CA2435372C - Process for purifying 20(s)-camptothecine - Google Patents
Process for purifying 20(s)-camptothecine Download PDFInfo
- Publication number
- CA2435372C CA2435372C CA2435372A CA2435372A CA2435372C CA 2435372 C CA2435372 C CA 2435372C CA 2435372 A CA2435372 A CA 2435372A CA 2435372 A CA2435372 A CA 2435372A CA 2435372 C CA2435372 C CA 2435372C
- 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.)
- Expired - Lifetime
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
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.
Description
01-1188 ff-Ko, l t 111 CA 02435372 2003-07-18 BOEHRINGER INGELHEIM PHARMA KG
75058fft.205 Process for purring 20 S~-Camptothecine s The invention relates to a process for purifying 20(5)-camptothecine contaminated by a vinyl-camptothecine derivative. _.
Background to the invention 20(5)-camptothecine (20(5)-CPT) is a natural alkaloid of formula (I) O
io (~
wherein Rl denotes ethyl.
OH O
20{S)-CPT and its derivatives, being topoisomerase I inhibitors, have tumour-inhibiting properties (e.g. Giovanelle, B.C. et al., Cancer Research, 51: 302-3055, 1991, European 15 Patent applications EP 0 074 256, EP 0 088 642, US Patents US 4,473,692, US
4,545,880, US
4,604,463 and International Patent Application WO 92/05785).
;, 20(5)-CPT can be obtained as a crude product from the Chinese tree Camptotheca acuminata {Nyssaceae) (Wall M. et al., J. Am. Chem. Soc. 88: 3888-3890, 1966) or from the Indian tree 20 Nothapodytes foetida (nimmoniana) (formerly known as: Mappie foetida Miers) (Govindachari, T.R. et al., Phytochemistry 11: 3529-3531, 1972), inter alia.
These crude products, particularly the one obtained from Nothapodytes foetida, contain 20(S)-CPT contaminated by a CPT derivative of formula (I) wherein Rl denotes vinyl (20-vinyl-25 CPT).
Traditionally, the crude products are purified by complex chromatographic methods or by converting the camptothecine into the aqueous phase and eliminating impurities by extraction Ol-1188 prio-Ko 2/1l CA 02435372 2003-07-18 _2-with water-insoluble solvents (e.g. WO 94/19353). However, contamination by 20-vinyl-CPT
cannot be efficiently dealt with by these methods.
The problem of the present invention is therefore to provide a process which allows the 20(S)-CPT starting product to be purified without using complex chromatographic methods.
Description of the invention Surprisingly, it has been found that 20(S)-CPT can be virtually completely freed from contamination with 20-vinyl-CPT by first treating the starting material with an aqueous base, lo hydrogenating and subsequently acidifying it and then isolating the product.
The invention thus relates to a 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 a polar aprotic solvent; and (e) separating off the camptothecine crystals.
The invention further relates to a process for preparing 20(S)-camptothecine of formula (I) wherein Rl denotes ethyl, from 20-vinyl-camptothecine of formula (I) wherein Rl denotes vinyl, which comprises the following steps:
(a) combining an aqueous base and the starting material containing 20(S)-camptothecine, forming a compound of formula (II), O
l N OH
N
OMet R;,""~
OH O
wherein Ri denotes vinyl; and 01-11 ~8 prio -~Ko 3 / 11 CA 02435372 2003-07-18 Met denotes a metal;
(b) hydrogenating the resulting mixture in the presence of a transition metal catalyst;
(c) acidifying the aqueous phase to form camptathecine crystals;
(d) adding at least one polax aprotic solvent; and (e) separating off the camptothecine crystals.
Detailed descn~tion of the invention to The term "starting material containing camptothecine " as used above and hereinafter refers to a contaminated material containing 20(S)-CPT, crude camptothecine, camptothecine-containing plant extracts, synthetic camptothecine, derivatives of camptothecine as described for example in International Patent Application WO 92/05785, or reaction products containing camptothecine.
