WO2009011654A1

WO2009011654A1 - Process for the preparation of cyclic spiropiperidines

Info

Publication number: WO2009011654A1
Application number: PCT/SE2008/050877
Authority: WO
Inventors: Svetlana Ivanova; Santosh Kavitake; Sythana Suresh Kumar; Sidda Lingesha; Marguerite Mensonides-Harsema; Eric Merifield; John Pavey; Vinod Kumar; David Ennis
Original assignee: Astrazeneca Ab
Priority date: 2007-07-17
Filing date: 2008-07-16
Publication date: 2009-01-22
Also published as: WO2009011653A1

Abstract

The present invention relates to new processes for the preparation of compounds of formula I, especially the compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-1'H,3H-spiro[1- benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4-5 [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid and to new intermediates useful in the preparation thereof.

Description

Process for the preparation of cyclic spiropiperidines

The present invention relates to new processes for the preparation of compounds of formula I, especially the compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-lΗ,3H-spiro[l- benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy}-4-

[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid and to new intermediates useful in the preparation thereof.

Compounds of Formula I show good CCRl and CCR3 inhibitory activity. In addition they have particularly low affinity for the human ether-a-go-go-related gene (hERG)-encoded potassium channel and therefore are advantageous with regard to safety windows. Compounds of Formula I are useful in the treatment of respiratory diseases such as for example asthma or COPD.

The compounds of formula I , especially compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro- 1 Η,3H-spiro[ 1 -benzofuran-2,4'-piperidin]- l'-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid, the preparation and the medical uses thereof, are described in detail in patent application WO2008/010765, which is hereby included by reference.

Compound of formula I is presented by formula I

wherein:

R¹ is halogen;

R⁵ is hydrogen or halogen;

R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, or a pharmaceutically acceptable salt thereof. In one embodiment R¹ is chlorine or fluorine. In another embodiment R¹ is chlorine.

In yet a further embodiment R⁵ is hydrogen and chlorine. In one embodiment R⁵ is chlorine. In another embodiment R⁵ is hydrogen.

In one embodiment R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, such as methyl. In a further embodiment R⁶ and R⁷ are both methyl. In one embodiment R⁶ and R⁷ are both hydrogen.

For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group.

For the avoidance of doubt it is to be understood that in this specification 'C_1-6' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.

In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl or i-hexyl. The term Ci_-4 alkyl having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or tert-butyl.

In this specification, unless stated otherwise, the term "aryl" refers to an aromatic or partial aromatic group having 5 to 10 carbon atoms such as for example, phenyl or naphthyl. In this specification, unless stated otherwise, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl as defined above.

In this specification, unless stated otherwise, the terms "halo" and "halogen" may be fluorine, iodine, chlorine or bromine. It will be appreciated that throughout the specification, the number and nature of substituents on rings in the compounds of the invention will be selected so as to avoid sterically undesirable combinations.

Compounds of the present invention have been named with the aid of computer software (ACDLabs 8.0/Name(IUPAC)).

The compounds of formula I and pharmaceutically acceptable salts thereof may exist in solvated, for example hydrated, as well as unsolvated forms or as cocrystals, and the present invention encompasses all such forms.

Compounds of formula I above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulphate, acetate, ascorbate, benzoate, fumarate, hemifumarate, furoate, succinate, maleate, tartrate, citrate, oxalate, xinafoate, methanesulphonate,/?-toluenesulphonate, benzenesulphonate, ethanesulphonate, 2-naphthalenesulfonate, mesytilenesulfonate, nitrate acid, 1,5-naphthalene-disulphonate, p-xylenesulphonate, aspartate or glutamate.

They may also include basic addition salts such as an alkali metal salt for example sodium or potassium salts, an alkaline earth metal salt for example calcium or magnesium salts, a transition metal salt such as a zinc salt, an organic amine salt for example a salt of triethylamine, diethylamine, morpholine, 7V-methylpiperidine, 7V-ethylpiperidine, piperazine, procaine, dibenzylamine, 7V,7V-dibenzylethylamine, choline or 2-aminoethanol or amino acids for example lysine or arginine.

