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WO2013008091A1 - Manufacturing of epothilone derivatives and the use thereof - Google Patents

Manufacturing of epothilone derivatives and the use thereof Download PDF

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Publication number
WO2013008091A1
WO2013008091A1 PCT/IB2012/001379 IB2012001379W WO2013008091A1 WO 2013008091 A1 WO2013008091 A1 WO 2013008091A1 IB 2012001379 W IB2012001379 W IB 2012001379W WO 2013008091 A1 WO2013008091 A1 WO 2013008091A1
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WIPO (PCT)
Prior art keywords
compound
ixabepilone
formula
absent
acyl
Prior art date
Application number
PCT/IB2012/001379
Other languages
French (fr)
Inventor
Audun Heggelund
Vidar BJØRNSTAD
Original Assignee
Xellia Pharmaceuticals Aps
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Xellia Pharmaceuticals Aps filed Critical Xellia Pharmaceuticals Aps
Publication of WO2013008091A1 publication Critical patent/WO2013008091A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a process for the preparation of Ixabepilone and also to novel intermediates useful in the process according to the present invention.
  • Ixabepilone is an anti cancer agent acting as a microtubule inhibitor, and which in particular are efficient in the treatment of cancer not reacting to other anti cancer agents, such as e.g. paclitaxel.
  • Ixabepilone is marketed under the trade name Ixempra® and are approved for the treatment of aggressive metastatic or locally advanced breast cancer which not responding to the current prevailing chemotherapies.
  • Ixabepilone known under the CAS no. 219989-84-1 has the following structure:
  • Ixabepilone may be prepared from a starting material named epothilone B having the structural formula:
  • Epothilone B Ixabepilone as a compound is described in the USRE4191 1.
  • USRE4191 1 furthermore disclose a process for synthesizing Ixabepilone.
  • the US 6,365,749 describes a process for making ixabepilone by reacting epothilone B with a palladium catalyst in the presence of a nucleophilic donor.
  • the USRE39356 do also describe a process for making Ixabepilone by reacting epothilone B with an azide donor agent and a reducing agent in the presence of a phase transfer catalyst and a palladium catalyst.
  • R 3 is H
  • X is O or N
  • Ri or R 2 is either absent or independently H, alkyl or acyl; and provided that when X is O, then Ri is absent.
  • the compound of formula I is useful in the preparation of Ixabepilone.
  • a compound of formula I wherein alkyl is C 1 -C8 alkyl and acyl is C1 -C8 acyl.
  • a compound of formula I is provided, wherein X is O.
  • a compound of formula I is provided, wherein R ⁇ is absent and R 2 is H. According yet another embodiment of the present invention, a compound of formula I is provided, wherein X is N. According yet another embodiment of the present invention, a compound of formula I is provided, wherein X is N and Ri is H.
  • a compound of formula I wherein X is N and R 2 is selected from the group consisting of H and Ac.
  • the present invention provides a process for preparing a compound of Formula I according to claim 1 , comprising the step of reacting epothilone B with a nucleophile of the structure H N-XRtRi wherein
  • X is O or N
  • Ri or R 2 is either absent or independently H, alkyl or acyl, provided that when X is
  • Ixabepilone may be prepared as is illustrated in Scheme 1.
  • the compound H 2 N-XR ! R 2 used according to the present invention includes nitrogen nucleophiles wherein X denotes a heteroatom such as O or N.
  • the heteroatom X carries one or two entities Rj and R 2 according to its preferred valency.
  • R 2 may be either absent, or independently H, or an alkyl or acyl group e.g. straight or branched alkyl or straight or branched acyl, wherein said alkyl or acyl may be substituted or un-substituted.
