CA2435372A1 - Process for purifying 20(s)-camptothecine - Google Patents
Process for purifying 20(s)-camptothecine Download PDFInfo
- Publication number
- CA2435372A1 CA2435372A1 CA002435372A CA2435372A CA2435372A1 CA 2435372 A1 CA2435372 A1 CA 2435372A1 CA 002435372 A CA002435372 A CA 002435372A CA 2435372 A CA2435372 A CA 2435372A CA 2435372 A1 CA2435372 A1 CA 2435372A1
- Authority
- CA
- Canada
- Prior art keywords
- camptothecine
- purifying
- denotes
- crystals
- vinyl
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for purifying 20(S) camptothecine:
(see formula I) wherein R1 is ethyl, by transforming the lactone ring of the 20(S) camptothecine into a carboxylate salt with the help of an aqueous base, hydrogenating the mixture that is obtained in the presence of a transition metal catalyst, acidifying the aqueous phase to form camptothecine crystals, adding a polar aprotic solvent, optionally heating and cooling the mixture and separating the camptothecine crystals.
(see formula I) wherein R1 is ethyl, by transforming the lactone ring of the 20(S) camptothecine into a carboxylate salt with the help of an aqueous base, hydrogenating the mixture that is obtained in the presence of a transition metal catalyst, acidifying the aqueous phase to form camptothecine crystals, adding a polar aprotic solvent, optionally heating and cooling the mixture and separating the camptothecine crystals.
Claims (10)
1. Process for purifying 20(S)-camptothecine, which comprises the following steps:
(a) combining an aqueous base and a starting material containing 20(S)-camptothecine, thereby converting the lactone ring of the 20(S)-camptothecine into a carboxylate salt;
(b) hydrogenating the resulting mixture in the presence of a transition metal catalyst;
(c) acidifying the aqueous phase, thereby forming camptothecine crystals;
(d) adding at least one polar aprotic solvent; and (e) separating off the camptothecine crystals.
(a) combining an aqueous base and a starting material containing 20(S)-camptothecine, thereby converting the lactone ring of the 20(S)-camptothecine into a carboxylate salt;
(b) hydrogenating the resulting mixture in the presence of a transition metal catalyst;
(c) acidifying the aqueous phase, thereby forming camptothecine crystals;
(d) adding at least one polar aprotic solvent; and (e) separating off the camptothecine crystals.
2. Process for purifying 20(S)-camptothecine according to claim 1, characterised in that the starting material containing 20(S)-camptothecine is a natural plant product.
3. Process for purifying 20(S)-camptothecine according to claim 1 or 2, characterised in that the starting material containing 20(S)-camptothecine consists essentially of a mixture of the compounds of formula (I), wherein R1 denotes ethyl or vinyl.
4. Process for purifying 20(S)-camptothecine according to one of the preceding claims, characterised in that the base in step (a) is sodium hydroxide.
5. Process for purifying 20(S)-camptothecine according to one of the preceding claims, characterised in that the mixture obtained in step (a) is hydrogenated in the presence of a palladium catalyst at a temperature of 0 °C to 100 °C and at a pressure of 0.5 bar to 5.0 bar.
6. Process for purifying 20(S)-camptothecine according to one of the preceding claims, characterised in that the aqueous phase obtained in step (b) is treated with an acid selected from among HCl, HBr, HI, HNO3, H3PO4, H2SO4, acetic acid and trifluoroacetic acid or mixtures of these acids at a temperature of 30 °C to 80 °C.
7. Process for purifying 20(S)-camptothecine according to one of the preceding claims, characterised in that the aqueous phase obtained in step (c) is treated with one or more polar aprotic solvents of formula wherein R2 denotes hydrogen or a C1-4 alkyl group;
R3 and R4 independently of each other denote a C1-4 alkyl group; or R2 and R3 together denote a-(CH2)m- or a NR5-(CH2)m- group, while R5 denotes a C1-4 alkyl group;
m is 3 or 4; and n is 2 or 3, at a temperature of 30 °C to 120 °C.
R3 and R4 independently of each other denote a C1-4 alkyl group; or R2 and R3 together denote a-(CH2)m- or a NR5-(CH2)m- group, while R5 denotes a C1-4 alkyl group;
m is 3 or 4; and n is 2 or 3, at a temperature of 30 °C to 120 °C.
8. Process for purifying 20(S)-camptothecine according to claim 7, characterised in that the polar aprotic solvent is selected from among N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), N,N-dimethylethylene urea (DMEU) and N,N-dimethylpropylene urea (DMPU) or mixtures of these solvents.
9. Process for purifying 20(S)-camptothecine according to one of the preceding claims, characterised in that the 20(S)-camptothecine crystals in step (d) are separated off by filtration.
10. Process for preparing 20(S)-camptothecine of formula (I) wherein R1 denotes ethyl from a 20-vinyl-camptothecine of formula (I) wherein R1 denotes vinyl, which comprises the following steps:
(a) combining an aqueous base and the starting material containing 20-vinyl-camptothecine, to form a compound of formula (II), wherein R1 denotes vinyl; and Met denotes a metal;
(b) hydrogenating the resulting mixture in the presence of a transition metal catalyst;
(c) acidifying the aqueous phase to form camptothecine crystals;
(d) adding at least one polar aprotic solvent; and (e) separating off the camptothecine crystals.
