WO2009011653A1

WO2009011653A1 - A process for the preparation of intermediates and their us in the synthesis of spiropiperidine compounds

Info

Publication number: WO2009011653A1
Application number: PCT/SE2008/050876
Authority: WO
Inventors: Martin Cooper; Barry Elkins; Scott Gibson; Eric Gu; Ian Hassall; Martin Hemmerling; Svetlana Ivanova; Bo-Göran Josefsson; Marguerite Mensonides-Harsema; Eric Merifield; John Pavey; Mike Rogers; Wang Zhengyu
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2007-07-17
Filing date: 2008-07-16
Publication date: 2009-01-22
Anticipated expiration: 2010-01-17
Also published as: WO2009011654A1

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

A process for the preparation of intermediates and their use in the synthesis of spiropiperidine compounds

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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 and 2-{2-Chloro-5-{[(25)-3-(5-chloro-l'H,3H-spiro[l- benzofuran-2,4'-piperidin]-r-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:

R , 1 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 or 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 "cycloalkyl" refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system. The term "C₃-₆Cycloalkyl" may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 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, sulfphate, 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 as set out below.

The compounds of formula I may be prepared using the process as shown below in schemes 1 to 3.

Scheme 1 : Spiropiperidine synthesis salt

Piperidinol (XXXI) Bromobenzene

48% aq. HBr/HOAc

(C) reflux

Spirocycle.HBr

One embodiment of the invention relates to a process for the preparation of spiropiperidine comprising the following steps; a) reacting bocpiperidone with trimethylsulfoxonium iodide to form an epoxy piperidine in the presence of a base and solvent, and b) reacting 2-Bromo-4-chloroanisole with isopropylmagnesium chloride to form the aryl Grignard reagent, which is then reacted with the epoxy piperidine to form a piperidinol (XXXI) in the presence of a catalyst and a suitable solvent, and c) reacting piperidinol (XXXI) with hydrobromic acid to obtain spiropiperidine in a suitable solvent.

A person skilled in the art would recognise which solvents, bases, Grignard reagents and catalysts may be used in the process according to scheme 1.

Step a)

Suitable bases that may be used for the preparation of the Epoxy pip are, but not limited to,

LiOR^x, NaOR^x, KOR^X, where R^x is Ci_-6 alkyl such as for example tert-butoxide.

Suitable solvents that may be used for the preparation of the Epoxy pip are, but not limited to, dimethylsulphoxide, THF, diethyl ether, tert-butyl methyl ether, dimethoxyethane, dimethylacetamide, NMP or toluene.

Step b)

Suitable Grignard reagents that may be used in the process for making the aryl Grignard reagent in Scheme 1 include but are not limited to, compounds of formula R^yMgR^v or R^V2Mg, wherein R^y represents Cl, Br or I and R^v represents Ci_-6 alkyl, C_3-7 cycloalkyl or optionally substituted phenyl such as for example isopropylamagnesium chloride.

Suitable catalysts that may be used in the process for making the piperidinol include but are not limited to copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulphide complex, copper (I) iodide or copper (I) cyanide. Suitable solvents that may be used in the process for making the piperidinol include but are not limited to THF, 2-methyltetrahydrofuran, diethyl ether, tert-butyl methyl ether, dimethoxyethane, toluene or hexanes.

Step c)

Suitable solvents that may be used in the process for making the Spirocycle.HBr include but are not limited to water and acetic acid.

Suitable temperatures for the processes in Scheme 1 are of from 0⁰C to 100⁰C.

One embodiment relates to the process according to scheme 2 for the preparation of Glycidyl Ether.

Scheme 2: Glycidyl Ether synthesis Protection

Methyl Ester Chloro Phenol Chloro Diol

O-R^w Amide Glycidyl Ether (XXXIII) (XXXV)

where LG is a leaving group, R¹ may be any substituent providing an ester function such as for example Ci_-6 alkyl 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, optionally substituted arylalkyl e.g. benzyl, R^w is any suitable protection group such as for example PMB and R⁵ is hydrogen or halogen.

Further examples of R^w are, but not limited to, alkyl (e.g. Ci-6 alkyl), ether (e.g. methoxymethyl, tetrahydropyranyl), optionally substituted arylalkyl (e.g. benzyl or para- methoxybenzyl) and silyl groups of formula (R^q)₃Si- where each R^q independently represents an alkyl (e.g.

alkyl) or aryl (e.g. phenyl) group, for example, tert- butyldimethylsilyl or triethylsilyl.

A person skilled in the art would recognise which solvent, bases and catalyst may be used in the process according to scheme 2.

Suitable protecting groups and conditions for their application are described in 'Protective

Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and

'Protective Groups in Organic Synthesis', 3rd edition, T.W. Greene and P. G. M. Wuts,

Wiley-Interscience (1999).

Suitable bases that may be used in the process for making the O-R^w ester where R^w is PMB include but are not limited to cesium carbonate, potassium carbonate, 1,8-

Diazabicyclo[5.4.0]undec-7-ene, triethylamine, ethyldiisopropylamine or sodium hydride. Suitable solvents that may be used in the process for making the O-R^w ester where R^w is

PMB include but are not limited to dichloromethane, toluene, Λ/,Λ/-dimethylformamide, N- methylpyrrolidone, tert-butyl methyl ether, methanol, ethanol, isopropanol and acetonitrile.

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

XXXIII include but are not limited to THF, water, methanol, ethanol, isopropanol, or mixtures thereof such as a water / THF mixture.

Suitable bases that may be used for the preparation of the compound of formula XXXV are, but not limited to cesium carbonate, potassium carbonate, sodium hydride or potassium tert-butoxide.

Step e)

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

XXXV include but are not limited to butyronitrile, acetonitrile, toluene, tetrahydrofuran,

DMF or NMP. 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.

Suitable temperatures for the processes in Scheme 2 are of from 0⁰C to 100⁰C depending on the step and the solvent used.

Another embodiment of the invention relates to a process for the preparation of the compound of formula XXXV comprising the following steps; d) reacting O-R^w ester with methylamine to obtain the compound of formula XXXIII,

O-R" Ester (XXXIII) where R¹ may be any substituent providing an ester function such as for example C_1-6 alkyl 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, optionally substituted arylalkyl e.g. benzyl, R^w is any suitable protection group, R⁵ is hydrogen or halogen and LG is a leaving group and e) reacting the compound of formula XXXIII with an epoxide to form the compound of formula XXXV,

(XXXIII)

R^w is any suitable protection group, R⁵ is hydrogen or halogen and LG is a leaving group.