  • alkyl or acyl may be C 1-C8 alkyl oi C 1.C8 acyl, respectively.
  • Cl- C8 alkyl are meant to embrace methyl, ethyl, propyl, isopropyl, butyl and isobutyl etc.. It is furthermore to be understood that C 1-C8 acyl are meant to embrace formyl, acetyl, propionyl, butyryl etc.
  • R ⁇ is absent, while R 2 may be any of the mentioned entities.
  • the nitrogen nucleophile is an optionally substituted hydroxylamine.
  • X is N
  • the nitrogen nucleophile is an optionally substituted hydrazine.
  • the starting material epothilone B (1) is treated with the nitrogen nucleophile H 2 N- XRiR 2 in the presence of a palladium catalyst.
  • the substrate suffers ring-opening and formation of the structure 2 as an intermediate.
  • Activation of the carboxylic acid group with a suitable activation system affords the activated compound 3.
  • Act in Scheme 1 refers to any group that activates the carboxylic acid group for attack from a nucleophile.
  • EDC stands for N-(3-dimethylaminopropyl)- V'- ethylcarbodiimide hydrochloride and HOBt stands for 1 -hydro xybenzotriazole hydrate.
  • Ring closing provides the intermediate structure 4, while reductive cleavage of the N-X bond releases the target Ixabepilone (5).
  • Ixabepilone may be prepared according to Scheme 2.
  • Epothilone B (1) is treated with O-benzylhydroxylamine with formation of the ring-opened intermediate 6 (Bn in 6 meaning benzyl).
  • Activation of the carboxylic acid with the EDC/HOBt system affords the compound 7 which is transformed to compound 8 in an intramolecular reaction between the nitrogen nucleophile and the activated carboxylic acid.
  • Compound 8 is treated with powdered Zn in acetic acid, resulting in cleavage of the N-0 bond and formation of Ixabepilone (5).
  • nitrogen nucleophiles that may be used according to the present invention are the free forms of hydroxylamine and hydrazine, and various derivatives of the mentioned compounds such as e.g. O-alkylhydroxylamines and N- alkylhydrazines, and acylated hydrazines, e.g. acethydrazide (CH 3 CONH-NH 2 ).
  • hydroxylamine as a nucleophile in the preparation of Ixabepilone according to the invention is outlined in Scheme 3.
  • Epothilorie B (1) is treated with hydroxylamine with formation of the ring-opened intermediate 12.
  • Activation of the carboxylic acid with the EDC/HOBt system affords the compound 13 which is transformed to compound 14 in an intramolecular reaction between the nitrogen nucleophile and the activated carboxylic acid.
  • Compound 14 is treated with powdered Zn in acetic acid, resulting in cleavage of the N-0 bond and formation of Ixabepilone (5).
  • Nucleophile is NH2NH2
  • Epothilone B 25 mg
  • Catalyst (0.01 eq.)
  • Ligand 0.02eq.
  • NH 2 -NH 2 .H 2 0 1.5 eq.
  • the reaction mixture was diluted by 25 ml DMC and washed with water followed by brine solution.
  • the crude compound was dried over sodium sulphate and concentrated under vacuum.
  • the compound was purified by silica gel column chromatography using 5% MeOH:DCM as a solvent.
  • Nucleophile NH 2 NHAc 25 mg of Epothilone B, 0.1 eq of allyl palladium chloride dimer, 0.1 eq of xantphos and 1,5 eq of NH 2 -NHAc was added to a 25 ml round bottom flask under nitrogen atmosphere. 2 ml of degassed DCM was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours under nitrogen atmosphere. Complete conversion was observed by TLC. Reaction mixture was diluted with 25 ml DMC and washed with water followed by brine solution. Then further dried over sodium sulphate and concentrated under vacuum.
  • Nucleophile is NH 2 NH 2 ,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to novel intermediates of Formula (I), wherein R3 is H, X is O or N, R1 or R2 is either absent or independently H, alkyl or acyl, and provided that when X is O, then R1 is absent and the process for the preparation of ixabepilone utilizing said intermediates.

