WO2021106864A1 - Procédé de préparation de dérivés de pyrazolo [1,5-a] pyrimidine - Google Patents

Procédé de préparation de dérivés de pyrazolo [1,5-a] pyrimidine Download PDF

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WO2021106864A1
WO2021106864A1 PCT/JP2020/043659 JP2020043659W WO2021106864A1 WO 2021106864 A1 WO2021106864 A1 WO 2021106864A1 JP 2020043659 W JP2020043659 W JP 2020043659W WO 2021106864 A1 WO2021106864 A1 WO 2021106864A1
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compound
group
benzyl
formula
carbamate
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PCT/JP2020/043659
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English (en)
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Francis G. Fang
Hyeong-Wook Choi
Andrew James Amin ROUPANY
Michael Geoffrey Neil Russell
Mingde David SHAN
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Eisai R&D Management Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to processes useful for producing pyrazolo[1,5-a] pyrimidine derivatives such as 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid.
  • Protease-activated receptor is a type of trimeric G protein-coupled seven-transmembrane receptor and belongs to the receptor family mediating the cell action of serine proteases.
  • PAR1, PAR2, PAR3 and PAR4 have been cloned so far.
  • Serine proteases cleave an extracellular amino-terminal peptide chain of the PAR molecule at a specific site and thus expose a new amino-terminal peptide chain having a receptor activation sequence consisting of 5 or 6 amino acid residues.
  • the newly exposed amino-terminal peptide chain cleaved by a serine protease bonds as a chain-like ligand to the extracellular loop 2, which is the active site of PAR2 itself and thus activates PAR2.
  • PAR2 is known to be activated by trypsin, tryptase, kallikrein (mainly kallikreins 2, 4, 5, 6, and 14), blood coagulation factor VIIa, blood coagulation factor Xa and the like, and also activated when a synthetic peptide consisting of 5 or 6 amino acids synthesized based on the receptor activation sequence enters exogenously.
  • PAR2 is widely distributed in vivo such as in blood vessels, prostate gland, small intestine, large intestine, liver, kidney, pancreas, stomach, lung, brain and skin and is known to be an aggravating factor in various diseases such as allergy.
  • US2018/0057499 discloses pyrazolo[1,5-a] pyrimidine compounds having a PAR2 inhibitory action. These pyrazolo[1,5-a] pyrimidine compounds are provided for the treatment of inflammatory skin disease including atopic dermatitis, contact dermatitis, skin eczema, psoriasis and dry skin dermatitis or inflammatory bowel disease including ulcerative colitis, Crohn’s disease or infectious enteritis.
  • the present invention provides improved methods for producing pyrazolo[1,5-a] pyrimidine derivatives such as 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid (referred to herein as compound X).
  • compound X 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid
  • Compound X is produced by the coupling of two fragments, BB1 and D as illustrated below.
  • the present invention provides an improved process for the production of both the BB1 fragment and the fragment D. Hence, the invention provides an improved process for the production of compound X.
  • the first aspect of the invention therefore provides a process for the production of compound BB1, or a salt thereof, wherein: (a) compound 4 is converted to compound 6a wherein R 1 is a nitrogen protecting group selected from an amide protecting group or an amine protecting group; wherein R 1a is an amide protecting group; and wherein R 2 is selected from C 1 -C 4 alkyl or benzyl; (b) compound 6a is reacted in the presence of a base and a methylating agent to form compound 7a; and (c) compound 7a is deprotected to form BB1, or a salt thereof.
  • BB1 salts that may be prepared according to the process of the present invention include HCl, HBr, trifluoroacetate, formate, methanesulfonate, benzenesulfonate and para-toluenesulfonate salts.
  • the salt is a HCl salt.
  • An embodiment of the first aspect provides a process wherein, when R 1 is an amide protecting group, the N-atom and the R 1 group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide and when R 1 is an amine protecting group, it is selected from benzyl, ⁇ -methylbenzyl or para-methoxy benzyl; R 1a is an amide protecting group, wherein the N-atom and the R 1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide; and R 2 is selected from methyl, ethyl, isopropyl, t-butyl or benzyl.
  • a further embodiment of the first aspect provides a process wherein when R 1 is an amide protecting group, the N-atom and the R 1 group form t-butyl carbamate and when R 1 is an amine protecting group it is benzyl; R 1a is an amide protecting group, wherein the N-atom and the R 1a group form t-butyl carbamate; and R 2 is ethyl.
  • the conversion of compound 4 to compound 6a as set out in step (a) above can be carried out by (a) the asymmetric transfer hydrogenation of compound 4a to form a compound of formula 5a wherein R 1a is an amide protecting group, where the N-atom and the R 1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide and wherein R 2 is selected from methyl, ethyl, isopropyl, t-butyl or benzyl in the presence of a non-tethered Noyori catalyst and a hydrogen donor; and (b) reacting compound 5a in the presence of a base to form compound 6a.
