Processes for preparing triazole glycolate oxidase inhibitors
AssigneeCantero Therapeutics, Inc.
InventorsElham AKBARIROMANI, Pooran CHAND, Sunil Kumar CHOUDHARY, Miguel Xavier FERNANDES, Yves LEBLANC, Hans MAAG, Omkar REVU, Pavan SHEKHAWAT
Life of this patent
Estimating the term…
Abstract
The present disclosure provides processes for preparing 1,2,3-triazole-4-carboxylic acid related compounds of formula (I) and (II) via a Suzuki coupling reaction. The Suzuki coupling reaction is achieved by coupling a compound of formula (IV), a boron-containing derivative of 1,2,3-triazole-4-carboxylate, with a cycloalkyl phenyl halide or sulfonate of formula (V):
Claims75
A process for preparing a compound represented by formula (II):
- a tautomer thereof, or a salt thereof, comprising:
- a) contacting a compound of formula (IV):
- or a salt thereof, with a compound of formula (V):
- a first transition-metal catalyst, and a first base in a first solvent to form a compound of formula (III):
- or a salt thereof, and
- b) removing the PG group of the compound of formula (III) or the salt thereof to provide the compound of formula (II), the tautomer thereof, or the salt thereof,
- wherein:
- subscripts m and n are each independently 1 or 2;
- R1 is C1-6 alkyl;
- R2 and R3 are each independently H or halogen;
- X1 represents a boron-containing group;
- X2 is halogen or a sulfonate;
- and
- in formula (IV) or (III) is represented by the formula:
- or a mixture thereof, and
- PG is an amine-protecting group.
The process of claim, wherein the amine-protecting group is [2-(trimethylsilyl)ethoxy]methyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl.
The process of claim, wherein the amine-protecting group is 4-methoxybenzyl.
The process of any one of claims to, wherein X1 is represented by the formula:
- 1) —BY2, wherein Y is —OH, C1-6 alkyl, C1-6 alkoxy, C6-10 aryloxy, or a carboxylate group;
- 2) —BY, wherein Y is a bidentate C2-8 alkoxy group, a bidentate C6-10 aryloxy group, or a bidentate carboxylate group;
- 3) a 9-borabycyclo[3,3,1]nonane (9-BBN) group;
- 4) -BY3M, wherein Y is F or C1-6 alkoxy and M is an alkaline metal ion, an ammonium ion, or a phosphonium ion;
- or
- 5) -BYM, wherein Y is a tridentate C3-10 alkoxy group and M is an alkaline metal ion, an ammonium ion, or a phosphonium ion.
The process of claim, wherein X1 is —B(OH)2, —B(OEt)2, —B(OiPr)2, —BF3M, —B(OiPr)3M, —B(OiPr)3M,
- wherein M is Li+, Na+, or K+.
The process of claim, wherein X1 is represented by the formula:
The process of any one of claims to, wherein X2 is Cl, Br, I, OMs, OTs, or OTf.
The process of claim, wherein X2 is Br.
The process of any one of claims to, wherein the first transition-metal catalyst is a first palladium catalyst, a ruthenium catalyst, a rhodium catalyst, a cobalt catalyst, a nickel catalyst, an iron catalyst, a copper catalyst, or a combination thereof.
The process of claim, wherein the first palladium catalyst is Pd(acac)2, [Pd(allyl)Cl]2, Pd(CH3CN)2Cl2, Pd(dba)2, Pd(CH3COO)2, Pd2(dba)3, Pd2(dba)3-CHCl3, Pd(PPh3)4, Pd(OAc)2, Pd(PCy3)2Cl2, Pd(PPh3)2Cl2, Pd[P(o-tol)3]2Cl2, Pd(amphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(dtbpf)Cl2, Pd(CH3CN)4(BF4)2, PdCl2, XPhos-Pd-G3,
- Pd-PEPPSI™-IPr, Pd—PEPPSI™-SIPr, or Pd-PEPPSI™-IPent.
The process of claim, wherein the first palladium catalyst is Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, or Pd(dtbpf)Cl2.
The process of any one of claims to, the first transition-metal catalyst is in a substoichiometric amount.
The process of any one of claims to, the first base is sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate tribasic, potassium phosphate tribasic, sodium acetate, potassium acetate, cesium acetate, or a combination thereof.
