WO2008035377A2 - Novel intermediates for the preparation of camptothecin analogues - Google Patents

Novel intermediates for the preparation of camptothecin analogues Download PDF

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Publication number
WO2008035377A2
WO2008035377A2 PCT/IN2007/000381 IN2007000381W WO2008035377A2 WO 2008035377 A2 WO2008035377 A2 WO 2008035377A2 IN 2007000381 W IN2007000381 W IN 2007000381W WO 2008035377 A2 WO2008035377 A2 WO 2008035377A2
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salt
formula
compound
atleast
amount
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WO2008035377A3 (en
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B. Vishnukant
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Shilpa Medicare Ltd.
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    • 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
    • C07D491/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for the preparation of camptothecin analogues useful as anti-cancer drugs, in particular camptothecin analogue irinotecan and its salts thereof. More particularly, the invention relates to novel intermediate compound of formula (Ia) and its use in the process for the preparation of camptothecin analogues and its salts thereof.
  • Another object of the invention is to provide process for the preparation of compounds of formula (Ia)
  • Camptothecin analogues with out involving chromatography purification at any stage of the process more particularly for the preparation of Irinotecan and its salts thereof.
  • An objective of the invention is to provide an easy and economically viable process for the commercial scale preparation of Irinotecan and its pharmaceutically acceptable salts.
  • An embodiment of the invention provides intermediate compounds of formula (I a ),its salt and its use in the preparation of camptothecin analogues of formula (VII).
  • Step- I product (1Og) in dry pyridine (160ml).
  • 4-Dimethylamino pyridine (23.3g) followed by 4-piperidino piperidine carbomylchloride (25.3g) to it.
  • ethylacetate (200ml) .Separate layers, evaporate ethyl acetate layer to dryness.Dissolve the residue in chloroform 215ml), washed with 10% aqueous sodium bicarbonate solution (6x 215ml), followed by water (6x 215ml).
  • Step IV Preparation of Irinotecan Hydrochloride Trihydrate

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to novel intermediate compounds of formula (Ia) and its salts thereof, wherein R is an amino protecting group, R1 is selected from the group consisting of hydrogen, an alkyl, araalkyl, hydroxymethyl, carboxymethyl, acyloxymethyl, trialkylsilyl or an N-substituted alkyl amine where nitrogen forms the linking atom. The invention also relates to the use of these novel intermediate compounds of formula (Ia) for the preparation of camptothecin analogues and its salts, more particularly the anti-cancer drug irinotecan and its pharmaceutically accepted salts.

Description

NOVEL INTERMEDIATES FOR THE PREPARATION OF CAMPTOTHECIN ANALOGUES
Field of the invention ;
The present invention relates to a process for the preparation of camptothecin analogues useful as anti-cancer drugs, in particular camptothecin analogue irinotecan and its salts thereof. More particularly, the invention relates to novel intermediate compound of formula (Ia) and its use in the process for the preparation of camptothecin analogues and its salts thereof.
Background of the invention ;
US Patent No. 6,121,451 reveals a process for preparing antineoplastic drug 7-ethyl-10- hydroxy camptothecin 10-[l,4'-carboxylate] or CPT-I l (V) free base. In the described process a compound therein identified as 14CPT (I) is first reacted with compound of formula (II) to form an intermediate of formula (III), which is further reacted with 4-piperidino piperidine carbomyl chloride of formula (IV) to produce CPT-I l free base (V) as shown below.
Figure imgf000002_0001
(III)
Figure imgf000002_0002
(IV)
Figure imgf000002_0003
(V) WO 03/089413 reveals the novel compound of formula (VI).
Figure imgf000003_0001
Formula (Vl) and its use in the preparation of camptothecin analogues and particularly irinotecan free base and its pharmaceutically acceptable salts.
Alternative materials and methods for preparing irinotecan and camptothecin analogues are described in the prior art. The prior art processes reported for the preparation of Irinotecan and its salts involves chromatographic purification step at one or the other stage of the process. However, in the process of present invention for the preparation of Irinotecan and its salt the tedious step of chromatographic purification has been totally eliminated. Thus the process of present invention is economical and easily viable for the commercial scale preparation of the anticancer drug. This provides an added advantage to the process of present invention over the prior art processes.