Preferably, the starting material is a natural crude product which is obtained in particular from Nothapadytes foetida. As a rule, it is a mixture of the compound of formula {I) wherein Rl denotes ethyl, and the compound of formula (I) wherein Rl denotes vinyl. It generally contains 0.9 to 1.5 wt.-%, preferably 1.0 to 1.4 wt.-% of the vinyl compound.
In addition, the 2o starting material may contain other camptothecine derivatives such as, for example, 9-methoxy-CPT, 10-methoxy-CPT, 11-methoxy-CPT, 10-hydroxy-CPT and 11-hydroxy-CPT.
As a rule, the starting material contains up to 1 wt.-% of one or more of these additional CPT
derivatives, particularly 0.2 to 0.8 wt.% of 9-methoxy-CPT.
The term "aqueous base" as used above and hereinafter in connection with step (a) of the purification process according to the invention relates to a base which generates enough hydroxide ions in the aqueous medium, preferably in pure water, to convert the lactone group of the camptothecine derivatives contained in the starting material completely into the corresponding hydroxycarboxylates. Metal hydroxides are preferred, particularly alkali metal or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide. Sodium hydroxide is most preferred 01-1188prio-Ko 4/11 CA 02435372 2003-07-18 The metal hydroxide is preferably used in the form of a dilute aqueous solution, preferably in the form of a 1 to 25 %, particularly a 3 to 10 % aqueous solution. As a rule, sufficient metal hydroxide is used to make the camptothecine derivatives go completely into solution;
preferably, 1 to 20 mol, more preferably 5 to 15 mol, particularly 7.5 to 12.5 mol of metal hydroxide are used per 1 mol of starting material.
In step (b) a transition metal catalyst, preferably a heterogeneous transition metal catalyst, particularly platinum, platinum oxide, nickel, palladium or rhodium on a carrier material such as activated charcoal or aluminium oxide is added to the resulting mixture.
Palladium on to activated charcoal containing 1 to 15 wt.%, preferably 2 to 10 wt.%, particularly about 5 wt.-% of palladium is particularly preferred.
The quantity of transition metal catalyst is selected so as to ensure total hydrogenation of the vinylic CPT derivative. Preferably, 0.01 to 0.50 parts by weight, particularly 0.02 to 0.10 1s parts by weight of transition metal catalyst (including carrier materials) are used, based on 1 part by weight of the starting material.
The resulting mixture is subjected to the action of hydrogen gas, preferably at a temperature of - 20 °C to 100 °C, particularly 10 °C to 40 °C, most preferably at about room temperature.
The hydrogen pressure is not critical per se; the hydrogenation is preferably carried out at normal pressure or at slightly raised pressure, particularly at 0.9 to 5.0 bar, most preferably at about 1 bar.
2s Under these conditions, hydrogenation is generally complete within 1 to 20 hours, preferably 4 to 15 hours, particularly 6 to 10 hours.
After the hydrogenatian has ended, the transition metal catalyst is preferably eliminated by filtration, and the resulting reaction mixture is acidified in step (c). The acidification can be 3o done with an inorganic or organic acid. Preferred acids are inorganic acids such as HCI, HBr, HI, HN03, H~POa, Ha50a, or aliphatic carboxylic acids such as acetic acid and trifluoroacetic acid or mixtures of these acids, particularly concentrated hydrochloric acid.
Using the chosen acid, the pH is adjusted to 3.0 to 6.0, preferably 3.5 to 5.0, particularly about 4.0 to 4.5. The 01-11 &8 prio -KO .S l1 ~ CA 02435372 2003-07-18 -$-reaction with the acid is generally carried out at a temperature of 0 °C to 100 °C, preferably 30 °C to 80 °C, particularly 50 °C to 60 °C.
In a particularly preferred embodiment, acidification is carried out with 2 to 20 parts by weight, preferably 4 to 9 parts by weight, particularly 6 to 8 parts by weight of concentrated hydrochloric acid, based on 1 part by weight of starting material.
Under the conditions described, lactonisation to form the CPT is generally complete within 10 to 180 minutes, preferably 1 S to 60 hours, particularly within about 30 minutes.
to The reaction mixture obtained by acidification is generally in the form of a pure suspension.