A further embodiment relates to a process for the preparation of compounds of formula I according to scheme 3.

Scheme 3: Compound of formula I

Ester

where R¹ is halogen, R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, R^w is any suitable protection group and R^p may be hydrogen or any substituent providing an ester function such as C_1-6 alkyl 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, optionally substituted arylalkyl such as benzyl.

Another embodiment of the invention relates to a process for the preparation of the compounds of formula (XXXVIII) comprising the following steps;

(XXXV) (XXXVIII) f) treatment of a solution of the spiropiperidine HBr salt with aqueous ammonium hydroxide to liberate the free base and then reacting this with the compound of formula XXXV in a suitable solvent followed by deprotection to obtain the compound of formula XXXVIII, optionally as a salt. Suitable temperatures for step f) are of from 0⁰C to 110⁰C. A further embodiment relates to a process for the preparation of compounds of formula I comprising the following steps; f) treatment of a solution of the spiropiperidine HBr salt with aqueous ammonium hydroxide to liberate the free base and then reacting this with the compound of formula XXXV in a suitable solvent followed by deprotection to obtain the compound of formula XXXVIII, optionally as a salt, followed by gl) reacting the compound of formula XXXVIII with α-bromo carboxylic ester in a suitable solvent in the presence of a base at an elevated temperature, and g2) de-esterification with a solution of a base followed by isolation by filtration after pH adjustment to obtain compound of formula I.

In one embodiment where R^p is hydrogen, the compound of formula XXXVIII may be reacted with an α-bromocarboxylic acid in a suitable solvent in the presence of a base at a temperature of from 55 to 70 ⁰C. De-esterification would not be needed and the compound of formula ID would be isolated after pH adjustment.

A person skilled in the art would recognise which solvent, bases and reagents may be used in the process according to scheme 3. Step f)

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

XXXVII include but are not limited to ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

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

The deprotection of protecting groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999). Suitable acids that may be used in the process for making the compound of formula

XXXVIII where R^w is PMB include but are not limited to trifluoroacetic acid, formic acid, acetic acid or hydrochloric acid. Suitable solvents that may be used in the process for making the compound of formula

XXXVIII where R^w is PMB include but are not limited to DCM, toluene, tert-butyl methyl ether or THF.

Step g) Suitable bases that may be used in the process for making the Ester include but are not limited to cesium carbonate, potassium carbonate or sodium hydride.

Suitable solvents that may be used in the process for making the Ester 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 I include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide. Alternatively, some ester groups, for example where R^p is tert-butyl, can be de- esterified with acid and suitable acids which may be used for making the compound of formula I in such cases are TFA, formic acid, acetic acid or hydrochloric acid.

Suitable solvents that may be used in the process for making the compound of formula I include but are not limited to water, methanol, ethanol, isopropanol or mixtures thereof such as for example a water / ethanol mixture.

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

(S)-Glycidyl Ether (S)-Phenol TFA f-a) treatment of a solution of the spiropiperidine HBr salt with aqueous ammonium hydroxide to liberate the free base and then reacting this with the glycidylether in a suitable solvent followed by TFA treatment to obtain 5-chloro-2-{[(25)-3-(5-chloro-l 'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4-hydroxy-Λ/- methylbenzamide, as its TFA salt, and

(S)-Phenol TFA

2-{2-Chloro-5-{[(2S)-3-(5-chloro-1 'H,3H-spiro [1 -benzofuran-2,4'-piperidin]-1 '-yl)- 2-hydroxypropyl]oxy}-4-[(methylamino) carbonyl]phenoxy}-2-methylpropanoic acid g-a) reacting 5-Chloro-2-{[(25)-3-(5-chloro-l 'H,3H-spiro[l-benzofuran-2,4'-piperidin]-r- yl)-2-hydroxypropyl]oxy}-4-hydroxy-7V-methylbenzamide TFA with ethyl-2- bromoisobutyrate in a suitable solvent in the presence of a base at an elevated temperature, preferably at a temperature of from 55 to 70 ⁰C, and h-a) redissolving the obtained product is in ethanol and treatment with a solution of sodium hydroxide, whereafter the solvent is evaporated and the residue treated with aqueous ammonium acetate, filtered and washed with water/ethanol and then filtered, or h-b) adding aqueous citric acid and filtering off the solid, washing with water followed by ethanol, then recrystallising from ethanol/NMP and then from aqueous NMP.

Suitable temperatures for the steps f) and h) are of from 0⁰C to 150⁰C.

The first recrystallisation from an ethanol / NMP mixture reduces the level of the polymeric impurity to a low level. The second recrystallisation from a water / NMP mixture provides the product in the polymorphic form A.

Compounds of formulae (XXXI) to (XXXVIII) and ID and salts thereof are novel and comprise an independent aspect of the invention.

One embodiment relates to compound of formula XXXI, where R¹ is halogen

Another embodiment relates to compound 4-(5-Chloro-2-methoxybenzyl)-4- hydroxypiperidine-1-carboxylic acid, tert-butyl ester. A further embodiment relates to compound of formula XXXII where R⁵ is hydrogen or halogen

(XXXII).

One embodiment relates to compound 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)-7V- methylbenzamide .

A further embodiment relates to a compound of formula XXXIII, where R⁵ is hydrogen or halogen and R^w is hydrogen or any suitable protecting group, or a salt thereof

(XXXIII).

Another embodiment relates to compound of formula XXXIV, where R⁵ is hydrogen or halogen

(XXXIV).

One embodiment relates to compound 5-Chloro-4-(4-methoxy-benzyloxy)-7V-methyl-2- ((S)- 1 -oxiranylmethoxy)benzamide .

Another embodiment relates to a compound of formula XXXV, where, R⁵ is hydrogen or halogen and R^w is hydrogen or any suitable protecting group, or a salt thereof

A further embodiment relates to a compound of formula XXXVI, where R is halogen and R⁵ is hydrogen or halogen

XXXVI.

Yet a further embodiment relates to compound 5-Chloro-2-{[(25)-3-(5-chloro-3H-spiro[l- benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-(/?-methoxybenzyloxy)-7V- methylbenzamide .

Yet another embodiment relates to a compound of formula XXXVII, where R¹ is halogen, R⁵ is hydrogen or halogen and R^w is hydrogen or any suitable protecting group, or a salt thereof

(XXXVII).

