WO2014206903A1

WO2014206903A1 - METHODS FOR THE PREPARATION OF SUBSTITUTED [1,2,4]TRIAZOLO[1,5-a]PYRIDINES

Info

Publication number: WO2014206903A1
Application number: PCT/EP2014/063094
Authority: WO
Inventors: Mogens Larsen; Allan Carsten Dahl; John Mcparland
Original assignee: Leo Pharma A/S
Priority date: 2013-06-25
Filing date: 2014-06-23
Publication date: 2014-12-31
Also published as: TW201534607A

Abstract

The present invention relates to novel methods for the preparation of substituted [1,2,4]triazolo[1,5-a]pyridinesand intermediates for the same. The compounds are useful as PDE4 inhibitors.

Description

METHODS FOR THE PREPARATION OF SUBSTITUTED [l,2,4]TRIAZOLO[l,5-a]PYRIDINES

FIELD OF THE INVENTION The present invention relates to novel methods for the preparation of substituted

[l,2,4]triazolo[l,5-a]pyridines and intermediates for the same. The compounds are useful as PDE4 inhibitors.

BACKGROUND OF THE INVENTION

PCT/EP2012/076191 discloses [l,2,4]triazolopyridine compounds useful as PDE4 inhibitors as well as suitable methods for the preparation thereof.

WO2010/069322 discloses novel triazolopyridines useful as PDE4 inhibitors as well as suitable methods for the preparation thereof.

WO2008/125111 discloses triazolopyridines useful as PDE4 inhibitors as well as suitable methods for the preparation thereof.

In the development of new drug candidates, it is highly desirable to have access to a number of alternative methods for the preparation of target compounds in that some efficient small-scale synthesis may turn out to be difficult to up-scale to production scale quantities. Also, small-scale syntheses may involve reagents and solvents which are not feasible to utilize at a production scale level.

Preparation of substituted 2-(8-alkoxy-[l,2,4]triazolo[l,5-a]pyridin-2-yl)acetic acid esters which are useful intermediates in the preparation of certain PDE4 inhibitors (PCT/EP2012/076191, WO2010/069322) have previously been performed in several reaction steps utilizing i.a. highly reactive intermediates. The use of starting materials and intermediates comprising functional groups with high energy is of major concern. Hence, it is an object of the present invention to provide alternative methods for the preparation of substituted 2-(8-alkoxy-[l,2,4]triazolo[l,5-a]pyridin-2-yl)acetic acid and substituted 2-(8-alkoxy-[l,2,4]triazolo[l,5-a]pyridin-2-yl)acetic acid esters which are intermediates useful in the preparation of [l,2,4]triazolo[l,5-a]pyridine compounds of the type disclosed in WO2010/069322 and PCT/EP2012/076191, as well as to provide alternative methods for the preparation of [l,2,4]triazolo[l,5-a]pyridine compounds of the type disclosed in PCT/EP2012/076191 utilizing such intermediates, insofar that such alternative methods provide advantages with respect to one or more features like number of reactions steps, purity, yield, ease of purification, process economy, availability of starting materials and reagents, safety, predictability, etc.

SUMMARY OF THE INVENTION

It has been found by the present inventors that the alternative methods disclosed herein provides advantages over the known methods by a reduced number of reactions steps, by using other and less highly reactive compounds, by reducing work load regarding synthesis of substance and ease of the production method as some intermediates are not isolated, and by circumventing the isolation of a hazardous intermediate.

Hence, the present invention provides methods for the preparation of substituted

[ l,2,4]triazolo[ l,5-a]pyridines, e.g . a compound of formula (I). Also within the scope of the invention are intermediates used in the foregoing method for preparing compounds of formula (I), and methods of making such intermediates comprising one or more of the foregoing steps as indicated .

DETAILED DISCLOSURE OF THE INVENTION

In a first aspect, the present invention relates to a method for the preparation of a compound of formula (I)

wherein R₂ represents Ci_₆alkyl.

In one embodiment R₂ represents branced butyl. In another embodiment R₂ represents isobutyl.

Definitions The term "Ci-6-alkyl" is intended to mean a saturated, straight or branched hydrocarbon chain having from one to six carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. In some embodiments, "Ci-₆-alkyl" is a Ci-₄-alkyl group, e.g . methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl and tertiary butyl.

Correspondingly, "Ci-₃-alkyl" includes methyl, ethyl, propyl and isopropyl.

The term "halogen" is intended to mean one of fluoro, chloro, bromo and iodo. In one embodiment, the term "halogen" designates bromo or iodo. In another embodiment, the term "halogen" designates bromo.

Methods of preparation

The methods for the preparation of a compound of formula (I) includes the preparation of the starting material, a compound of formula (II)

(Π)

which is obtained by hydrogenating commercially available 3-methoxy-2-nitropyridine optionally under pressure. The reaction is typically conducted in a solvent, e.g. selected from but not limited to methanol, ethanol, 2-propanol, acetone, ethyl acetate (EtOAc), and tetrahydrofuran (TH F), and mixtures thereof, in the presence of a catalyst, e.g. selected from the transition metals either in elemental form, as a chemical compound, or supported on an inert solid, such as, but not limited to, platinium(IV) oxide or palladium on carbon. In one embodiment, the solvent is selected as a mixture of ethyl acetate and methanol in the presence of palladium on carbon as catalyst.

The reaction is typically conducted under pressure in the range of 1-5 bars, such as in the range of 3-5 bar. The reaction is typically conducted at a temperature in the range of 10-30 °C, such as in the range of 18-23°C. The reaction is typically allowed to proceed for 1-48 hours, such as 3-24 hours.

Steps (a) and (b)

The reaction steps (a) and (b) are performed as a one-pot reaction indicating that the intermediate compound (IV) is not isolated. In the N-aminating step (a), the compound of formula (II)

(Π)

is reacted with a reagent of formula (III), H₂N-X, wherein H₂N-X represents an N- amination reagent, to form the intermediate compound of formula (IV)

(IV)

wherein X^" represents an anion of the N-amination reagent, such as hydrogen sulfate, tosylate, mesityl sulfonate, phenolate, chloride; followed by the cyclising (b) of the above intermediate (IV) with a compound of formula (V)

(V)

wherein each Ri independently is selected from Ci_₆alkyl, to form a compound of formula (VI)

(VI) wherein R represents hydrogen or d-₆alkyl.

The N-amination reagent is selected from the commercial available hydroxylamine-O- sulfonic acid, O-tosyl hydroxylamine, O-mesitylsulfonyl hydroxylamine, phenyl hydroxylamines, chloroamine. In one embodiment the N-amination reagent is hydroxylamine-O-sulfonic acid .

The reaction (a) is typically conducted in a polar solvent, e.g . selected from, but not limited to, methanol, ethanol, 2-propanol, or water, and mixtures thereof, in the presence of a base, e.g. selected from l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (Et₃N), Ν,Ν-diisopropylethylamine (DIPEA), K₂C0₃ and lithium methoxide (LiOMe). In one embodiment, the solvent is an alcohol with an organic amine as base. Preferably, methanol is used as solvent and l,8-diazabicyclo[5.4.0] undec-7-ene is used as base. In another preferred embodiment, methanol is used as solvent and lithium methoxide is used as base.

Further, reaction (a) is typically conducted at a temperature in the range of 20-70 °C, such as in the range of 38-70°C. The reaction is typically allowed to proceed for 3-48 hours.

After heating the mixture for the time stated above, the cyclising (b) is conducted by the addition of compound of formula (V). The compound of formula (V) is commercial available for most of the possible combinations of Ri. In one embodiment said compound of formula (V) is wherein Ri independently represents methyl or ethyl. In another embodiment the compound is the commercial available dimethyl cyclopropane-1,1- dicarboxylate.

