WO2022091001A1 - Procédé de préparation de palbociclib - Google Patents

Procédé de préparation de palbociclib Download PDF

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WO2022091001A1
WO2022091001A1 PCT/IB2021/059991 IB2021059991W WO2022091001A1 WO 2022091001 A1 WO2022091001 A1 WO 2022091001A1 IB 2021059991 W IB2021059991 W IB 2021059991W WO 2022091001 A1 WO2022091001 A1 WO 2022091001A1
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formula
compound
base
palbociclib
ppm
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PCT/IB2021/059991
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English (en)
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Srinivas Reddy Dubbaka
Paul Mcdaid
Padraig Mary O'neill
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Pfizer Ireland Pharmaceuticals
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to improved processes for the preparation of palbociclib.
  • the invention further provides intermediates and processes for the preparation of intermediates useful for the preparation of palbociclib. Description of the Related Art
  • CDKs Cyclin-dependent kinases
  • Palbociclib 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2ylamino)- 8H-pyrido[2,3-d]pyrimidin-7-one, is a CDK4/6 inhibitor for use in the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy or fulvestrant with disease progression following endocrine therapy.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • Palbociclib and salts thereof are described in U.S. Patent Nos. 6,936,612, 7,456,168 and RE 47,739. Processes for the preparation of palbociclib, including salts and intermediates for the preparation thereof, are described in U.S. Patent No. 7,781 ,583 and International Publication No. WO 2008/032157. The preparation of palbociclib salts, and crystalline forms of such salts, is described in U.S. Patent Nos. 7,345,171 and 7,863,278. Solid forms of palbociclib are described in U.S. Patent No, 10,723,730 and International Publication No. WO 2014/128588. Formulations of palbociclib are described in U.S. Patent Publication No. 2018/0207100 and International Publication No. WO 2019/053650. The contents of each of the foregoing are incorporated herein by reference in their entirety.
  • the present invention provides improved processes for the preparation of palbociclib, or a salt thereof, including a pharmaceutically acceptable salt thereof, and intermediates useful for the preparation of palbociclib.
  • the invention provides a process for the preparation of palbociclib: comprising:
  • the process further comprises: (c) cooling the mixture in step (b) to provide a slurry and filtering to isolate palbociclib.
  • step (b) comprises washing the aqueous phase with one or more suitable organic solvents (such as CH2CI2, EtOAc, /-PrOAc or Anisole) at elevated temperature (preferably about 50-65°C), and adjusting the pH of the aqueous layer to about pH 12.5 with aqueous base (preferably aq. sodium hydroxide) at elevated temperature, preferably about 40°C.
  • suitable organic solvents such as CH2CI2, EtOAc, /-PrOAc or Anisole
  • the process further comprises: (c) isolating palbociclib by gradually cooling the resulting slurry in step (b) to about 15°C and then filtering and washing the solid material with water; and optionally (d) drying the solid material under vacuum at about 25°C to obtain palbociclib.
  • the invention provides a process for the preparation of a compound of Formula (I): comprising:
  • the invention provides a process for the preparation of a compound of Formula (I): comprising:
  • Boc-protected compound of Formula (I) may be converted to palbociclib, or a salt thereof, as further described herein or as known in the art.
  • the invention provides palbociclib, or a salt thereof, prepared according to any of the processes of the invention provided herein.
  • FIG. 1 shows ORTEP diagrams of the molecular structure of hydroxypyridone (VI) as a 50:50 mixture of tautomer (Vl-a) (A) and tautomer (Vl-b) (B).
  • a suitable solvent may include one or more suitable solvents (i.e. , a suitable solvent mixture).
  • the current commercial route to palbociclib involves coupling 6- bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-c/]pynmidin-7(8/-/)-one with tert-butyl 4- (6-aminopyridin-3-yl)piperazine-1 -carboxylate to give Intermediate-1 , followed by Heck reaction with butyl vinyl ether to give Intermediate-2.
  • Deprotection of Intermediate-2 by treatment with acid hydrolyzes the enol ether and removes the Boc-protecting group, providing palbociclib.
  • Scheme 1 The present invention provides more efficient and convergent routes to prepare palbociclib, involving direct coupling of a suitable 2-halopyridine precursor with an acetylsubstituted pyridone intermediate, e.g., compounds of Formulae (II) or (IV), in which the 6-acetyl or 3-acetyl group, respectively, is already installed.