To improve the crystallisation in step (d) one or more polar aprotic solvents are added thereto.
Suitable solvents of this kind are preferably sulphoxides such as dimethylsulphoxide (DMSO) or amides and urea derivatives of formula R~C~N~Ra I!
is O
wherein R2 denotes hydrogen or a Cl-4 alkyl group, particularly hydrogen or methyl;
R3 and R4 independently of each other denote a Ci-a alkyl group, particularly methyl; or R2 and R3 together denote a -(CHZ)m- or a NRS-(CH2)n- group, while ! . 2o RS denotes a Cl-4 alkyl group;
m is 3 or 4, particularly 3; and nis2or3, particularly selected from among N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), N,N-dimethylethylene urea (DMEI~ and N,N-25 dimethylpropylene urea (DMPL~ or mixtures of these solvents, most preferably DMF.
As a rule, 10 to 100 parts by weight, preferably 20 to 80 parts by weight, particularly 30 to 50 parts by weight of the polar aprotic solvent are used, based on 1 part by weight of the starting material used.
DI-1188 prio-.Ko 6111 CA 02435372 2003-07-18 The treatment with the polar aprotic solvent may be carned out at any desired temperature.
The reaction mixture is preferably stirred at a temperature of 30 °C to 120 °C, particularly 80 to 100 °C and then slowly cooled to ambient temperature.
The CPT crystals thus obtained are easily separated from the liquid phase in step (e), preferably by decanting, centrifuging, spinning, squeezing out or filtration, particularly by filtration.
As a rule, the CPT crystals thus obtained are washed with an alcohol, preferably methanol, 1o ethanol or isopropanol, particularly methanol, and dried.
The advantage of the procedure according to the invention is the high space/time yield and the high yield and purity of the 20(S)-camptothecine produced, which is obtained without any chromatographic purification substantially free from contaminants containing vinyl groups.
The Examples that follow serve to illustrate some processes for purifying camptothecine carned out by way of example. They are intended only as possible methods given as examples, without restricting the invention to their content.
2o Example 1 10.45 g of a crude product containing camptothecine, obtained from Nothapodytes foetida, containing 1.33 % of 20-vinyl-CPT and 0.47 % of 9-methoxy-CPT, is taken up in 260 ml of a a 2 N sodium hydroxide solution and 0.6 g of palladiumlactivated charcoal (5 %) are added.
The mixture is treated with hydrogen for 8 hours at ambient temperature under a pressure of 1 bar.
Then the reaction mixture is filtered and combined at 50-60 °C with 80 ml of concentrated hydrochloric acid and adjusted to a pH of 4.0 to 4.5.
so The suspension formed is combined with 400 ml of DMF and stirred far 2.5 hours at 90-100°C. The resulting suspension is slowly cooled to ambient temperature and filtered. The CPT crystals obtained are washed with 100 ml of methanol and dried at 55°C in vacuo.
01-1188 prio-.KO 7/1l CA 02435372 2003-07-18 - _.
9.85 g (94.2 % of material put in) of 20(S)-camptothecine are obtained, containing less than 0.05 % of 20-vinyl-CPT and 0.11 % of 9-methoxy CPT.
Example 2 10.45 g of a crude product containing camptothecine, obtained from Nothapodytes foetida, containing 1.33 % of 20-vinyl-CPT and 0.47 % of 9-methoxy-CPT is taken up in 260 ml of a 2 N sodium hydroxide solution and 0.6 g of palladiumJactivated charcoal (5 %) are added.
The mixture is treated with hydrogen for 8 hours at ambient temperature under a pressure of 1 1 o bar.
Then the reaction mixture is filtered and combined at 50-60 °C with 300 ml of a 10%
sulphuric acid and adjusted to a pH of 4.0 to 4.5.
The suspension formed is combined with 500 ml of DMF and stirred for 2.5 hours at 90-100°C. The resulting suspension is slowly cooled to ambient temperature and filtered. The CPT crystals obtained are washed with 100 ml of methanol and dried at 55°C in vacuo.