Objects of the invention:
An object of the invention is to provide novel intermediate compounds of formula (Ia)
Another object of the invention is to provide process for the preparation of compounds of formula (Ia)
Yet another object of the invention is to use novel intermediate compounds of formula (Ia) for the preparation of Camptothecin analogues and its salts thereof.
Still another object of the invention is to > provide a process using novel intermediate compound of formula (Ia, Ri= C2Hs) for the preparation of anti cancer drug Irinotecan and its pharmaceutically acceptable salts thereof.
Still yet another object of the invention is to provide a process for the preparation of
Camptothecin analogues with out involving chromatography purification at any stage of the process, more particularly for the preparation of Irinotecan and its salts thereof.
An objective of the invention is to provide an easy and economically viable process for the commercial scale preparation of Irinotecan and its pharmaceutically acceptable salts. Summary of the invention :
The present invention provides novel intermediate compounds of formula (Ia) and its salts thereof.
Figure imgf000004_0001
Formula (Ia)
Wherein R is amino protecting group defined as -CO (CH2) n CH3 (n= 0 to4); -CO (CH2) n CH2 X (X= Halogen; n= 0 to 4); -COCX3 (X= Halogen ) and R1 is hydrogen, alkyl, araalkyl, hydroxy methyl, carboxymethyl ,acyloxy methyl silyl or N-substituted alkyl amine -CH2-N-R2 where N is a linking nitrogen atom, wherein R2 and R3 substituents on the N-atom mBp be defined as follows. i) 15 R2 and R3 are each independently selected from hydrogen, alkyl, alkenyl, hydroxyalkyl, acyloxyalkyl or acycloxy alkyl substituted group. ϋ) R2 and R3 together with the nitrogen linking atom can form heterocyclic unit The novel intermediate compounds of the invention are useful in the preparation of anticancer camptothecin analogues and in particular irinotecan and their pharmaceutically
20 acceptable salts thereof.
The compounds of the invention are useful in the preparation of camptothecin analogues of formula (VII)
Figure imgf000004_0002
Wherein Ri is as defined above. Detailed description of the Invention:
An embodiment of the invention provides intermediate compounds of formula (Ia),its salt and its use in the preparation of camptothecin analogues of formula (VII).
Figure imgf000005_0001
In a preferred embodiment R] is an ethyl group. Accordingly this embodiment provides a novel intermediate compound of formula(Iaj Ri= C2H5) which is useful in the preparation of Irinotecan ( formula VII, Ri = C2H5) and its salts thereof.
In an another embodiment of the invention provides a process comprising step of contacting compounds of (formula Ia) with the compound of formula (I) above to yield Camptothecin analogues.
In yet another embodiment of the invention provides a process for the preparation of compound of formula (Ia). Wherein Rj is an ethyl group i.e. 4-amino protected-3-propionyl phenyl- l,4'-bipiperidine-l'-carboxylate comprising a step of contacting compound of formula (Ha) with 4-piperidino piperidine carbamyl chloride of formula (IV) or its hydrochloride salt under suitable reaction condition. A person skilled in the art by appropriate modifications of compound of formula (Ha) may derive other compounds of formula (Ia). The present invention provides compounds of formula (Ia), wherein R, Ri, R2 and R3 are as defined above. Also, provided in the present invention salts of formula (Ia). The compounds of formula (Ia) can exist as free base and also as their salts. The salts are acid addition salt prepared by contacting free base of compound of formula(Ia) with an acid selected from the group consisting of hydrochloric, hydrobromic, benzoic, tartaric, citric, fumaric, maleic and alkyl monocarboxylic and alkyl dicarboxylic acid having Ci -C4 alkyl chain
In a typical example compound of formula (Ia) wherein R is an amino protecting group, R] being ethyl or its salt thereof is contacted with 14CPT (I) to yield Irinotecan base, which is subsequently converted into its salt by adopting conventional methods. The reaction can be carried out by heating a mixture of compound of formula (Ia) and 14CPT (I) in a suitable solvent (s), for example an acid or mixture of protic solvent and / or acid. In an embodiment of the invention, the drug substance Irinotecan may comprise of most preferably not more than 0.1% compound of formula (Ia), which provides an evidence for the preparation of irinotecan by a) process involving compound of formula (Ia) as reactant, or b) a process involving compounds (Ha) and (IV) as reactants under suitable reaction conditions enabling these compounds to react to form compound of formula (Ia).
A drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof and a compound of formula (Ia) and /or its atleast one salt thereof in a detectable amount.
The drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof and a compound of formula (I3) and /or its atleast one salt thereof is present in an amount not more than 1%. The drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof and a compound of formula (I3) and /or its atleast one salt thereof is present in an amount not more than 0.5%.
The drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof and a compound of formula (I3) and /or its atleast one salt- thereof is present in an amount not more than 0.1%.
A drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof and 7-ethyl-lO-hydroxy-camptothecin and /or its atleast one salt thereof in a detectable amount.
The drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof and 7-ethyl-lO-hydroxy-camptothecin and /or its atleast one salt thereof is present in an amount, not more than 1 %.
The drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof, and 7-ethyl-lO-hydroxy-camptothecin and /or its atleast one salt thereof is present in an amount, not more than 0.5%. The drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof and 7-ethyl-lO-hydroxy-camptothecin and /or its atleast one salt thereof is present in an amount, not more than 0.1%.
A drug substance comprising therapeutically effective amount of irinotecan and /or its salt thereof and a compound of formula (Ia) and /or its atleast one salt thereof and 7-ethyl-10- hydroxy-camptothecin and /or its atleast one salt thereof each present in an amount not more than l%.
A drug substance comprising therapeutically effective amount of irinotecan and /or its salt thereof a compound of formula (Ia and /or its atleast one salt thereof and 7-ethyl-10- hydroxy-camptothecin and /or its atleast one salt thereof each present in an amount not more than 0.5%.
A drug substance comprising therapeutically effective amount of irinotecan and /or its salt thereof and a compound of formula (Ia) and /or its atleast one salt thereof and 7-ethyl- 10- hydroxy-camptothecin and /or its atleast one salt thereof each present in an amount not more than 0.1%. '
The schematic representation of the process of present invention is depicted herein below:
Figure imgf000007_0001
The invention is illustrated with the following examples and should not be construed to limit the scope of the present invention. The features of the present invention will become more apparent from the following description of the inventive concept and the description of the preferred embodiments and appended claims
Example I
Step I: Preparation of2~Acetimido-5-hydroxy-propiophenone(Ia;R=: C0CH3, R1=C2H5)
Charge acetic anhydride (30ml) into a reactor, add 2- Amino-5 -hydroxy - propiophenone[AHP](10g) to it. The mixture is heated to 130°C and maintained at this temperature for 2-3 hr. Monitor the reaction mixture by HPLC for the disappearance of AHP. Work up the reaction mixture by pouring on to crushed ice water (300ml) with stiring and continued stiring between 0°-5°C for at least an hour. Filter the precipitated solid, wash with water (100ml) to yield step - 1 product (1 Ig); HPLC purity not less than 99.00%. Step II: Preparation of ^acetimidoS-propionylphenyl-l^'-bipiperidine-l'-carboxylate (Ia; R=-C0CH3 and R1=C2 H5)
Dissolve Step- I product (1Og) in dry pyridine (160ml). Add 4-Dimethylamino pyridine (23.3g), followed by 4-piperidino piperidine carbomylchloride (25.3g) to it. Stirred the mixture at room temperature for 48h-60h. Monitor the reaction mixture by HPLC. Work up the reaction mixture when step- 1 product is NMT 3.0% by adding water (60ml).Extract with ethylacetate (200ml) .Separate layers, evaporate ethyl acetate layer to dryness.Dissolve the residue in chloroform 215ml), washed with 10% aqueous sodium bicarbonate solution (6x 215ml), followed by water (6x 215ml). Dry the washed chloroform over anhydrous sodium sulphate, filterand evaporate to dryness to yield step- II product (11.5g), HPLC purity not less than 95.00%. Step III: Preparation of Irinotecan base ( VII, Ri = C2H5)
Dissolve Step- II product(11.5) in ethyl alcohol (115ml) ,added con. HCl (25.4ml) , glacial acetic acid (115ml), 14CPT (10.62g) and heat the mixture to 1 10°- 1 15°C for a period of 24 hrs. Evaporate the reaction mixture to dryness, add water (345ml) and stir for 10-15 mih and filter the aqueous solution through celite bed. The filtered aqueous solution is extracted with chloroform (4x85ml). Separated organic and aqueous layer. Aqueous layer is evaporated to dryness under vacuum. Add ethyl alcohol (80ml) to dissolve the residue, add activated charcoal (1.15g) and heat to 70°C with string for an hour. Filter the hot solution and cool to room temperature with stirring and then to 00C for an overnight. The precipitated pale yellow solid is filtered to obtain is step- III product(10.4g) having HPLC purity of not less than
98.00%.