  • a suitable 2-halopyridine precursor e.g., compounds of Formulae (II) or (IV), in which the 6-acetyl or 3-acetyl group, respectively, is already installed.
  • the compounds of Formulae (II) and (IV) were prepared via the intermediacy of the compound of Formula (VI), N-cyclopentyl-3-acetyl-4-methyl-6-hydroxy-2-pyridone, and the corresponding 6-halopyridone compounds of Formulae (VII) and (VIII), which were prepared as shown in Scheme 3.
  • Scheme 3 Preparation of N-cyclopentyl-3-acetyl-4-methyl-6-hydroxy-2-pyridone (VI) was described in Example 2 of Chinese Patent No. 104478874, but no analytical details were supplied.
  • N-acetoacetylation of cyclopentylamine with ethyl acetoacetate required N-acetoacetylation of cyclopentylamine with ethyl acetoacetate to obtain N,N-bis(acetoacetyl)cyclopentylamine, followed by intramolecular condensation in the presence of an alkaline reagent to provide N- cyclopentyl-3-acetyl-4-methyl-6-hydroxy-2-pyridone as an oil.
  • the preparation of N,N- bis(acetoacetyl)cyclopentylamine could not be repeated under the conditions reported, with reaction of acetoacetates with primary or secondary amines likely giving only enamines, which did not react further under the reported conditions.
  • the diketene adduct with acetone, 2,2,6-trimethyl-1 ,3-dioxin-4-one was used to prepare the compound of Formula (VI).
  • Lipophilic trialkylamines such as tributylamine, were found to be preferred catalysts when 2,2,6-trimethyl-1 ,3-dioxin-4-one was used as the acetoacetylating agent. These bases were found to suppress the formation of the isomeric pyridones. Efficient methods have also been developed for separation of the compound of Formula (VI) from neutral by-products and from the main by-product, dehydroacetic acid.
  • the compound of Formula (VI) was prepared by base-catalyzed condensation of tert-butyl acetoacetate (or other alkyl esters) with N- cyclopentylacetoacetamide.
  • the compound of Formula (VI) was also prepared through a one-pot synthesis by reaction of N-cyclopentylacetoacetamide with diketene generated in situ from acetyl chloride and triethylamine and distillation (see Nakashige et al., Tetrahedron Letters, (2015), 56:3531 -3533; 2015), followed by treatment with a weak base such as N,N-dimethylaniline.
  • the compound of Formula (VI) was isolated as a highly crystalline solid when prepared by the methods of the current invention.
  • the compound of Formula (VI) was found by single crystal XRD (FIG. 1 ) to exist in the solid form as a mixture of two tautomeric forms, the 2-hydroxy tautomer (2-OH) (Vl-a) and the enol form of the acetyl moiety, (3(Ac)-OH) (Vl-b).
  • a third tautomer, having the 6-hydroxy (6-OH) (Vl-c) appears to be predominant in solution based on NMR data. Tautomeric forms are shown in in
  • reaction of the compound of Formula (VI) with POCh provided the compound of Formula (VII), 3-acetyl-6-chloro-1 -cyclopentyl-4-methylpyridin- 2(1 H)-one, while reaction with POBrs provided the compound of Formula (VIII), 3-acetyl- 6-bromo-1 -cyclopentyl-4-methylpyridin-2(1 H)-one.
  • the compounds of Formulae (VII) and (VIII) were obtained in good yields and with excellent regioselectivity.
  • the compounds of Formula (IV) and (II) were prepared as described in Scheme 5. Reaction of the compound of Formula (VII) with guanidine hydrochloride provided the compound of Formula (IV).
  • Other guanylation reagents can be used in this reaction, including guanidine salts, e.g., guanidine hydrochloride, guanidine carbonate salt and guanidine hydrogen carbonate, and N-acyl guanidine derivatives, such as N-formyl guanidine.
  • the compound of Formula (II) was coupled with the bromopyridine compound of Formula (lll-a) in the presence of a transition metal catalyst, a base, and optionally a ligand, to give the compound of Formulae (I), as shown in Scheme 7.
  • Suitable transition metal catalysts for the reactions in Scheme 7 include palladium(O), palladium(ll), copper(l) or copper(ll) catalysts (i.e., Pd(0), Pd(ll), Cu(l) or Cu(ll) catalysts).