  • R 1a is an amide protecting group, where the N-atom and the R 1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate,
  • an amide protecting group is for example t-butyl carbamate
  • the nitrogen atom of the piperidine ring will form part of the carbamate group.
  • R 1a and the nitrogen atom (N-atom) to which it is attached is t-butyl carbamate
  • the compound of formula 5a will have the chemical structure.
  • compound 5a is prepared in step (a) by the asymmetric transfer hydrogenation of compound 4a wherein R 1a is an amide protecting group, where the N-atom and the R 1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide, and wherein R 2 is selected from methyl, ethyl, isopropyl, t-butyl or benzyl in the presence of a non-tethered Noyori catalyst and a hydrogen donor.
  • R 1a is an amide protecting group, where the N-atom and the R 1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide
  • R 2 is selected from methyl, ethyl, isopropyl, t-butyl or benzyl
  • R 1a is an amide protecting group, where the N-atom and the R 1a group form a t-butyl carbamate group and R 2 is ethyl.
  • the conversion of compound 4a to compound 5a preferably produces compound 5a in an enantiomeric excess of the illustrated stereoisomer of greater than 40%, more preferably greater than 50%, more preferably greater than 60%, most preferably greater than 70%.
  • the non-tethered Noyori catalyst is preferably a Ru, Rh or Ir non-tethered Noyori catalyst, more preferably a Ru non-tethered Noyori catalyst.
  • the catalyst can have the structure (I) wherein A is methyl or a phenyl ring substituted with one or more of F or C 1 -C 4 alkyl and wherein B is a phenyl ring optionally substituted with one or more C 1 -C 4 alkyl; preferably wherein A is a phenyl ring substituted with one or more of F or Me and B is a phenyl ring optionally substituted with one or more of Me or isopropyl.
  • each C 1 -C 4 group is preferably independently selected from methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.
  • the group A can be selected from the group consisting of .
  • group B can be selected from the group consisting of .
  • the group B is selected from the group consisting of .
  • the catalyst can be selected from one or more of RuCl ( ⁇ -cymene) [(S,S)-Ts-DPEN], RuCl ( ⁇ -cymene) [(S,S)-Fs-DPEN] or RuCl (mesitylene) [(S,S)-Ts-DPEN].
  • the catalyst is RuCl( ⁇ -cymene) [(S,S)-Fs-DPEN].
  • the catalyst can be provided in an amount of from 0.005 to 0.1 mol equivalents, for example in an amount of from 0.025 to 0.01 mol equivalents, in an amount of 0.05 to 0.01 mol equivalents.
  • the catalyst can be provided in an amount of 0.005, 0.01, 0.025, 0.05 or 0.1 mol equivalents.
  • the process of the invention can be carried out at a temperature of from 20 to 50°C.
  • a temperature of from 20 to 50°C For example, from 20 to 40°C, from 20 to 30°C, from 20 to 25°C.
  • the process is carried out at a temperature of from 20 to 25°C.
  • the hydrogen donor is not limiting but can be selected from formic acid and triethylamine or an alcohol selected from EtOH or IPA or sodium formate.
  • the hydrogen donor is formic acid and triethylamine.
  • the hydrogen donor for example, the formic acid and triethylamine
  • the hydrogen donor can be degassed (for example by sparging with nitrogen) prior to the process for the production of compound 5a.
  • the process would then be carried out under an inert atmosphere (for example under nitrogen).
  • the ratio of formic acid to triethylamine is from 5:2 to 1:2.
  • the ratio of formic acid to triethylamine can be 2:1 to 1:1 or 3:2 to 1:1.
  • the ratio of formic acid to triethylamine can be 5:2, 2:1, 3:2, 1:2 or 1:2, preferably 5:2.
  • the conversion of compound 4a to compound 5a may be carried out in the presence of an organic co-solvent which is selected from, PhMe, DCM, DMF, MTBE, THF, 1,4-dioxane, EtOAc, MeCN and IPA.
  • organic co-solvent selected from, PhMe, DCM, DMF, MTBE, THF, 1,4-dioxane, EtOAc, MeCN and IPA.
  • compound 5a(i) is produced by the asymmetric transfer hydrogenation of compound 4a(i) in the presence of RuCl( ⁇ -cymene)[(S,S)-Fs-DPEN] and formic acid and triethylamine, at a temperature of from 20 to 50°C, wherein RuCl( ⁇ -cymene)[(S,S)-Fs-DPEN] is provided in an amount of from 0.005 to 0.1 mol equivalents and where the ratio of formic acid to triethylamine is from 5:2 to 1:2.