9.67 g (92.6 % of material put in) of 20(S)-camptothecine are obtained, containing 0.09 % of 9-methoxy CPT, the content of 20-vinyl-CPT being below the detection threshold.
75058fft.205 Process for purring 20 S~-Camptothecine s The invention relates to a process for purifying 20(5)-camptothecine contaminated by a vinyl-camptothecine derivative. _.
Background to the invention 20(5)-camptothecine (20(5)-CPT) is a natural alkaloid of formula (I) O
io (~
wherein Rl denotes ethyl.
OH O
20{S)-CPT and its derivatives, being topoisomerase I inhibitors, have tumour-inhibiting properties (e.g. Giovanelle, B.C. et al., Cancer Research, 51: 302-3055, 1991, European 15 Patent applications EP 0 074 256, EP 0 088 642, US Patents US 4,473,692, US
4,545,880, US
4,604,463 and International Patent Application WO 92/05785).
;, 20(5)-CPT can be obtained as a crude product from the Chinese tree Camptotheca acuminata {Nyssaceae) (Wall M. et al., J. Am. Chem. Soc. 88: 3888-3890, 1966) or from the Indian tree 20 Nothapodytes foetida (nimmoniana) (formerly known as: Mappie foetida Miers) (Govindachari, T.R. et al., Phytochemistry 11: 3529-3531, 1972), inter alia.
These crude products, particularly the one obtained from Nothapodytes foetida, contain 20(S)-CPT contaminated by a CPT derivative of formula (I) wherein Rl denotes vinyl (20-vinyl-25 CPT).
Traditionally, the crude products are purified by complex chromatographic methods or by converting the camptothecine into the aqueous phase and eliminating impurities by extraction Ol-1188 prio-Ko 2/1l CA 02435372 2003-07-18 _2-with water-insoluble solvents (e.g. WO 94/19353). However, contamination by 20-vinyl-CPT
cannot be efficiently dealt with by these methods.
The problem of the present invention is therefore to provide a process which allows the 20(S)-CPT starting product to be purified without using complex chromatographic methods.
Description of the invention Surprisingly, it has been found that 20(S)-CPT can be virtually completely freed from contamination with 20-vinyl-CPT by first treating the starting material with an aqueous base, lo hydrogenating and subsequently acidifying it and then isolating the product.
The invention thus relates to a 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 a polar aprotic solvent; and (e) separating off the camptothecine crystals.
The invention further relates to a process for preparing 20(S)-camptothecine of formula (I) wherein Rl denotes ethyl, from 20-vinyl-camptothecine of formula (I) wherein Rl denotes vinyl, which comprises the following steps:
(a) combining an aqueous base and the starting material containing 20(S)-camptothecine, forming a compound of formula (II), O
l N OH
N
OMet R;,""~
OH O
wherein Ri denotes vinyl; and 01-11 ~8 prio -~Ko 3 / 11 CA 02435372 2003-07-18 Met denotes a metal;
(b) hydrogenating the resulting mixture in the presence of a transition metal catalyst;
(c) acidifying the aqueous phase to form camptathecine crystals;
(d) adding at least one polax aprotic solvent; and (e) separating off the camptothecine crystals.
Detailed descn~tion of the invention to The term "starting material containing camptothecine " as used above and hereinafter refers to a contaminated material containing 20(S)-CPT, crude camptothecine, camptothecine-containing plant extracts, synthetic camptothecine, derivatives of camptothecine as described for example in International Patent Application WO 92/05785, or reaction products containing camptothecine.
Preferably, the starting material is a natural crude product which is obtained in particular from Nothapadytes foetida. As a rule, it is a mixture of the compound of formula {I) wherein Rl denotes ethyl, and the compound of formula (I) wherein Rl denotes vinyl. It generally contains 0.9 to 1.5 wt.-%, preferably 1.0 to 1.4 wt.-% of the vinyl compound.
