CA2435372A1 - Process for purifying 20(s)-camptothecine - Google Patents

Process for purifying 20(s)-camptothecine Download PDF

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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
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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
Application number
CA002435372A
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French (fr)
Other versions
CA2435372C (en
Inventor
Rainer Sobotta
Armin Rapp
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Boehringer Ingelheim Pharma GmbH and Co KG
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Individual
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Publication of CA2435372A1 publication Critical patent/CA2435372A1/en
Application granted granted Critical
Publication of CA2435372C publication Critical patent/CA2435372C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic 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
    • C07D491/12Heterocyclic 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
    • C07D491/14Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic 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
    • C07D491/02Heterocyclic 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
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

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  • 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.

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.
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.
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.
CA2435372A 2001-02-15 2002-02-09 Process for purifying 20(s)-camptothecine Expired - Lifetime CA2435372C (en)

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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

Also Published As

Publication number Publication date
NO20033614D0 (en) 2003-08-14
MXPA03007194A (en) 2003-12-04
DE50203824D1 (en) 2005-09-08
EE05131B1 (en) 2009-02-16
PL202135B1 (en) 2009-06-30
DE10106969C1 (en) 2002-10-02
NO20033614L (en) 2003-08-14
CN1491228A (en) 2004-04-21
WO2002064597A2 (en) 2002-08-22
HUP0303030A2 (en) 2003-12-29
BG108064A (en) 2005-04-30
EP1362051A2 (en) 2003-11-19
AU2002244711B2 (en) 2007-05-31
CN1228340C (en) 2005-11-23
HK1064092A1 (en) 2005-01-21
CZ300671B6 (en) 2009-07-15
JP4467884B2 (en) 2010-05-26
ES2246389T3 (en) 2006-02-16
IL157148A (en) 2008-08-07
IL157148A0 (en) 2004-02-08
KR20030076674A (en) 2003-09-26
BR0207261A (en) 2004-06-15
RS50496B (en) 2010-03-02
WO2002064597A3 (en) 2002-10-24
PL362128A1 (en) 2004-10-18
ATE301124T1 (en) 2005-08-15
YU61403A (en) 2006-05-25
UA74874C2 (en) 2006-02-15
EA200300837A1 (en) 2003-12-25
CZ20032211A3 (en) 2003-12-17
NZ528039A (en) 2006-02-24
EP1362051B1 (en) 2005-08-03
HRP20030654A2 (en) 2005-06-30
EE200300389A (en) 2003-12-15
SK10192003A3 (en) 2004-01-08
HUP0303030A3 (en) 2004-11-29
JP2004521909A (en) 2004-07-22
CA2435372C (en) 2010-04-20
KR100813087B1 (en) 2008-03-17
NO328106B1 (en) 2009-12-07
ZA200305364B (en) 2004-04-28
EA005618B1 (en) 2005-04-28

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