One embodiment relates to compound of formula XXXVIII, where R¹ is halogen and R⁵ is hydrogen or halogen

(XXXVIII). Another embodiment relates to 5-Chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'- piperidin] - 1 '-yl)-2-hydroxypropyl] oxy } -4-hydroxy-7V-methylbenzamide, trifluoroacetic acid salt.

Yet a further embodiment relates to compound of formula ID, where R¹ is halogen, R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, and R^p R^p may be hydrogen or any substituent providing an ester function such as for example C_1-6 alkyl 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, optionally substituted arylalkyl e.g. benzyl

One embodiment relates to compound 2-{2-Chloro-5-{[(2S)-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.

The invention further relates to the use of the intermediates in the preparation of compounds of formula I, especially 2-{2-Chloro-5-{[(2S)-3-(5-chloro-l'H,3H-spiro[l- benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy}-4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid.

One embodiment relates to the the use of compounds of formula (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (ID), and salts thereof, or compounds selected from 4-(5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid, tert-butyl ester, 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)-N-methylbenzamide,

5-Chloro-4-(4-methoxy-benzyloxy)-N-methyl-2-((S)-l-oxiranylmethoxy)benzamide, 5-Chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl] oxy} -4-(p-methoxybenzyloxy)-N-methylbenzamide, 5-Chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-hydroxy-N-methylbenzamide, trifluoroacetic acid, and 2-{2-Chloro-5-{[(2S)-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, as intermediates in the preparation of compounds of formula (I) as defined above, especially 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.

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;

DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

DCM Dichloromethane DME 1 ,2-Dimethoxyethane

DMF Λ/,Λ/-Dimethylformamide

DMSO Dimethylsulfoxide;

HPLC High Performance Liquid Chromatography;

LC/MS Liquid Column Chromatography / Mass Spectroscopy; NMP 7V-methyl-2-pyrrolidone

PMB /?-methoxybenzyl

TBME tert-Butylmethyl ether

TFA Trifluoroacetic acid;

THF Tetrahydrofuran BOC tert-butocycarbonyl 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]. Other starting materials are commercially available.

Example 1 2-{2-Chloro-5-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2, 4 '-piperidinj-l '-yl)-2- hydroxypropylloxy}-4-[(methylam.ino)carbonyllphenoxy}-2-methylpropanoic acid Method 1 Step 1: l-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester

Epoxy Pip

Bocpiperidone

Addition of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester as a DMSO solution to a prepared solution of trimethylsulfoxonium iodide and potassium tert-butoxide (Corey- Chaykovsky reagent) in DMSO, provided the epoxy-piperidine.

Potassium tert-butoxide (660 g, 5.89 mol) and DMSO (5.5 L) were charged to a reaction vessel and the mixture cooled to around 20 ⁰C with stirring. Trimethylsulfoxonium iodide (1.24 kg, 5.63 mol) was added in portions over a period of 15 - 20 min, maintaining the reaction temperature between 20 and 25 ⁰C. On completion of the addition, the mixture was maintained at this temperature until a yellow solution was obtained (1 - 1.5 h). DME (1.5 L) was added to the reaction flask and the solution cooled to 0 - 5 ⁰C. A pre-cooled solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1 kg, 5.02 mol) in a mixture of DME (1.5 L) and DMSO (500 ml) was transferred into the reaction mixture over a period of around 45 min, maintaining the reaction temperature between 0 and 5 ⁰C. On completion of the addition, the reaction mixture was held at this temperature for a further 1 - 1.5 h. TBME (4 L) was added to the reaction mixture followed by water (6 L) over a period of 30 - 40 min, maintaining the reaction temperature between 0 and 10 ⁰C, then stirring continued for a further 15 - 20 min at this temperature. The phases were separated and the aqueous layer was extracted with TBME (2 x 4 L). The combined organic layers were washed with water (2 x 6 L), dried over sodium sulphate, filtered and the solids washed with TBME (500 ml). The combined filtrates were concentrated under vacuum at below 45 ⁰C to a small volume (1.5 kg). TBME (20 L) was added to the concentrate and solvent was distilled off at below 45 ⁰C to leave a small volume (around 1.3 kg). THF (10 L) was added to the concentrate and solvent was distilled off to leave a solution of l-oxa-6- aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester in THF, 1.8 kg, 51.2% w/w, 0.92 kg contained weight, 86% yield.

¹H NMR (399.824 MHz, CDCl₃) δ 3.78 - 3.65 (m, 2H), 3.43 (ddd, J= 13.3, 9.5, 3.7 Hz, 2H), 2.69 (s, 2H), 1.85 - 1.74 (m, 2H), 1.50 - 1.40 (m, HH) APCI-MS: m/z 114 (MH⁺ - (CH₃)₃OCO).

Step 2: 4-(5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester

Bromobenzene _.._ _ .

CMP Grignard

2-Bromo-4-chloroanisole is treated with isopropylmagnesium chloride dissolved in THF to produce the Grignard reagent in situ. A catalytic amount of copper (I) bromide dimethyl sulphide complex (CuBr₁SMe₂) and a solution of l-oxa-6-aza-spiro[2.5]octane-6- carboxylic acid tert-butyl ester in THF are added to produce the desired piperidinol.

A solution of isopropylmagnesium chloride in THF (2 M, 2.96 kg, 3036 ml, 6.07 mol) was added to a stirred solution of 2-bromo-4-chloro-l-methoxybenzene (1.26 kg, 5.69 mol) in THF (5.5 kg) at a temperature of between 15 and 25 ⁰C and stirring continued at this temperature for 6 - 8 h. Copper(I) bromide dimethylsulphide complex (8.8 g, 42.8 mmol) was added to the reaction mixture and stirring continued at between 17 and 20 ⁰C for 10 min. A solution of l-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester in THF (3.1 kg, 39% w/w, 1.21 kg contained weight, 5.67 mol) was added to the reaction over a period of 20 min, maintaining the temperature between 15 and 20 ⁰C, followed by further THF (2.3 kg). After stirring at between 20 and 25 ⁰C for 10 - 12 h, the reaction mixture was cooled to between 5 and 10 ⁰C and a mixture of water (97 ml) and THF (220 g) added over 20 min followed by ethyl acetate (8 kg) and a solution of ammonium chloride (1.72 kg) in water (9.68 kg). The reaction mixture was warmed to between 25 and 30 ⁰C and stirred at this temperature for around 20 min. The layers were separated, the aqueous layer was extracted with ethyl acetate (8 kg) and the combined organic layers were washed with water 2 x 6 kg). The organic phase was concentrated under vacuum at 40 - 45 ⁰C to 2-3 L total volume then heptane (8 kg) added to the solution over a period of 30 min. After cooling to ambient temperature then further cooling to 0-5 ⁰C and holding at this temperature, the solid was collected by filtration, washed with a mixture of ethyl acetate and heptane (1:5, 1.4 kg) followed by heptane (1.5 kg) then dried to afford 4-(5-chloro-2- methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester as a solid, 1.65 kg (82%).

