HRP20150456T1 - Metoda pripreme argatroban monohidrata - Google Patents
Metoda pripreme argatroban monohidrata Download PDFInfo
- Publication number
- HRP20150456T1 HRP20150456T1 HRP20150456TT HRP20150456T HRP20150456T1 HR P20150456 T1 HRP20150456 T1 HR P20150456T1 HR P20150456T T HRP20150456T T HR P20150456TT HR P20150456 T HRP20150456 T HR P20150456T HR P20150456 T1 HRP20150456 T1 HR P20150456T1
- Authority
- HR
- Croatia
- Prior art keywords
- angle
- spade
- relative intensity
- argatroban
- preparing
- Prior art date
Links
- 229960003856 argatroban Drugs 0.000 title claims 19
- 238000000034 method Methods 0.000 title claims 12
- KXNPVXPOPUZYGB-IOVMHBDKSA-N (2R,4R)-1-[(2S)-5-(diaminomethylideneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]-1-oxopentyl]-4-methyl-2-piperidinecarboxylic acid Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NCC(C)C2 KXNPVXPOPUZYGB-IOVMHBDKSA-N 0.000 title 1
- AIEZTKLTLCMZIA-CZSXTPSTSA-N (2r,4r)-1-[(2s)-5-(diaminomethylideneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]pentanoyl]-4-methylpiperidine-2-carboxylic acid;hydrate Chemical compound O.OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NCC(C)C2 AIEZTKLTLCMZIA-CZSXTPSTSA-N 0.000 claims 10
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 claims 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 6
- 238000001816 cooling Methods 0.000 claims 4
- 239000002904 solvent Substances 0.000 claims 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims 3
- 238000001953 recrystallisation Methods 0.000 claims 3
- 238000010992 reflux Methods 0.000 claims 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 239000003610 charcoal Substances 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 claims 2
- 230000008025 crystallization Effects 0.000 claims 2
- 238000010438 heat treatment Methods 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 238000002360 preparation method Methods 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- 239000011541 reaction mixture Substances 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 241000786363 Rhampholeon spectrum Species 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 238000007707 calorimetry Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- 230000008018 melting Effects 0.000 claims 1
- 150000004682 monohydrates Chemical class 0.000 claims 1
- 238000000634 powder X-ray diffraction Methods 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Claims (11)
1. Metoda pripreme aratroban monohidrata koja sadrži najmanje jedan korak od:
Koncentriranje reakcijske smjese koja sadrži sirovinski argatroban u ostatak koji se može miješati;
Otapanje ostatka sa sirovinskim argatrobanom s organskim otapalom i izdvajanje pročišćenog argatrobana kristalizacijom tretiranjem organskog otapala sa kristalizirajućim otapalom izabranim između izopropanola i n-propanola;
Izdvanjanje argatroban monohidrata rekristalizacijom pročišćenog argatrobana, izoliranog u prethodnom koraku, iz metanolno-vodene otopine dodatkom obezbojavajućeg ugljena, zagrijavanjem na refluks temperaturi, zatim filtracijom ugljena te hlađenje s refluks temperature na temperaturu između 15-25°C u vremenu između 11-17 sati.
2. Metoda pripreme argatroban monohidrata prema zahtjevu 1, pri čemu je kristalizirajuće otapalo izopropanol.
3. Metoda pripreme argatroban monohidrata prema zahtjevu 1 koja sadrži daljnji korak:
Pripreme sirovinskog argatrobana iz (2R,4R)-1-[NG-nitro-N2-(3-metil-8-kinolinsulfonil)-1-arginil]-4-metil-2-piperidin karboksilne kiseline u metanolu/octenoj kiselini.
4. Metoda pripreme argatroban monohidrata prema zahtjevu 1, pri čemu je reakcijska smjesa tretirana s vodenim bazičnim otapalom za namještanje pH smjese između 7,0-7,5.
5. Metoda pripreme argatroban monohidrata prema zahtjevu 4, pri čemu je bazično otapalo izabrano između natrijevog hidroksida, natrijevog bikarbonata i amonijaka u koncentraciji 10-30%.
6. Metoda pripreme argatroban monohidrata prema zahtjevu 1, pri čemu je kristalizacija ili rekristalizacija iz metanolno-vodenog medija postignuta podvrgavanjem smjese sljedećem temperaturnom gradijentu: zagrijavanje na 90-95°C, održavanje na refluks temperaturi 1-3 sata, hlađenje na 70-75°C tijekom najmanje jednog sata i održavanje na toj temperaturi najmanje jedan sat, hlađenje na 20°C tijekom 2-6 sati i održavanje na toj temperaturi najmanje 6 sati.
7. Metoda prema zahtjevu 1, pri čemu metanolno-vodeni medij ima koncentraciju od 10-20% alkohola i kvantitativno iznosi do 50 volumena po gramu pročišćenog argatrobana.