  • compound 5a is converted into compound 6a using base.
  • the base can be selected from one or more of potassium t-butoxide, sodium t-butoxide, sodium hydride, DBU or sodium methoxide, preferably potassium t-butoxide.
  • the conversion can be carried out in an anhydrous solvent such as MTBE, THF, 2-methyl tetrahydrofuran, DME, or 1,4-dioxane, preferably THF.
  • the conversion can be carried out at a temperature of from -10 to 40°C, preferably -5 to 0°C.
  • the reaction can be carried out for 0.5-6h, preferably 1-2h.
  • the resulting compound 6a can be recrystallised.
  • compound 6a can be dissolved in a solvent and then recrystallised by the addition of an anti-solvent optionally with cooling.
  • a suitable crystallisation solvent system includes a combination of a non-polar solvent and a polar solvent.
  • suitable non-polar solvents include n-heptane and hexane.
  • suitable polar solvents include MTBE, EtOAc or THF.
  • the crystallisation solvent system is n-heptane/MTBE. Crystallisation of compound 6a can involve heating of the system to a temperature as high as the boiling point of the solvent system and then slowly cooling the system to room temperature or to a temperature below room temperature such as about 0°C.
  • the recrystallised compound 6a is collected (for example by filtration).
  • compound 6a is recrystallised to produce a compound having an ee greater than 90%, more preferably greater than 95%.
  • the first aspect of the invention provides a process for the conversion of compound 4 into compound 6a comprising, (a)converting compound 4b wherein the R 1b group is a benzyl group or a substituted benzyl group such as ⁇ -methylbenzyl or para-methoxybenzyl, and R 2 is selected from methyl, ethyl, isopropyl, t-butyl or benzyl, into a compound 6b; (b) forming a chiral salt of compound 6b; (c) resolving the chiral salt of compound 6b by recrystallisation and then desalting the chiral salt; and (d) converting compound 6b to compound 6a wherein R 1a is an amide protecting group, where the N-atom and the R 1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide.
  • R 1a is an
  • the group R 1b and the nitrogen atom of the piperidine ring can form a protected amine.
  • the R 1b can be an unsubstituted benzyl group or a substituted benzyl group, such as ⁇ -methylbenzyl or ⁇ -methoxybenzyl.
  • compound 6b is converted into a compound of formula 6a where R 1a and the N-atom form a t-butyl carbamate group by hydrogenation of compound 6b in the presence of a catalyst and di-tert-butyl dicarbonate.
  • the formation of compound 6b from compound 4b can be carried out in the presence of a reagent for example, an organoboron reducing agent such as K-Selectride, L-Selectride or N-Selectride to form lactone 6b.
  • a reagent for example, an organoboron reducing agent such as K-Selectride, L-Selectride or N-Selectride to form lactone 6b.
  • the formation of lactone 6b is preferably carried out in the presence of a solvent such as PhMe, DCM or THF, preferably THF.
  • the lactone 6b formation can be carried out at a reaction temperature of from -78°C to 30°C.
  • Enantiomerically enriched compound 6b is produced via a chiral salt. Reaction of compound 6b with an acid such as (2S,3S)-2,3-bis(benzoyloxy)succinic acid - forms a chiral salt.
  • the chiral salt may be precipitated out in an organic/aqueous solvent system such as methyl acetate/water, EtOAc/water, methyl formate/water, ethyl formate/water, EtOAc/butanone, EtOAc/1-butanol, EtOAc/DCM, 1-butanol/PhMe, t-amyl alcohol/PhMe, MeCN/water, THF/water, MeOH/water, EtOH/water, IPA/water or IPA/water.
  • the solvent system is MeOAc/water.
  • the formation of the chiral salt can be carried out at a temperature of from 0 to 100°C. In particular, the reaction mixture is heated and then slowly cooled to facilitate crystallisation.
  • the obtained chiral salt can be recrystallised from an organic/aqueous solvent system such as methyl acetate/water, EtOAc/water and EtOAc/1-butanol to further improve optical purity.
  • an organic/aqueous solvent system such as methyl acetate/water, EtOAc/water and EtOAc/1-butanol to further improve optical purity.
  • the solvent system is methyl acetate/water.
  • the chiral salt is then desalted, for example by contact with a base, to produce enantiomerically enriched compound 6b.
  • the base can be an aqueous solution of a base such as LiOH, NaOH, KOH, NaHCO 3 , KHCO 3 , Na 2 CO 3 , K 2 CO 3, Cs 2 CO 3 , or K 3 PO 4, preferably NaOH.
  • the desalting of the chiral salt to yield enantiomerically enriched 6b can be carried out in an organic solvent, such as EtOAc, PhMe, MTBE or DCM, preferably EtOAc.