¹H NMR (399.824 MHz, CDCl₃) δ 7.19 (dd, J= 8.7, 2.8 Hz, IH), 7.09 (d, J= 2.8 Hz, IH), 6.82 (d, J= 8.7 Hz, IH), 3.92 - 3.71 (m, 5H), 3.11 (t, J= 11.7 Hz, 2H), 2.80 (br s, 2H), 2.46 (s, exch D₂O, IH), 1.60 - 1.42 (m, HH) APCI-MS: m/z 256/258 (MH⁺ - (CH₃)₃OCO).

Step 3: 5-Chloro-3H-spiro[l-benzofuran-2,4 '-piperidine], hydrobromic acid salt

Piperidinol

5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester is heated under reflux in a mixture of hydrobromic acid and acetic acid to form the hydrobromic acid salt of the 5-chlorospiropiperidine.

Aqueous hydrobromic acid (48% w/w, 62 ml) was added dropwise to a stirred mixture of 4-(5-chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester (20 g, 56 mmol) and acetic acid (40 ml) over a period of 40 min at a temperature of between 40 and 50 ⁰C. Stirring was continued at this temperature for a further 30 - 40 min on completion of the addition. The reaction mixture was then heated to reflux for between 6 and 8 h when HPLC analysis showed complete reaction. After cooling to between 20 and 30 ⁰C, ethanol (60 ml) was charged to the reaction and stirring continued at between 20 and 25 ⁰C for 20 min. After cooling to between -10 and -15 ⁰C and stirring for 30 min, the solid product was collected by filtration, washed with ethanol (2 x 20 ml) and dried to afford 5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine], hydrobromic acid salt as an off- white solid, 13.5 g (79%). The combined filtrates were concentrated in vacuo to a volume of 40 ml then ethanol (20 ml) added and the mixture cooled to between -5 and -10 ⁰C. The solid product was collected by filtration and washed with ethanol (2 x 10 ml). After drying, further 5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine], hydrobromic acid salt, 1.4 g

(8.2%) was obtained.

¹H NMR (399.826 MHz, D₆-DMSO) δ 8.57 (br s, 2 H), 7.28 (m, IH), 7.15 (dd, J= 8.5, 2.3

Hz, IH), 6.80 (d, J= 8.7 Hz, IH), 3.27 - 3.08 (m, 4H), 3.12 (s, 2H), 2.06 - 1.89 (m, 4H).

APCI-MS: m/z 224/226 (MH⁺)

Step 4: 5-chloro-2-hydroxy-4-methoxybenzoic acid methyl ester.

Methyl Ester ^{Chloro Pheno1}

Sulfuryl chloride (274.8 g, 2.0 mol) was charged to a stirred solution of 2-hydroxy-4- methoxybenzoic acid methyl ester (308.2 g, 1.7 mol) in dichloromethane (3.18 L) maintained at between 25 and 30 ⁰C. After stirring for 6 h the amount of starting material remaining was 2.3% by HPLC area. Acetic acid (203 g, 3.4 mol) was added to the reaction mixture followed by water (750 ml). The organic phase was separated then solvent distilled off at atmospheric pressure whilst adding methanol so as to maintain roughly constant reaction volume until a head temperature of 60 ⁰C was achieved. A total of 3.5 L methanol was added. The product suspension was cooled to 0 to 5°C, the solid was collected by filtration, washed with methanol (2 x 200 ml) and dried under vacuum at 50 - 60 ⁰C. The crude solid (342 g) was re-slurried in methanol (3.4 L) then collected by filtration and dried under vacuum at 50 - 60 ⁰C to afford 5-chloro-2-hydroxy-4-methoxybenzoic acid methyl ester as a solid (316.6 g, 86.5%). 1H NMR (399.824 MHz, CDCl₃) δ 10.92 (s, IH), 7.81 (s, IH), 6.50 (s, IH), 3.93 (s, 3H), 3.92 (s, 3H) Step 5: 5-chloro-2,4-dihydroxybenzoic acid methyl ester

Chloro Phenol

Aluminium chloride (531 g, 4.0 mol) and toluene (3.45 L) were charged to a reaction vessel and stirred. Dodecanethiol (966 g, 4.8 mol) was added over 25 min and the mixture stirred to give a solution then heated to 40 to 50 ⁰C. A solution of 5-chloro-2-hydroxy-4- methoxybenzoic acid methyl ester (345.0 g, 1.6 mol) in toluene (3.45L) was then added over 2 h at 40 to 50⁰C. The reaction mixture was maintained at this temperature for a further 2 h following the addition when less than 1.0% starting material remained. The reaction was quenched by the slow portionwise addition of water (520 ml) (exothermic) and this was followed by a further water charge (3.45 L), resulting in two clear phases. The organic phase was separated off and filtered at 40 to 50 ⁰C. A solvent replacement into heptane was performed under reduced pressure at 55 ⁰C and the product suspension cooled. The solid was collected by filtration, washed with heptane and dried under vacuum to provide 5-chloro-2,4-dihydroxybenzoic acid methyl ester (281.3 g, 87.3%).

¹H NMR (399.826 MHz, D₆-DMSO) δ 11.29 (s, IH), 10.57 (s, IH), 7.69 (s, IH), 6.53 (s,

IH), 3.85 (s, 3H).