The reaction (b) is typically conducted by add ing a base in combination with the compound of formula (V), e.g. selected from l,8-diazabicyclo[5.4.0] undec-7-ene (DBU), triethylamine (Et₃N), Ν,Ν-diisopropylethylamine (DIPEA), K₂C0₃ and lithium methoxide (LiOMe). In one embodiment, an organic amine is used as base. Preferably, 1,8- diazabicyclo[5.4.0] undec-7-ene is used as base. In another preferred embodiment, lithium methoxide is used as base.

The reaction (b) is typically conducted at a temperature in the range of 60-75°C, such as in the range of 65-75°C. The reaction is typically allowed to proceed for 6-24 hours, such as 16-18 hours. After heating the mixture for the time stated above, and in case, it is the compound of formula (VI) wherein R represents H that is the preferred product, a base, e.g . a metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide, e.g . sodium hydroxide, is added to the mixture. After hydrolysis of compound of formula (VI) wherein R represents Ci_₆alkyl to compound of formula (VI) wherein R represents H and removal of any organic solvent from the mixture, the mixture is washed with an organic solvent which is immiscible with water, preferably with methyl tert-butyl ether or ethyl acetate. The compound of formula (VI) wherein R represents H is then precipitated by addition of sulphuric acid .

The resulting crude product (VI) may be isolated by conventional means, e.g. by filtration .

In one embodiment of the invention, the compound of formula (VI) is wherein R is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl, or tertiary butyl . In another embodiment the compound of formula (VI) is wherein R is hydrogen . In another embodiment the compound of formula (VI) is wherein R is isobutyl.

Step (c)

With regard to the halogenation of the compound of formula (VI) wherein R represents h drogen or d-₆alkyl, with a halogenating agent to form a compound of formula (VIII)

wherein R represents hydrogen or Ci-₆alkyl, and Hal represents halogen, the reaction is typically conducted in an aprotic polar solvent or mixtures thereof, e.g . selected from acetonitrile (MeCN), Ν,Ν-dimethylformamide (DMF), tetrahydrofuran (THF) and methyl tert-butyl ether (MTBE) and mixtures thereof. In one embodiment, the solvent is a mixture of acetonitrile and N,N-dimethylformamide.

The halogenating agent is typically selected from N-bromosuccinimide, N-iodosuccin- imide and N-chlorosuccinimide. In one embodiment the halogenating agent is N- bromosuccinimide.

The reaction is typically conducted at a temperature in the range of 50-70 °C, such as in the range of 55-68°C.

The resulting crude product (VIII) may be recovered by conventional means, known to those skilled in the art.

In one embodiment of the invention the compound of formula (VIII) is wherein R is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl or tertiary butyl. In another embodiment the compound of formula (VIII) is wherein Hal is iodo or bromo. In another embodiment the compound of formula (VIII) is wherein R is hydrogen and Hal is bromo. In another embodiment compound of formula (VIII) is wherein R is isobutyl and Hal is bromo.

Preparation of the compound of formula (IX)

The compound of formula (IX), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3H- isobenzofuran-l-one, which is also described in WO2010/069322 as compound 316,

to be used in the Suzuki coupling reaction (d) is prepared by reacting 5-bromo-3H- isobenzofuran-l-one and bis(pinacolato)diborone, both starting materials being commercial available. The reaction is typically conducted in an aprotic polar solvent or mixtures thereof, e.g. selected from acetonitrile (MeCN), Ν,Ν-dimethylformamide (DMF), tetrahydrofuran (THF), methyl-tert-butylether (MTBE), and dioxane or mixtures thereof, preferably DMF or dioxane. The reaction is performed in the presence of a base, e.g. selected from potassium acetate, potassium carbonate, potassium phosphate, preferably potassium carbonate or potassium acetate. The reaction is catalysed by a catalyst based on a transition metal, e.g. palladium(II)acetate or and [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II), complex with dichloromethane. In one embodiment, the solvent is Ν,Ν-dimethylformamide (DMF), the base is potassium carbonate and the catalyst is palladium(II)acetate. In another embodiment, the solvent is dioxane, the base is potassium acetate, and the catalyst is and [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II), complex with dichloromethane.

The resulting crude product (IX) may be isolated by conventional means, known to those skilled in the art. In one embodiment, the resulting crude product (IX) is re-precipitated by dissolving the product in a polar solvent, preferably ethyl acetate, filtering through silicagel, and concentration of the resulting solution. In another embodiment, the crude product (IX) is washed by trituration in an unpolar solvent, preferably cyclohexane, followed by filtration. Step (d)

The Suzuki coupling reaction is performed by reacting the above compound of formula (VIII) wherein R represents hydrogen or d-₆alkyl, and Hal represents halogen, with the above compound of formula (IX), catalysed by a Pd catalyst in the presence of a base, to form a compound of formula XI)

wherein R represents hydrogen or Ci_₆alkyl.

The Pd catalyst is typically selected from, but not limited to, bis(triphenylphosphine)- palladium(II)dichloride, tetrakis(triphenylphosphine)palladium(0) or [l, l'-bis(diphenyl- phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane. In another embodiment, the reactive catalyst is formed by mixing a source of Pd, such as, but not limited to, tris(dibenzylideneacetone)dipalladium(0) and bis(dibenzylideneacetone)- palladium(O), with a ligand such as, but not limited to, tricyclohexylphosphine. In one embodiment the Pd catalyst is bis(triphenylphosphine)palladium(II)dichloride. In another embodiment, the Pd catalyst is [l, l'-bis(diphenylphosphino)ferrocene]dichloro- palladium(II), complex with dichloromethane. In yet another embodiment, the Pd catalyst is formed by mixing tris(dibenzylideneacetone)dipalladium(0) with tricyclohexylphosphine.

The reaction is typically conducted in a mixture of dioxane and water. The ratio of waten dioxane is typically in the range 30 : 70 to 5: 95 w/w, preferable in the range 25 : 75 to 15 : 85 w/w. In one embodiment, the ratio of waten dioxane is 20 : 80 w/w.

The reaction is typically conducted in the presence of a base e.g. selected from triethylamine, K₃P0₄, Na₂C0₃ and K₂C0₃. In one embodiment, the base is triethylamine. Further, the reaction is typically conducted at a temperature in the range of 70°C to reflux of the solvent mixture, preferably in the range 80-85°C. In one embodiment of the invention the compound of formula (XI) is wherein R is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl or tertiary butyl. In another embodiment the compound of formula (XI) is wherein R is hydrogen. In another embodiment the compound of formula (XI) is wherein R is isobutyl.

Alternative way of preparing the compound of formula (XI)

An alternative way of preparing the compound of formula (XI), wherein R represents hydrogen or Ci-₆alkyl, via a Suzuki coupling reaction is carried out by:

(i) reacting the above compound of formula (VIII) wherein R represents hydrogen or Ci_ 6alkyl and Hal represents halogen, with the above compound of formula (IX), catalysed by a Pd catalyst in the presence of a base, to form a compound of formula (X)

wherein R represents hydrogen or Ci_₆alkyl; and

(ii) ring closing of the compound of formula (X), wherein R represents hydrogen or Ci- 6alkyl, to form the compound of formula (XI), wherein R represents hydrogen or Ci- 6alkyl.

The Pd catalyst in the reaction (i) is typically selected from, but not limited to, bis(triphenylphosphine)palladium(II)dichloride, tetrakis(triphenylphosphine)palladium(0) or [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloro- methane. In another embodiment, the reactive catalyst is formed by mixing a source of Pd, such as, but not limited to, tris(dibenzylideneacetone)dipalladium(0) and

bis(dibenzylideneacetone)palladium(0), with a ligand such as, but not limited to, tricyclohexylphosphine. In one embodiment the Pd catalyst is bis(triphenylphosphine)- palladium(II)dichloride. In another embodiment, the Pd catalyst is [l,l'-bis(diphenyl- phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane. In yet another embodiment, the Pd catalyst is formed by mixing tris(dibenzylideneacetone)- dipalladium(O) with tricyclohexylphosphine.

The reaction (i) is typically conducted in a mixture of dioxane and water in the presence of a base e.g . selected from triethylamine, K₃P0₄, Na₂C0₃ and K₂C0₃. In one

embodiment the base is K₃P0₄. In another embodiment the base is K₂C0₃.