Description

Manufacturing of epothilone derivatives and the use thereof. Field of invention
The present invention relates to a process for the preparation of Ixabepilone and also to novel intermediates useful in the process according to the present invention.
Background
Ixabepilone is an anti cancer agent acting as a microtubule inhibitor, and which in particular are efficient in the treatment of cancer not reacting to other anti cancer agents, such as e.g. paclitaxel. Ixabepilone is marketed under the trade name Ixempra® and are approved for the treatment of aggressive metastatic or locally advanced breast cancer which not responding to the current prevailing chemotherapies.
Ixabepilone known under the CAS no. 219989-84-1 has the following structure:
Figure imgf000002_0001
Ixabepilone
Ixabepilone may be prepared from a starting material named epothilone B having the structural formula:
Figure imgf000002_0002
Epothilone B Ixabepilone as a compound is described in the USRE4191 1. USRE4191 1 furthermore disclose a process for synthesizing Ixabepilone.
The US 6,365,749 describes a process for making ixabepilone by reacting epothilone B with a palladium catalyst in the presence of a nucleophilic donor.
The USRE39356 do also describe a process for making Ixabepilone by reacting epothilone B with an azide donor agent and a reducing agent in the presence of a phase transfer catalyst and a palladium catalyst.
Summary of the invention
According to one embodiment of the present invention, a compound of formula I is provided
Figure imgf000003_0001
Formula I
wherein R3 is H ;
X is O or N,
Ri or R2 is either absent or independently H, alkyl or acyl; and provided that when X is O, then Ri is absent.
The compound of formula I is useful in the preparation of Ixabepilone.
According to another embodiment, a compound of formula I is provided, wherein alkyl is C 1 -C8 alkyl and acyl is C1 -C8 acyl.
According yet another embodiment of the present invention, a compound of formula I is provided, wherein X is O.
According yet another embodiment of the present invention, a compound of formula I is provided, wherein R\ is absent and R2 is H. According yet another embodiment of the present invention, a compound of formula I is provided, wherein X is N. According yet another embodiment of the present invention, a compound of formula I is provided, wherein X is N and Ri is H.
According yet another embodiment of the present invention, a compound of formula I is provided, wherein X is N and R2 is selected from the group consisting of H and Ac.
According to another embodiment of the present invention, a compound represented by the formula
Figure imgf000004_0001
According to yet another embodiment of the present invention, a compound represented by the formula
Figure imgf000004_0002
According to another embodiment of the present invention, a compound represented by the formula
Figure imgf000005_0001
Finally, the present invention provides a process for preparing a compound of Formula I according to claim 1 , comprising the step of reacting epothilone B with a nucleophile of the structure H N-XRtRi wherein
X is O or N,
Ri or R2 is either absent or independently H, alkyl or acyl, provided that when X is
O, then R[ is absent,
in the presence of a palladium catalyst.
The present compounds and process of the invention are further illustrated by the following detailed description of the present invention.
Using the compound of the present invention, Ixabepilone may be prepared as is illustrated in Scheme 1.
Figure imgf000006_0001
Activation
of acid
Figure imgf000006_0002
Reduction
Figure imgf000006_0003
Ixabepilone
Scheme 1
The compound H2N-XR!R2 used according to the present invention includes nitrogen nucleophiles wherein X denotes a heteroatom such as O or N. The heteroatom X carries one or two entities Rj and R2 according to its preferred valency.
Figure imgf000006_0004
or R2 may be either absent, or independently H, or an alkyl or acyl group e.g. straight or branched alkyl or straight or branched acyl, wherein said alkyl or acyl may be substituted or un-substituted. According to one embodiment, alkyl or acyl may be C 1-C8 alkyl oi C 1.C8 acyl, respectively. It is to be understood that Cl- C8 alkyl are meant to embrace methyl, ethyl, propyl, isopropyl, butyl and isobutyl etc.. It is furthermore to be understood that C 1-C8 acyl are meant to embrace formyl, acetyl, propionyl, butyryl etc. If X is O, then R\ is absent, while R2 may be any of the mentioned entities. In the case X is O, the nitrogen nucleophile is an optionally substituted hydroxylamine. In the case X is N, the nitrogen nucleophile is an optionally substituted hydrazine.
The starting material epothilone B (1) is treated with the nitrogen nucleophile H2N- XRiR2 in the presence of a palladium catalyst. The substrate suffers ring-opening and formation of the structure 2 as an intermediate. Activation of the carboxylic acid group with a suitable activation system affords the activated compound 3. The term "Act" in Scheme 1 refers to any group that activates the carboxylic acid group for attack from a nucleophile. One example of a suitable activation system is the EDC/HOBt system where EDC stands for N-(3-dimethylaminopropyl)- V'- ethylcarbodiimide hydrochloride and HOBt stands for 1 -hydro xybenzotriazole hydrate. Ring closing provides the intermediate structure 4, while reductive cleavage of the N-X bond releases the target Ixabepilone (5).