Process

Thus, the present invention relates to a process for the preparation of compounds of formula I.

In one embodiment relates to a process as shown in scheme 4. Scheme 4

wherein R¹ is halogen, R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, R^e and R^J are independently any substituent forming an ester group such as, but not limited to C_1-6 alkyl, optionally substituted arylalkyl e.g. benzyl or R^J is hydrogen, and LG is a leaving group.

Through an earlier alkylation of the phenolic hydroxy group the protection / deprotection steps can be avoided, making the overall process two steps shorter than the process given in Schemes 1-3 of WO2008/010765.

Another embodiment of the invention relates to a process for the preparation of the compound of formula I comprising the following steps;

(XXXIX) a) reacting the benzoic acid ester with an α-bromocarboxylic ester or α-bromocarboxylic acid in a suitable solvent and in the presence of a base to form the compound of formula XXXIX, MeNH₂, solvent

b) reacting the compound of formula XXXIX a suitable solvent with a solution of methylamine to provide the compound of formula XXXX,

c) reacting the compound of formula XXXX with the epoxide to give the compound of formula XXXXI, using a suitable solvent and base,

(XXXXI d) reacting the spirocycle with the compound of formula XXXXI to afford the compound of formula ID, using a suitable solvent and base,and

de-esterification

e) de-esterification of the compound of formula ID to provide the compound of formula I in the cases where R^J is not hydrogen, wherein R¹ is halogen, R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, R^e and R^J are independently any substituent forming an ester group such as C i-₆ alkyl or optionally substituted arylalkyl or R^J is hydrogen, and LG is a leaving group.

Examples of leaving groups are, but not limited to, halogen, SO₂R¹¹ where R^u =

such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i- pentyl, t-pentyl, n-hexyl or i-hexyl, or optionally substituted aryl such as phenyl, tosyl or 3- nitrophenyl.

Suitable epoxides may be glycidyl nosylate, optically pure epichlorohydrin, glycidyl tosylate, glycidyl benzenesulphonate or glycidyl mesylate. Examples of substituent forming an ester group are, but not limited to methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl or i- hexyl, or arylalkyl or optionally substituted aryl such as phenyl, or 3-nitrophenyl.

A person skilled in the art would recognise which solvents, bases and catalysts may be used in the process according to scheme 4. Step a)

Suitable solvents that may be used in the process for making the compound of formula

XXXIX include but are not limited to DMF, NMP, ethanol, methanol or isopropanol.

Suitable bases that may be used in the process for making the compound of formula

XXXIX include but are not limited to cesium carbonate, potassium carbonate or sodium hydride.

Optionally step a) may be perfomred in the presence of a catalyst (e.g. a phase transfer catalyst could be used for this process with certain solvents / bases

Step b)

Suitable solvents that may be used in the process for making the compound of formula XXXX include but are not limited to dichloromethane, toluene, Λ/,Λ/-dimethylformamide,

7V-methylpyrrolidone, tert-butyl methyl ether, methanol, ethanol, isopropanol, acetonitrile, water or mixtures thereof.

Step c)

Suitable solvents that may be used in the process for making the compound of formula XXXXI include but are not limited to butyronitrile, acetonitrile, toluene, tetrahydrofuran,

DMF, NMP or mixtures thereof.

Suitable bases that may be used in the process for making the compound of formula XXXXI include but are not limited to caesium carbonate, potassium carbonate or sodium hydride. Step ά)

Suitable solvents that may be used in the process for making the compound of formula ID include but are not limited to ethyl acetate, isopropyl acetate, toluene, THF, ethanol, methanol, isopropanol or mixtures thereof.