Step 6: 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)benzoic acid methyl ester

O-PMB Ester 4-Methoxybenzylchloride (37.3 g, 238 mmol) was added to a stirred suspension of 5- chloro-2,4-dihydroxybenzoic acid methyl ester (45.0 g, 222 mmol) and DBU (37.8 g, 248 mmol) in DMF (450 ml) over a period of 3 h at 25 ⁰C with stirring. The reaction was then heated to 65 ⁰C and held for 1 h. After cooling back to 20 ⁰C, water (495 ml) was added, the product was collected by filtration, washed with water (2 x 50 ml) followed by acetonitrile (2 x 50 ml) then dried under vacuum at 50 ⁰C. The crude product (53.5 g, 75%) was suspended in acetonitrile (250 ml), heated to reflux and held for 15 min, cooled to 40 ⁰C then held for 1 h. The solid was collected by filtration, washed with acetonitrile (2 x 25 ml) then dried under vacuum at 50 ⁰C to provide 5-chloro-2-hydroxy-4-(4- methoxybenzyloxy)benzoic acid methyl ester as a solid 42.9 g (60%). 1H-NMR (CDCl₃, 300 MHz): δ 10.89 (s, IH), 7.83 (s, IH), 7.37 (d, J= 8.1 Hz, 2H), 6.93 (d, J= 8.1Hz, 2H), 6.56 (s, IH), 5.09 (s, 2H), 3.92 (s, 3H), 3.82 (s, 3H) APCI-MS (-ve): m/z 321 [M(-H)]^~ Step 7: 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)-N-methylbenzamide

O-PMB Ester O-PMB Amide

An aqueous solution of methylamine (40% w/w, 500 ml) was added to a stirred suspension of 5-chloro-2-hydroxy-4-(4-methoxybenzyloxy)benzoic acid methyl ester (100 g, 0.31 moles) in THF (500 ml). The mixture was heated to 50 - 56 ⁰C and the resulting clear solution held at this temperature for 4 h, then cooled to ambient temperature and stirred overnight. Solvent was distilled off under reduced pressure until 600 ml had been removed, maintaining a roughly constant reaction volume by the dropwise addition of water (600 ml). The temperature of the reaction mixture increased from 22 ⁰C to 47 ⁰C during the course of the distillation. The resulting suspension was cooled to 5 ⁰C and stirred for 30 min. The product was collected by filtration and dried under vacuum at 50 ⁰C to leave 5- chloro-2-hydroxy-4-(4-methoxybenzyloxy)-7V-methylbenzamide as a solid (94.6 g, 95% yield). 1H NMR (399.826 MHz, D₆-DMSO) δ 8.93 (br s, IH), 7.93 (s, IH), 7.39 (d, J= 9.5 Hz, 2H), 6.96 (d, J= 9.5 Hz, 2H), 6.69 (s, IH), 5.11 (s, 2H), 3.76 (s, 3H), 2.78 (s, 3H) APCI-MS: m/z 322/324 (MH⁺) Step 8: 5-Chloro-4-(4-methoxybenzyloxy)-N-methyl-2-((S)-l-oxiranylmethoxy)benzamide

O-PMB Amide (S)-Glycidyl Ether

A solution of 3-nitrobenzenesulfonic acid (5)-l-oxiranylmethyl ester in butyronitrile (0.317 kg of a 28.2 % w/w solution, 89.4 g contained weight, 345 mmol, 1.1 eq) was diluted with butyronitrile (0.238 kg) and cooled to 7 ⁰C with stirring. 5-Chloro-2-hydroxy-4-(4- methoxybenzyloxy)-7V-methylbenzamide (100 g, 0.311 mmol, 1.0 eq) was added followed by cesium carbonate (25.3 g, 77.7 mmol) and the mixture heated to 55 ⁰C. Two further portions of cesium carbonate (25.3 g each, 77.7 mmol) were added to the reaction mixture after holding at 55 ⁰C for 30 min and cooling the reaction mixture back to 7 ⁰C prior to each addition. After 1 h 40 min further cesium carbonate (25.3 g, 77.7 mmol) was added to the reaction mixture and after an additional 1 h, a final portion of cesium carbonate (50.7 g 156 mmol) was added to the reaction mixture at 55 ⁰C. On completion of the reaction, water (1 kg) added and the reaction mixture cooled to 7 ⁰C. After stirring for 1 h, the solid product was collected by filtration, washed with water (150 ml) and methanol (100 ml) then dried under vacuum at 45 ⁰C to leave 5-chloro-4-(4-methoxybenzyloxy)-7V-methyl-2- ((5)-l-oxiranylmethoxy)benzamide as a white solid, 93.6 g (79.7%). 1H NMR (399.826 MHz, D₆-DMSO) δ 8.01 - 7.93 (m, IH), 7.78 (s, IH), 7.42 (d, J= 9.1 Hz, 2H), 7.03 (s, IH), 6.98 (d, J= 9.1 Hz, 2H), 5.20 (s, 2H), 4.55 (dd, J= 11.5, 2.6 Hz, IH), 4.12 (dd, J= 11.7, 6.0 Hz, IH), 3.76 (s, 3H), 3.49 - 3.44 (m, IH), 2.90 (t, J= 4.6 Hz, IH), 2.81 (d, J= 4.6 Hz, 3H), 2.78 - 2.74 (m, IH). APCI-MS: m/z 378/380 (MH⁺) Step 9: 5-Chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy}-4-hydroxy-N-methylbenzamide, trifluoroacetic acid salt

(S)-Glycidyl Ether (S)-Phenol TFA

A suspension of 5-chloro-3H-spiro[l-benzofuran-2,4'-piperidine], hydrobromic acid salt (Step3; 42.85 g, 141 mmol) in toluene (440 ml) was stirred with aqueous ammonium hydroxide solution (28% w/w, 55 ml) for 30 min. The mixture was then filtered to remove a small amount of a solid and the layers allowed to separate. The aqueous phase was extracted with toluene (220 ml) and combined with the organic phase from the first separation to leave a solution of 5-chlorospiro[3H-benzofuran-2,4'-piperidine] in toluene. To this was added 5-chloro-4-(4-methoxybenzyloxy)-Λ/-methyl-2-((5)-l- oxiranylmethoxy)benzamide (Step 8; 50 g, 132 mmol) and the mixture heated at 80 ⁰C for 22 h. The turbid solution was filtered at 80 ⁰C then cooled to ambient temperature to leave 5-chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-(p-methoxybenzyloxy)-7V-methylbenzamide as a suspension in toluene. To this suspension was added trifluoroacetic acid (220 g, 1.93 mol) at a temperature of between 20 and 25 ⁰C with stirring. After stirring for 3 h at this temperature, the mixture was concentrated by distillation under vacuum until a residue of ca 200 ml remained. Isopropanol (150 ml) was added and solvent distilled off until the volume of the residue was ca 200 ml. This operation was repeated one more time. Methanol (200 ml) was added and solvent distilled off at atmospheric pressure until 200 ml of distillate had been removed. The residue was dissolved in methanol (400 ml) and stirred overnight. Some sticky solid was removed by filtration and the filtrate was distilled at atmospheric pressure, replacing the solvent removed with isopropanol (300 ml). The suspension was cooled in an ice-water bath then the solid product was collected by filtration, washed with isopropanol (2 x 50 ml) then dried in a vacuum oven at 50 ⁰C to leave a 5-chloro-2-{[(25)-3-(5-chloro- 3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4-hydroxy-7V- methylbenzamide, trifluoroacetic acid salt as an off- white powder, 66.1 g (84% over 2 stages). 1H-NMR (D₆-DMSO, 400 MHz): δ 8.05 (d, J=4.6, NH), 7.73 (s, IH), 7.30 (m, IH), 7.18- 7.14 (m, IH), 6.82-6.78 (m, IH), 6.73 (s, IH), 4.42 (m, IH), 4.05 (s, 2H), 3.57 (m, 2H), 3.45-3.40 (m, IH), 3.27-3.11 (m, 5H), 2.81 (d, J=4.8, 3H), 2.18-2.08 (m, 4H); APCI-MS: m/z 481 (MH⁺). APCI-MS: m/z 481/483/485 (MH⁺). Spectral data on an isolated sample of the intermediate PMB-protected compound:

¹H NMR (399.826 MHz, D₆-DMSO) δ 8.33 - 8.27 (m, IH), 7.83 (s, IH), 7.43 (dd, J= 6.7, 2.1 Hz, 2H), 7.25 - 7.22 (m, IH), 7.10 (dd, J= 8.6, 2.4 Hz, IH), 7.02 (s, IH), 6.98 (d, J = 6.7 Hz, 2H), 6.74 (d, J= 8.5 Hz, IH), 5.27 (s, exch D₂O, IH), 5.23 (s, 2H), 4.29 - 4.22 (m, IH), 4.11 - 4.02 (m, 2H), 3.76 (s, 3H), 3.00 (s, 2H), 2.80 (m, 3H), 2.70 - 2.56 (m, 2H), 1.88 - 1.70 (m, 4H). Remaining signals were coincident with DMSO at 2.5 ppm. APCI-MS: m/z 601/603/605 (MH⁺)

Step 10: 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.

polymorph A

Method 1

5-Chloro-2-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-hydroxy-7V-methylbenzamide TFA (135.5 g) was placed in a 2 L jacketed vessel and treated sequentially with caesium carbonate (3.0 eq), ethyl-2- bromoisobutyrate (3.0 eq) and then DMF (675 ml). The mixture was heated to 60 ⁰C and stirred overnight at this temperature. The mixture was cooled to 20 ⁰C, treated with water (1.0 L) and then extracted with ethyl acetate (I x 600 ml and 1 x 400 ml). The ethyl acetate extracts were combined and evaporated to dryness to give an orange oil (221.07 g). The residue was redissolved in ethanol (675 ml) and treated with a solution of sodium hydroxide (27.2 g in 270 ml water) with stirring. After 30 min the solvent was evaporated and the residue was treated with ammonium acetate (140 g) in water (1.35 L). The resulting slurry was stirred overnight and then filtered. The filter cake was slurry washed with water (1 x 135 ml and 1 x 540 ml), ethanol (270 ml), TBME (135 ml), treated with ethanol (1 L) at 60 ⁰C for 18 h and then filtered. The filter cake was washed with ethanol (135 ml). The solid was dried overnight in a vacuum oven at 50⁰C to give the titled zwitterion as polymorph A (102.3 g; 80% over 2 steps)

¹H-NMR (D₆-DMSO, 400 MHz): δ 13.41 (br s, IH), 9.60 - 9.35 (m, IH), 8.13 (d, J= 4.6 Hz, IH), 7.75 (s, IH), 7.30 (s, IH), 7.16 (d, J= 8.7 Hz, IH), 6.80 (d, J= 8.5 Hz, IH), 6.19 (s, IH), 4.40 (br.s, IH), 4.00 (d, J= 4.4 Hz, 2H), 3.62 - 3.15(m, 6H), 3.11 (s, 2H), 2.82 (d, J= 4.7 Hz, 3H), 2.50 (m, 4H), 1.60 (s, 6H); APCI-MS: m/z 567 (MH⁺).

Spectral data for an isolated sample of the intermediate ester: 1H NMR (399.826 MHz, D₆-DMSO) δ 8.27 (m, IH), 7.85 (s, IH), 7.23 (m, IH), 7.10 (dd, J= 8.5, 2.3 Hz, IH), 6.74 (d, J= 8.5 Hz, IH), 6.54 (s, IH), 5.26 (m, exch D₂O, IH), 4.23 (q, J= 7.1 Hz, 2H), 4.16 - 4.02 (m, 3H), 3.92 (dd, J= 9.2, 6.2 Hz, IH), 3.00 (s, 2H), 2.80 (d, J= 4.9 Hz, 3H), 1.87 - 1.68 (m, 4H), 1.61 (s, 6H), 1.21 (t, J= 14.9 Hz, 3H). Remaining signals partially overlapping DMSO signal. APCI-MS: m/z 595/597/599 (MH⁺) Method 2

A solution of 5-chloro-2-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)- 2-hydroxypropyl]oxy}-4-hydroxy-7V-methylbenzamide, trifluoroacetic acid salt (25.0 g, 42.0 mmol) in NMP (67 ml) was added over a period of 45 min to a stirred suspension of caesium carbonate (41.O g, 126 mmol) in NMP (67 ml), maintaining the temperature of the mixture below 30 ⁰C, followed by an NMP line rinse (4 ml). Ethyl 2-bromoisobutyrate (24.6 g, 126 mmol) was then added to the reaction mixture over a period of 45 min followed by an NMP line rinse (4 ml). The reaction mixture was heated to 70 ⁰C and stirred at this temperature for 11.5 h. After cooling to ambient temperature, the mixture was diluted with TBME (50 ml) then water (175 ml) was added over a period of around 1 h (exothermic addition). Further TBME (105 ml) was charged and the mixture stirred for around 30 min then the layers were allowed to separate. The aqueous layer was extracted with TBME (2 x 70 ml) and the combined organic layers were concentrated to a volume of approximately 90 ml. Ethanol (110 ml) was added and the volume reduced to 90 ml by evaporation. A further ethanol charge (110 ml) was added and the volume reduced again to 90 ml by evaporation to afford 2-{2-chloro-5-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran- 2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid ethyl ester as a solution in ethanol, total weight 81.31 g.