The reaction (i) is typically conducted at a temperature in the range of 70°C to reflux of the solvent mixture, preferably in the range 80-85°C.

The resulting crude product (X) may be isolated by conventional means, known by those skilled in the art.

The reaction (ii) is typically conducted in an aprotic polar solvent, e.g . an ether or a cyclic ether selected from dioxane, diethyl ether, tert-butyl methyl ether, in the presence of an acid, e.g . sulphuric acid . In one embodiment the solvent is dioxane and the acid is sulphuric acid.

The reaction (ii) is typically conducted at reflux of the reaction mixture.

Another alternative way of preparing the compound of formula (XI)

Another alternative way of preparing the compound of formula (XI) is by performing the preparation of the compound of formula (IX) and step (d) as a one-pot reaction, indicating that work-up of the compound of formula (IX) is circumvented . A further advantage is that the expensive Pd catalyst is used for both reactions, reducing the cost of Pd catalyst for the production.

Several impurities can form during this one-pot synthesis of the compound of formula (XI), e.g . the compound of formula (X), the compound of formula (VI), the homo coupled product arising from the compound of formula (VIII), and the homo coupled product arising from 5-bromo-3H-isobenzofuran-l-one. By the present one-pot synthesis it has been found that the compound of formula (XI) could be isolated in a reasonable yield and reasonable quality.

The other alternative way of preparing the compound of formula (XI), wherein R represents hydrogen or Ci_₆alkyl is carried out by : (i) reacting 5-bromo-3H-isobenzofuran-l-one and bis(pinacolato)diborone, both starting materials being commercial available, to form the compound of formula (IX)

and then

(ii) adding the compound of formula (VIII)

wherein R represents hydrogen or Ci_₆alkyl, and Hal represents halogen, to the reaction mixture containing the compound of formula (IX), and letting the compounds of formula (VIII) and (IX) react to form the compound of formula (XI)

wherein R represents hydrogen or Ci_₆alkyl.

The resulting crude product (XI) may be isolated by conventional means, known by those skilled in the art.

The reaction (i) is typically conducted in an aprotic polar solvent or mixtures thereof, e.g. selected from acetonitrile (MeCN), Ν,Ν-dimethylformamide (DM F), tetrahydrofuran (THF), methyl-tert-butylether (MTBE), and dioxane or mixtures thereof, preferably DMF or dioxane. The reaction is performed in the presence of a base, e.g . selected from potassium acetate, potassium carbonate, potassium phosphate, preferably potassium carbonate or potassium acetate. The reaction is catalysed by a suitable Pd catalyst. In one embodiment, the solvent is dioxane, the base is potassium acetate, and the catalyst is [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane.

The reaction (ii) is typically conducted by adding a compound of the formula (VIII) to the reaction mixture resulting from reaction (i), optionally in combination with the addition of water to the reaction mixture. In one embodiment, water is added in combination with the compound of formula (VIII).

The reaction (i) is typically performed at elevated temperature, such as 50-105°C, preferably 70-90°C, most preferably at 73-81°C.

The reaction (ii) is typically performed at elevated temperature, such as 50-105°C, preferably 60-80°C, most preferably 68-75°C.

In one embodiment, the compound of formula (VIII) is wherein Hal represents bromine, and R represents hydrogen. Step (e)

When R represents hydrogen in the compound of formula (XI), the following alkylation step (e) is conducted to form the compound of formula (I) wherein R₂ represents Ci- ₆alkyl, by reacting said compound of formula (XI) with an alkylating agent (XII), R₂-Hal, wherein R₂ represents Ci-₆alkyl and Hal represents halogen.

In one embodiment the alkylating agent is the compound of formula (XII) wherein R₂ represents Ci-₆alkyl, e.g. methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl or tertiary butyl, and Hal represents bromo or iodo. In another embodiment R₂ represents isobutyl and Hal represents iodo.

The reaction is typically conducted in an aprotic polar solvent or mixtures thereof, e.g. selected from acetonitrile (MeCN), Ν,Ν-dimethylformamide (DMF), tetrahydrofuran (THF) and methyl-tert-butylether (MTBE) and mixtures thereof in the presence of a base, e.g. selected from, but not limited to, Cs₂C0₃ or potassium carbonate. In one embodiment, the solvent is Ν,Ν-dimethylformamide (DMF) and the base is Cs₂C0₃. In another embodiment, the solvent is Ν,Ν-dimethylformamide and the base is potassium carbonate. Purification of the compound of formula (I), and (XI) wherein R represents C_halky!

The resulting crude product (crude I/XI) may advantageously be purified by

crystallization, precipitation, chromatography or the like.

In one embodiment the resulting crude I/XI is crystallized in water/DMF/citric acid; isolated by filtration and dried; subsequently dissolved in CH₂CI₂ and treated with PL- DETA resin; filtered through celite; after exchange of solvent to EtOH, the product is crystallized from EtOH/water and isolated by filtration and dried.

In one embodiment, the product was crystallized from ethanol with 3-10% V/V water by heating to reflux, followed by cooling to typically 18-20°C over eight hours, and then aging of the crystals at that temperature for at least 12 hours. Finally, the product is isolated by filtration and dried.

The intermediates

In another aspect, the present invention relates to intermediates which are useful in the preparations of a compound of the formula (I) wherein R₂ represents Ci_₆alkyl .

In one embodiment the invention relates to the intermediate compound of formula (VI)

(VI)

wherein R represents hydrogen or d-₆alkyl. In another embodiment R represents hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl, or tertiary butyl. In another embodiment R represents hydrogen. In another embodiment R represents isobutyl.

In another embodiment the invention relates to a compound of formula (VI')

(VI') wherein R' represents Ci_₆alkyl, and R represents hydrogen or Ci-₆alkyl.

In another embodiment the invention relates to an intermediate compound of formula (VIII)

wherein R represents hydrogen or d-₆alkyl, and Hal represents halogen. In another embodiment R represents hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl or tertiary butyl and Hal represents iodo or bromo. In another embodiment R represents hydrogen and Hal represents bromo. In another embodiment R represents isobutyl and Hal represents bromo.

EXPERIMENTAL^

Methods and reagents

The reactions were performed under an atmosphere of nitrogen or argon unless otherwise stated. All reagents and solvents were of commercial grade and used as received without any further purification.

Assay by NMR was performed either by the ERETIC Method {Akoka, S., Barantin, L, and Trierweiler, M. Anal. Chem. 1999, 71 , 2554-2557) (method A) or using 2,3,5,6-tetra- chloronitrobenzene as internal standard (method B).

LC-MS (Method A): Column : Waters Aquity UPLC HSS T3 Ι .δμπτι , 2.1 x 50 mm, column temperature : 60°C, detection : UV, PDA 210-400 nm, eluents: (A) 10 mM Ammonium acetate with 0.1% HCOOH and (B) Acetonitrile with 0. 1% HCOOH . The following gradient was used :

Time % A % B Flow

minutes ml/min

0.0 95 05 1.2

0.9 05 95 1.2 0.91 05 95 1.3

1.2 05 95 1.3

1.21 05 95 1.2

1.4 95 05 1.2

LC-MS (Method B): Column : Luna C18, 2.0 x 50 mm, column temperature: 30°C, detection : UV, 254nm, eluents: (A) 0.1% HCOOH in water and (B) 0.1% HCOOH in Acetonitrile. The following gradient was used :

Time % A % B Flow

minutes ml/min

0.00 95 05 0.6

7.00 05 95 0.6

8.00 05 95 0.6

8.20 95 05 0.6

11.00 95 05 0.6

UPLC: Column : Zorbax Eclipse Plus, 3.0 x 100 mm, column temperature: 45°C, detection : UV, 319nm, eluents: (A) 0.1% HCOOH in water and (B) 100% Acetonitrile. The following gradient was used :