8. Metoda pripreme argatroban monohidrata prema zahtjevu 1 koja sadrži daljnji korak sušenja dobivenog kristaliničnog precipitata argatroban monohidrata.
9. Metoda pripreme argatroban monohidrata koja sadrži korake definirane u zahtjevima 1-8.
10. Metoda pripreme anhidričnog argatrobana koja sadrži najmanje jedan korak od:
Pripreme argatroban monohidrata prema metodi definiranoj u zahtjevima 1-8;
Njegova rekristalizacija, nakon otapanja u vodi, brzim hlađenjem na 10-20°C unutar ne više od 2 minute.
11. Pročišćeni argatroban karakteriziran sljedećim parametrima:
Točka tališta 183-185°C;
I.R. spektar (KBr) (cm-1) – 3399, 1270, 1160;
Diferencijalna pretražna kalorimetrija s endotermnim pomakom na oko 160°C;
XRPD: pik br. 1 kut (2θ) 6.800, relativni intenzitet (%) 100; pik br. 2 kut (2θ) 7.840, relativni intenzitet (%) 12; pik br. 3 kut (2θ) 9.800, relativni intenzitet (%) 13; pik br. 4 kut (2θ) 10.020, relativni intenzitet (%) 13; pik br. 5 kut (2θ) 10.700, relativni intenzitet (%) 6; pik br. 6 kut (2θ) 11.780, relativni intenzitet (%) 5; pik br. 7 kut (2θ) 13.080, relativni intenzitet (%) 12; pik br. 8 kut (2θ) 13.540, relativni intenzitet (%) 32; pik br. 9 kut (2θ) 14.540, relativni intenzitet (%) 21; pik br. 10 kut (2θ) 16.900, relativni intenzitet (%) 8; pik br. 11 kut (2θ) 17.540 , relativni intenzitet (%) 18; pik br. 12 kut (2θ) 18.640, relativni intenzitet (%) 14; pik br. 13 kut (2θ) 19.060, relativni intenzitet (%) 13; pik br. 14 kut (2θ) 19.620, relativni intenzitet (%) 13; pik br. 15 kut (2θ) 20.000, relativni intenzitet (%) 20; pik br. 16 kut (2θ) 21.420, relativni intenzitet (%) 16; pik br. 17 kut (2θ) 21.780, relativni intenzitet (%) 21; pik br. 18 kut (2θ) 22.660, relativni intenzitet (%) 15; pik br. 19 kut (2θ) 23.680, relativni intenzitet (%) 15; pik br. 20 kut (2θ) 24.080, relativni intenzitet (%) 16;pik br. 21 kut (2θ) 24.740, relativni intenzitet (%) 25; pik br. 22 kut (2θ) 25.340, relativni intenzitet (%) 9; pik br. 23 kut (2θ) 26.480, relativni intenzitet (%) 10; pik br. 24 kut (2θ) 27.580, relativni intenzitet (%) 10; pik br. 25 kut (2θ) 28.220, relativni intenzitet (%) 7; pik br. 26 kut (2θ) 29.120, relativni intenzitet (%) 8; pik br. 27 kut (2θ) 29.740, relativni intenzitet (%) 11; pik br. 28 kut (2θ) 31.820, relativni intenzitet (%) 9; pik br. 29 kut (2θ) 34.840, relativni intenzitet (%) 7; pik br. 30 kut (2θ) 40.580, relativni intenzitet (%) 6;
Otapa se u izopropanolu.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000106A ITPD20080106A1 (it) | 2008-04-07 | 2008-04-07 | Metodo di preparazione di argatroban monoidrato |
| PCT/EP2009/054085 WO2009124906A2 (en) | 2008-04-07 | 2009-04-06 | Method for preparing argatroban monohydrate |
| EP09730279.8A EP2285799B1 (en) | 2008-04-07 | 2009-04-06 | Method for preparing argatroban monohydrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20150456T1 true HRP20150456T1 (hr) | 2015-07-03 |
Family
ID=40297115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20150456TT HRP20150456T1 (hr) | 2008-04-07 | 2015-04-28 | Metoda pripreme argatroban monohidrata |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US8378106B2 (hr) |
| EP (2) | EP2687522A1 (hr) |
| JP (1) | JP5696035B2 (hr) |
| CA (1) | CA2719778C (hr) |
| DK (1) | DK2285799T3 (hr) |
| ES (1) | ES2537067T3 (hr) |
| HR (1) | HRP20150456T1 (hr) |
| HU (1) | HUE025930T2 (hr) |
| IT (1) | ITPD20080106A1 (hr) |
| PL (1) | PL2285799T3 (hr) |
| PT (1) | PT2285799E (hr) |
| SI (1) | SI2285799T1 (hr) |