Suitable bases that may be used in the process for making the compound of formula ID include but are not limited to ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Step e)

Suitable solvents that may be used in the process for making the compound of formula I include but are not limited to DCM, toluene, tert-butyl methyl ether, THF or mixtures thereof.

Depending on the nature of the group R^J, de-esterification under either acidic or basic conditions may be appropriate.

In one embodiment, where R^J is tert-butyl, the acid used in step e) is selected from TFA, formic acid, acetic acid or hydrochloric acid.

Suitable temperatures for the steps a) to e) of from 0⁰C to 120⁰C, depending on the solvent used.

Suitable temperatures for step a) is of from 60⁰C to 65⁰C and for step e) is of from 16°C to

25°C.

Compounds of formulae (XXXIX) to (XXXXI) and salts thereof are novel and comprise an independent aspect of the invention.

One embodiment relates to compound of formula XXXIX or a salt thereof, wherein R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl and R^e and R^J are independently any substituent forming an ester group such as C_1-6 alkyl or optionally substituted arylalkyl or R^J is hydrogen

(XXXIX)

Another embodiment relates to compound 4-(l-tert-Butoxycarbonyl-l-methylethoxy)-5- chloro-2-hydroxybenzoic acid, methyl ester

A further embodiment relates to the compound of formula XXXX or a salt thereof, wherein R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, and R^J is any substituent forming an ester group such as C_1-6 alkyl or optionally substituted arylalkyl or hydrogen,

<^XXXX)

One embodiment relates to compound 2-(2-Chloro-5-hydroxy-4- methylcarbamoylphenoxy)-2-methylpropionic acid, tert-butyl ester.

Another embodiment relates to a compound of formula XXXXI, or a salt thereof, wherein R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Q- ₆alkyl and R^J is any substituent forming an ester group such as Ci_-6 alkyl or optionally substituted arylalkyl or hydrogen,

A further embodiment relates to compound 2-[2-Chloro-4-methylcarbamoyl-5-((S)-l- oxiranylmethoxy)-phenoxy]-2-methylpropionic acid, tert-butyl ester.

The invention further relates to the use of the intermediates in the preparation of compounds of formula I.

One embodiment relates to the the use of compounds of formula (XXXIX), (XXXX),

(XXXXI) and salts thereof, or compounds selected from

4-(l-tert-Butoxycarbonyl-l-methylethoxy)-5-chloro-2-hydroxybenzoic acid, methyl ester,

2-(2-Chloro-5-hydroxy-4-methylcarbamoylphenoxy)-2-methylpropionic acid, tert-butyl ester, and

2-[2-Chloro-4-methylcarbamoyl-5-((S)-l-oxiranylmethoxy)-phenoxy]-2-methylpropionic acid, tert-butyl ester, as intermediates in the preparation of compounds of formula I as defined above.

Examples

The invention will now be further explained by reference to the following illustrative examples.

Each exemplified compound represents a particular and independent aspect of the invention.

The following abbreviations are used:

APCI-MS Atmospheric Pressure Chemical Ionisation Mass Spectroscopy;

DCM Dichloromethane

DMF 7V,7V-Dimethylformamide HPLC High Performance Liquid Chromatography;

LC/MS Liquid Column Chromatography / Mass Spectroscopy;

NMP Λ/-methyl-2-pyrrolidone

TFA Trifluoroacetic acid;

THF Tetrahydrofuran ReI vol relative volume

ReI wt relative weight General Methods

¹H NMR and ¹³C NMR spectra were recorded on a Varian Inova 400 MHz or a Varian Mercury-VX 300 MHz or a Varian Unity Inova 400 MHz or a Varian Unity Inova 300 MHz instrument. The central peaks of chloroform-J (5_H 7.27 ppm), dimethylsulfoxide-Jg (5H 2.50 ppm), acetonitrile-dj (5H 1.95 ppm) or methanol-^ (6H 3.31 ppm) were used as internal references. Flash chromatography was carried out using silica gel (0.040-0.063 mm, Merck). Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.