Time % A % B Flow

minutes ml/min

0.00 80 20 0.5

1.00 80 20 0.5

15.00 05 95 0.5

17.00 05 95 0.5

17.10 80 20 0.5

25.00 80 20 0.5

EXAMPLE 1

Preparation of 3-methoxypyhdin-2-amine (the compound of formula (II))

Ethyl acetate (350mL) and methanol (350mL) were mixed and sparged with nitrogen for 15 minutes. The starting material 3-methoxy-2-nitropyridine (70g, 454mmol) was dissolved in the mixture of solvents, and some insoluble material was removed by filtration. Then 10-20wt% Pd on Carbon (water wet, 1.2g) was added and the flask was placed in a Parr Shaker. The flask was pressurized with hydrogen and shaken for 3.5 hours, and then the reaction was complete, as detected by LC-MS (method A). The catalyst was removed by filtration through a layer of celite, and the filter cake was washed with two portions of methanol (50mL each). The combined filtrates were evaporated to dryness using a rotary evaporator (temperature of water batch 60°C) under vacuum. The resulting solid was dried further in oven at 40°C under vacuum. Yield : 55.7g (99%) of the title compound. ^-NMR (300 MHz, DMSO-d₆) δ (ppm) 7.50 (dd, J = 5.0, 1.5 Hz, 1H), 6.99 (dd, J = 7.9, 1.4 Hz, 1H), 6.50 (dd, J = 7.8, 5.1 Hz, 1H), 5.61 (broad, 2H), 3.76 (s, 3H). This procedure was repeated starting from 3-methoxy-2-nitropyridine (70g, 454mmol). Reaction time 6 hours. Yield 54.6g (97%). NMR as for the first portion.

Preparation of l-(8-methoxy-[l,2,41triazolo[l,5-a1pyridine-2-yl)cyclopropanecarboxylic acid (a compound of formula (VI))

3-Methoxypyridin-2-amine (25g, 201mmol) was stirred with methanol (375mL), and hydroxylamine-O-sulphonic acid (22.8g, 202mmol) was added portion wise over approximately 10 minutes, keeping the temperature between 20 - 25°C. Transfer was ensured with a rinse of methanol (30mL). After stirring for another 15 minutes, 1,8- diazabicyclo[5.4.0]undec-7-ene (30.6g, 201mmol) was added slowly over approximately 5 minutes. The mixture was heated to reflux for 4-6 hours, and cooled to approximately 40°C. l,8-diazabicyclo[5.4.0]undec-7-ene (30.6g, 201mmol) and dimethyl cyclo- propane-l,l-dicarboxylate (63.8g, 403mmol) were added, and the mixture was heated to reflux for 16-18 hours. The mixture was cooled with an ice-water bath, and sodium hydroxide (50.5g) dissolved in water (250mL) was added slowly, keeping the

temperature below 30°C. The cooling batch was removed, and the mixture was stirred at 20-25°C for 3-3.5 hours. This procedure was repeated starting from 3-methoxypyridin- 2-amine (25g, 201mmol), and the two reaction mixtures were combined before proceeding.

The two combined reaction mixtures were concentrated on a rotary evaporator applying a vacuum and using a water bath for heating; 720-740mL distillate was collected. The mixture was diluted with water (380ml_) and extracted twice with MTBE (300ml_). MTBE was removed using a rotary evaporator applying a vacuum and using a water bath for heating. The mixture was cooled with an ice-water bath, and sulfuric acid (6M, 140- 145mL) was added slowly, keeping the temperature below 20°C. Then pH was approximately 3 as determined using a pH test strip. The mixture was stirred for 16-18 hours at ambient temperature, and the product was isolated by filtration, washed with water (two portions of 50mL each), and dried in an oven at 40°C under vacuum. The dry solid (48g) was stirred with water (360mL). The product was isolated by filtration, washed with water (50mL), and dried in an oven at 40°C under vacuum. Yield : 44g (47%). ^-NMR (300 MHz, DMSO-d₆) δ (ppm) 12.65 (s, 1H), 8.44 (dd, J = 5.0, 2.7 Hz, 1H), 7.13 - 6.99 (m, 2H), 3.97 (s, 3H), 1.59 - 1.36 (m. 4H). Another batch of the title compound was synthesized according to the procedure above starting from two portions of 3-methoxypyridin-2-amine (25g each, 201mmol) (420 mL of water was used for the final suspension). Yield 47g (50%). NMR as for the first portion.

Preparation of l-(5-bromo-8-methoxy-[l,2,41triazolo[l,5-alpyridin-2-yl)cyclo- propanecarboxylic acid (a compound of formula (VIII)) The starting material l-(8-Methoxy-[l,2,4]triazolo[l,5-a]pyridine-2-yl)cyclopropane carboxylic acid (87.65g, 376mmol) was stirred with acetonitrile (875mL) and dimethylformamide (180ml_), and the mixture was heated to 55-65°C. N-Bromo- succinimide (72. lg, 405mmol) was added in six portions over six hours, and then the heating was removed. The mixture was allowed to cool to ambient temperature, and poured into water (3.7L). The product was isolated by filtration, washed with water (lOOmL), and dried in an oven at 40°C under vacuum. Yield 84g (72%). ^JH-NMR (300 MHz, DMSO-de) δ (ppm) 12.70 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 1.49 (m, 4H). Preparation of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-isobenzofuran-l-one (the compound of formula (IX))

Dimethylformamide (1.5L) was sparged with nitrogen for half an hour. Then 5-bromo- 3H-isobenzofuran-l-one (150g, 704mmol), bis(pinacolato)diboron (215g, 847mmol), potassium carbonate (207g, 2.12mol), and Pd(II) acetate (7.9g, 35mmol) were added, and the mixture was heated to 80-105°C for 20 hours. The mixture was cooled to 40°C and poured into water (4.5L). A solid was isolated by filtration and dried in an oven at elevated temperature under vacuum. The solid was stirred with ethyl acetate (3L) for 2.5 hours, and undissolved material was removed by filtration though a plug of celite. The filtrate was concentrated using a rotary evaporator under vacuum using a water bath for heating, final volume approximately 400mL. The mixture was heated to reflux, allowed to cool to ambient temperature, and cooled with an ice-water bath for approximately half an hour. The title compound was isolated by filtration, washed with ice cold ethyl acetate (two portions of 50ml_ each), and dried in an oven at 40°C using vacuum. Yield 76g (41%). HH-NMR (300 MHz, DMSO-d₆) δ (ppm) 7.99-7.95 (m, 1H), 7.87-7.83 (m, 2H), 5.43 (s, 2H), 1.34 (s, 12H). A second crop was obtained from the mother liquor and washings; yield 5.6g (3%). NMR as for the first crop. Preparation of 4-[2-(l-carboxycyclopropyl)-8-methoxy-[l,2,41triazolo[l,5-alpyridin-5- yl^"l-2-(hydroxymethyl)benzoic acid (a compound of formula (X))

A mixture of dioxane (1.41L) and water (940mL) was sparged with nitrogen for approximately 20 minutes. l-(5-bromo-8-methoxy-[l,2,4]triazolo[l,5-a]pyridin-2- yl)cyclopropanecarboxylic acid (82.5g, 264mmol), 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3H-isobenzofuran-l-one (75.6g, 291mmol), and tripotassium phosphate (224g, 1.06mol) were added, and the mixture was stirred for approximately half an hour at ambien temperature. Tricyclohexylphosphine (3.7g, 13mol) and tris(dibenzylideneacetone)dipalladium(0) (6g, 6.6mmol) were added, and the mixture was heated for reflux for approximately two hours.

The mixture was cooled to ambient temperature giving a mixture with two liquid phases; the phases were separated. The organic phase was filtered, and concentrated to a final volume of 300-400ml_ using a rotary evaporator applying a vacuum and using a water bath for heating. The residue was added 2M sodium hydroxide (200mL) and stirred for approximately 1.5 hours. The mixture was extracted twice with MTBE (200mL). The resulting aqueous solution was filtered, and MTBE was removed using a rotary evaporator applying a vacuum and using a water bath for heating.