Step IV: Preparation oflrinotecan Hydrochloride Trihydrate
Take Step- III (10.4g) product in DM H2O (93.6ml) and add cone. HCl (19.80ml). Heat the mixture to 60°when a pale yellow solution is obtained. Add activated charcoal (1.04g) and continue to maintain the mixture at this temperature for further 30 min and filter. Cool the filtered solution to room temperature and then to 0°C with stirring for an overnight. Filter the separated solid, dry the solid under high vacuum to yield irinotecan hydrochloride trihydrate (6.13g); HPLC purity 99.65%
Example II
Step I: Preparation of 2-propionimido-5-hvdroxy-propiophenone(Ia;R= COCH2 CHj,
RrC2H5)
Charge chloroacetic anhydride (27ml) into a reactor, add 2- Amino-5-hydroxy - propiophenone[AΗP](9g) to it. The mixture is heated to 130°C and maintained at this temperature for 2-3 hr. Monitor the reaction mixture by HPLC for the disappearance of AHP. Work up the reaction mixture by pouring on to crushed ice water (270ml) with stiring and continued stiring between 0°-5°C for at least an hour. Filter the precipitated solid, wash with water (100ml), dried and crystallised to yield step - I product (13.5g); HPLC purity not less than 98.00%.
Step II: Preparation of 4- propionimido -3-propionylphenyl-l,4'-bipiperiditie-l'- carboxylate (Ia; R= COCH2 CH3and R1=C2 H5
Dissolve Step- 1 product (12g) in dry pyridine (192ml). Add 4-Dimethylamino pyridine (24), followed by 4rpiperidino piperidine carbomylchloride (26.4g) to it. Stirred the mixture at room temperature for 48h-60h. Monitor the reaction mixture by ΗPLC. Work up the reaction mixture when step- 1 product is NMT 3.0% by adding water (72ml). Extract with ethylacetate (240ml) .Separate layers, evaporate ethyl acetate layer to dryness. Dissolve the residue in chloroform 260ml), washed with 10% aqueous sodium bicarbonate solution (6x 260ml), followed by water (6x 260ml).Dry the washed chloroform over anhydrous sodium sulphate, filterand evaporate to dryness to yield step- II product (11.5g), ΗPLC purity not less than 94.00%.
Step III: Preparation of Irinotecan base ( VII, Rj = C2Hs)
Dissolve Step- II product(11.5) in ethyl alcohol (115ml) ,added con. HCl (25.4ml) , glacial acetic acid (115ml), 14CPT (10.62g) and heat the mixture to 1 10°- 1 15°C for a period of 24 hrs» Evaporate the reaction mixture to dryness, add water (345ml) and stir for 10-15 min and filter the aqueous solution through celite bed. The filtered aqueous solution is extracted with chloroform (4x85ml). Separated organic and aqueous layer. Aqueous layer is evaporated to dryness under vacuum. Add ethyl alcohol (80ml) to dissolve the residue, add activated charcoal (1.15g) and heat to 7O0C with string for an hour. Filter the hot solution and cool to room temperature with stirring and then to 0°C for an overnight. The precipitated pale yellow solid is filtered to obtain is step- III product(10.0 g) having HPLC purity of not less than 98.00%. Step IV: Preparation oflrinotecan Hydrochloride Trihydrate: Take Step- III (10.Og) product in DM H2O (90.0ml) and add cone. HCl (19.00ml). Heat the mixture to 60°when a pale yellow solution is obtained. Add activated charcoal (1.0Og) and continue to maintain the mixture at this temperature for further 30 min and filter.Cool the filtered solution to room temperature and then to 00C with stirring for an overnight. Filter the separated solid, dry the solid under high vacuum to yield irinotecan hydrochloride trihydrate (5.9g); HPLC purity 99.60%
Example HI
Step I: Preparation of 2-chloroacetimido-5-hvdroxy-propiopfιenone(Ia:R= COCH2CI ,
R1=C2H5 Charge chloro acetic anhydride (30ml) into a reactor, add 2- Amino-5-hydroxy - propiophenone [AHP](I Og) to it. The mixture is heated to 130°C and maintained at this temperature for 2-3 hr. Monitor the reaction mixture by HPLC for the disappearance of AHP. Work up the reaction mixture by pouring on to crushed ice water (300ml) with stiring and continued stiring between 0°-5°C for at least an hour. Filter the precipitated solid, wash with water (100ml), dried and crystallised to yield step - I product (Hg); HPLC purity not less than 98.50%.