  • Compound 6b is then converted to compound 6a by removal of the protecting group R 1b and replacement with the protecting group R 1a .
  • R 1a and the nitrogen atom to which it is attached is t-butyl carbamate
  • R 1b can be replaced with R 1a by a hydrogenation reaction of compound 6b in the presence of di-tert-butyl dicarbonate and a catalyst, preferably palladium on carbon.
  • the resulting compound 6a can be recrystallised to further increase the enantiomeric excess.
  • compound 6a can be dissolved in a solvent and then recrystallised by the addition of an anti-solvent optionally with cooling.
  • the recrystallised compound 6a is collected, for example by filtration.
  • compound 6a is recrystallised to produce a compound having an ee greater than 90%, more preferably greater than 95%.
  • a suitable crystallisation solvent system would include a combination of a non-polar solvent and a polar solvent.
  • suitable non-polar solvents include n-heptane and hexane.
  • suitable polar solvents include MTBE, EtOAc or THF.
  • the crystallisation solvent system is n-heptane/MTBE. Crystallisation of compound 6a can involve heating of the system to a temperature as high as the boiling point of the solvent system and then slowly cooling the system to room temperature or to a temperature below room temperature such as about 0°C.
  • a second aspect of the invention provides a process for the production of compound 5a wherein the R 1a is an amide protecting group, where the N-atom and the R 1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide, and wherein R 2 is selected from methyl, ethyl, isopropyl, t-butyl or benzyl; by the asymmetric transfer hydrogenation of compound 4a in the presence of a non-tethered Noyori catalyst and a hydrogen donor.
  • the definition of the non-tethered Noyori catalyst, the amount of the catalyst, the process temperature and the hydrogen donor as set out for the conversion of compound 4a to compound 5a as described in the first aspect of the invention also apply to the conversion of compound 4a to compound 5a of the second aspect of the invention.
  • the process of the second aspect of the invention can be carried out in the presence of a catalyst which is selected from one or more of RuCl ( ⁇ -cymene) [(S,S)-Ts-DPEN], RuCl ( ⁇ -cymene) [(S,S)-Fs-DPEN] or RuCl(mesitylene)[(S,S)-Ts-DPEN].
  • a catalyst which is selected from one or more of RuCl ( ⁇ -cymene) [(S,S)-Ts-DPEN], RuCl ( ⁇ -cymene) [(S,S)-Fs-DPEN] or RuCl(mesitylene)[(S,S)-Ts-DPEN].
  • the catalyst is RuCl ( ⁇ -cymene) [(S,S)-Fs-DPEN].
  • the process of the second aspect of the invention particular provides the catalyst in an amount of from 0.005 to 0.1 mol equivalents.
  • the process of the second aspect of the invention is preferably carried out at a temperature of from 20 to 50 °C.
  • the hydrogen donor is preferably selected from formic acid and triethylamine or an alcohol selected from EtOH or IPA and sodium formate.
  • the hydrogen donor is formic acid and triethylamine, the ratio of formic acid to triethylamine is from 5:2 to 1:2.
  • R 1a is preferably an amide protecting group, where the N-atom and the R 1a group form a t-butyl carbamate group and R 2 is ethyl.
  • the second aspect of the invention particularly relates to a process for the formation of compound 5a(i) by the asymmetric transfer hydrogenation of compound 4b(i), in the presence of RuCl( ⁇ -cymene)[(S,S)-Fs-DPEN] and formic acid and triethylamine, at a temperature of from 20 to 50 °C, wherein RuCl( ⁇ -cymene)[(S,S)-Fs-DPEN] is provided in an amount of from 0.005 to 0.1 mol equivalents and where the ratio of formic acid to triethylamine is from 5:2 to 1:2.
  • a third aspect of the invention relates to the production of compound 4b.
  • Compound 4b(i) is prepared in steps (b) and (c) by contacting compound 2b(i) with an acid, preferably HCl followed by heating of the reaction mixture with EtOH.
  • Compound 2b(i) is prepared in step (a) by incubation of compound 1b(i) with a base such as Cs 2 CO 3 , in a solvent, such as MeCN and subsequent treatment with ethyl 2-bromoacetate.
  • Compound 4a can be prepared from compound 4b(i) by replacing the benzyl protecting group of compound 4b(i) with an oxycarbonyl group such that R 1a and the N-atom form a t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide protecting group.
  • the compound 4a is prepared from compound 4b(i) by the replacement of the benzyl protecting group with a Boc- protecting group by reaction of compound 4b(i) with di-tert-butyl dicarbonate in the presence of a catalyst, preferably palladium on carbon and hydrogen.
  • Compound 4b(i) can be converted into another compound 4b by replacing the benzyl protecting group with a substituted benzyl group selected from ⁇ -methylbenzyl or para-methoxybenzyl.
