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WO2008086510A2 - Process to make lestaurtinib - Google Patents

Process to make lestaurtinib Download PDF

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Publication number
WO2008086510A2
WO2008086510A2 PCT/US2008/050830 US2008050830W WO2008086510A2 WO 2008086510 A2 WO2008086510 A2 WO 2008086510A2 US 2008050830 W US2008050830 W US 2008050830W WO 2008086510 A2 WO2008086510 A2 WO 2008086510A2
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WO
WIPO (PCT)
Prior art keywords
lestaurtinib
alkyl
cycloalkyl
borohydride
formula
Prior art date
Application number
PCT/US2008/050830
Other languages
French (fr)
Other versions
WO2008086510A3 (en
Inventor
Eric J. Stoner
Original Assignee
Abbott Laboratories
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 Abbott Laboratories filed Critical Abbott Laboratories
Priority to US12/522,993 priority Critical patent/US20100179318A1/en
Publication of WO2008086510A2 publication Critical patent/WO2008086510A2/en
Publication of WO2008086510A3 publication Critical patent/WO2008086510A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • This invention pertains to a process to make lestaurtinib, also known as (9S- (9 ⁇ , 1 O ⁇ , 12 ⁇ ))-2,3 ,9, 10, 11 , 12-hexahydro- 10-hydroxy- 10-(hy droxymethy l)-9-methy 1-9 ,12- epoxy-lH-diindolo[l,2,3-fg:3',2',l'-kl]pyrrolo[3,4-i][l,6]benzodiazocin-l-one (CAS Registry No. 111358-88-4).
  • Lestaurtinib is an semi-synthetic, orally bioavailable receptor-tyrosine kinase inhibitor that has been shown to have therapeutic utility in treating diseases such as acute myeloid leukemia, chronic myeloid leukemia and acute lymphocytic leukemia. It is a synthetic derivative of K-252a, a fermentation product ofNonomurea longicatena, and belongs to a class of indolocarbazole alkaloids.
  • a synthesis of lestaurtinib also known as (9S- (9a, 1 O ⁇ , 12 ⁇ ))-2,3,9, 10, 11 , 12-hexahydro-l 0-hydroxy-l 0-(hydroxymethyl)-9-methyl-9, 12- epoxy-lH-diindolo[l,2,3-fg:3',2',l'-kl]pyrrolo[3,4-i][l,6]benzodiazocin-l-one (CAS Registry No. 111358-88-4), is reported in U.S. 4,923,986.
  • the '986 synthesis uses lithium aluminum hydride at low temperature, reaction conditions that are not easily scalable due to the necessity of lower temperature and reactivity of the reductant. There is therefore an existing need in the chemical process arts for a scalable process for making lestaurtinib that avoids the necessity of lithium aluminum hydride and lower temperatures.
  • One embodiment of this invention therefore, comprises a process for making lestaurtinib (I)
  • R is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkyl or alkyl, alkenyl or alkynyl, each of which is substituted with aryl, heteroaryl or cycloalkyl and a borohydride reagent in a solvent comprising an aromatic hydrocarbon and an alcohol having formula R ⁇ 0H, wherein R is alkyl; and isolating the lestaurtinib.
  • Still another embodiment comprises a process for making lestaurtinib comprising reacting, from about 15 0 C to about 45 0 C, a compound having formula K-252a
  • Still another embodiment comprises a process for making lestaurtinib comprising reacting, from about 15 0 C to about 45 0 C, a compound having formula K-252a
  • Still another embodiment comprises a process for making lestaurtinib comprising reacting, from about 15 0 C to about 45 0 C, a compound having formula (K-252a)
  • Still another embodiment comprises any of the foregoing process conducted over about one-half to about ten hours.
  • Still another embodiment comprises any of the immediately foregoing process conducted over about 6 hours.
  • This invention pertains to a process to make lestaurtinib comprising reducing an ester-containing intermediate to an alcohol at ambient temperature using a borohydride reagent in a solvent comprising two liquids.
  • US 4,923,986 reports a synthesis of lestaurtinib using an aluminum hydride reagent at low temperature, a less easily scalable process due to the necessity of temperature adjustment, presumably to minimize reduction of a synthetically vunerable amide moiety also present on the molecule.
  • the process of this invention uses reaction conditions for reducing esters that, taken as a whole, are wholly surprising in view of the '986 patent.
  • variable moieties are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied. It is also meant to be understood that a specific embodiment of a variable moiety may be the same or different as another specific embodiment having the same identifier.
  • alkenyl means C 3 -alkyl, C 4 -alkyl, Cs-alkyl and C 6 -alkyl.
  • alkyl as used herein, means Ci-alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl and C 6 -alkyl.
  • alkynyl means C 3 -alkyl, C 4 -alkyl, Cs-alkyl and C 6 -alkyl.
  • aromatic hydrocarbon means benzene, toluene, ortho-xylene, meta-xylene, para-xylene and 1,3,5-mesitylene.
  • aryl as used herein, means phenyl which is unfused or fused with benzene.
  • borohydride reagent means lithium borohydride, sodium
  • cycloalkyl means C 3 -cycloalkyl, C 4 -cycloalkyl, C 5 -cycloalkyl and C 6 -cycloalkyl.
  • heteroaryl means furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl.
  • the borohydride reagent formed by addition of lithium borohydride, sodium borohydride, potassium borohydride or calcium borohydride to an alcohol may be a combination comprising M 1 BH 3 (OR 2 ), M 1 BH 2 (OR 2 ) 2 and M ⁇ HtOR 2 ⁇ . It is also meant to be understood that the aromatic hydrocarbon and an alcohol having
  • R OH of this invention may have limited solubility in one another, hovever, the aformentioned solubility will not preclude separation of the two components.
  • the term "isolating the lestaurtinib,” as used herein, means separating lestaurtinib from impurities. Separating lestaurtinib from impurities is typically accomplished by means such as centrifugation, filtration with or without vacuum, filtration under positive pressure, distillation, evaporation, crystallization, constant volume distillation, extraction, filtration through acidic, basic or neutral alumina, filtration through acidic, basic or neutral charcoal, filtration through a porous paper, plastic or glass barrier, column chromatography on silica gel, ion exchange chromatography, recrystallization, normal-phase high performance liquid chromatography, reverse-phase high performance liquid chromatography, trituration, combinations thereof and the like.
  • K-252a was treated with a mixture of methanol (2Kg/Kg K-252a) and toluene (8 Kg/Kg K-252a) at ambient temperature to produce a slurry to which was added sodium borohydride caplets (0.16 Kg/Kg K-252a) in portions over 6 hours.
  • the solids in the reactor dissolved to provide a biphasic solution which was stirred for 3 hours, after which time 0.2% of K-252a remained.
  • the lower layer was isolated, diluted with methanol (1 lKg/KG K- 252a), and quenched with glacial acetic acid (0.41 Kg/Kg K-252a), which caused a small amount of amorphous lestaurinib to form.
  • One-half of the remaining methanol solvate was dissolved in acetone (36 Kg/Kg K-252a) and methanol (24 Kg/Kg K-252a) at 55 0 C. This solution was polish filtered and added to the first distillation solution. Following dilution with isopropanol (12 Kg/Kg K-252a), the combination was distilled to half volume at atmospheric pressure. The remaining methanol solvate was dissolved in a mixture to acetone (36 Kg/Kg K-252a) and methanol (24 Kg/Kg K-252a) at 55 0 C. This solution was also polish filtered and added to the distillation residue.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A a process to make lestaurtinib, also known as (9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro- 10-hydroxy-10-(hydroxymethyl)-9-methyl-9,12-epoxy-1H-diindolo [1,2,3-fg:3',2',l'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one is disclosed.