Concentrated sulfuric acid was added to the aqueous solution under stirring until pH was approximately 3, as determined using a pH test strip; 25ml_ concentrated sulfuric acid was added. The mixture was stirred over night at ambient temperature. A solid was isolated by filtration and dried to some extent in an oven at elevated temperature and applying a vacuum, giving 287g of material.

More water is removed from the material by adding dioxane (500mL) and concentrating the mixture using a rotary evaporator, applying a vacuum (approximately 250mbar) and using a water bath for heating (bath temperature: 60°C). This is repeated two times more. Dioxane (2.5L) was added to the residue and the mixture was heated to reflux for approximately 5 minutes, and cooled to 17°C over approximately 1.5 hours. The raw product was isolated by filtration, washed with dioxane (lOOmL), and dried in an oven at 40°C applying a vacuum, giving 124g of material. The assay by NMR (method A) was 59wt% (average of two determinations) with regard to the title compound. The material was stirred with water (1.22L) over night and isolated again by filtration. The filter cake was washed with water (200ml_) and dried in an oven at 45°C under vacuum. Yield 73g, assay by NMR 89wt% (method A, average of two determinations) (yield 64%). ^-NMR (600MHz, DMSO-de) δ (ppm) 12.75 (s, 2H), 8.22 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.94 (dd, J = 8.1, 1.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.92 (s, 2H), 4.03 (s, 3H), 1.53 (q, J = 3.9 Hz, 2H), 1.43 (q, J = 3.9 Hz, 2H), contained 3-4mol% l-[8-methoxy-5-(l-oxo-3H-isobenzofuran-5-yl)-[l,2,4]triazolo[l,5- a]pyridin-2-yl]cyclopropanecarboxylic acid.

Preparation of l-[8-methoxy-5-(l-oxo-3H-isobenzofuran-5-yl)-[l,2,41triazolo[l,5- alpyridin-2-yllcyclopropanecarboxylic acid (a compound of formula (XI))

4-[2-(l-carboxycyclopropyl)-8-methoxy-[l,2,4]triazolo[l,5-a]pyridin-5-yl]-2- (hydroxymethyl)benzoic acid (73g, assay 89wt% by NMR, 169mmol) was stirred with dioxane (1.6L) and concentrated sulfuric acid (7mL). The mixture was heated to reflux for 23 hours. The mixture was cooled to ambient temperature and the product was isolated by filtration and washed with dioxane (200mL). The product was dried in a vacuum oven at 45°C, giving 84g (assay by NMR 73wt%, method A, average of two determinations) (yield 99%) of the title compound. H NMR (300 MHz, DMSO-d₅) δ

(ppm) 9.97 (s, 1H), 8.22 (d, J = 1.4 Hz, 1H), 8.13 (dd, J = 8.1, 1.5 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.51 (s, 2H), 4.04 (s, 3H), 1.60-1.39 (m, 4H). Preparation of isobutyl l-r8-methoxy-5-(l-oxo-3H-isobenzofuran-5-yl)-ri,2,41- triazolo[l,5-alpyridin-2-yllcyclopropanecarboxylate (a compound of formula (I))

The starting material l-[8-methoxy-5-(l-oxo-3H-isobenzofuran-5-yl)-[l,2,4]- triazolo[l,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (83g, assay by NMR 73wt%, 166mmol) was mixed with dimethylformamide (870mL), cesium carbonate (147g,

451mmol), and l-iodo-2-methylpropane (64g, 348mmol). The mixture was heated to approximately 75°C until completion of the reaction as determined by LC-MS (method A). The mixture was cooled slightly, and a 5% solution of citric acid in water (4L) was added slowly (effervescence). The mixture was stirred for approximately 1.5 hours and filtered. The filter cake was washed with water (400mL) and drained on the filter, giving 189g of wet material. The wet filter cake was stirred with ethanol (2.2L) and heated to reflux. The mixture was filtered hot in order to remove some insoluble material, and the filtrate was allowed to cool to ambient temperature with stirring. The product was isolated by filtration, washed with ice cold ethanol (300ml_), and dried in a vacuum oven at 45°C. Yield 66g (assay by NMR 102%, method A, average of two determinations) (yield 95%). ^JH NMR (300 MHz, DMSO-d₆) δ (ppm) 8.22 (broad s, 1H), 8.13 (dd, J = 8.0, 1.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 5.51 (s, 2H), 4.04 (s, 3H), 3.84 (d, J = 6.5 Hz, 2H), 1.80 (nonet, J = 6.7 Hz, 1H), 1.63-1.40 (m, 4H), 0.78 (d, J = 6.7 Hz, 6H).

EXAMPLE 2

Preparation of 3-methoxypyridin-2-annine (the compound of formula (II))

A reactor was charged with methanol (80L), ethyl acetate (80L), and 3-methoxy-2- nitropyridine (15.85kg, 102.8mol) and the mixture was stirred at 18-23°C until a solution was formed. Then 5wt% Pd on Carbon (50% wet, 274g) was added. The reactor was pressurized and purged three times with nitrogen and then pressurized and purged three times with hydrogen. The reactor was pressurized with hydrogen to 3 bars, and the mixture was stirred at 18-23°C until completion of the reaction (as determined by TLC, eluent: ethyl acetate). The reactor was vented and then pressurized and purged three times with nitrogen. The catalyst was removed by filtration, and the filter cake was washed with a mixture of methanol (24L) and ethyl acetate (24L), and the filtrates were combined.

Methanol (80L) was added to the combined filtrates, and the mixture was concentrated to approximately 200L by distillation at <45°C under vacuum. The procedure of adding methanol (80L) followed by distillation (to a volume of approximately 200L) was repeated until the content of ethyl acetate is <0.5wt% of the content of methanol and ethyl acetate as determined by ^-NMR. The product 3-methoxypyridin-2-amine was obtained as a solution in methanol with a total weight of 161kg. A sample was evaporated to dryness to determine the

concentration of the product in the methanol solution and to obtain an NMR of the product. The solution contained 12.41kg of the product (yield 97%), ^-NMR conformed to NMR of the small batch of 3-methoxypyridin-2-amine above.

Half of the solution of 3-methoxypyridine-2-amine in methanol (80kg methanol solution containing 6.21kg substance, 50.0mol) was transferred to a reactor. The temperature of the solution was adjusted to 16-20°C, and hydroxylamine-O-sulfonic acid (6.21kg, 54.9mol) was added in two equal portions keeping the temperature below 30°C. The temperature of the solution was adjusted to 16-20°C, and l,8-diazabicyclo[5.4.0]undec- 7-ene (8.40kg, 55.2mol) was added using a pump over at least 60 minutes keeping the temperature below 30°C. The mixture was then stirred at approximately 38-42°C for 48 hours. A sample was withdrawn and concentrated to dryness, and NMR of the residue showed 75% amination of the pyridine nitrogen. l,8-diazabicyclo[5.4.0]undec-7-ene (8.36kg, 54.9mol) was added using a pump over at least 60 minutes keeping the temperature below 30°C. Then dimethyl cyclopropane-1,1- dicarboxylate (15.80kg, 99.7mol) was added, and the mixture was heated to 65-70°C and stirred for at least 16 hours. The mixture was cooled to 20-25°C and sodium hydroxide (20% solution in water, 75.0kg) was added over at least 60 minutes keeping the temperature below 40°C. The mixture was distilled at≤40°C under vacuum to a final volume of 80L, 93.8kg of distillate was collected. LC-MS (Method B) showed full hydrolysis of the intermediate methyl l-(8-methoxy-[l,2,4]triazolo[l,5-a]pyridin-2- yl)cyclopropanecarboxylate to the title compound.

The temperature of the mixture was adjusted to 20-25°C and water (46kg) and ethyl acetate (55.5kg) were added. The mixture was stirred for approximately 15 minutes, and then the phases were allowed to settle. The phases were separated and the water phase was extracted with another portion of ethyl acetate (55.5kg), and the phases were separated.