  • a fourth aspect of the invention provides a method for the production of BB1 from a compound 6a wherein the R 1a is an amide protecting group, where the N-atom and the R 1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide, preferably where the N-atom and the R 1a group form a group selected from t-butyl carbamate, wherein (a) compound 6a is reacted in the presence of a base and a methylating agent to form compound 7a, and (b) compound 7a is deprotected to form BB1, or a salt thereof.
  • Step (a) requires reaction of the compound 6a to form compound 7a.
  • a suitable methylating agent include MeI, or dimethyl sulfate, preferably MeI.
  • a suitable base include one or more of LiOH, NaOH, KOH, Mg(OH) 2 , or Ca(OH) 2 , preferably KOH.
  • compound 6a is treated with a methylating agent and a base in the presence of an anhydrous solvent.
  • a suitable anhydrous solvent include one or more of MTBE, THF, 2-methyl tetrahydrofuran, DME or 1,4-dioxane, preferably THF.
  • the reaction mixture can be heated, for example at 50-100 °C.
  • the reaction can be carried out for a period of from 2 hours to one day.
  • R 1a is a Boc protecting group
  • removal of the Boc protecting group may be carried out by treatment with an acid solution in an organic solvent.
  • the acid solution can be one or more of HCl, HBr, HI, H 2 SO 4 , or TFA.
  • the organic solvent is preferable dioxane.
  • the deprotection of compound 7a is carried out using HCl in dioxane.
  • the deprotection can be carried out at a temperature of from 0 °C to room temperature.
  • the deprotection can be carried out for a period of from 30 min to 6 h. After concentration of the reaction mixture under reduced pressure, the residual salt can be directly used in subsequent amide coupling reactions.
  • the fifth aspect of the invention relates to a process for the production of a compound C, said process comprising reaction of a compound of formula B with a compound of formula in the presence of a PdCl 2 (PPh 3 ) 2 catalyst, a solvent and a base, at a temperature of from 40 to 100 °C.
  • the base can be selected from K 3 PO 4 , CsF, KF, NaHCO 3 , K 2 CO 3 , Cs 2 CO 3 or Na 2 CO 3 , preferably Na 2 CO 3.
  • the solvent can be selected from water, THF, 1,4-dioxane, DMF, MeCN, PhMe and DME, preferably THF or a mixture of water and THF. The reaction is preferably carried out for a period of 6 to 16 hours.
  • the reaction can be carried out at a temperature of from 40 to 100 °C, preferably at a temperature of from 40 to 80 °C, more preferably at a temperature of from 40 to 60 °C.
  • a process for the production of a compound C in the presence of a PdCl 2 (PPh 3 ) 2 catalyst, THF and Na 2 CO 3 , at a temperature of from 40 to 60 °C.
  • the Na 2 CO 3 according to this aspect may be aqueous Na 2 CO 3 .
  • Compound C can be used in a process for the formation of compound D, said process comprising contacting compound C under conditions to hydrolyse the alkyl ester.
  • compound C is treated with a base such as LiOH, KOH or NaOH, preferably LiOH.
  • the hydrolysis reaction can be carried out in water or in a mixture of water and a miscible solvent, such as water and THF, MeOH, EtOH, IPA, 1,4-dioxane, tBuOH, DMF, DME and/or MeCN, preferably THF, MeOH and water.
  • compound C is hydrolysed in the presence of LiOH.H 2 O.
  • the sixth aspect of the invention provides a process for the formation of compound X, said process comprising reacting a compound of formula BB1 or a salt thereof with a compound of formula D to form compound E and the subsequent deprotection of compound E to form compound X.
  • the reaction of the compound of formula BB1 with a compound of formula D can be carried out using the compound BB1 or a salt of BB1.
  • the residual salt from the conversion of compound 7a to the compound BB1 may be used.
  • the compound of BB1 can be used as the hydrochloride salt.
  • the compound of formula BB1 or a salt thereof is produced according to the first aspect of the invention and/or the compound of formula D is produced according to the fifth aspect of the invention.
  • a further aspect of the present invention provides a compound of formula 5a(i) as described herein above.
  • the compound of formula 5a(i) has an ee of greater than 40 %, preferably greater than 50%, more preferably greater than 60%, even more preferably greater than 70%.
  • a still further aspect of the present invention provides a compound 6a(i) as described herein above having an ee of greater 90%.
  • the compound of formula 6a(i) has an ee greater than 95%, preferably greater than 98%, more preferably greater than 99%.
  • a still further aspect of the present invention provides a compound 7a(i) as described herein above.
  • the compound of formula 7a(i) has an ee greater than 95%, preferably greater than 98%, more preferably greater than 99%.
  • a still further aspect of the present invention provides a compound 6b(i) as described herein above.
