. | Synthesis of 9, 10-anthracenedione diethyldithiocarbamates | |
| JP2011246385A (ja) | 含フッ素スルホニルイミド化合物の製造方法 | |
| CN104744393A (zh) | 制备氰亚氨基-1,3-噻唑烷的方法 | |
| WO2008119734A3 (en) | Process for the manufacture of organic compounds | |
| JP2015524456A5 (hr) | ||
| CN109053590B (zh) | 一种制备4,6-二氯-2-氨基嘧啶的方法 | |
| EA200600542A1 (ru) | Способ для производства thip |