A solution of 2-{2-chloro-5-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r- yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid ethyl ester in ethanol (952 g total weight, contained weight 366.2 g, 614 mmol) was diluted with ethanol (1.09 L) and warmed to 44 ⁰C with stirring. To this was added a solution of sodium hydroxide (73.8 g, 1.85 mol) in water (732 ml) over a period of 30 min. After holding at 40 - 45 ⁰C for 2.5 h, the solution was decanted away from the polymeric by product and filtered. A solution of citric acid (101 g) in water (1.46 L) was added to the filtrate over a period of 1 h 50 min. The solid was collected by filtration, washed with water (1.5 L), ethanol (1.5 L then 375 ml) and dried in a vacuum oven at 65 ⁰C to yield crude 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 as a pale yellow solid, weight 301.63 g (86%). A slurry of crude 2-{2-chloro-5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2-methylpropanoic acid (9.0 g) in NMP (54 ml) was heated to 80 ⁰C with stirring to dissolve the solid then cooled to around 65 ⁰C. Ethanol (333 ml) was charged over a period of 35 min, maintaining the reaction temperature between 60 and 70 ⁰C, which caused crystallization of the product. After a further 30 min at this temperature the slurry was cooled to between 10 and 15 ⁰C over 1 hr, then held at this temperature for around 30 min. The solid was collected by filtration, washed with ethanol (45 ml), pulled dry on the filter then dried in a vacuum oven at 60 ⁰C. 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 was obtained as a white solid, weight 5.49 g (61%).

The resulting solid (5 g) was slurried in NMP (50 ml) and heated to 60 ⁰C and held at between 60 and 65 ⁰C for 30 min with stirring. Water (50 ml) was charged to the resulting solution over a period of 35 min, maintaining the temperature between 60 and 65 ⁰C, which caused crystallization of the product. After a further 30 min at this temperature the slurry was cooled to ambient temperature then held at this temperature for 30 min. The mixture was further cooled to between 0 and 4 ⁰C and held for 30 min. The solid was collected by filtration, washed with water (25 ml), ethanol (25 ml), pulled dry on the filter then dried in a vacuum oven at 60 ⁰C. 2-{2-Chloro-5-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'- piperidin]- 1 '-yl)-2-hydroxypropyl]oxy} -4-[(methylamino)carbonyl]phenoxy} -2- methylpropanoic acid was obtained as a white solid (polymorph A), weight 4.82 g (96%).

The title compound exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2Θ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):

(1) 5.1, 10.2 and 12.9, or

(2) 5.1, 8.9 and 13.2, or (3) 8.9, 10.2, 12.9, 15.1, 17.0 and 21.2 or

(4) 5.1, 8.9, 10.2, 14.6, 15.4, 21.2 and 25.8 or

(5) 5.1, 8.9, 10.2, 12.6, 14.6, 15.1 and 17.0 or

(6) 5.1, 10.2, 12.6, 13.2, 14.6, 15.1, 17.0, 17.9, 21.2 and 21.8 or

(7) 5.1, 8.9, 10.2, 12.6, 13.2, 14.6, 14.9, 16.4, 19.2, 21.8 and 27.1 or

(8) 5.1, 8.9, 10.2, 12.6, 12.9, 13.2, 14.6, 14.9, 15.1, 15.4, 16.4, 17.9, 19.2, 20.0, 21.8 and 25.8

The diffractogram is shown in figure 1 of patent application WO2008/010765.

Claims

1. A process for the preparation of spiropiperidine comprising the following steps; a) reacting bocpiperidone with trimethylsulfoxonium iodide to form an epoxy piperidine in the presence of a base and solvent, and b) reacting 2-Bromo-4-chloroanisole with isopropylmagnesium chloride to form the aryl Grignard reagent, which is then reacted with the epoxy piperidine to form a piperidinol (XXXI) in the presence of a catalyst and a suitable solvent, and c) reacting piperidinol (XXXI) with hydrobromic acid to obtain spiropiperidine in a suitable solvent.

2. The process according to claim 1, wherein the bases in step a) are selected from LiOR^x, NaOR^x, KOR^X, where R^x is C_1-6 alkyl such as for example tert-butoxide, and the solvent in step a) are selected from dimethylsulphoxide, THF, diethyl ether, tert-butyl methyl ether, dimethoxy ethane, dimethylacetamide, NMP or toluene.

3. The process according to claim 1, wherin the wherein the Grignard reagents in step b) is selected from compounds of formula R^yMgR^v or R^V ₂Mg, wherein R^y represents Cl, Br or I and R^v represents Ci_-6 alkyl, C_3-7 cycloalkyl or optionally substituted phenyl, and the catalysts that may be used in the process for making the piperidinol include but are not limited to in step b) is selected from copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulphide complex, copper (I) iodide or copper (I) cyanide, and the solvents in step b) is selected from THF, 2-methyltetrahydrofuran, diethyl ether, tert- butyl methyl ether, dimethoxyethane, toluene or hexanes.

4. A process for the preparation of a glycidyl Ether: Protection

Methyl Ester Chloro Phenol Chloro Diol

O-R^w Amide Glycidyl Ether (XXXIII) (XXXV)

where LG is a leaving group, R¹ is hydrogen or any substituent providing an ester function such as Ci_-6 alkyl 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, optionally substituted arylalkyl such as benzyl, R^w is any suitable protection group such as for example PMB and R⁵ is hydrogen or halogen, using suitable solvents, bases and catalyst.

5. The process according to claim 4, where the bases used in the process for making the O- R^w ester, where R^w is PMB are selected from cesium carbonate, potassium carbonate, 1,8-

Diazabicyclo[5.4.0]undec-7-ene, triethylamine, ethyldiisopropylamine or sodium hydride, and the solvents that may be used in the process for making the O-R^w ester where R^w is PMB are selected from dichloromethane, toluene, Λ/,Λ/-dimethylformamide, TV- methylpyrrolidone, tert-butyl methyl ether, methanol, ethanol, isopropanol or acetonitrile, and the solvents in step d) are selcted from THF, water, methanol, ethanol, isopropanol, or mixtures thereof such as a water / THF mixture.

6. A process for the preparation of the compound of formula XXXV comprising the following steps; d) reacting O-R^w ester with methylamine to obtain the compound of formula XXXIII,

and e) reacting the compound of formula XXXIII with an epoxide to form the compound of formula XXXV,

where R¹ is hydrogen or any substituent providing an ester function such as Ci_-6 alkyl 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, optionally substituted arylalkyl such as benzyl, optionally substituted arylalkyl e.g. benzyl, R^w is any suitable protection group, R⁵ is hydrogen or halogen and LG is a leaving group.