Figure imgf000008_0001
6
EDC/HOBt
Figure imgf000008_0002
Zn/AcOH
Figure imgf000008_0003
Ixabepi!one
Scheme 2
According to one aspect of the present invention, Ixabepilone may be prepared according to Scheme 2. Epothilone B (1) is treated with O-benzylhydroxylamine with formation of the ring-opened intermediate 6 (Bn in 6 meaning benzyl). Activation of the carboxylic acid with the EDC/HOBt system affords the compound 7 which is transformed to compound 8 in an intramolecular reaction between the nitrogen nucleophile and the activated carboxylic acid. Compound 8 is treated with powdered Zn in acetic acid, resulting in cleavage of the N-0 bond and formation of Ixabepilone (5). Other examples of nitrogen nucleophiles that may be used according to the present invention are the free forms of hydroxylamine and hydrazine, and various derivatives of the mentioned compounds such as e.g. O-alkylhydroxylamines and N- alkylhydrazines, and acylated hydrazines, e.g. acethydrazide (CH3CONH-NH2).
Figure imgf000009_0001
habepilone
5
14
Scheme 3
The use of hydroxylamine as a nucleophile in the preparation of Ixabepilone according to the invention is outlined in Scheme 3. Epothilorie B (1) is treated with hydroxylamine with formation of the ring-opened intermediate 12. Activation of the carboxylic acid with the EDC/HOBt system affords the compound 13 which is transformed to compound 14 in an intramolecular reaction between the nitrogen nucleophile and the activated carboxylic acid. Compound 14 is treated with powdered Zn in acetic acid, resulting in cleavage of the N-0 bond and formation of Ixabepilone (5).
Figure imgf000010_0001
EDC/HOBt
Figure imgf000010_0002
Ixabepilone
Scheme 4 The use of acethydrazide as a nucleophile in the preparation of Ixabepilone according to the invention is outlined in Scheme 4. When epothilone B (1) is treated with acethydrazide the ring-opened intermediate 9 is formed. Activation of the carboxylic acid with the EDC/HOBt system affords the compound 10 which is transformed into compound 11 by cyclisation analogously to the process in Scheme 2. Compound 11 is treated with powdered Zn in acetic acid, resulting in cleavage of the N-N bond and formation of Ixabepilone (5) as the target compound. Examples:
Example 1 - according to Scheme 1,
Figure imgf000011_0001
Nucleophile is NH2NH2,
Epothilone B (25 mg), Catalyst (0.01 eq.), Ligand (0.02eq.,), NH2-NH2.H20 (1.5 eq.) was added to a 25 ml round bottom flask. Degassed DCM (2 mL) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 h under nitrogen atmosphere.
No conversion was observed by TLC after 12 h at room temperature. Excess amount of catalyst and nucleophile was added and the stirring continued. After 6 days, a new spot was identified by TLC along with starting material. 80% conversion was observed by TLC.
The reaction mixture was diluted by 25 ml DMC and washed with water followed by brine solution. The crude compound was dried over sodium sulphate and concentrated under vacuum. The compound was purified by silica gel column chromatography using 5% MeOH:DCM as a solvent.
Example 2 - according to Scheme 4
Figure imgf000011_0002
Nucleophile NH2NHAc, 25 mg of Epothilone B, 0.1 eq of allyl palladium chloride dimer, 0.1 eq of xantphos and 1,5 eq of NH2-NHAc was added to a 25 ml round bottom flask under nitrogen atmosphere. 2 ml of degassed DCM was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours under nitrogen atmosphere. Complete conversion was observed by TLC. Reaction mixture was diluted with 25 ml DMC and washed with water followed by brine solution. Then further dried over sodium sulphate and concentrated under vacuum.
Example 3 - according to Scheme 3
Figure imgf000012_0001
Nucleophile NH2OH,
25 mg of Epothilone B, 0.1 eq of allyl palladium chloride dimer 0.1 eq of xantphos, 1.5 eq of NH2-OH.HCl and 5 eq of triethyl amine was added to a 25 ml round bottom flask. 2 ml of degassed DCM was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 h under nitrogen atmosphere. Complete conversion was observed by TLC. The reaction mixture was diluted with 25 ml DMC and washed with water followed by brine solution and dried over sodium sulphate and concentrated under vacuum. The crude compound was absorbed to a silica gel and eluted with 5% MeOH:DCM. Sample was submitted for MS after work-up and observed desired MS, see figure 1.
Example 4 - according to Scheme 1
Figure imgf000012_0002
Nucleophile is NH2NH2,
A 25 ml round bottom flask was charged with degasses THF:H20 (1 :0.5, 1.5 mL), then 25 mg of EpothiloneB and 1,5 eq of hydrazine hydrate was added under nitrogen atmosphere. 0.1 eq of Tetrakis(triphenylphosphine) palladium was added under nitrogen atmosphere. The reaction mixture was warmed to 45 °C for 12 h.
Excess amount of catalyst and nucleophile was added. The reaction mixture was kept at 45 °C for additional 12 h. Complete conversion was observed with TLC. The reaction mixture was diluted with 25 ml DCM and washed with water followed by brine solution, dried over sodium sulphate and concentrated under vacuum. The crude compound was submitted for 1H NMR & LC-MS, see Figure 2 and Figure 3.