Description

PROCESS TO MAKE LESTAURTINIB
FIELD OF THE INVENTION
This invention pertains to a process to make lestaurtinib, also known as (9S- (9α, 1 Oβ, 12α))-2,3 ,9, 10, 11 , 12-hexahydro- 10-hydroxy- 10-(hy droxymethy l)-9-methy 1-9 ,12- epoxy-lH-diindolo[l,2,3-fg:3',2',l'-kl]pyrrolo[3,4-i][l,6]benzodiazocin-l-one (CAS Registry No. 111358-88-4).
BACKGROUND OF THE INVENTION
Lestaurtinib is an semi-synthetic, orally bioavailable receptor-tyrosine kinase inhibitor that has been shown to have therapeutic utility in treating diseases such as acute myeloid leukemia, chronic myeloid leukemia and acute lymphocytic leukemia. It is a synthetic derivative of K-252a, a fermentation product ofNonomurea longicatena, and belongs to a class of indolocarbazole alkaloids. A synthesis of lestaurtinib, also known as (9S- (9a, 1 Oβ, 12α))-2,3,9, 10, 11 , 12-hexahydro-l 0-hydroxy-l 0-(hydroxymethyl)-9-methyl-9, 12- epoxy-lH-diindolo[l,2,3-fg:3',2',l'-kl]pyrrolo[3,4-i][l,6]benzodiazocin-l-one (CAS Registry No. 111358-88-4), is reported in U.S. 4,923,986. The '986 synthesis uses lithium aluminum hydride at low temperature, reaction conditions that are not easily scalable due to the necessity of lower temperature and reactivity of the reductant. There is therefore an existing need in the chemical process arts for a scalable process for making lestaurtinib that avoids the necessity of lithium aluminum hydride and lower temperatures.
SUMMARY OF THE INVENTION
One embodiment of this invention, therefore, comprises a process for making lestaurtinib (I)
Figure imgf000002_0001
(I) comprising reacting, from about 15°C to about 45°C, a compound having formula K-252
Figure imgf000003_0001
(K-252), wherein R is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkyl or alkyl, alkenyl or alkynyl, each of which is substituted with aryl, heteroaryl or cycloalkyl and a borohydride reagent in a solvent comprising an aromatic hydrocarbon and an alcohol having formula R~0H, wherein R is alkyl; and isolating the lestaurtinib.
Still another embodiment comprises a process for making lestaurtinib comprising reacting, from about 150C to about 450C, a compound having formula K-252a
Figure imgf000003_0002
(K-252a), and a borohydride reagent in a solvent comprising toluene and an alcohol having formula
2
R OH; and isolating the lestaurtinib.
Still another embodiment comprises a process for making lestaurtinib comprising reacting, from about 150C to about 450C, a compound having formula K-252a
Figure imgf000003_0003
(K-252a), and a borohydride reagent in a solvent comprising toluene and methanol; and isolating the lestaurtinib.
Still another embodiment comprises a process for making lestaurtinib comprising reacting, from about 150C to about 450C, a compound having formula (K-252a)
Figure imgf000004_0001
(K-252a), and sodium borohydride in toluene and methanol; and isolating the lestaurtinib.
Still another embodiment comprises any of the foregoing process conducted over about one-half to about ten hours.
Still another embodiment comprises any of the immediately foregoing process conducted over about 6 hours.
DETAILED DESCRIPTION OF THE INVENTION
This invention pertains to a process to make lestaurtinib comprising reducing an ester-containing intermediate to an alcohol at ambient temperature using a borohydride reagent in a solvent comprising two liquids. US 4,923,986 reports a synthesis of lestaurtinib using an aluminum hydride reagent at low temperature, a less easily scalable process due to the necessity of temperature adjustment, presumably to minimize reduction of a synthetically vunerable amide moiety also present on the molecule. The process of this invention uses reaction conditions for reducing esters that, taken as a whole, are wholly surprising in view of the '986 patent.
Variable moieties are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied. It is also meant to be understood that a specific embodiment of a variable moiety may be the same or different as another specific embodiment having the same identifier.
The term "alkenyl," as used herein, means C3-alkyl, C4-alkyl, Cs-alkyl and C6-alkyl.
The term "alkyl," as used herein, means Ci-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl and C6-alkyl.
The term "alkynyl," as used herein, means C3-alkyl, C4-alkyl, Cs-alkyl and C6-alkyl.