The temperature of the water phase was adjusted to 20-25°C and 6M sulfuric acid (65.4kg) was added with cooling over at least 60 minutes keeping the temperature below 25°C, pH of the mixture was then < 1. The mixture was stirred at 18-22°C for at least four hours. The raw product of the title compound was isolated by filtration, washed with water (20kg), and dried on the filter with vacuum for at least two hours.

The procedure above was repeated with the second half of the solution of 3-methoxy- pyridine-2-amine in methanol (80kg methanol solution), giving a second portion of the raw product of the title compound.

A reactor was charged with water (124kg) and the two portions of raw product were added. The mixture was stirred for at least 30 minutes. The product was isolated by filtration, washed with water (25kg), and dried at elevated temperature under vacuum. Yield 5.48kg (24%). ^-NMR conformed to NMR for the small batch of the title compound above. Assay by ^-NMR (DMSO-d₅, method B): 102 wt%. A second crop of product was isolated from the mother liquors from the two portions of raw product by adjusting the pH to 2.5 - 3. The product was isolated by filtration and re- suspended in water. The product was isolated by filtration, washed with water and dried under vacuum. Yield 5.76kg (25%). ^-NMR conformed to NMR for the small batch of the title compound above. Assay by ^-NMR (DMSO-d₆, method B): 101 wt%.

Preparation of l-(5-bromo-8-methoxy-[l,2,41triazolo[l,5-alpyridin-2-yl)cyclopropane- carboxylic acid (a compound of formula (VIII)) A reactor was charged with acetonitrile (21kg), dimethylformamide (5kg), and l-(8- methoxy-[l,2,4]triazolo[l,5-a]pyridin-2-yl)cyclopropanecarboxylic acid (5.30kg, 22.7mol). The mixture was heated to 58-62°C, and N-bromosuccinimide (5.05kg, 28.4mol) was added in five equal portions, keeping the temperature at approximately 60°C. The mixture was stirred at approximately 60°C until completion (LC-MS, Method B), cooled to 20-25°C, and discharged from the reactor.

Water (106kg) was added to the reactor and half the reaction mixture was added at 20- 25°C over 30-90 minutes. The mixture was stirred at 20-25°C for two hours and the solid was isolated by filtration. Water (106kg) was added to the reactor, and the second half of the reaction mixture is added at 20-25°C over 30-90 minutes. The mixture is stirred at 20-25°C for two hours and the solid was isolated by filtration, adding to the first portion already on the filter. The filter cake was washed with water (two portions of 11kg each), and the solid was dried at elevated temperature applying a vacuum. Yield : 5.39kg raw product.

Water (43L), acetonitrile (11L), dimethylformamide (2.1L), and 5.37kg raw product were charged to a reactor. The temperature was adjusted to 20-25°C and the mixture was stirred for at least six hours. The product was isolated by filtration, washed with water (two portions of 5.5-6.0L each), and dried at elevated temperature under vacuum. Yield 4.65kg (66%) of the title compound. -I-NMR conformed to NMR of the small batch above. Assay by NMR (solvent DMSO-d₅, method B) : 99.99%.

Preparation of 5-(4,4_i5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-isobenzofuran-l-one (the compound of formula (IX))

Dioxane (51.5kg) was charged to a reactor and sparged with oxygen free nitrogen for at least one hour. Then 5-bromo-3H-isobenzofuran-l-one (5.00kg, 23.5mol),

bis(pinacolato)diboron (7.16kg, 28.2mol), potassium acetate (9.91kg, 70.4mol), and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladiunn(II), complex with

dichloromethane (0.96kg, 1.2mol) were added, and the mixture was heated to approximately 90°C for at least 18 hours. TLC showed full conversion (eluent:

hexane:ethyl acetate 85 : 15, eluted three times). The mixture was cooled to 20-25°C, and ethyl acetate (45.3kg) was added. The mixture was filtered through silicagel (25.0kg), and the filter cake was washed with ethyl acetate (135kg).

The filtrates were combined and concentrated at≤45°C under vacuum. Finally, a pressure of 155mbar and a temperature of 40°C were maintained for 30 minutes. The isolated solid was stirred with cyclohexane (39.0kg) at 20-25°C for at least 60 minutes. The mixture was filtered and the solid was washed with cyclohexane (8.0kg). The product was dried at elevated temperature under vacuum. Yield 4.65kg (76%). ^-NMR conforms to NMR of the small batch above. Preparation of l-r8-methoxy-5-(l-oxo-3H-isobenzofuran-5-yl -ri,2,41triazolori ,5- alpyridin-2-yllcyclopropanecarboxylic acid (a compound of formula (XI))

A reactor was charged with dioxane (36.0kg), l-(5-bromo-8-methoxy-[l,2,4]triazolo- [l,5-a]pyridin-2-yl)cyclopropanecarboxylic acid (4.63kg, 14.8mol), 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-isobenzofuran-l-one (4.25kg, 16.3mol), water (9.26kg), triethylamine (6.02kg, 59.5mol), and [l,l'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II), complex with dichloromethane (306g, 0.375mol), and the mixture was heated to 80-85°C. The reaction was followed by UPLC, and when the reaction was complete, the mixture was cooled to 20-25°C.

Ethyl acetate (42kg) and water (46kg) were added, and the mixture was stirred for at least 15 minutes. The reaction mixture was filtered through celite (5.00kg) and the filter cake was washed with water (23kg). The filtrates were combined, stirred for 15 minutes, and allowed to settle. The phases were separated. The water phase was stirred with ethyl acetate (40kg), and the mixture was filtered through celite (5.07kg). The phases were separated.

Citric acid (5wt% in water, approximately 10kg) was added slowly to the water phase with stirring to lower the pH to 4-4.5, and then the mixture was stirred at 20-25°C for at least two hours. The product was isolated by filtration, washed with water (47kg), and dried at elevated temperature under vacuum. Yield 3.72kg (69%). ^-NMR conforms to NMR of the small batch above. Preparation of isobutyl l-[8-methoxy-5-(l-oxo-3H-isobenzofuran-5-yl)-[l,2,41triazolo- [l,5-alpyndin-2-yllcyclopropanecarboxylate (a compound of formula (I))

Λ/,/V-Dimethylformamide (35.5kg), l-[8-methoxy-5-(l-oxo-3H-isobenzofuran-5-yl)- [l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (3.69kg, lO. lmol), potassium carbonate (2.79kg, 20.2mol), and l-iodo-2-methylpropane (2.79kg, 15.2mol) were charged to a reactor, and the mixture was heated to 70-75°C until completion of the reaction as determined by UPLC. The temperature of the mixture was adjusted to 20-25°C and the mixture was discharged from the reactor and divided in two portions.

Citric acid (5wt% in water, 70kg) was charged to a reactor and half of the reaction mixture was added at 20-25°C (effervescence). The transfer of as much as possible of this portion of reaction mixture was ensured with a rinse of citric acid solution (5wt% in water, 3.8kg). After stirring for an additional two hours, the raw product was isolated by filtration, washed with water (9kg), and drained on the filter. This procedure was repeated with the second half of the reaction mixture. The two portions of raw product were dried at elevated temperature under vacuum giving a total of 4.26kg of solid.

The obtained solid was stirred with dichloromethane (113kg) and PL-DETA resin at 20- 25°C for at least two hours. The mixture was filtered through celite (8.5kg) and the filter cake was washed with dichloromethane (28kg). The combined filtrates were distilled at <45°C under vacuum to a volume of approximately 64L. Ethanol (50kg) was added and distillation was continued until the mixture had a volume of 80-90L. The addition of ethanol and distillation was repeated twice, the final volume of the mixture was approximately 80L. Ethanol (41kg) and water (5.2kg) were added, and the mixture was heated to reflux. The mixture was cooled to 18-20°C over eight hours and stirred at that temperature for at least 12 hours. The product was isolated by filtration, washed with ethanol (two portions of 7kg each), and dried at elevated temperature under vacuum. Yield 3.44kg (81%) of the title compound. ^-NMR conformed to NMR of the small batch above.