In addition, the 2o starting material may contain other camptothecine derivatives such as, for example, 9-methoxy-CPT, 10-methoxy-CPT, 11-methoxy-CPT, 10-hydroxy-CPT and 11-hydroxy-CPT.
As a rule, the starting material contains up to 1 wt.-% of one or more of these additional CPT
derivatives, particularly 0.2 to 0.8 wt.% of 9-methoxy-CPT.
The term "aqueous base" as used above and hereinafter in connection with step (a) of the purification process according to the invention relates to a base which generates enough hydroxide ions in the aqueous medium, preferably in pure water, to convert the lactone group of the camptothecine derivatives contained in the starting material completely into the corresponding hydroxycarboxylates. Metal hydroxides are preferred, particularly alkali metal or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide. Sodium hydroxide is most preferred 01-1188prio-Ko 4/11 CA 02435372 2003-07-18 The metal hydroxide is preferably used in the form of a dilute aqueous solution, preferably in the form of a 1 to 25 %, particularly a 3 to 10 % aqueous solution. As a rule, sufficient metal hydroxide is used to make the camptothecine derivatives go completely into solution;
preferably, 1 to 20 mol, more preferably 5 to 15 mol, particularly 7.5 to 12.5 mol of metal hydroxide are used per 1 mol of starting material.
In step (b) a transition metal catalyst, preferably a heterogeneous transition metal catalyst, particularly platinum, platinum oxide, nickel, palladium or rhodium on a carrier material such as activated charcoal or aluminium oxide is added to the resulting mixture.
Palladium on to activated charcoal containing 1 to 15 wt.%, preferably 2 to 10 wt.%, particularly about 5 wt.-% of palladium is particularly preferred.
The quantity of transition metal catalyst is selected so as to ensure total hydrogenation of the vinylic CPT derivative. Preferably, 0.01 to 0.50 parts by weight, particularly 0.02 to 0.10 1s parts by weight of transition metal catalyst (including carrier materials) are used, based on 1 part by weight of the starting material.
The resulting mixture is subjected to the action of hydrogen gas, preferably at a temperature of - 20 °C to 100 °C, particularly 10 °C to 40 °C, most preferably at about room temperature.
The hydrogen pressure is not critical per se; the hydrogenation is preferably carried out at normal pressure or at slightly raised pressure, particularly at 0.9 to 5.0 bar, most preferably at about 1 bar.
2s Under these conditions, hydrogenation is generally complete within 1 to 20 hours, preferably 4 to 15 hours, particularly 6 to 10 hours.
After the hydrogenatian has ended, the transition metal catalyst is preferably eliminated by filtration, and the resulting reaction mixture is acidified in step (c). The acidification can be 3o done with an inorganic or organic acid. Preferred acids are inorganic acids such as HCI, HBr, HI, HN03, H~POa, Ha50a, or aliphatic carboxylic acids such as acetic acid and trifluoroacetic acid or mixtures of these acids, particularly concentrated hydrochloric acid.
Using the chosen acid, the pH is adjusted to 3.0 to 6.0, preferably 3.5 to 5.0, particularly about 4.0 to 4.5. The 01-11 &8 prio -KO .S l1 ~ CA 02435372 2003-07-18 -$-reaction with the acid is generally carried out at a temperature of 0 °C to 100 °C, preferably 30 °C to 80 °C, particularly 50 °C to 60 °C.
In a particularly preferred embodiment, acidification is carried out with 2 to 20 parts by weight, preferably 4 to 9 parts by weight, particularly 6 to 8 parts by weight of concentrated hydrochloric acid, based on 1 part by weight of starting material.
Under the conditions described, lactonisation to form the CPT is generally complete within 10 to 180 minutes, preferably 1 S to 60 hours, particularly within about 30 minutes.
to The reaction mixture obtained by acidification is generally in the form of a pure suspension.
To improve the crystallisation in step (d) one or more polar aprotic solvents are added thereto.