The following methods were used for LC/MS analysis:

Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI; Flow rate

0.7 ml/min; Wavelength 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile +

0.1% TFA; Gradient 15-95%/B 2.7 min, 95% B 0.3 min.

Instrument Agilent 1100; Column Hi Chrom Ace Phenyl 3.0 x 50 mm; Mass APCI; Flow rate 1.25 ml/min; Wavelength 230 nm; Solvent A: water + 0..03% TFA; Solvent B: acetonitrile + 0.03% TFA; Gradient 5-95% B 6 min, 95% B 1.5 min.

The following method was used for LC analysis:

Method A. Instrument Agilent 1100; Column: Kromasil Cl 8 100 x 3 mm, 5μ particle size, Solvent A: 0.1 %TF A/water, Solvent B: 0.08%TFA/acetonitrile Flow: 1 ml/min,

Gradient 10-100% B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and

280 nm.

Method B. Instrument Agilent 1100; Column: XTerra C8, 100 x 3 mm, 5 μ particle size,

Solvent A: 15 mM NH₃/water, Solvent B: acetonitrile Flow: 1 ml/min, Gradient 10-100% B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and 280 nm.

The following intermediates and starting materials can be prepared following the procedures described in WO2004005295:

5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine], hydrobromic acid salt All the starting materials are commercially available except 5-chloro-2,4- dihydroxybenzoic acid methyl ester which was prepared using commercially available 2 hydroxy 4- methoxy benzoic acid methyl ester. Example 1

2-{2-Chloro-5-{[(2S)-3-(5-chloro-l 'H, 3H-spiro[l-benzofuran-2, 4 '-piperidinl-1 '-yl)-2- hydroxypropyl]oxy}-4-ffmethylamino)carbonyl]phenoxy}-2-methylpropanoic acid. Preparation of chloro diol(5-Chloro,2,4-dihydroxy benzoic acid methyl ester) Synthetic scheme:-

Methyl ester

Chloro phenol-Crude I Issoommeerr Dichloro impurity

2-hydroxy, 4-Methoxy benzoic acid methyl ester

Methanol

Chloro phenol Chloro diol (5- Chloro, 2,4- dihydroxy Benzoic acid methyl ester

Step a) Preparation of Chloro phenol

To a solution of methyl ester (10. Og, 1.0 mol.eq) in DCM (110.0 ml,l 1.0 rel.vol) sulfuryl chloride (9.07g 8.89@100%, 1.20 mol.eq) was drop wise added over a period of 15 minutes. Reflux The reaction mixture (39⁰C) was refiuxed until the reaction was completed (approximately 17hrs). The reaction mass was cooled to 25⁰C and water added (50.0ml, 5.0 rel.vol). The dichloromethane layer was separated and evaporated to dryness under vacuum (80-100 mbr) at 30-35⁰C. The crude chloro phenol was slurried in methanol (40.0ml 4.0 rel.vol) to remove isomer and the dichloro impurity formed. The cake was filtered and washed with methanol (10.0ml, 1.0 rel.vol) and the the product dried under vacuum (80 -lOOmbr) at 40⁰C until a constant weight was obtained. Purity by HPLC: 99.7%, Isomer: 0.3%(By HPLC area%) Yield: 84%. Melting point: 130.8 - 132.1⁰C. ¹U NMR (200 MHz, CDC13): δ 10.93(s, IH), 7.81(s, IH), 6.50(s, IH), 3.93 (s, 3H), 3.92 (s, 3H) Step b) Preparation of Chloro diol: Anhydrous aluminium chloride (153.87g 1.154 mol.eq) was charged into R.B Flask. Toluene (1000.0 ml, 10.0 rel.vol) was charged at 25 to 27⁰C and stirred. The reaction mass was a suspension, which was than slowly charged with dodecanethiol (327.0ml 1.6156 mol.eq), whereafter the mixture became a clear solution. T temperature of the reaction mixture was raised to 40-50⁰C. Chloro Phenol (100. Og, 0.4616mol, 1.0 mol.eq) was dissolved in toluene (1000.0ml, 10.0 rel.vol) and slowly added to the reaction mixture. The reaction mixture was stirred for 60-90 minutes at 40-50⁰C. The reaction was monitored by HPLC .After completion of the reaction water (1.5 rel.vol) (Exothermic addition) was charged to the reaction mixture at 50⁰C and stirred for 15 min. Again, water (10.0 rel. vol.) was charged followed by 30 minutes stirring at 40-45⁰C. The hot reaction mixture (40 to 50⁰C) was transferred into separating funnel where the hot organic layer was separated from the reaction mixture at 40-45⁰C (The solid precipitated out on cooling). The organic layer was concentrated up to « 10 rel. vol at 50-55⁰C under reduced pressure (150mbr). n- Heptane (10.0 rel.vol) was slowly charged to a solution containing chloro diol at 50⁰C. The contents was cooled to 30⁰C. A white solid precipitated out which was stirred for 30 min. The mixture was further cooloed to 0-5⁰C and stirred for 30 min. The solid was filtered in Buckner funnel and suck dried. The material was further dried under vacuum (150mbr) at 45 to 50⁰C until the constant weight was obtained. HPLC: 99.6%, (By HPLC area %) Yield: 85.6 %. Melting point: 116.8 -118.2⁰C. 1R NMR (200 MHz, CDC13): δ 10.84(S, IH), 7.82(s, IH), 6.61(s, IH), 6.08(s, IH), 3.93(s, 3H).