Step II: Preparation of 4-chloroacetimido-3-propionylphenyl-l,4'-bipiperidine-l'~ carboxylate (Ia; R=-COCH2Cl and R1=C2 H5) Step- I product (1Og) in dry pyridine (160ml). Add 4-Dimethylamino pyridine (18.3g), followed by 4-piperidino piperidine carbomylchloride (20.Og) to it. Stirred the mixture at room temperature for 48h-60h. Monitor the reaction mixture by HPLC. Work up the reaction mixture when step- 1 product is NMT 3.0% by adding water (60ml). Extract with ethylacetate (200ml) .Separate layers, evaporate ethyl acetate layer to dryness. Dissolve the residue in chloroform 215ml), washed with 10% aqueous sodium bicarbonate solution (6x 215ml), followed by water (6x 215ml).Dry the washed chloroform over anhydrous sodium sulphate, filterand evaporate to dryness to yield step- II product (11. Og), HPLC purity not less than
95.00%.
Step III: Preparation of Irinotecan base ( VII, R] = C2H5) Dissolve Step- II product(l l.O) in ethyl alcohol (110ml) ,added con. HCl (24.2ml) , glacial acetic acid (110ml), 14CPT (10.Og) and heat the mixture to 110°- 115°C for a period of 24 hrs. Evaporate the reaction mixture to dryness, add water (345ml) and stir for 10-15 min and filter the aqueous solution through celite bed. The filtered aqueous solution is extracted with chloroform (4x85ml). Separated organic and aqueous layer. Aqueous layer is evaporated to dryness under vacuum. Add ethyl alcohol (80ml) to dissolve the residue, add activated charcoal (1.15g) and heat to 700C with string for an hour. Filter the hot solution and cool to room temperature with stirring and then to 00C for an overnight. The precipitated pale yellow solid is filtered to obtain is step- III product(lθ.θg) having HPLC purity of not less than 98.00%. Step IV: Preparation of Irinotecan Hydrochloride Trihydrate
Take Step- III (10.0 g) product in DM H2O (90.0ml) and add cone. HCl (19. OmI). Heat the mixture to 60°when a pale yellow solution is obtained. Add activated charcoal (1.04g) and continue to maintain the mixture at this temperature for further 30 min and filter.Cool the filtered solution to room temperature and then to 00C with stirring for an overnight. Filter the separated solid, dry the solid under high vacuum to yield irinotecan hydrochloride trihydrate (6.03g); HPLC purity 99.62%

Claims

We* Claim:
1. A compound of formula (Ia) and its salts thereof.
Figure imgf000012_0001
Formula (Ia) R5
Wherein R is amino protecting group defined as -CO (CH2) n CH3 (n= 0 to4); -CO (CH2) n
CH2 X (X= Halogen; n= 0 to 4); -COCX3 (X= Halogen) and Ri is hydrogen, alkyl, araaikyl, hydroxy methyl, carboxymethyl, acyloxy methyl silyl or N-substituted alkyl amine -CH2-N-
R2 where N is a linking nitrogen atom, wherein R2 and R3 substituents on the N-atom may be defined as follows. i)R2 and R3 are each independently selected from hydrogen, alkyl, alkemyl, hydroxyalkyl, acyloxyalkyl or acycloxy alkyl substituted group.
U)R2 and R3 together with the nitrogen linking atom can form heterocyclic unit
2. A compound of claim 1, wherein Ri is an ethyl group.
3. A compound of claim 1 that is an acid addition salt of compound of formula(Ia) with an acid selected from hydrochloric, hydrobromic,benzoic, tartaric, citric, fumaric, maleic ,alkyl monocarboxylic acid and alkyl dicarboxylic acid having C1-C4 alkyl chain.