  • the invention provides a process for the preparation of the compound of Formula (IV):
  • (IV), or a salt thereof comprising: (a) reacting a compound of Formula (VII) or (VIII) prepared by the process according to any of the embodiments described herein: with a guanylation reagent and a base in a suitable solvent, to provide the compound of Formula (IV).
  • the process further comprises: (b) isolating the compound of Formula (IV) by extraction into an aqueous acidic solution, adjusting the pH with base to basic pH, and collecting the precipitated compound of Formula (IV) by filtration.
  • the reactant in step (a) is preferably the compound of Formula (VII).
  • the reactant in step (a) is the compound of Formula (VIII).
  • the guanylation reagent is a guanidine salt selected from the group consisting of guanidine hydrochloride, guanidine carbonate salt and guanidine hydrogen carbonate.
  • Optional substituent groups when R x is optionally substituted phenyl or optionally substituted benzyl are selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, C1-C4 haloalkyl, and C1-C4 haloalkoxy.
  • the N-acyl guanidine reagent is N-formyl guanidine (i.e., R x is H), and the intermediate of Formula (IV X ) is hydrolyzed to provide the compound of Formula (IV).
  • the base used in preparation of the compound of Formula (IV) in step (a) is preferably an alkali metal hydroxide, alkoxide or carbonate base, or an alkaline earth hydroxide, alkoxide or carbonate base. More preferably, the base is sodium hydroxide, sodium tert-butoxide, sodium tert-pentoxide, potassium hydroxide, potassium tert- butoxide, potassium tert-pentoxide, potassium carbonate or cesium carbonate.
  • the solvent in step (a) of the guanylation reaction comprises a tertiary alcohol. More preferably, the solvent is tert-butanol or tert-amyl alcohol.
  • the invention provides a compound of Formula (IV): or a salt thereof.
  • the invention provides a process for the preparation of the compound of Formula (II): or a salt thereof, comprising:
  • the process may further comprise:
  • step (f) optionally providing the compound of Formula (II) as a free base by dissolving the salt isolated in step (e) in a suitable solvent, typically comprising water, neutralizing with a suitable base, and then extracting the free base of Formula (II) with a suitable organic solvent or crystallizing the free base of Formula (II) from a suitable solvent.
  • a suitable solvent typically comprising water, neutralizing with a suitable base, and then extracting the free base of Formula (II) with a suitable organic solvent or crystallizing the free base of Formula (II) from a suitable solvent.
  • Suitable bases include amine bases, such as triethylamine.
  • Suitable solvents for use in the crystallization in step (f) include alcohol solvents.
  • step (b) comprises isolating the compound of Formula (X).
  • the compound of Formula (X) may be isolated by cooling the reaction mixture of step (a), extracting the salt into dilute aqueous acid, and adjusting the pH to basic pH with base and collecting the compound of Formula (X) by filtration.
  • the formylation reagent in step (a) is a formic acid ortho ester or a formamide acetal selected from the group consisting of N,N-dimethyl formamide dimethyl acetal (DMF-DMA) and trimethyl orthoformate (TMOF).
  • DMF-DMA N,N-dimethyl formamide dimethyl acetal
  • TMOF trimethyl orthoformate
  • the solvent in step (a) is an aromatic hydrocarbon and the dehydrative conditions in step (a) comprise heating the solution comprising the compound of Formula (IV) and the formylation reagent at about 90°C for about 2 hours.
  • the hydrolysis in step (c) comprises reacting the compound of Formula (X) with an organic or inorganic acid in a suitable solvent or solvent mixture, typically comprising water, to provide the compound of Formula (II), or a salt thereof.
  • the acid is aqueous hydrochloric acid (HCI).
  • the hydrolysis in step (c) comprises heating a solution comprising the compound of Formula (X) and aqueous HCI at about 50°C for about 2-4 hours.
  • the HCI salt of Formula (II) is quite insoluble and may be isolated by filtration from the aqueous solvent mixture.
  • the compound of Formula (II) may be conveniently prepared as a free base by use of acids that provide water soluble salts in the hydrolysis in step (c).
  • acids that provide water soluble salts in the hydrolysis in step (c) include sulfuric acid and methanesulfonic acid provided the corresponding salts of Formula (II), simplifying the extractive workup.
  • Neutralization of the acidic reaction mixture comprising such water soluble salts with base and extraction with a suitable organic solvent permits isolation of the compound of Formula (II) as a free base without isolation of the salt formed in step (c).