The process of claim, wherein the first base is potassium carbonate.
The process of any one of claims to, wherein the compound of formula (V) is in an amount of from 1.0 to 2.0 equivalents, from 1.1 to 2.0 equivalents, from 1.1 to 1.5 equivalents, or about 1.2 equivalents, relative to the compound of formula (IV).
The process of claim, wherein the compound of formula (V) is in an amount of about 1.2 equivalents relative to the compound of formula (IV).
The process of any one of claims to, wherein the first solvent is water, C1-4 alcohol, benzene, toluene, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF), acetonitrile (ACN), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), dimethoxyethane (DME), ethylene glycol, or a combination thereof.
The process of claim, the first solvent comprises dioxane and water.
The process of any one of claims to, wherein step a) is conducted at a temperature of from 60° C. to 110° C., from 70° C. to 110° C., from 70° C. to 100° C., from 70° C. to 90° C., or about 80° C.
The process of claim, wherein step a) is conducted at a temperature of about 80° C.
The process of any one of claims to, wherein, in step b), the PG group is removed by treating with a first acid in a second solvent.
The process of claim, wherein the first acid is trifluoroacetic acid.
The process of claim, wherein the second solvent is dichloromethane or 1,2-dichloroethane.
The process of any one of claims to, wherein a reaction mixture of step b) further comprises a transferring agent.
The process of claim, wherein the transferring agent is anisole.
The process of any one of claims to, further comprising:
- c) contacting the compound of formula (II), the tautomer thereof, or the salt thereof with a second base in a third solvent;
- and
- d) acidifying with a second acid to provide a compound of formula (I):
- a tautomer thereof, or a salt thereof.
The process of claim, wherein the second base is lithium hydroxide, sodium hydroxide, or potassium hydroxide.
The process of claim, wherein the second base is sodium hydroxide.
The process of any one of claims to, wherein the third solvent is water, C1-4 alcohol, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF), acetonitrile (ACN), dimethoxyethane (DME), or a combination thereof.
The process of claim, wherein the third solvent comprises tetrahydrofuran and water.
The process of any one of claims to, wherein the second acid is HCl.
The process of any one of claims to, wherein the step d) is conducted in an aqueous solution.
The process of any one of claims to, wherein the compound of formula (II) is represented by the formula selected from the group consisting of:
The process of any one of claims to, wherein R1 is methyl.
The process of any one of claims to, wherein the compound of formula (I) is represented by the formula selected from the group consisting of:
The process of any one of claims to, wherein R2 and R3 are each independently halogen.
The process of claim, wherein R2 and R3 are each F.
The process of any one of claims to, further comprising prior to step a):
- a1) contacting a compound of formula (VI):
- or a salt thereof, with a boron reagent, a second palladium catalyst, and a third base in a fourth solvent to form the compound of formula (IV) or the salt thereof, wherein X is Cl, Br, or I.
The process of claim, wherein the boron reagent is tetrahydroxydiboron, bis(catecholato)diboron, bis(hexylene glycolato)diboron, bis(neopentyl glycolato)diboron, or bis(pinacolato)diboron.
The process of claim, wherein the boron reagent is bis(pinacolato)diboron.
The process of any one of claims to, the second palladium catalyst is Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, or Pd(dtbpf)Cl2.
The process of any one of claims to, wherein the third base is potassium acetate.
The process of any one of claims to, wherein the fourth solvent is 1,4-dioxane.
The process of any one of claims to, wherein the compound of formula (VI) is represented by the formula
A process for preparing a compound represented by the formula (Ia-1):
- a tautomer thereof, or a salt thereof, comprising:
- a1) converting a compound of formula (VI-1a-1):
- or a salt thereof, with bis(pinacolato)diboron, Pd(dppf)Cl2·CH2Cl2, and potassium acetate in 1,4-dioxane to a compound of formula (IV-1a-2):
- or a salt thereof,
- a) contacting the compound of formula (IV-1a-2) or the salt thereof with 1-bromo-4-(3,3-difluorocyclobutyl)benzene, Pd(dppf)Cl2·CH2Cl2, and potassium carbonate in a mixture of 1,4-dioxane and water to form a compound of formula (IIIa-1a-1):
- or a salt thereof,
- b) treating the compound of formula (IIIa-1a-1) or the salt thereof, with trifluoroacetic acid and anisole in dichloromethane to provide a compound of formula (IIa-1):
- a tautomer thereof, or a salt thereof,
- c) saponifying the compound of formula (IIa-1), the tautomer thereof, or the salt thereof with an aqueous solution of sodium hydroxide in tetrahydrofuran;
- and
- d) acidifying with an aqueous solution of HCl to provide the compound of formula (Ia-1), the tautomer thereof, or the salt thereof.