Step 1. 4-(l-tert-butoxycarbonyl-l-methylethoxy)-5-chloro-2-hydroxybenzoic acid methyl ester

To a solution of 5-chloro-2,4-dihydroxybenzoic acid methyl ester (10.2 g, 10.0 g at 100% w/w, 0.0493 mol, 1.0 mol eq) in TV-methyl pyrrolidone (40 ml, 4.0 rel vol), was added potassium carbonate (17.40 g, 17.05 g at 100% w/w, 0.1233 mol, 2.5 mol eq) with stirring. 2-Bromo-2-methyl-propionic acid tert-butyl ester (67.42 g, 66.07 g at 100% w/w, 0.2961 mol, 6.0 mol eq) was added in one portion together followed by tetrabutylammonium bromide (3.25 g, 3.18 g at 100 % w/w, 0.0098 moles, 0.2 mol eq). The temperature of the reaction mass was raised to 60-65⁰C and maintained at this temperature for 16 h. On completion, the reaction mixture was cooled 30-35 ⁰C. The insoluble potassium salts were removed by filtration through Celite and the solids were washed with TV-methyl pyrrolidone (20 ml, 2.0 rel vol). The pH of the combined filtrates was adjusted to around 4 using dilute HCl solution then water (100 ml, 10.0 rel vol) added. The solution was extracted with dichloromethane (100 ml, 10 rel vol), the organic layer was washed with water (150 ml, 15.0 rel vol) then evaporated to dryness at 35 ⁰C under vacuum. The excess of 2-bromo-2-methyl-propionic acid tert-butyl ester and 2-methylacrylic acid tert-butyl ester by product were removed by applying a high vacuum (20-25 mbar) at 60 - 65 ⁰C for approximately one h. 4-(l-tert-Butoxycarbonyl-l-methylethoxy)-5-chloro-2- hydroxybenzoic acid methyl ester was obtained as an oil, weight 16.0 g (72.2% yield). ¹R NMR (300 MHz, CDCl₃): δ 10.73 (s, IH), 7.82 (s, IH), 6.36 (s, IH), 3.92 (s, 3H), 1.66 (s, 6H), 1.44 (s, 9H).