  • the invention provides a compound of Formula (X): where Y is N(C-I-C4 alkyl)2 or O(Ci-C4 alkyl).
  • the compound of Formula (X) may be prepared as described in the second aspect herein, or any of the embodiments or combination of embodiments thereof.
  • the invention provides a process for the preparation of the compound of Formula (I): comprising:
  • the invention provides another process for the preparation of the compound of Formula (I): comprising:
  • X is selected from the group consisting of bromo, chloro, iodo, trifluoromethanesulfonate, and tosylate (i.e., Br, Cl, I, OTf, and OTs).
  • X is bromo.
  • the transition metal catalyst in the fourth and fifth aspects is a palladium catalyst.
  • Suitable palladium catalysts include palladium(O) or palladium(ll) reagents and complexes.
  • suitable palladium reagents include palladium(O) bis(dibenzylideneacetone) (Pd(dba)2), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)s), palladium ⁇ I) chloride (PdCl2), palladium ⁇ I) acetate (Pd(OAc)2), allylpalladium(ll) chloride dimer ([AllylPdCI]2), palladium on carbon (Pd/C), bis(triphenylphosphine)palladium(ll) dichloride (PdCl2(PPh3)2), [1 ,1 '- bis(diphenylphosphino)ferrocene]palladium(ll) dichloride (PdCl2(dppf)2), tetraaminepalladium(ll
  • the palladium catalyst is selected from the group consisting of Pd(dba)2, Pd2(dba)3, [AllylPdCI]2, PdCl2, Pd(OAc)2 and Pd/C. More preferably, the palladium catalyst is a Pd(ll) catalyst selected from the group consisting of [AllylPdCI]2, PdCl2, and Pd(OAc) 2 .
  • the process further comprises a ligand.
  • the transition metal catalyst is a palladium catalyst
  • the ligand is a phosphine ligand.
  • Suitable phosphine ligands for use with palladium catalysts include monophosphine or diphosphine ligands.
  • Examples of monophosphine ligand include: Xphos, P(tBu) 3 , RuPhos, tBuXphos, CyJohnphos, Johnphos, SPhos, tBuBrettphos, Me4tBuXPhos, DavePhos, BrettPhos, Bippyphos, di(1-adamantyl)-n-butylphosphine (CataCXium A), di-t-butylphosphine oxide, P(o-tol)3, Jackiephos, P(2-furyl)s, PH2tBu, PH2Cy, PH2Me, 4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (Amphos), 2- dicyclohexylphosphino-2’-methylbiphenyl, and 2-methyl-2’-dicyclohexyl-phosphino- biphenyl (MebiphPCy2 or MePhos).
  • biphosphine ligands include: the biphosphine ligand is selected from the group consisting of XantPhos, Binap, dppf, DPEPhos, Josiphos SL-J009-1 , dppp, DMPM, 1 ,2-bis(dicyclohexylphosphino)ethane, dppe, tris(2,4-di-tert-butylphenyl) phosphite monophoshine, and tBuXanthphos.
  • the phosphine ligand is selected from the group consisting of Me4tBuXPhos, tBuBrettphos, tBuXphos, Xantphos, Bippyphos, Johnphos, Josiphos SL-J009-1 , DPEphos and 1 ,1'-bis(diphenylphosphino)ferrocene (dppf).
  • the transition metal catalyst is a copper catalyst.
  • Suitable copper catalysts include copper(l) or copper(ll) reagents and complexes.
  • suitable copper reagents include copper(l) iodide (Cui), copper(l) trifluoromethanesulfonate (CuOTf), copper(ll) trifluoromethanesulfonate (Cu(OTf)2), tetrakis(acetonitrile > )copper(l)tetrafluoroborate (Cu(BF4)(MeCN)4) or tetrakis(acetonitrile) copper(l) hexafluorophosphate (Cu(PF6)(MeCN)4).
  • the copper catalyst is copper(l) iodide (Cui).
  • the process when the transition metal catalyst is a copper catalyst, the process further comprises a ligand, including, e.g., a diamine, phenanthroline, dipyridyl or phenolic ligand.