The term "aromatic hydrocarbon," as used herein, means benzene, toluene, ortho-xylene, meta-xylene, para-xylene and 1,3,5-mesitylene.
The term "aryl," as used herein, means phenyl which is unfused or fused with benzene.
The term "borohydride reagent," as used herein, means lithium borohydride, sodium
1 2 borohydride, potassium borohydride and compounds having formula M BHj(OR ), M BH2(OR )2 and M BH(OR )3, wherein M is lithium, sodium or potassium.
The term "cycloalkyl," as used herein, means C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl and C6-cycloalkyl.
The term "heteroaryl," as used herein, means furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl.
It is meant to be understood that, in a preferred embodiment for the practice of this invention, the borohydride reagent formed by addition of lithium borohydride, sodium borohydride, potassium borohydride or calcium borohydride to an alcohol may be a combination comprising M1BH3(OR2), M1BH2(OR2)2 and M^HtOR2^. It is also meant to be understood that the aromatic hydrocarbon and an alcohol having
2 formula R OH of this invention may have limited solubility in one another, hovever, the aformentioned solubility will not preclude separation of the two components.
The term "isolating the lestaurtinib," as used herein, means separating lestaurtinib from impurities. Separating lestaurtinib from impurities is typically accomplished by means such as centrifugation, filtration with or without vacuum, filtration under positive pressure, distillation, evaporation, crystallization, constant volume distillation, extraction, filtration through acidic, basic or neutral alumina, filtration through acidic, basic or neutral charcoal, filtration through a porous paper, plastic or glass barrier, column chromatography on silica gel, ion exchange chromatography, recrystallization, normal-phase high performance liquid chromatography, reverse-phase high performance liquid chromatography, trituration, combinations thereof and the like.
The following example is meant to further embody the compounds and processes of this invention.
EXAMPLE 1
K-252a was treated with a mixture of methanol (2Kg/Kg K-252a) and toluene (8 Kg/Kg K-252a) at ambient temperature to produce a slurry to which was added sodium borohydride caplets (0.16 Kg/Kg K-252a) in portions over 6 hours. The solids in the reactor dissolved to provide a biphasic solution which was stirred for 3 hours, after which time 0.2% of K-252a remained. The lower layer was isolated, diluted with methanol (1 lKg/KG K- 252a), and quenched with glacial acetic acid (0.41 Kg/Kg K-252a), which caused a small amount of amorphous lestaurinib to form. Stirring at room temperature converted the amorphate to lestaurinib methanolate. The methanol solvate was collected by vacuum filtration and washed with methanol (2 Kg/Kg K-252a) and water (2 Kg/Kg K-252a). One third of the methanol solvate was dissolved in acetone (36 Kg/Kg K-252a) and methanol (24 Kg/Kg K-252a) at 550C. The solution was polish filtered through a series of polypropylene filters. Following filtration it was diluted with isopropanol (12 Kg/Kg K-252a) and distilled to one-half volume at atmospheric pressure. One-half of the remaining methanol solvate was dissolved in acetone (36 Kg/Kg K-252a) and methanol (24 Kg/Kg K-252a) at 550C. This solution was polish filtered and added to the first distillation solution. Following dilution with isopropanol (12 Kg/Kg K-252a), the combination was distilled to half volume at atmospheric pressure. The remaining methanol solvate was dissolved in a mixture to acetone (36 Kg/Kg K-252a) and methanol (24 Kg/Kg K-252a) at 550C. This solution was also polish filtered and added to the distillation residue. Following dilution with isopropanol (12 Kg/Kg K-252a), the combination was distilled to half volume at atmospheric pressure. During distillation, solids precipitated from the solution. The distillation was continued at constant volume with isopropanol addition until an internal temperature of 820C was achieved for one hour. After cooling to O0C, the mixture was filtered. The filtrant was washed with isopropanol (2 Kg/Kg K-252a), and the solids were dried under vacuum at 750C.
The foregoing is meant to be illustrative of this invention and not limiting. Obvious variations and changes are meant to be within the scope of this invention, as defined in the claims.