The process of claim, step a1) is conducted at a temperature of about 80° C.;
- step a) is conducted at a temperature of about 80° C.;
- step b) is conducted at a temperature of about 50° C.;
- and step c) is conducted at a temperature of about 55° C.;
- and step d) is conducted at a temperature of about 20-25° C.
The process of claim, wherein, in step a), 1-bromo-4-(3,3-difluorocyclobutyl)benzene is in an amount of from 1.0 to 1.5 equivalents relative to the compound of formula (IV-1a-2).
The process of any one of claims to, wherein, in step a), Pd(dppf)Cl2·CH2Cl2 is in an amount of from 0.05 to 0.1 equivalent relative to the compound of formula (IV-1a-2).
The process of any one of claims to, wherein, in step a), potassium carbonate is in an amount of from 2.0 to 4.0 equivalents relative to the compound of formula (IV-1a-2).
The process of any one of claims to, wherein the compound of formula (IV-1a-2) produced by step a1) is directly used in the next step without further purification.
The process of any one of claims to, wherein the compound of formula (IIIa-1) is isolated in a combined yield of at least 50% from both steps a1) and a).
The process of any one of claims to, wherein the compound of formula (IIa-1) produced by step b) is directly used in next step without further purification.
The process of any one of claims to, wherein step d) is conducted by acidifying an aqueous extract of a reaction mixture of step c).
The process of any one of claims to, further comprising:
- e) converting the compound of formula (Ia-1), the tautomer thereof, or the salt thereof, to a mono-sodium salt of the compound of formula (Ia-1) represented by the formula:
- a di-sodium salt of the compound of formula (Ia-1) represented by the formula:
- or a mixture thereof, or a tautomer thereof.
The process of claim, wherein step e) is conducted by:
- i) treating the compound of formula (Ia-1) or a tautomer thereof with an aqueous solution of sodium hydroxide in water;
- ii) forming a slurry having a pH value of about 9.5;
- and
- iii) lyophilizing the slurry to provide the mono-sodium salt of the compound of formula (Ia-1) represented by the formula:
- or a tautomer thereof,
- wherein sodium hydroxide is in an amount of less than 1.0 equivalent relative to the compound of formula (Ia-1), on a salt-free and anhydrous basis.
The process of claim, wherein sodium hydroxide is in an amount of about 0.88 equivalent relative to the compound of formula (Ia-1), on a salt-free and anhydrous basis.
A compound represented by formula (X):
- a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is H or C1-6 alkyl;
- and R2 and R3 are each independently H or halogen.
The compound of claim, represented by formula (Xa):
The compound of claim, represented by formula (Xb):
The compound of any one of claims to, wherein R1 is H.
The compound of any one of claims to, wherein R1 is C1-6 alkyl.
The compound of claim, wherein R1 is methyl.
The compound of any one of claims to, wherein R2 and R3 are each independently halogen.
The compound of claim, wherein R2 and R3 are each —F.
The compound of claim, selected from the group consisting of:
A pharmaceutical composition comprising a compound according to any one of claims to, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A method for treating primary hyperoxaluria, type I (PH1) comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims to or a pharmaceutical composition according to claim .
The method of claim, the subject has kidney and/or bladder stones.
The method of claim, wherein the compound reduces glyoxylate level in the subject.
The method of any one of claims to, wherein the compound reduces an accumulation of oxalate in kidney and/or urinary tract.
A method for treating kidney and/or bladder stones comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims to or a pharmaceutical composition according to claim.
The method of claim, wherein the compound reduces an accumulation of oxalate in kidney and/or urinary tract.
A method for inhibiting glycolate oxidase comprising contacting glycolate oxidase with an effective amount of a compound according to any one of claims to or a pharmaceutical composition according to claim.
The method of claim, the compound reduces glyoxylate level.
The method of any one of claims to, wherein the compound is
- a tautomer thereof, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.