  • Suitable ligands include N,N’-dimethylethylenediamine, trans-N,N’- dimethylcyclohexane-1 ,2-diamine, N,N,N’,N’-tetramethylethylenediamine, 8-hydroxy- quinoline, 8-hydroxyquinoline N-oxide, 4,7-diphenyl-1 ,10-phenanthroline (bathophenanthroline), 4-4' -dimethoxy-2-2' -bipyridine, 2,6-dimethylanilino(oxo)acetic acid (DMPAO), 4,4'-di-tert-butyl-2,2'-dipyridyl (Bbbpy), 4, 7-dimethoxy-1 ,10- phenanthroline, 2,2'
  • the transition metal catalyst is a copper catalyst
  • the ligand is is selected from the group consisting of trans-N,N'-dimethylcyclohexane-1 ,2-diamine, bathophenanthroline, A/-(2,6-dimethylphenyl)-6-hydroxypicolinamide, and 8-hydroxy- quinoline N-oxide.
  • the base is an alkaline earth carbonate, alkoxide or phosphate base.
  • the base is potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, or potassium phosphate.
  • the solvent comprises tetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), toluene, xylene, DMF, DMSO or dioxane.
  • Suitable solvents for use with palladium catalysts include non-polar solvents, e.g., toluene or xylene, and alcohol solvents.
  • Suitable solvents for use with copper catalysts include polar aprotic solvents or ethereal solvents, e.g., DMF, DMSO, or dioxane.
  • the invention provides a compound of Formula (I): prepared by the process described in the fourth or fifth aspects, or any of the embodiments or combinations of embodiments thereof.
  • the invention provides a process for the preparation of palbociclib: or a salt thereof, comprising:
  • the process further comprises: (e) crystallizing the free base of palbociclib from a suitable solvent to provide the crystalline free base of palbociclib (Form A), where Form A is as described in International Publication No. WO 2014/128588.
  • the crystallization solvent in step (e) is a mixture of anisole and n-butanol.
  • the crystalline free base of palbociclib (Form A) is characterized as having:
  • a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of: (a) 8.0 ⁇ 0.2, 10.1 ⁇ 0.2 and 11.5 ⁇ 0.2 20; or (b) 8.0 ⁇ 0.2, 10.1 ⁇ 0.2, 10.3 ⁇ 0.2, and 11.5 ⁇ 0.2 20;
  • the invention provides palbociclib, or a salt thereof, prepared by the process of the seventh aspect, or any of the embodiments or combinations of embodiments thereof.
  • the invention provides crystalline free base of palbociclib (Form A), prepared by the process of the seventh aspect, wherein the process further comprises step (e) as described.
  • the invention provides a process for the preparation of a compound of Formulae (VII) or (VIII): comprising:
  • the process further comprises: (b) isolating the compound of Formula (VII) or (VIII) by adding water to destroy excess halogenating agent, adjusting the pH with base to neutral, extracting with an organic solvent and concentrating the organic solvent layer to provide the compound of Formula (VII) or (VIII).
  • the halopyridone is the compound of Formula (VII), and the halogenating agent is POCh. In other embodiments of the tenth aspect, the halopyridone is the compound of Formula (VIII), and the halogenating agent is POBrs.
  • the halogenation process includes a solvent, where the solvent comprises a halogenated solvent, an aromatic hydrocarbon solvent, a dipolar aprotic solvent, or an ethereal solvent.
  • the solvent comprises dichloromethane, toluene, chlorobenzene, acetonitrile, tetrahydrofuran, CPME or MTBE
  • the invention provides a process for the preparation of a compound of Formula (VI), or a tautomer thereof: comprising:
  • the process further comprises: (b) isolating the compound of Formula (VI) by extraction into an aqueous basic solution, adjusting the pH with acid to neutral/acidic pH, and collecting the precipitated compound of Formula (VI) by filtration; and optionally (c) recrystallizing the compound of Formula (VI) from a suitable solvent.
  • suitable solvents include alcohols and polar aprotic solvents, such as MeOH or acetonitrile.
  • the acetoacetylating reagent is 2,2,6-trimethyl-1 ,3-dioxin-4-one, tert-butyl acetoacetate or diketene.
  • the base is a trialkylamine base. In some embodiments of the eleventh aspect, the base is an alkali metal or alkaline earth alkoxide base. In some embodiments of the eleventh aspect, the base is N,N- dimethylaniline.
  • guanylation reagent is a guanidine salt selected from the group consisting of guanidine hydrochloride, guanidine carbonate salt and guanidine hydrogen carbonate.
  • step (c) hydrolysis of the compound of Formula (X) in the presence of an acid in a suitable solvent to provide the compound of Formula (II), or a salt thereof.