  • the compound of formula 6b(i) has an ee greater than 50%, more preferably greater than 75%, even more preferably greater than 95%.
  • a still further aspect of the present invention provides a chiral salt of compound 6b(i).
  • the chiral salt of compound 6b(i) is the (2S,3S)-2,3-bis(benzoyloxy)succinate salt.
  • FIG.1 shows an X-Ray Powder Diffraction (XRPD) diffractogram of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c] pyridine-6(2H)-carboxylate (7b’).
  • XRPD X-Ray Powder Diffraction
  • the stereochemical descriptor represents the configuration of the major isomer.
  • a mixture of rotamers means a mixture of isomers having different conformations caused by intramolecular rotations around single bonds such as C-C, C-N or C-O.
  • Method A Compounds were analysed using the following conditions: Experiments were performed on a Waters SQD mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector and ELSD detector. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses an Acquity CSH C18 1.7 ⁇ m 50 x 2.1 mm column, maintained at 40 °C and a 0.6 mL/min flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% MeCN containing 0.1% formic acid (solvent B) for the first 0.2 min followed by a gradient up to 5% solvent A and 95% solvent B over the next 1.5 min. This was maintained for 0.5 min before returning to 95% solvent A and 5% solvent B over the next 0.05 min and maintained for 0.25 min. Total run time was 2.5 min.
  • Method B Compounds were analysed using the following conditions: Experiments were performed on a Waters SQD mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector and ELSD detector. The spectrometer has an electrospray source operating in positive and negative ion mode.
  • This system uses an Acquity BEH C18 1.7 ⁇ m 50 x 2.1 mm column, maintained at 40 °C and a 0.6 mL/min flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% MeCN containing 0.1% formic acid (solvent B) for the first 0.2 min followed by a gradient up to 5% solvent A and 95% solvent B over the next 1.5 min. This was maintained for 0.5 min before returning to 95% solvent A and 5% solvent B over the next 0.05 min and maintained for 0.25 min. Total run time was 2.5 min.
  • Method B Compounds were analysed using a Daicel ChiralCel OB-H 5 ⁇ m 250 x 4.6 mm column, maintained at 35 °C and a 0.8 mL/min flow rate. 10 ⁇ L of the compound was injected as a 1 mg/mL solution in EtOH. The solvent system used was a 75:15:10 mixture of heptane/IPA/MeOH at an isocratic gradient for 20 min. UV analysis was carried out at 204 and 220 nm.
  • Method C Compounds were analysed using a Daicel ChiralPak IC 5 ⁇ m 250 x 4.6 mm column, maintained at 30 °C and a 1 mL/min flow rate.
  • optical rotations The optical rotation was measured on a DIP-1000 type polarimeter (JASCO) using a 100 mm path length microcell at 20 °C. The measurement using Na D line was repeated five times and the mean value was used for calculation of specific rotation.
  • JASCO DIP-1000 type polarimeter
  • reaction conditions used for the preparation of tert-butyl (3R,4S)-4-(2-ethoxy-2-oxoethyl)-3-hydroxypiperidine-1-carboxylate as described herein below in step 1 of the preparation of 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid were chosen on the basis of the results of the optimisation experiments.
  • Step 1 Preparation of tert-butyl (3R,4S)-4-(2-ethoxy-2-oxoethyl)-3-hydroxypiperidine-1-carboxylate (5a(i))
  • tert-butyl 4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-1-carboxylate 9.40 g, 32.9 mmol
  • RuCl[(S,S)-FsDPEN]( ⁇ -cymene) (0.235 g, 0.329 mmol)
  • Step 2 Preparation of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c] pyridine-6(2H)-carboxylate (6a(i))
  • tert-butyl (3R,4S)-4-(2-ethoxy-2-oxoethyl)-3-hydroxypiperidine-1-carboxylate 7.13 g, 24.8 mmol
  • anhydrous THF (170 mL) under nitrogen at -2 °C (internal temp) was added dropwise, over 2 min, a 1 M THF solution of potassium tert-butoxide (2.48 mL, 2.48 mmol).
  • Step 3 Preparation of tert-butyl (3R,4S)-3-methoxy-4-(2-methoxy-2-oxoethyl) piperidine-1-carboxylate (7a(i))
  • tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c]pyridine-6(2H)-carboxylate (3.38 g, 14.0 mmol)
  • MeI 8.32 mL, 133 mmol
  • KOH 6.28 g, 112 mmol
  • Step 4 Preparation of methyl 2-((3R,4S)-3-methoxypiperidin-4-yl) acetate hydrochloride (BB1.HCl)
  • BB1.HCl 2-((3R,4S)-3-methoxypiperidin-4-yl) acetate hydrochloride
  • Step 5 Preparation of ethyl 5-chloro-7-((2-fluoro-6-methylphenyl) amino) pyrazolo[1,5-a] pyrimidine-2-carboxylate
  • ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (WO 2011105628) (43.6 g, 168 mmol) and 2-fluoro-6-methylaniline (18.48 ml, 160 mmol) in anhydrous 1-methyl-2-pyrrolidinone (128 mL) under nitrogen was stirred at 97 °C for 17 h. The mixture was cooled to 50 °C and water was added dropwise until a cloudy solution persisted (ca.