(a) combining an aqueous base and the starting material containing 20-vinyl-camptothecine, to form a compound of formula (II), wherein R1 denotes vinyl; and Met denotes a metal;
(b) hydrogenating the resulting mixture in the presence of a transition metal catalyst;
(c) acidifying the aqueous phase to form camptothecine crystals;
(d) adding at least one polar aprotic solvent; and (e) separating off the camptothecine crystals.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10106969.3 | 2001-02-15 | ||
| DE10106969A DE10106969C1 (en) | 2001-02-15 | 2001-02-15 | Process for the purification and production of 20 (S) -camptothecin |
| PCT/EP2002/001375 WO2002064597A2 (en) | 2001-02-15 | 2002-02-09 | Method for purifying 20(s)-camptothecin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2435372A1 true CA2435372A1 (en) | 2002-08-22 |
| CA2435372C CA2435372C (en) | 2010-04-20 |
Family
ID=7674093
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2435372A Expired - Lifetime CA2435372C (en) | 2001-02-15 | 2002-02-09 | Process for purifying 20(s)-camptothecine |
Country Status (27)
| Country | Link |
|---|---|
| EP (1) | EP1362051B1 (en) |
| JP (1) | JP4467884B2 (en) |
| KR (1) | KR100813087B1 (en) |
| CN (1) | CN1228340C (en) |
| AT (1) | ATE301124T1 (en) |
| AU (1) | AU2002244711B2 (en) |
| BG (1) | BG108064A (en) |
| BR (1) | BR0207261A (en) |
| CA (1) | CA2435372C (en) |
| CZ (1) | CZ300671B6 (en) |
| DE (2) | DE10106969C1 (en) |
| EA (1) | EA005618B1 (en) |
| EE (1) | EE05131B1 (en) |
| ES (1) | ES2246389T3 (en) |
| HK (1) | HK1064092A1 (en) |
| HR (1) | HRP20030654A2 (en) |
| HU (1) | HUP0303030A3 (en) |
| IL (2) | IL157148A0 (en) |
| MX (1) | MXPA03007194A (en) |
| NO (1) | NO328106B1 (en) |
| NZ (1) | NZ528039A (en) |
| PL (1) | PL202135B1 (en) |
| RS (1) | RS50496B (en) |
| SK (1) | SK10192003A3 (en) |
| UA (1) | UA74874C2 (en) |
| WO (1) | WO2002064597A2 (en) |
| ZA (1) | ZA200305364B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI396690B (en) * | 2006-04-27 | 2013-05-21 | Yakult Honsha Kk | Process for preparing camptothecin analogs |
| ES2425621T3 (en) * | 2008-05-29 | 2013-10-16 | Microbiopharm Japan Co., Ltd. | Methods for producing camptothecin derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5527913A (en) * | 1993-02-25 | 1996-06-18 | The Stehlin Foundation For Cancer Research | Methods for purifying camptothecin compounds |
-
2001
- 2001-02-15 DE DE10106969A patent/DE10106969C1/en not_active Expired - Fee Related
-
2002
- 2002-02-09 CN CNB028049918A patent/CN1228340C/en not_active Expired - Fee Related
- 2002-02-09 KR KR1020037010605A patent/KR100813087B1/en not_active IP Right Cessation
- 2002-02-09 IL IL15714802A patent/IL157148A0/en active IP Right Grant
- 2002-02-09 BR BR0207261-0A patent/BR0207261A/en not_active Expired - Fee Related
- 2002-02-09 PL PL362128A patent/PL202135B1/en not_active IP Right Cessation
- 2002-02-09 EE EEP200300389A patent/EE05131B1/en not_active IP Right Cessation
- 2002-02-09 DE DE50203824T patent/DE50203824D1/en not_active Expired - Lifetime
- 2002-02-09 AT AT02712902T patent/ATE301124T1/en active
- 2002-02-09 EP EP02712902A patent/EP1362051B1/en not_active Expired - Lifetime
- 2002-02-09 EA EA200300837A patent/EA005618B1/en not_active IP Right Cessation
- 2002-02-09 CA CA2435372A patent/CA2435372C/en not_active Expired - Lifetime
- 2002-02-09 ES ES02712902T patent/ES2246389T3/en not_active Expired - Lifetime
- 2002-02-09 CZ CZ20032211A patent/CZ300671B6/en not_active IP Right Cessation
- 2002-02-09 MX MXPA03007194A patent/MXPA03007194A/en active IP Right Grant
- 2002-02-09 JP JP2002564528A patent/JP4467884B2/en not_active Expired - Lifetime
- 2002-02-09 RS YUP-614/03A patent/RS50496B/en unknown
- 2002-02-09 SK SK1019-2003A patent/SK10192003A3/en unknown
- 2002-02-09 NZ NZ528039A patent/NZ528039A/en unknown
- 2002-02-09 WO PCT/EP2002/001375 patent/WO2002064597A2/en active IP Right Grant
- 2002-02-09 HU HU0303030A patent/HUP0303030A3/en unknown
- 2002-02-09 AU AU2002244711A patent/AU2002244711B2/en not_active Ceased
- 2002-09-02 UA UA2003098461A patent/UA74874C2/en unknown
-
2003
- 2003-07-11 ZA ZA200305364A patent/ZA200305364B/en unknown
- 2003-07-29 IL IL157148A patent/IL157148A/en not_active IP Right Cessation
- 2003-08-06 BG BG108064A patent/BG108064A/en active Pending
- 2003-08-13 HR HR20030654A patent/HRP20030654A2/en not_active Application Discontinuation
- 2003-08-14 NO NO20033614A patent/NO328106B1/en not_active IP Right Cessation
-
2004
- 2004-09-08 HK HK04106806A patent/HK1064092A1/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20220209 |