  • the formylation reagent in step (a) is a formic acid ortho ester or a formamide acetal selected from N,N-dimethyl formamide dimethyl acetal (DMF-DMA)] and trimethyl orthoformate (TMOF).
  • step (a) is an aromatic hydrocarbon and the dehydrative conditions in step (a) comprise heating the solution comprising the compound of Formula (IV) and the formylation reagent at about 90°C for about 2 hours.
  • step (c) is an organic or inorganic acid.
  • step (c) is aqueous hydrochloric acid (HCI) and the hydrolysis in step (c) comprises heating a solution comprising the compound of Formula (X) and HCI at about 50°C for about 2-4 hours.
  • HCI aqueous hydrochloric acid
  • step (a) further comprises a ligand.
  • step (a) further comprises a ligand.
  • E29 The process of embodiment E28, wherein the ligand is trans-N,N'- dimethylcyclohexane-1 ,2-diamine, bathophenanthroline, A/-(2,6-dimethylphenyl)-6- hydroxypicolinamide, or 8-hydroxyquinoline N-oxide.
  • E30 The process of any one of embodiments E18 to E29, wherein the base in step (a) is an alkali metal carbonate, alkali metal alkoxide, alkali metal phosphate, alkaline earth carbonate, alkaline earth alkoxide or alkaline earth phosphate base.
  • step (a) is potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, or potassium phosphate.
  • (a) comprises tetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether
  • a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of: (a) 8.0 ⁇ 0.2, 10.1 ⁇ 0.2 and 11.5 ⁇ 0.2 20; or (b) 8.0 ⁇ 0.2, 10.1 ⁇ 0.2, 10.3 ⁇ 0.2, and 11.5 ⁇ 0.2 20;
  • a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of: (a) 8.0 ⁇ 0.2, 10.1 ⁇ 0.2 and 11.5 ⁇ 0.2 20; or (b) 8.0 ⁇ 0.2, 10.1 ⁇ 0.2, 10.3 ⁇ 0.2, and 11.5 ⁇ 0.2 20;
  • step (b) comprises washing the aqueous phase with one or more suitable organic solvents (such as CH2CI2, EtOAc, /-PrOAc or Anisole) at elevated temperature (preferably about 50-65°C), and adjusting the pH of the aqueous layer to about pH 12.5 with aqueous base (preferably aq. sodium hydroxide) at elevated temperature, preferably about 40°C.
  • suitable organic solvents such as CH2CI2, EtOAc, /-PrOAc or Anisole
  • the invention provides a compound of Formula (IV): or a salt thereof.
  • a 5L 4 neck round bottom (RB) flask was charged with cyclopentylamine (230 g, 2.7011 moles) at 25-30°C.
  • the RB flask was charged with xylene (1080 mL).
  • Tributylamine 50 g, 0.2701 mole was added to the RB flask at 25-30°C.
  • the flask was charged with 2,2,6-trimethyl-1 ,3-dioxin-4-one (399.3 g, 2.8091 mole) and the reaction mixture heated to 110°C for 20-30 min.
  • the reaction mass was stirred at 105-110°C with a gentle reflux for 300-330 min.
  • the reaction mass was cooled to 25-30°C for 20-30 min.
  • the flask was charged with DM water (1085 mL) at 25-30°C and the reaction stirred for 15 min. The layers were allowed to settle for 10 minutes and separated. The xylene layer was extracted with DM water (5 x 1085 mL) and the layers were separated. The xylene layer was extracted with additional DM water (2 x 550 mL) and the layers were separated. The combined aqueous layer was filtered to remove junk material.
  • N-cyclopentyl-3-oxo-butanamide (33.8 g, 0.2 moles) was charged into a 1 liter 4 neck RB flask.
  • Tributylamine (3.7 g, 0.02 moles) was added to the RB flask at 25-30°C.
  • the flask was charged with xylene (101 mL).
  • the reaction mixture was headed at 110°C (Bath temperature 130-140°C) for 20-30 min.
  • a solution of 2,2,6-trimethyl-1 ,3-dioxin-4- one (71 g, 0.5 moles) in xylene (85 mL) was prepared and added to the RB flask.
  • the reaction mixture was heated at 100-110°C for 300 min.
  • the reaction mixture was stirred at 100-110°C for 180 min.
  • the reaction was cooled to 25-30°C.