Claims

WE CLAIM:
1. A process for making lestaurtinib (I)
Figure imgf000008_0001
(I) comprising reacting, from about 150C to about 450C, a compound having formula K-252
Figure imgf000008_0002
(K-252), wherein R is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkyl or alkyl, alkenyl or alkynyl, each of which is substituted with aryl, heteroaryl or cycloalkyl, and a borohydride reagent in a solvent comprising an aromatic hydrocarbon and an alcohol having formula R OH; and isolating the lestaurtinib.
2. The process of claiml conducted over about one-half to about ten hours.
3. The process of claim 2 conducted over about six hours.
PCT/US2008/050830 2007-01-11 2008-01-11 Process to make lestaurtinib WO2008086510A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/522,993 US20100179318A1 (en) 2007-01-11 2008-01-11 Process to make lestaurtinib

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US88455007P 2007-01-11 2007-01-11
US60/884,550 2007-01-11
US97206008A 2008-01-10 2008-01-10
US11/972,060 2008-01-10

Publications (2)

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WO2008086510A2 true WO2008086510A2 (en) 2008-07-17
WO2008086510A3 WO2008086510A3 (en) 2008-10-09

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GINGRICH DE ET AL: "Synthesis and kinase inhibitory activity of 3'-(S)-epi-K-252a" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, 2002, pages 2829-2831, XP002490424 *
GINGRICH DE ET AL: "Synthesis, modeling, and in Vitro activity of (3'S)-epi-K-252a analogues. Elucidating the stereochemical requirements of the 3'-sugar alcohol and trkA Tyrosine kinase activity" JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, 2005, pages 3776-3783, XP002490423 *

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