| WO (1) | WO2009124906A2 (hr) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20110545A1 (it) | 2011-04-04 | 2012-10-05 | Lundbeck Pharmaceuticals Italy S P A | Metodo per la preparazione di intermedi di processo per la sintesi di argatroban monoidrato |
| CN102408468B (zh) * | 2011-09-20 | 2012-11-21 | 海南灵康制药有限公司 | 一种阿加曲班化合物及其制法 |
| CN103772486B (zh) * | 2014-01-06 | 2016-01-20 | 天津大学 | 一种阿加曲班新晶型及其制备方法 |
| CN105218627A (zh) * | 2015-11-19 | 2016-01-06 | 天津市亨必达化学合成物有限公司 | 一种阿加曲班手性中间体水解物的纯化方法 |
| CN110452285B (zh) * | 2019-09-12 | 2021-05-25 | 北京悦康科创医药科技股份有限公司 | 一种阿加曲班单晶及其培养方法与应用 |
| CN110981934B (zh) * | 2019-11-12 | 2021-05-25 | 鲁南制药集团股份有限公司 | 一种阿加曲班水合物的合成方法 |
| CN111961114A (zh) * | 2020-08-03 | 2020-11-20 | 扬州中宝药业股份有限公司 | 一种阿加曲班中间体及其制备方法与应用 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4201863A (en) | 1974-11-08 | 1980-05-06 | Mitsubishi Chemical Industries, Limited | N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US4210863A (en) | 1977-03-28 | 1980-07-01 | Huntron Instruments, Inc. | Extendible probe for use with test instruments |
| US4258192A (en) | 1977-12-16 | 1981-03-24 | Mitsubishi Chemical Industries Limited | N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| JPS5533499A (en) * | 1978-08-31 | 1980-03-08 | Mitsubishi Chem Ind Ltd | N2-arylsulfonyl-l-arginineamide and its pharmaceutically acceptable salt |
| IE48623B1 (en) | 1978-08-31 | 1985-03-20 | Mitsubishi Chem Ind | Alpha-(n-arylsulfonyl-l-argininamides,processes for their preparation and pharmaceutical compositions containing these substances |
| JPH0627535B2 (ja) | 1988-07-18 | 1994-04-13 | 株式会社メント研究所 | 無段変速機 |
| US5925760A (en) | 1996-08-07 | 1999-07-20 | Mitsubishi Chemical Corporation | Method for preparing N2 -arylsulfonyl-L-argininamides |
| JPH10101649A (ja) * | 1996-08-07 | 1998-04-21 | Mitsubishi Chem Corp | Ｎ２ −アリールスルホニル−ｌ−アルギニンアミド類の製造方法 |
| CN100427480C (zh) * | 2006-11-10 | 2008-10-22 | 天津市炜杰科技有限公司 | 阿加曲班水合物的制备方法 |
-
2008
- 2008-04-07 IT IT000106A patent/ITPD20080106A1/it unknown
-
2009
- 2009-04-06 PL PL09730279T patent/PL2285799T3/pl unknown
- 2009-04-06 WO PCT/EP2009/054085 patent/WO2009124906A2/en active Application Filing
- 2009-04-06 EP EP13189067.5A patent/EP2687522A1/en not_active Withdrawn
- 2009-04-06 ES ES09730279.8T patent/ES2537067T3/es active Active
- 2009-04-06 SI SI200931194T patent/SI2285799T1/sl unknown
- 2009-04-06 CA CA2719778A patent/CA2719778C/en active Active
- 2009-04-06 JP JP2011503414A patent/JP5696035B2/ja active Active
- 2009-04-06 HU HUE09730279A patent/HUE025930T2/en unknown
- 2009-04-06 PT PT97302798T patent/PT2285799E/pt unknown
- 2009-04-06 EP EP09730279.8A patent/EP2285799B1/en active Active
- 2009-04-06 US US12/935,512 patent/US8378106B2/en active Active
- 2009-04-06 DK DK09730279T patent/DK2285799T3/en active
-
2015
- 2015-04-28 HR HRP20150456TT patent/HRP20150456T1/hr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP2687522A1 (en) | 2014-01-22 |
| US20110028726A1 (en) | 2011-02-03 |
| CA2719778C (en) | 2016-07-26 |
| US8378106B2 (en) | 2013-02-19 |
| WO2009124906A2 (en) | 2009-10-15 |
| WO2009124906A3 (en) | 2009-12-03 |
| DK2285799T3 (en) | 2015-04-27 |
| CA2719778A1 (en) | 2009-10-15 |
| ITPD20080106A1 (it) | 2009-10-08 |
| PL2285799T3 (pl) | 2015-08-31 |
| EP2285799A2 (en) | 2011-02-23 |
| SI2285799T1 (sl) | 2015-07-31 |
| HUE025930T2 (en) | 2016-05-30 |
| EP2285799B1 (en) | 2015-02-25 |
| ES2537067T3 (es) | 2015-06-02 |
| PT2285799E (pt) | 2015-07-01 |
| JP2011516519A (ja) | 2011-05-26 |
| JP5696035B2 (ja) | 2015-04-08 |
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