  • a solution of potassium carbonate (30.4 g) was prepared in DM water (300 mL).
  • the potassium carbonate solution (240 mL) was added to the flask at 25-30°C.
  • the reaction mixture was filtered to remove interfacial material and then allowed to settle for 10 min. The layers were separated.
  • the filtered precipitate was washed with the potassium carbonate solution (60 mL) and the wash layer was added to the organic layer at 25-30°C and stirred for 30 min. The layers were allowed to settle and separated.
  • the aqueous layers were combined and washed with additional xylene (110 mL), then stirred at 25-30°C for 15 min.
  • the layers were allowed to settle for 10 min and separated.
  • the washed aqueous layer was charged into a 1 -liter RB flask at 25-30°C.
  • the pH of the aqueous layer was adjusted to pH 1.4-1 .6 with concentrated HCI (39 mL).
  • the reaction mass was stirred for 120 min.
  • the reaction was filtered and the solid was washed with MeOH (100 mL).
  • the wet solid was collected at 25-30°C and had a weight of 41 ,2g.
  • the solid was dried under vacuum in a vacuum oven at 25-30°C for 720-840 min.
  • the dry weight of the crude compound of Formula (VI) was 35 g, with a purity of 62.5 % (by HPLC).
  • the crude compound of Formula (VI) was obtained as an approximately 4:1 molar ratio of the desired hydroxypyridone to the dehydroacetic acid.
  • the material was recrystallized from 3 volumes acetonitrile (or 10 volumes methanol) to afford pure compound of Formula (VI) in 50-55% overall molar yield.
  • Acetyl chloride (25 mL,1 eq.) was added dropwise to a stirred solution of triethylamine (55 mL, 1.12 eq.) in diethyl ether (500 mL). The resultant slurry was stirred at room temperature for 16 hrs. The reaction flask was heated at 60 °C and diethyl ether was removed by distillation. The reaction vessel was then cooled, filled with nitrogen, and the collection flask exchanged. The distillation apparatus pressure was reduced to 250- 300 torr and the distillation assembly was then lowered into a preheated oil bath (120 °C). A distillation fraction was collected at 53 °C to afford diketene (5.8 g, 43%) as a clear, colorless oil.
  • the reaction mixture was heated to 60°C and diketene (0.8 g, 1 .6 eq.) was added in toluene (5 mL, 10v) for 15 min at 60°C.
  • the reaction mixture was heated to reflux at 110°C and the reflux was maintained for 6 hours.
  • the mixture was cooled and 10% aq. potassium carbonate solution (10 mL) added and stirred for 20 min at room temperature.
  • the organic phase was separated and extracted with aq.10% potassium carbonate solution (5 mL).
  • the combined aqueous phase was washed with toluene (5 mL).
  • the aqueous phase was acidified to 1 .5 pH using cone. HCI and stirred for 1 hour at room temperature.
  • the mixture was filtered and washed with water (5 mL).
  • the material was dried under vacuum for 4 hours to obtain pure compound of Formula (VI) (0.35 g, yield:25.2% with respect to CPA) as a pale brown solid.
  • the reaction mixture was unloaded and stored at 25 °C to 30°C.
  • the mixture was quenched by addition of 300 mL 1 N HCI solution.
  • 300 mL toluene was added, and the mixture was stirred for 15 minutes.
  • the layers were allowed to settle and separate, and the mixture was extracted with 100 mL toluene.
  • the layers were separated, and the combined organic layer was washed with 300 mL DM water.
  • the layers were separated again, and the combined toluene layer was stored at 25 to 30°C.
  • the toluene layer was transferred to a 1 L round bottom (RB) flask.
  • a solution of potassium carbonate (17.968 g, 130.01 mmol, 100 mass%) in 180mL DM water was prepared.
  • the 10% potassium carbonate solution was added to the toluene layer and stirred for 30 minutes.
  • the reaction mass was filtered, and the layers were allowed to settle and were separated.
  • the toluene layer was stirred for 30 minutes with an additional 60mL portion of 10% potassium carbonate solution. The layers were allowed to settle and were separated.
  • the crude mass was charged into a 500 mL4N RB and methanol (110 mL, 2718.9 mmol, 100 mass%) was added.
  • the crude mass was heated to reflux and stirred to provide a clear solution. The heating was switched off and the mass cooled gradually to 30°C. The mass was cooled further to 0°C and stirred for 1 hour at 0 to 5°C.