Step 2. 2-(2-Chloro-5-hydroxy-4-methylcarbamoylphenoxy)-2-methylpropionic acid tert- butyl ester

To an aqueous solution of methylamine (40% w/w, 160 ml, 12.6 rel vol) was added 4-(l- tert-butoxycarbonyl-l-methylethoxy)-5-chloro-2-hydroxybenzoic acid methyl ester (16.0 g, 12.27 g at 100%, 0.035 mol, 1.0 mol eq) and the mixture stirred for 1-2 h at 25 to 30 ⁰C. After completion of the reaction, the reaction mixture was filtered through a Celite bed to separate some insoluble material. The Celite bed was washed with water (32 ml, 2.60 rel vol) and the combined filtrates de-gassed under vacuum (150 mbar) at 30-35 ⁰C. The resulting solution was diluted with water (240 ml, 19.56 rel vol) and the pH of the solution adjusted to 7.5 using 10% w/w hydrochloric acid solution (85 ml, 6.9 rel vol). The resulting suspension was stirred for 1 to 2 h at 25-30 ⁰C. The suspended solid was collected by filtration, washed with water (32 ml, 2.60 rel vol) then dried under vacuum

(80-100 mbar) at 40-45 ⁰C to provide 2-(2-chloro-5-hydroxy-4-methylcarbamoylphenoxy)-

2-methylpropionic acid tert-butyl ester, weight 8.0 g (65.5%).

¹R NMR (300 MHz, CDCl₃): δ 12.44 (s, IH), 7.33 (s, IH), 6.37 (s, IH), 6.15 (br s, IH),

2.98 (d, 3H), 1.65(s, 6H), 1.45 (s, 9H)

Step 3. 2-[2-Chloro-4-methylcarbamoyl-5-((S)-l-oxiranylmethoxy)phenoxy]-2- methylpropionic acid tert-butyl ester

2-(2-Chloro-5 -hydroxy-4-methylcarbamoylphenoxy)-2-methylpropionic acid tert-butyl ester (5.0 g, 0.0145 mol, 1.0 mol eq) was dissolved in acetonitrile (40 ml, 8.0 rel vol) and caesium carbonate (5.21 g, 5.18 g at 100%, 0.0159 mol, 1.10 mol eq) added. A solution of 3-nitrobenzenesulfonic acid (5)-l-oxiranylmethyl ester in butyronitrile (30.7% w/w, 12.89 g, 3.95 g at 100% w/w, 0.0152 mol, 1.05 mol eq) was diluted with acetonitrile (20 ml, 4.0 rel vol) and added to the reaction mixture. The reaction mixture was heated to 45-50 ⁰C and held at this temperature for 4 h. After cooling the reaction mixture to 20 to 25 ⁰C, acetonitrile (5.0 ml, 1.0 rel vol) and water (60 ml, 12.0 rel vol) were added. The reaction mixture was stirred for 12 h at 20 to 25 ⁰C. The reaction mixture was then further cooled to 5 ⁰C then the solid product collected by filtration and washed with water (20 ml, 4.0 rel vol). The crude product was dissolved in toluene (20 ml, 4.0 rel vol) at 40 ⁰C then the solution was concentrated to 3.0 rel vol under vacuum (200 mbar) at around 50 ⁰C. The concentrate was cooled to 20 to 25 ⁰C and stirred for approximately for 3 h. The solid product was collected by filtration and dried under vacuum at 40-45 ⁰C to give 2-[2-chloro- 4-methylcarbamoyl-5-((5)-l-oxiranylmethoxy)-phenoxy]-2-methylpropionic acid tert- butyl ester weight 3.8 g (65.4%).