4. A process for the preparation of camptothecin analogues or its salts thereof, the said process comprising first step of contacting compound of formula (Ia)
with compound
Figure imgf000012_0002
(I) and a second step of preparing a salt of camptothecin analogues thus obtained.
5. A process of claim 4 , wherein irinotecan or its salt thereof is prepared by contacting compound of formula (Ia ,R1=C2H5) or its salt thereof with compound of formula (I).
6. A process for preparing compounds of formula(Ia) comprising step of contacting compound of of formula (Ha) with 4-piperidinopiperidine carbamyl chloride (IV).
7. A drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof and compound of formula(Ia ) and /or its atleast one salt thereof in a detectable amount.
8. The drug substance of claim 7, wherein compound of formula(Ia ) and /or its atleast one salt thereof present in an amount not more than about 1%.
9. The drug substance of claim 1, wherein compound of formula(Ia ) and /or its atleast one salt thereof present in an amount not more than about 0.5%.
10. The drug substance of claim 7, wherein compound of formula(Ia ) and /or its atleast one salt thereof present in an amount not more than about 0.1%.
11. A drug substance comprising therapeutically effective amount of irinotecan and/ or its salt thereof and 7- ethyl- 1 O-hydroxy-camptothecin and /or its atleast one salt thereof in a detectable amount.
12. The drug substance of claim 11, wherein 7-ethyl-l O-hydroxy-camptothecin and /or its atleast one salt thereof present in an amount, not more than about 1%.
13'. The drug substance of claim 11, wherein 7-ethyl-l O-hydroxy-camptothecin and /or its atleast one salt thereof present in an amount, not more than about 0.5%.
14. The drug substance of claim 11, wherein 7-ethyl-l O-hydroxy-camptothecin and /or its atleast one salt thereof present in an amount, not more than about 0.1%.
15. A drug substance comprising therapeutically effective amount of irinotecan and/or its salt thereof and compound of formula(Ia) and /or its atleast one salt thereof and 7-ethyl-10- hydroxy-camptothecin and /or its atleast one salt thereof each present in a detectable amount.
16. The drug substance of claim 15, wherein compound of formula(Ia) and /or its atleast one salt thereof and 7-ethyl-l O-hydroxy-camptothecin and /or its atleast one salt thereof each present in an amount not more thanl%.
17 . The drug substance of claim 15, wherein compound of formula(Ia) and /or its atleast one salt thereof and 7-ethyl-l O-hydroxy-camptothecin and /or its atleast one salt thereof each present in an amount not more than 0.5%.
18.*The drug substance of claim 15 wherein compound of formula(Ia )and /or its atleast one salt alt thereof and 7-ethyl-lO-hydroxy-camptothecin and /or its atleast one salt thereof each present in an amount not more than 0.1 %.
19. Compounds of claiml , process for preparation and its use in the process of preparation of camptothecin analogues as herein substantially described with refernce to the detailed description and examples.
PCT/IN2007/000381 2006-09-18 2007-08-31 Novel intermediates for the preparation of camptothecin analogues WO2008035377A2 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2399919A1 (en) * 2009-11-18 2011-12-28 Cadila Healthcare Limited (S)-4,11-diethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano [3',4':6,7] indolizino [1.2-b]quinoline-4,9-diyl bis([1,4'-bipiperidine]-carboxylate and its use
CN102643283A (en) * 2012-05-08 2012-08-22 江苏红豆杉生物科技有限公司 Method for preparing irinotecan hydrochloride trihydrate pure product
EP2881396A1 (en) * 2013-12-03 2015-06-10 Synbias Pharma AG Method for the synthesis of irinotecan
CN104955830A (en) * 2012-11-13 2015-09-30 比奥纽默里克药物公司 Methods for the total chemical synthesis of enantiomerically-pure 7-(2'-trimethylsilyl) ethyl camptothecin

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EP2881396A1 (en) * 2013-12-03 2015-06-10 Synbias Pharma AG Method for the synthesis of irinotecan
WO2015082240A1 (en) * 2013-12-03 2015-06-11 Synbias Pharma Ag Method for the synthesis of irinotecan
AU2014359552B2 (en) * 2013-12-03 2017-03-30 Synbias Pharma Ag Method for the synthesis of irinotecan
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