  • Step 6 Preparation of ethyl 5-chloro-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo[1,5-a] pyrimidine-2-carboxylate (B) To a solution of ethyl 5-chloro-7-((2-fluoro-6-methylphenyl) amino) pyrazolo [1,5-a] pyrimidine-2-carboxylate (39.90 g, 114 mmol) in DMF (400 mL) was added Cs 2 CO 3 (44.7 g, 137 mmol) then MeI (21.46 mL, 343 mmol) and the mixture was stirred at 40 °C (internal temperature) for 1 h.
  • Step 7 Preparation of ethyl 5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl)amino) pyrazolo[1,5-a] pyrimidine-2-carboxylate
  • C A solution of ethyl 5-chloro-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo [1,5-a] pyrimidine-2-carboxylate (41.1 g, 113 mmol) in THF (600 mL) and water (140 mL) was sparged with nitrogen for 3 h then Na 2 CO 3 (30.0 g, 283 mmol), (4-chloro-3,5-difluorophenyl)boronic acid (27.2 g, 142 mmol) and PdCl 2 (PPh 3 ) 2 (3.98 g, 5.66 mmol) were added whilst sparging continued.
  • Step 8 Preparation of 5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo [1,5-a] pyrimidine-2-carboxylic acid
  • D To a suspension of ethyl 5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo[1,5-a] pyrimidine-2-carboxylate (44.43 g, 93.563 mmol) in THF (900 mL) and MeOH (300 mL) was added water (300 mL) and lithium hydroxide monohydrate (11.78 g, 281 mmol) and the mixture was stirred at RT with a mechanical stirrer for 23 h.
  • Step 9 Preparation of methyl 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo[1,5-a] pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl) acetate
  • E To a suspension of 5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo [1,5-a] pyrimidine-2-carboxylic acid (6.63 g, 14.8 mmol) and methyl 2-((3R,4S)-3-methoxypiperidin-4-yl) acetate hydrochloride (3.16 g, 14.1 mmol) in DMF (125 mL) at 0 °C was added HOBT (3.52 g, 18.4 m
  • Step 10 Preparation of 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo [1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl) acetic acid (X) To a solution of methyl 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl)amino) pyrazolo [1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl) acetate (9.30 g, 15.1 mmol) in 1,4-dioxane (104 mL) at 10 °C was added a solution of LiOH monohydrate (1.11 g, 26.4 mmol) in water
  • Step 1 Preparation of ethyl 1-benzyl-4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-4-carboxylate (2b(i))
  • a 22 L reactor equipped with a mechanic stirrer was charged with potassium t-butoxide (829 g, 7.39 mol) and THF (8.0 L). After dissolution of all the solid at ambient temperature, the mixture was cooled to 6 °C and treated with a solid ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (1b(i)) (1.00 kg, 3.36 mol) portion wise over 15 min maintaining the internal temperature below 29 °C.
  • Step 2 Preparation of ethyl 2-(1-benzyl-3-oxopiperidin-4-yl) acetate (4b(i))
  • Ethyl 1-benzyl-4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-4-carboxylate (2b(i)) (1.079 kg, 3.106 mol) was charged into a 20 L reactor equipped with a mechanic stirrer, treated with conc. HCl (2.16 L, 25.9 mol), and heated to 95 °C for 6 h. After addition of EtOH (10.8 L), stirring was continued at 75 °C for additional 5 h.
  • Step 3 Preparation of (+/-)-6-benzylhexahydrofuro[2,3-c] pyridin-2(3H)-one (6b(i))
  • a solution of ethyl 2-(1-benzyl-3-oxopiperidin-4-yl)acetate (4b(i)) (792 g, 2.88 mol) in THF (5.05 L) was cooled to -75 °C and treated with 1 M K-Selectride in THF (2.88 L, 2.88 mol) over 2 h maintaining the internal temperature below -70 °C. After stirring at -75 °C for additional 1 h, the reaction was quenched with tBuOH (138 mL, 1.44 mmol).