IH NMR (300 mHz, CDC13): δ 8.20 (s, IH), 7.71-7.69 (broad d IH), 6.60 (s, IH), 4.39- 4.33 (d, IH), 4.00-3.92 (dd, IH), 3.41-3.34 (m, IH), 2.97-2.96 (d, 3H), 2.94-2.90 (IH, overlapping), 2.83-2.79 (m, IH), 1.63 (s, 6H), 1.43 (s, 9H). Step 4. 2-{2-chloro-5-{[(2s)-3-(5-chloro-3h-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid tert- butvl ester

A mixture of 5-chloro-l Η,3H-spiro[l-benzofuran-2,4'-piperidine], hydrobromic acid salt (3.2 g, 0.0105 mol, 1.05 mol eq) and potassium carbonate (1.52 g, 0.011 mol, 1.10 mol eq) in ethanol (40 ml, 10.0 rel vol) was stirred for 30 min at ambient temperature. 2-[2-Chloro- 4-methylcarbamoyl-5 -((S)- 1 -oxiranylmethoxy)phenoxy] -2-methylpropionic acid tert-butyl ester (4.0 g, 0.010 mol, 1.0 mol eq) was added and the temperature of the reaction mixture raised to 48-50 ⁰C and held for 8 - 9 h. The reaction mixture was cooled to 20-25 ⁰C, water (24 ml, 6.0 rel vol) was added and stirring continued for 1 h. The precipitated solid was collected by filtration and washed with water (8.0 ml, 2.0 rel vol). The solid was dissolved in ethyl acetate (30 ml, 7.5 rel vol), the resulting solution was washed with water (30 ml, 7.5 rel vol) then evaporated to dryness under vacuum (100 mbar) at 40-45 ⁰C. n- Heptane (20 ml, 5.0 rel vol) was added to the residue and the slurry stirred for 30 min. The solid was collected by filtration then dried under vacuum (150 mbar) at 40-45 ⁰C to afford 2-{2-chloro-5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid tert- butyl ester, weight 4.5 g (72.1%).

¹HNMR (SOO mHz₅ CDCl₃)I o S-IQ (S, IH), 8.14-8.11 (broad d, IH), 7.10-7.04 (m, 2H), 6.70-6.65 (d, IH), 6.57 (s, IH), 4.12-4.08(d, 2H), 3.90-3.82 (m, IH), 2.99-2.76 (m, 7H), 2.66-2.51 (m, 4H), 2.04-1.78 (m, 4H), 1.62 (s,6H), 1.44 (s 9H).

Step 5. 2-{2-Chloro-5-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy}-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid.

Trifluoroacetic acid (2.0 ml, 2.0 rel vol) was added to a stirred suspension of 2-{2-chloro- 5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy}- 4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid tert-butyl ester (1.0 g, 0.0016 mol, 1.0 mol eq) in toluene (6.0 ml, 6.0 rel vol) at 20 to 25 ⁰C resulting in a clear solution and stirring continued for 12 h. The reaction mixture was evaporated to dryness under reduced pressure (10 mbar) at 40 ⁰C and the gummy residue was dissolved in water (10 ml, 10.0 rel vol). A solution of ammonium acetate (3.0 g, 0.0389 mol, 24.32 mol eq, 3.0 rel wt) in water (15 ml, 15 rel vol) was added and the thick suspension stirred for 1 to 2 h. The water layer was decanted and isopropanol (20 ml, 20.0 rel vol) added to the suspension and the mixture stirred for 30 min. The solid was collected by filtration and dried under vacuum (150 mbar) at 40 ⁰C to provide 2-{2-chloro-5-{[(25)-3-(5-chloro-3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid, weight 0.83 g (91.2%). APCI-MS: m/z 567 (MH⁺).

Claims

1. A process for the preparation of the compound of formula I comprising the following steps;

solvent

(XXXIX) a) reacting the benzoic acid ester with an α-bromocarboxylic ester or α-bromocarboxylic acid in a suitable solvent and in the presence of a base to form the compound of formula XXXIX,

MeNH₂, solvent

(XXXIX)

(XXXX) (XXXXI) c) reacting the compound of formula XXXX with the epoxide to give the compound of formula XXXXI, using a suitable solvent and base,

deprotection

e) de-esterification of the compound of formula ID to provide the compound of formula I in the cases where R^J is not hydrogen, wherein R¹ is halogen, R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or d-βalkyl, R^e and R^J are independently any substituent forming an ester group such as C ₁.6 alkyl or optionally substituted arylalkyl or R^J is hydrogen, and LG is a leaving group.