EXAMPLE 3

Preparation of l-(8-methoxy-[l,2,41triazolo[l,5-alpyridine-2-yl)cyclopropanecarboxylic acid (a compound of formula (VI))

3-Methoxypyridin-2-amine (10. Og, 80.6mmol) was stirred with methanol (150mL), and hydroxylamine-O-Sulphonic acid (9.12g, 80.6mmol) was added portion wise over 4 minutes keeping the temperature between 20 - 25°C. Transfer was ensured with a rinse of methanol (4mL). Then lithium methoxide (3.07g, 80.9mmol) was added portion wise over 4 minutes keeping the temperature between 19 - 25°C. The mixture was heated to reflux for 16-18 hours, and cooled to approximately 30°C. Lithium methoxide (3.07g, 80.9mmol) and dimethyl cyclopropane-l,l-dicarboxylate (25.5g, 161mmol) were added, and the mixture was heated to reflux for 16-18 hours. The mixture was cooled with an ice-water bath, and a mixture of 32% sodium hydroxide (62.5g) and water (57.5g) was added slowly keeping the temperature below 22°C. Stirring for two hours at ambient temperature gave full conversion of the intermediate methyl l-(8-methoxy-[l,2,4]- triazolo[l,5-a]pyridin-2-yl)cyclopropanecarboxylate to the title compound (according to LC-MS, method A).

The mixture was concentrated on a rotary evaporator applying a vacuum and using a water bath for heating. Concentration was stopped when 125mL distillate was collected. Water (76mL) and MTBE (60ml_) were added to the residue, and the mixture was stirred for 5-10 minutes at ambient temperature. The phases were separated, and the water phase was stirred with MTBE (60mL) for 5-10 minutes. The phases were separated. MTBE was removed from the water phase using a rotary evaporator applying a vacuum and using a water batch for heating : 13mL distillate was collected. The residue was stirred with cooling on an ice-water batch and cone, sulfuric acid was added slowly keeping the temperature below 20°C. Addition of approximately 12mL cone, sulfuric acid gave pH 3, as determined using a pH test strip. The resulting suspension was stirred for 67-68 hours. The raw product was isolated by filtration, washed with water (20mL), and dried in a vacuum oven at elevated temperature with a bleed of air, giving 12.6g of solid. The raw product (10.46g) was stirred with water (75mL) at ambient temperature for 21 hours. The product was isolated by filtration, washed with water (20mL), and dried in a vacuum oven at elevated temperature with a bleed of air. Yield 9.08g (58%) of the title compound. ^-NM conformed to NMR data in example 1. Assay by ^-NMR (DMSO-d₆, method A, average of two determinations) : 96%.

EXAMPLE 4 Preparation of l-[8-methoxy-5-(l-oxo-3H-isobenzofuran-5-yl)-[l_f2_f41triazolo[l _f5- alpyridin-2-yllcyclopropanecarboxylic acid (a compound of formula (XI)) Dioxane (76mL) was degassed by sparging with argon for 28 minutes. Then 5-bromo- 3H-isobenzofuran-l-one (8.19g, 38.4mmol), bis(pinacolato)diboron (12.25g,

48.2mmol), potassium acetate (12.68g, 129.2mmol), and [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II), complex with dichloromethane (1.31g, 1.60mmol) were added. The mixture was heated to 73-81°C for two hours, at which time 5-bromo-3H- isobenzofuran-l-one was fully consumed as determined by LC-MS (method A). The mixture was cooled slightly and l-(5-bromo-8-methoxy-[l,2,4]triazolo-[l,5-a]pyridin-2- yl)cyclopropanecarboxylic acid (lO.OOg, 32.0mmol) and water (40mL) were added. The mixture was heated again to 68-75°C for 21 hours.

The mixture was cooled to ambient temperature and stirred with water (lOOmL) and ethyl acetate (lOOmL), and triethyl amine was added until pH 8 was reach in the water phase (pH test strip, 13ml_ triethyl amine was used). After stirring for 15 minutes, the mixture was filtered and the filter cake was washed with water (20mL). The combined filtrates were transferred to a separatory funnel, mixed by shaking, and allowed to settle. The phases were separated and the water phase was stirred for 20 minutes with ethyl acetate (lOOmL). The mixture was filtered, and the tiny filter cake was washed with water (15mL). The combined filtrates were transferred to a separatory funnel, mixed by shaking, and allowed to settle. The phases were separated.

The water phase was stirred with cooling in a water-ice bath, and 3M sulfuric acid was added to lower the pH to approximately 4 (pH test strip, approximately 20mL of sulfuric acid was used). The resulting suspension was stirred at ambient temperature for 18 hours. More 3M sulfuric acid (4mL) was added to further adjust pH to approximately 4. The suspension was stirred for another hour at ambient temperature, and the product was isolated by filtration, washed with water (25ml_), and dried in a vacuum oven at elevated temperature with a bleed of air. Yield 8.96g (assay by 'H-NMR 76wt%, method A, DMSO-d₆, average of two determinations) (yield 58%) of the title compound. ^-NMR conformed to NMR data in Example 1.

CLAUSES

In view of the description the present inventors have in particular provided : Clause 1. A method for the preparation of a compound of formula (I)

wherein R₂ represents Ci-₆alkyl, comprising carrying out one or more of the following reaction steps : (a) N-aminating a compound of formula (II)

(Π)

with a reagent of formula (III) H₂N-X (III) wherein H₂N-X represents an N-amination reagent to form a compound of formula (IV)

(IV)

wherein X^" represents an anion of an N-amination reagent;

(b) cyclising the compound of formula (IV) with a compound of formula (V)

0 0

(V)

wherein each of Ri independently is selected from C_halky!, to form a compound of formula (VI)

(VI)

wherein R represents hydrogen or Ci_₆alkyl;

(c) reacting the compound of formula (VI) with a halogenating agent to form a compound of formula (VIII)

wherein R represents hydrogen or Ci-₆alkyl, and Hal represents halogen;

(d) reacting the compound of formula (VIII) with the compound of formula (IX)

in the presence of a Pd catalyst, to form a compound of formula (XI)

wherein R represents hydrogen or Ci-₆alkyl; and when R in formula (XI) represents hydrogen

(e) reacting said compound of formula (XI) with an alkylating agent (XII)

R₂-Hal (XII)

wherein R₂ represents Ci-₆alkyl and Hal represents halogen, to form the compound of formula (I) wherein R₂ represents Ci_₆alkyl .

Clause 2. The method according to clause 1 wherein the reagent of formula (III) is hydroxylamine-O-sulfonic acid .

Clause 3. The method according to any one of the preceding clauses wherein step (a) is conducted in a polar solvent in the presence of a base.

Clause 4. The method according to clause 3 wherein in step (a) the solvent is methanol and the base is l,8-diazabicyclo[5.4.0] undec-7-ene.

Clause 5. The method according to any one of the preceding clauses wherein step (b) is conducted in the presence of a base. Clause 6. The method according to clause 5 wherein the base is l,8-diazabicyclo[5.4.0]- undec-7-ene.

Clause 7. The method according to clause 5 wherein the base is lithium methoxide. Clause 8. The method according to any one of the preceding clauses wherein in formula (V), Ri independently represents methyl or ethyl.

Clause 9. The method according to any one of the preceding clauses wherein the halogenating agent in step (c) is selected from N-bromosuccinimide, N-iodosuccinimide and N-chlorosuccinimide.

Clause 10. The method according to clause 9 wherein the halogenating agent is N- bromosuccinimide. Clause 11. The method according to any one of the preceding clauses wherein step (c) is conducted in an aprotic polar solvent or mixtures thereof. Clause 12. The method according to clause 11 wherein the solvent is a mixture of acetonitrile (MeCN) and Ν,Ν-dimethylformarriide (DMF).

Clause 13. The method according to any one of the preceding clauses wherein step (d) is conducted in a mixture of dioxane and water in the presence a Pd catalyst and a base.