Claims

Claims:
1. A compound of formu
Figure imgf000014_0001
Formula I
wherein R3 is H,
X is O or N,
Ri or R2 is either absent or independently H, alkyl or acyl,
when X is O, then R\ is absent.
2. A compound according to claim 1 wherein alkyl is CI -C 8 alkyl and acyl is C l - acyl
3. A compound according to claim 1 wherein X is O
4. A compound according to claim 3 wherein Rf is absent and R2 is H.
5. A compound represented by the formula
Figure imgf000014_0002
6. A compound according to claim 1 or 2 wherein X is N
7. A compound according to claim 6 wherein Ri is H.
8. A compound according to claim 6 wherein R2 is selected from the group consisting of H and Ac.
9. A compound represented by the formula
Figure imgf000015_0001
1 1. A process for preparing a compound of Formula I according to claim 1 comprising the step of reacting epothilone B with a nucleophile of the structure H2N-XRiR2 wherein
X is O or N,
Ri or R2 is either absent or independently H, alkyl or acyl,
when X is O, then R! is absent, in the presence of a palladium catalyst.
PCT/IB2012/001379 2011-07-13 2012-07-13 Manufacturing of epothilone derivatives and the use thereof WO2013008091A1 (en)

Applications Claiming Priority (2)

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US61/507,207 2011-07-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103183681A (en) * 2013-03-06 2013-07-03 浙江海正药业股份有限公司 New crystal form of ixabepilone, and preparation method thereof
WO2013164102A1 (en) * 2012-04-30 2013-11-07 Xellia Pharmaceuticals Aps Process for preparation of ixabepilone and intermediates useful in said process.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999002514A2 (en) * 1997-07-08 1999-01-21 Bristol-Myers Squibb Company Epothilone derivatives
WO1999027890A2 (en) * 1997-12-04 1999-06-10 Bristol-Myers Squibb Company A process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs
WO2001070716A1 (en) * 2000-03-20 2001-09-27 Bristol-Myers Squibb Company A process for the preparation of epothilone analogs and intermediates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999002514A2 (en) * 1997-07-08 1999-01-21 Bristol-Myers Squibb Company Epothilone derivatives
WO1999027890A2 (en) * 1997-12-04 1999-06-10 Bristol-Myers Squibb Company A process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs
WO2001070716A1 (en) * 2000-03-20 2001-09-27 Bristol-Myers Squibb Company A process for the preparation of epothilone analogs and intermediates

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013164102A1 (en) * 2012-04-30 2013-11-07 Xellia Pharmaceuticals Aps Process for preparation of ixabepilone and intermediates useful in said process.
CN103183681A (en) * 2013-03-06 2013-07-03 浙江海正药业股份有限公司 New crystal form of ixabepilone, and preparation method thereof

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