2. The process according to claim 1, wherein the leaving group is selected from halogen, SO₂R¹¹ where R^u = C^aUcyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl or i-hexyl, or optionally substituted aryl such as phenyl, tosyl or 3-nitrophenyl, and the epoxides are selected from glycidyl nosylate, optically pure epichlorohydrin, glycidyl tosylate, glycidyl benzenesulphonate or glycidyl mesylate, and the substituent forming an ester group are selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl or i-hexyl, or optionally substituted aryl such as phenyl or 3-nitrophenyl.

3. The process according to claim 1, wherein the solvent in step a) is selected from DMF,

NMP, ethanol, methanol or isopropanol, and the base is selected from cesium carbonate, potassium carbonate or sodium hydride.

4. The process according to claim 1, wherein the solvent in step b) is selected from dichloromethane, toluene, NN-dimethylformamide, N-methylpyrrolidone, tert-butyl methyl ether, methanol, ethanol, isopropanol, acetonitrile, water or mixtures thereof.

5. The process according to claim 1, wherein the solvent in step c) is selected from butyronitrile, acetonitrile, toluene, tetrahydrofuran, DMF, NMP or mixtures thereof, and the base is selected from caesium carbonate, potassium carbonate or sodium hydride.

6. The process according to claim 1, wherein the solvent in step d) is selected from ethyl acetate, isopropyl acetate, toluene, THF, ethanol, methanol, isopropanol or mixtures thereof, and the base is selected from ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

7. The process according to claim 1, wherein the solvent in step d) is selected from DCM, toluene, tert-butyl methyl ether, THF or mixtures thereof.

8. The process according to claim 1, wherein R^J is tert-butyl, the acid used in step e) is selected from TFA, formic acid, acetic acid or hydrochloric acid.

9. Compound of formula XXXIX or a salt thereof, wherein R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl and R^e and R^J are independently any substituent forming an ester group such as Ci_-6 alkyl or optionally substituted arylalkyl or R^j is hydrogen

(XXXiX) _{? or} compound 4-(l-ter?-Butoxycarbonyl-l-methylethoxy)-5-chloro-2-hydroxybenzoic acid, methyl ester.

10. Compound of formula XXXX or a salt thereof, wherein R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, and R^J is any substituent forming an ester group such as Ci_₆ alkyl or optionally substituted arylalkyl or hydrogen,

(XXXX) ^ _or compound 2-(2-Chloro-5-hydroxy-4-methylcarbamoylphenoxy)-2-methylpropionic acid, tert-butyl ester.

11. Compound of formula XXXXI, or a salt thereof, wherein R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, and R^e and R are independently any substituent forming an ester group such as Ci_6 alkyl or optionally substituted arylalkyl or R^J is hydrogen,

compound 2-[2-Chloro-4-methylcarbamoyl-5-((S)-l-oxiranylmethoxy)-phenoxy]-2- methylpropionic acid, tert-butyl ester.

12. The use compounds of formula (XXXIX), (XXXX), (XXXXI) and salts thereof, or compounds selected from 4-(l-tert-Butoxycarbonyl-l-methylethoxy)-5-chloro-2-hydroxybenzoic acid, methyl ester,

2-(2-Chloro-5 -hydroxy-4-methylcarbamoylphenoxy)-2-methylpropionic acid, tert-butyl ester, and

2-[2-Chloro-4-methylcarbamoyl-5-((S)-l-oxiranylmethoxy)-phenoxy]-2-methylpropionic acid, tert-butyl ester, as intermediates in the preparation of compounds of formula I

wherein:

R¹ is halogen;

R⁵ is hydrogen or halogen;

R⁶ and R⁷ are independently selected from hydrogen or C_halky!.