  • the solid was filtered and washed with 20m L methanol.
  • reaction was alternatively conducted under neat conditions (using 20 eq. of POCI3).
  • DMF-DMA Dimethylformamide dimethylacetal
  • a suspension of compound of Formula (IV) (44.3g, 1.0 equiv.) in toluene (842mL).
  • the reaction mixture was heated at 90°C for 2 hours (full conversion to the compound of Formula (II) and formylated compound of Formula (X) was observed by UPLC/MS).
  • methane sulfonic acid (46.2g, 3.0 equiv.) were slowly added for 20 min and stirred for 4 hours. After completion of reaction, cooled to 25-30°C and layers were separated.
  • the compound of Formula (lll-a) (59.7g, 1 .0 equiv.) and the compound of Formula (II) (50g, 1.0 equiv.) were suspended in t-amyl alcohol (WOOmL) under nitrogen atmosphere.
  • Bis[2-(diphenylphosphino)-phenyl]ether (DPEphos) (3.29g, 0.035equiv.) and allylpalladium (II) chloride dimer (0.815g, 0.0125equiv.) and sodium-t-butoxide (25.2g, 1 ,5equiv.) were added under nitrogen atmosphere and the reaction mixture was purged with nitrogen for 15-20 min at 25-30°C.
  • the compound of Formula (lll-a) (239.0 mg, 1 eq), the compound of Formula (II )(200.0 mg, 1 eq), CS2CO3 (341 .4 mg, 1.5 eq), Pd/C 10% (14.9 mg, 0.02 eq) and dppf (11 .6 mg, 0.03 eq) were suspended in 3 mL CPME.
  • the mixture was degassed (Schlenk line 5x). The reaction mixture was heated overnight ( ⁇ 16h) at 120°C under argon. The reaction mixture was cooled to rt and poured into DCM/H2O. The mixture was extracted with DCM, dried, filtered and evaporated to provide the compound of Formula (I).
  • the compound of Formula (IV) (200 mg) was combined with the compound of Formula (lll-a) (1 eq) in THF (6 mL) under Argon. Pd2(dba)s (5 mol%), BrettPhos (10 mol%), and CS2CO3 (2equiv) were added and the reaction mixture was heated under argon at 80°C. After 16 hours, the ratio of starting material ofl formula (IV) to product of Formula (V) was ⁇ 0.1 : 1 by NMR and LIPLC.
  • ligands including XantPhos, Amphos,DavePhos, RuPhos, S-Phos, DPE- Phos, and MePhos were used.
  • the compound of Formula (V) was obtained in lower yields using these ligands, with the diarylated product observed as a major impurity.
  • the compound of Formula (V) (30 mg, 1 eq) was combined with DMF-DMA (1 O .L, 1 eq) in toluene (5 mL) and heated at 90°C. After 30 min, about 20% of starting material remained by LIPLC. After 3 hours, the reaction had reached full conversion to material with m/z 548. The mixture was evaporated. The product was filtered through silica (EtOAc:DCM (1 :1 )+5% MeOH). The compound of Formula (I) was isolated as the product as a yellow solid. 1 H, 13 C, HSQC, and HMBC NMR were consistent with authentic samples of Formula (I).
  • Formic acid (8mL) was added to the neat compound of Formula (I) (2.0 g, 1.0 equiv.) under nitrogen atmosphere. The resulted mixture was heated to 40-42°C over 5 to 10 min. and then stirred for 1.5 to 2.0 h. After completion of reaction, the reaction mixture was diluted with water (15 mL). The resulted aqueous solution was extracted with CH2CI2, EtOAc, 'PrOAc or Anisole (25 ml *2 times) at 50-65°C to remove the impurities. The aqueous layer was adjusted to ca. pH 12.5 using 33% (w/w) aq. sodium hydroxide (30 mL) over 30 min at 40°C. The resulted slurry was cooled to 15°C over 50 min to 80 min and stirred for 30 min at 15°C. Filtered the solid and washed with water

Abstract

La présente invention concerne des procédés améliorés pour la préparation de palbociclib. L'invention concerne en outre des intermédiaires et des procédés pour la préparation d'intermédiaires utiles pour la préparation de palbociclib.
PCT/IB2021/059991 2020-10-29 2021-10-28 Procédé de préparation de palbociclib WO2022091001A1 (fr)

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