  • Step 4 Preparation of (3aS,7aR)-6-benzylhexahydrofuro[2,3-c] pyridin-2(3H)-one (2S,3S)-2,3-bis(benzoyloxy) succinate (8b(i))
  • (2S,3S)-2,3-bis(benzoyloxy) succinate (8b(i)) A mixture of (+/-)-6-benzylhexahydrofuro [2,3-c] pyridin-2(3H)-one (6b(i)) (445.4 g, 1.93 mol) and (2S,3S)-2,3-bis(benzoyloxy) succinic acid (621 g, 1.73 mol) was dissolved in methyl acetate (13 L) and water (1.3 L).
  • the crystalline salt was suspended in water (300 mL) and methyl acetate (3000 mL) and heated to 60 °C for 2 h. The mixture was cooled to 45 °C over 1 h, stirred at 45 °C for 6 h and cooled to 20 °C over 8 h. The resulting precipitate was filtered, rinsed with methyl acetate (220 mL), and dried over N2 purge to give the compound 8b(i) (180g, 86% ee). The compound was recrystallized again by the same procedure from methyl acetate (700 mL) and water (70 mL) to give the compound 8b(i) (175 g, 15.4%).
  • Step 5 Preparation of (3aS,7aR)-6-benzylhexahydrofuro[2,3-c] pyridin-2(3H)-one (6b(i)) (3aS,7aR)-6-benzylhexahydrofuro[2,3-c]pyridin-2(3H)-one (2S,3S)-2,3-bis(benzoyloxy)succinate (8b(i)) (170 g, 288.3 mmol, 91%ee) was suspended in EtOAc (3386 mL) and water (270 mL) and then treated with 1 N sodium hydroxide (577 mL, 577 mmol).
  • Step 6 Preparation of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c] pyridine-6(2H)-carboxylate (6a(i))
  • the reaction mixture was purged with hydrogen gas and stirred under hydrogen gas (1.07 bar) for 1 d.
  • Celite 95 g
  • the mixture was stirred at rt for 1 h, filtered through a short pad of silica gel (60 g) and Celite (90 g), and rinsed with MeOH (2.1 L).
  • the filtrate was concentrated in vacuo and chased with EtOAc and n-heptane to give crude compound (86 g).
  • the crude product was dissolved in MTBE (263 mL), heated to 60 °C, and treated with n-heptane (1053 mL). The mixture was stirred at 60 °C for 30 min, slowly cooled to rt and then to 0 °C and stirred at 0 °CC for 1 h. The precipitate was filtered and rinsed with a 3:1 mixture of MTBE/n-heptane (150mL) and dried over N2 purge to give the compound 6a(i) (50.8 g, 74%).
  • Olex2 Dolomanov et al., 2009
  • the structure was solved with the ShelXS (Sheldrick, 2008) structure solution program, using the Direct Methods solution method.
  • the model was refined with version 2014/6 of XL (Sheldrick, 2008) using Least Squares minimisation.

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Abstract

L'invention concerne des procédés et des intermédiaires utiles pour la production de dérivés de pyrazolo [1,5-a] pyrimidine.
PCT/JP2020/043659 2019-11-25 2020-11-24 Procédé de préparation de dérivés de pyrazolo [1,5-a] pyrimidine WO2021106864A1 (fr)

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Cited By (1)

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WO2023233033A1 (fr) 2022-06-03 2023-12-07 Domain Therapeutics Nouveaux inhibiteurs de par-2

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US20030199541A1 (en) * 2000-08-01 2003-10-23 Maxime Lampilas Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents
WO2011105628A1 (fr) 2010-02-26 2011-09-01 Mitsubishi Tanabe Pharma Corporation Composés pyrazolopyrimidines et leur utilisation comme inhibiteur de la pde10
US20180057499A1 (en) 2016-08-31 2018-03-01 Eisai R&D Management Co., Ltd. PYRAZOLO[1,5-a]PYRIMIDINE COMPOUND
WO2019163956A1 (fr) * 2018-02-26 2019-08-29 エーザイ・アール・アンド・ディー・マネジメント株式会社 SEL DE COMPOSÉ PYRAZOLO [1,5-a] PYRIMIDINE ET CRISTAUX DE CELUI-CI

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US20030199541A1 (en) * 2000-08-01 2003-10-23 Maxime Lampilas Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents
WO2011105628A1 (fr) 2010-02-26 2011-09-01 Mitsubishi Tanabe Pharma Corporation Composés pyrazolopyrimidines et leur utilisation comme inhibiteur de la pde10
US20180057499A1 (en) 2016-08-31 2018-03-01 Eisai R&D Management Co., Ltd. PYRAZOLO[1,5-a]PYRIMIDINE COMPOUND
WO2019163956A1 (fr) * 2018-02-26 2019-08-29 エーザイ・アール・アンド・ディー・マネジメント株式会社 SEL DE COMPOSÉ PYRAZOLO [1,5-a] PYRIMIDINE ET CRISTAUX DE CELUI-CI
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