Clause 14. The method according to clause 13 wherein the ratio of watendioxane is ratio of watendioxane is 20: 80 w/w. Clause 15. The method according to clause 13 wherein the Pd catalyst is

bis(triphenylphosphine)palladium(II)dichloride or l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II), complex with dichloromethane.

Clause 16. The method according to clause 13 wherein the base is triethylamine (Et₃N).

Clause 17. The method according to any one of the preceding clauses wherein step (e) is conducted in an aprotic polar solvent in the presence of a base.

Clause 18. The method according to clause 17 wherein the solvent is N,N-dimethyl- formamide (DMF).

Clause 19. The method according to clause 17 wherein the base is Cs₂C0₃ or K₂C0₃

Clause 20. The method according to any one of the preceding clauses wherein R represents hydrogen.

Clause 21. The method according to any one of the preceding clauses wherein R represents branched butyl. Clause 22. The method according to clauses 21 wherein R represents isobutyl.

Clause 23. The method according to any one of the preceding clauses wherein R₂ represents branched butyl. Clause 24. The method according clause 23 wherein R₂ represents isobutyl.

Clause 25. An intermediate compound of formula (VI')

wherein R' represents Ci_₆alkyl and R represents hydrogen or Ci-₆alkyl. Clause 26. An intermediate compound of formula (VI)

(VI)

wherein R represents hydrogen or d-₆alkyl.

Clause 27. An intermediate compound according to clause 26 which is l-(8-methoxy- [l,2,4]triazolo[l,5-a]pyridine-2-yl)cyclopropanecarboxylic acid.

Clause 28. An intermediate compound of formula (VIII) which is l-(5-bromo-8- methoxy-[l,2,4]triazolo[l,5-a]pyridin-2-yl)cyclopropanecarboxylic acid.

Clause 29. A method for preparing a compound of formula (VI)

(VI)

wherein R represents hydrogen or Ci_₆alkyl;

comprising step (a) and (b) as defined in clause 1.

Clause 30. A method for reparing a compound of formula (VIII)

wherein R represents hydrogen or Ci-₆alkyl, and Hal representshalogen; comprising step (c) as defined in clause 1.

Clause 31. A method for preparing a compound of formula (I)

wherein R₂ represents Ci-₆alkyl, comprising step (a) and (b) as defined in clause 1. Clause 32. A method for preparing a compound of formula (I)

wherein R₂ represents Ci_₆alkyl, comprising step (a), (b) and (c) as defined in clause 1. Clause 33. A method for preparing a compound of formula (XI)

wherein R represents hydrogen or d-₆alkyl;

comprising step (d) as defined in clause 1.

Clause 34. A method for preparing a compound of formula (XI)

wherein R represents hydrogen or d-₆alkyl; comprising :

(i) reacting the compound of formula (VIII)

wherein R represents hydrogen or Ci-₆alkyl, and Hal represents halogen; with the compound of formula (IX)

in the presence of a Pd catalyst, to form a compound of formula (X)

wherein R represents hydrogen or Ci-₆alkyl; and (ii) ring closing of the compound of formula (X) to form the compound of formula (XI), wherein R represents hydrogen or Ci_₆alkyl.

Clause 35. The method according to clause 34 wherein step (i) is conducted in an mixture of dioxane and water in the presence of a Pd catalyst and a base.

Clause 36. The method according to any one of the preceding clauses 34-35 wherein, in step (i), the Pd catalyst is formed by mixing tricyclohexylphosphine and

tris(dibenzylideneacetone)dipalladium(0).

Clause 37. The method according to any one of the preceding clauses 34-36 wherein, in step (i), the base is K₃P0₄.

Clause 38. The method according to any one of the preceding clauses 34-37 wherein step (ii) is conducted in an aprotic polar solvent in the presence of an acid .

Clause 39. The method according to clause 38 wherein, in step (ii), the solvent is dioxane and the acid is sulphuric acid. Clause 40. A method for preparing a compound of formula (XI)

wherein R represents hydrogen or d-₆alkyl; comprising

(i) reacting 5-bromo-3H-isobenzofuran-l-one and bis(pinacolato)diborone, to form the compound of formula (IX)

and then

(ii) adding the compound of formula (VIII)

wherein R represents hydrogen or Ci_₆alkyl, and Hal represents halogen, to the reaction mixture containing the compound of formula (IX), and letting the compounds of formula (VIII) and (IX) react to form the compound of formula (XI), wherein R represents hydrogen or Ci_₆alkyl.

Clause 41. The method according to clause 40 wherein step (i) is conducted in dioxane in the presence of a Pd catalyst and a base.

Clause 42. The method according to any one of the preceding clauses 40-41 wherein, in step (i), the Pd catalyst is [ l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane.

Clause 43. The method according to any one of the preceding clauses 40-42 wherein, in step (i), the base is potassium acetate.

Clause 44. The method according to clause 40 wherein step (ii) water is added in combination with the compound of formula (VIII).

Claims

1. A method for the preparation of a compound of formula (I)

wherein R₂ represents Ci-₆alkyl,

comprising carrying out one or more of the following reaction steps : (a) N-aminating a compound of formula (II)

with a reagent of formula (III)

H₂N-X (III)

wherein H₂N-X represents an N-amination reagent

to form a compound of formula (IV)

(IV)

wherein X^" represents an anion of an N-amination reagent; (b) cyclising the compound of formula (IV) with a compound of formula (V)

(V)

(VI) wherein R represents hydrogen or Ci_₆alkyl;

(c) reacting the compound of formula (VI) with a halogenating agent to form a com ound of formula (VIII)

wherein R represents hydrogen or Ci-₆alkyl, and Hal represents halogen;

(d) reacting the compound of formula (VIII) with the compound of formula (IX)

(IX) in the resence of a Pd catalyst, to form a compound of formula (XI)

wherein R represents hydrogen or Ci_₆alkyl; and when R in formula (XI) represents hydrogen

(e) reacting said compound of formula (XI) with an alkylating agent (XII)

R₂-Hal (XII)

wherein R₂ represents Ci-₆alkyl and Hal represents halogen, to form the compound of formula (I) wherein R₂ represents Ci-₆alkyl .

2. The method according to claim 1 wherein the reagent of formula (III) is hydroxylamine-O-sulfonic acid . 3. The method according to any one of the preceding claims wherein step (a) is conducted in a polar solvent in the presence of a base.

4. The method according to any one of the preceding claims wherein the halogenating agent in step (c) is selected from N-bromosuccinimide, N-iodosuccinimide and N- chlorosuccinimide.

5. The method according to any one of the preceding claims wherein step (c) is conducted in a mixture of acetonitrile (MeCN) and Ν,Ν-dimethylformamide (DMF). 6. The method according to any one of the preceding claims wherein step (d) is conducted in a mixture of dioxane and water in the presence a Pd catalyst.

7. The method according to any one of the preceding claims wherein R represents hydrogen or isobutyl.

8. The method according to any one of the preceding claims wherein R₂ represents branched butyl .

9. The method according claim 8 wherein R₂ represents isobutyl .

10. An intermediate compound of formula (VI)

(VI)

wherein R represents hydrogen or d-₆alkyl.

11. An intermediate compound of formula (VIII) which is l-(5-bromo-8-methoxy- [ l,2,4]triazolo[ l,5-a]pyridin-2-yl)cyclopropanecarboxylic acid .

A method for preparing a compound of formula (VI)

(VI)

wherein R represents hydrogen or Ci_₆alkyl;

comprising step (a) and (b) as defined in claim 1.

A method for preparing a compound of formula (VIII)

wherein R represents hydrogen or Ci-₆alkyl, and Hal represents halogen;

comprising step (c) as defined in claim 1.

14. A method for preparing a compound of formula (I)

wherein R₂ represents Ci.₆alkyl, comprising step (a) and (b) as defined in claim 1. 15. A method for preparing a compound of formula (I)

wherein R₂ represents Ci.₆alkyl, comprising step (a), (b) and (c) as defined in claim 1.