Suitable solvents of this kind are preferably sulphoxides such as dimethylsulphoxide (DMSO) or amides and urea derivatives of formula R~C~N~Ra I!
is O
wherein R2 denotes hydrogen or a Cl-4 alkyl group, particularly hydrogen or methyl;
R3 and R4 independently of each other denote a Ci-a alkyl group, particularly methyl; or R2 and R3 together denote a -(CHZ)m- or a NRS-(CH2)n- group, while ! . 2o RS denotes a Cl-4 alkyl group;
m is 3 or 4, particularly 3; and nis2or3, particularly selected from among N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), N,N-dimethylethylene urea (DMEI~ and N,N-25 dimethylpropylene urea (DMPL~ or mixtures of these solvents, most preferably DMF.
As a rule, 10 to 100 parts by weight, preferably 20 to 80 parts by weight, particularly 30 to 50 parts by weight of the polar aprotic solvent are used, based on 1 part by weight of the starting material used.
DI-1188 prio-.Ko 6111 CA 02435372 2003-07-18 The treatment with the polar aprotic solvent may be carned out at any desired temperature.
The reaction mixture is preferably stirred at a temperature of 30 °C to 120 °C, particularly 80 to 100 °C and then slowly cooled to ambient temperature.
The CPT crystals thus obtained are easily separated from the liquid phase in step (e), preferably by decanting, centrifuging, spinning, squeezing out or filtration, particularly by filtration.
As a rule, the CPT crystals thus obtained are washed with an alcohol, preferably methanol, 1o ethanol or isopropanol, particularly methanol, and dried.
The advantage of the procedure according to the invention is the high space/time yield and the high yield and purity of the 20(S)-camptothecine produced, which is obtained without any chromatographic purification substantially free from contaminants containing vinyl groups.
The Examples that follow serve to illustrate some processes for purifying camptothecine carned out by way of example. They are intended only as possible methods given as examples, without restricting the invention to their content.
2o Example 1 10.45 g of a crude product containing camptothecine, obtained from Nothapodytes foetida, containing 1.33 % of 20-vinyl-CPT and 0.47 % of 9-methoxy-CPT, is taken up in 260 ml of a a 2 N sodium hydroxide solution and 0.6 g of palladiumlactivated charcoal (5 %) are added.
The mixture is treated with hydrogen for 8 hours at ambient temperature under a pressure of 1 bar.
Then the reaction mixture is filtered and combined at 50-60 °C with 80 ml of concentrated hydrochloric acid and adjusted to a pH of 4.0 to 4.5.
so The suspension formed is combined with 400 ml of DMF and stirred far 2.5 hours at 90-100°C. The resulting suspension is slowly cooled to ambient temperature and filtered. The CPT crystals obtained are washed with 100 ml of methanol and dried at 55°C in vacuo.
01-1188 prio-.KO 7/1l CA 02435372 2003-07-18 - _.
9.85 g (94.2 % of material put in) of 20(S)-camptothecine are obtained, containing less than 0.05 % of 20-vinyl-CPT and 0.11 % of 9-methoxy CPT.
Example 2 10.45 g of a crude product containing camptothecine, obtained from Nothapodytes foetida, containing 1.33 % of 20-vinyl-CPT and 0.47 % of 9-methoxy-CPT is taken up in 260 ml of a 2 N sodium hydroxide solution and 0.6 g of palladiumJactivated charcoal (5 %) are added.
The mixture is treated with hydrogen for 8 hours at ambient temperature under a pressure of 1 1 o bar.
Then the reaction mixture is filtered and combined at 50-60 °C with 300 ml of a 10%
sulphuric acid and adjusted to a pH of 4.0 to 4.5.
The suspension formed is combined with 500 ml of DMF and stirred for 2.5 hours at 90-100°C. The resulting suspension is slowly cooled to ambient temperature and filtered. The CPT crystals obtained are washed with 100 ml of methanol and dried at 55°C in vacuo.
9.67 g (92.6 % of material put in) of 20(S)-camptothecine are obtained, containing 0.09 % of 9-methoxy CPT, the content of 20-vinyl-CPT being below the detection threshold.
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, wherein 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, wherein 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 any one of claims 1 to 3, wherein the base in step (a) is sodium hydroxide.