7. The process according to claim 4 or 6, where the solvents in step d) are selected from

THF, water, methanol, ethanol, isopropanol, or mixtures thereof such as a water / THF mixtureand the bases in step d) are selected from cesium carbonate, potassium carbonate, sodium hydride or potassium tert-butoxide, and the solvents in step e) are selected from butyronitrile, acetonitrile, toluene, tetrahydrofuran,

DMF or NMP, and the leaving groups are selected from 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, n-pentyl, n- hexyl or i-hexyl, or optionally substituted aryl such as phenyl, tosyl or 3-nitrophenyl, and the epoxides may be glycidyl nosylate, optically pure epichlorohydrin, glycidyl tosylate, glycidyl benzenesulphonate or glycidyl mesylate.

8. A process for the preparation of compounds of formula I

Ester

where R¹ is halogen, R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, R^w is any suitable protection group and R^p is hydrogen or any substituent providing an ester function such as C_1-6 alkyl 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, optionally substituted arylalkyl such as benzyl.

9. A process for the preparation of the compounds of formula (XXXVIII) comprising the following steps;

Spirocycle

(XXXV) (XXXVIII) f) treatment of a solution of the spiropiperidine HBr salt with aqueous ammonium hydroxide to liberate the free base and then reacting this with the compound of formula XXXV in a suitable solvent followed by deprotection to obtain the compound of formula XXXVIII, optionally as a salt.

10. A process for the preparation of compounds of formula I comprising the following steps; f) treatment of a solution of the spiropiperidine HBr salt with aqueous ammonium hydroxide to liberate the free base and then reacting this with the compound of formula XXXV in a suitable solvent followed by deprotection to obtain the compound of formula XXXVIII, optionally as a salt, followed by gl) reacting the compound of formula XXXVIII with α-bromo carboxylic ester in a suitable solvent in the presence of a base at an elevated temperature, and g2) de-esterification with a solution of a base followed by isolation by filtration after pH adjustment to obtain compound of formula I.

11. The process according to claims 8 to 10 where the bases in step f) are selected from ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and the solvents in step f) are selected from ethyl acetate, isopropyl acetate, toluene, THF, ethanol, methanol or isopropanol, and the acids where R^w is PMB in step f) are selected from trifluoroacetic acid, formic acid, acetic acid or hydrochloric acid, and the solvents where R^w is PMB in step f) are selected from DCM, toluene, tert-butyl methyl ether or THF, and the bases bases in step gl) are selected from cesium carbonate, potassium carbonate or sodium hydride, and the solvents in step gl) are selected from DMF, NMP, ethanol, methanol or isopropanol, and the bases in step g2) are selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, and the acids in step g2) are selected from TFA, formic acid, acetic acid or hydrochloric acid, and the solvents in step g2) are selected from water, methanol, ethanol, isopropanol or mixtures thereof such as for example a water / ethanol mixture.

12. A process for the preparation of 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 comprising the following

(S)-Glycidyl Ether (S)-Phenol TFA f-a) treatment of a solution of the spiropiperidine HBr salt with aqueous ammonium hydroxide to liberate the free base and then reacting this with the glycidylether in a suitable solvent followed by TFA treatment to obtain 5-chloro-2-{[(25)-3-(5-chloro-l 'H,3H- spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy} -4-hydroxy-N- methylbenzamide, as its TFA salt, and

(S)-Phenol TFA

2-{2-Chloro-5-{[(2S)-3-(5-chloro-1 'H,3H-spiro [1 -benzofuran-2,4'-piperidin]-1 '-yl)- 2-hydroxypropyl]oxy}-4-[(methylamino) carbonyl]phenoxy}-2-methylpropanoic acid g-a) reacting 5-Chloro-2-{[(25)-3-(5-chloro-l 'H,3H-spiro[l-benzofuran-2,4'-piperidin]-r- yl)-2-hydroxypropyl]oxy}-4-hydroxy-7V-methylbenzamide TFA with ethyl-2- bromoisobutyrate in a suitable solvent in the presence of a base at an elevated temperature, and h-a) redissolving the obtained product is in ethanol and treatment with a solution of sodium hydroxide, whereafter the solvent is evaporated and the residue treated with aqueous ammonium acetate, filtered and washed with water/ethanol and then filtered, or h-b) adding aqueous citric acid and filtering off the solid, washing with water followed by ethanol, then recrystallising from ethanol/NMP and then from aqueous NMP.

13. A compound of formula XXXI, where R is halogen

compound 4-(5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid, tert- butyl ester.

14. A compound of formula XXXII where R⁵ is hydrogen or halogen.

(XXXII), or compound 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)-Λ/-methylbenzamide.

15. A compound of formula XXXIII, where R⁵ is hydrogen or halogen and R^w is hydrogen or any suitable protecting group, or a salt thereof

(XXXIII), or

16. A compound of formula XXXIV, where R⁵ is hydrogen or halogen

(XXXIV), or compound 5-Chloro-4-(4-methoxy-benzyloxy)-N-methyl-2-((5)-l- oxiranylmethoxy)benzamide.

17. A compound of formula XXXV, where R⁵ is hydrogen or halogen and R^w is hydrogen or any suitable protecting group, or a salt thereof

18. A compound of formula XXXVI, where R¹ is halogen and R⁵ is hydrogen or halogen

XXXVI, or compound 5-Chloro-2-{[(25)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-(p-methoxybenzyloxy)-Λ/-methylbenzamide.

19. A compound of formula XXXVII, where R¹ is halogen, R⁵ is hydrogen or halogen and R^w is hydrogen or any suitable protecting group, or a salt thereof

(XXXVII).

20. A compound of formula XXXVIII, where R¹ is halogen and R⁵ is hydrogen or halogen

(XXXVIII), or 5-Chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-hydroxy-7V-methylbenzamide, trifluoroacetic acid salt.

21. A compound of formula ID, where R¹ is halogen, R⁵ is hydrogen or halogen, R⁶ and R⁷ are independently selected from hydrogen or Ci-₆alkyl, and R^p is hydrogen or any substituent providing an ester function such as Ci_-6 alkyl 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, optionally substituted arylalkyl such as benzyl

22. The use of compounds of formula (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (ID), and salts thereof, or compounds selected from 4-(5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid, tert-butyl ester, 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)-N-methylbenzamide, 5-Chloro-4-(4-methoxy-benzyloxy)-N-methyl-2-((S)-l-oxiranylmethoxy)benzamide, 5-Chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl] oxy } -4-(p-methoxybenzyloxy)-N-methylbenzamide, 5-Chloro-2-{[(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy}-4-hydroxy-N-methylbenzamide, trifluoroacetic acid, and 2-{2-Chloro-5-{[(2S)-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, 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 Ci-₆alkyl.