5. Process for purifying 20(S)-camptothecine according to any one of claims 1 to 4, wherein 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 any one of claims 1 to 5, wherein 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 any one of claims 1 to 6, wherein 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)n- group;
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)n- group;
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, wherein 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 any one of claims 1 to 8, wherein 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 |
|---|---|---|---|
| DE10106969A DE10106969C1 (en) | 2001-02-15 | 2001-02-15 | Process for the purification and production of 20 (S) -camptothecin |
| DE10106969.3 | 2001-02-15 | ||
| PCT/EP2002/001375 WO2002064597A2 (en) | 2001-02-15 | 2002-02-09 | Method for purifying 20(s)-camptothecin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2435372A1 CA2435372A1 (en) | 2002-08-22 |
| CA2435372C true 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 |
| KR101600114B1 (en) * | 2008-05-29 | 2016-03-04 | 니혼 마이크로바이오팜 가부시키가이샤 | Production method for camptothecin derivative |
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 CZ CZ20032211A patent/CZ300671B6/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 MX MXPA03007194A patent/MXPA03007194A/en active IP Right Grant
- 2002-02-09 JP JP2002564528A patent/JP4467884B2/en not_active Expired - Lifetime
- 2002-02-09 SK SK1019-2003A patent/SK10192003A3/en unknown
- 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 CN CNB028049918A patent/CN1228340C/en not_active Expired - Fee Related
- 2002-02-09 AU AU2002244711A patent/AU2002244711B2/en not_active Ceased
- 2002-02-09 EE EEP200300389A patent/EE05131B1/en not_active IP Right Cessation
- 2002-02-09 CA CA2435372A patent/CA2435372C/en not_active Expired - Lifetime
- 2002-02-09 PL PL362128A patent/PL202135B1/en not_active IP Right Cessation
- 2002-02-09 EA EA200300837A patent/EA005618B1/en not_active IP Right Cessation
- 2002-02-09 KR KR1020037010605A patent/KR100813087B1/en not_active IP Right Cessation
- 2002-02-09 NZ NZ528039A patent/NZ528039A/en unknown
- 2002-02-09 ES ES02712902T patent/ES2246389T3/en not_active Expired - Lifetime
- 2002-02-09 RS YUP-614/03A patent/RS50496B/en unknown
- 2002-02-09 HU HU0303030A patent/HUP0303030A3/en unknown
- 2002-02-09 WO PCT/EP2002/001375 patent/WO2002064597A2/en active IP Right Grant
- 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
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100433436B1 (en) | Method for the Synthesis of a Benzimidazole Compound | |
| US6686482B2 (en) | Process for preparing piperonal | |
| CA2435372C (en) | Process for purifying 20(s)-camptothecine | |
| CN105061428B (en) | Method for refining tadalafil | |
| US6476225B2 (en) | Process for purifying 20(S)-camptothecin | |
| JP2008231062A (en) | Preparation method of mirtazapine | |
| US4150038A (en) | Conversion of hesperidin into hesperetin | |
| WO2006008302A2 (en) | Improved process for the manufacture of mirtazapine | |
| CA2509561A1 (en) | Synthesis of heteroaryl acetamides | |
| CN100475811C (en) | A process for the semisynthesis of deserpidine | |
| EP1253149B1 (en) | Sulfate salt of quinolonecarboxylic acid derivative and use thereof | |
| US4029647A (en) | Synthesis of biotin | |
| CN110734443A (en) | Preparation method of tadalafil-related substances I | |
| CN112142595A (en) | Preparation method and purification method of ethyl 2, 4, 5-trifluorobenzoylacetate | |
| CN113387959A (en) | Synthetic method of thieno [3,2-c ] pyridine-6-carboxylic acid methyl ester | |
| CN1403457A (en) | Prepn process of 2,6-dichloropurine | |
| WO2006046096A2 (en) | A polymorphic form of narwedine and its use in the synthesis of galantamine | |
| CN1120037A (en) | Process for the preparation of an indole drivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20220209 |