WO2013021309A1

WO2013021309A1 - Intermediate and process for the preparation of a sulfonamide derivative

Info

Publication number: WO2013021309A1
Application number: PCT/IB2012/053861
Authority: WO
Inventors: Thomas Pierre DUPONT; Nicolas Mickaël FEDOU; Julian Duncan Smith; Steven John Robert TWIDDLE
Original assignee: Pfizer Limited
Priority date: 2011-08-11
Filing date: 2012-07-27
Publication date: 2013-02-14

Abstract

The invention relates to a crystalline form of 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3- yl)methyl]amino}-2-oxoethyl)phenyl]-1,1-dimethylethyl}acetamide, a process for preparing the same and its use in the preparation of the 2 agonist N-[(4'-hydroxybiphenyl-3- yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl} phenyl)acetamide which is useful in the treatment of respiratory diseases.

Description

Intermediate and process for the preparation of a sulfonamide derivative

The present invention relates to a substantially crystalline form of 2-chloro-N-{2-[3-(2-{[(4'- hydroxybiphenyl-3-yl)methyl]amino}-2-oxoethyl)phenyl]-1 ,1 -dimethylethyl}-a ce ta m i d e of formula (1 ):

a process for preparing the same and its use in the preparation of the β2 agonist Λ/-[(4'- hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl) amino]phenyl}ethyl)amino]-2-methylpropyl} phenyl)acetamide wh i ch i s us efu l i n t h e treatment of respiratory diseases.

The compound N-[(4'-hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy- 3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl} phenyl)acetamide is a β2 agonist useful in the treatment e.g. respiratory diseases such as asthma or COPD which is described in WO 2005/080313. A process suitable for large scale manufacture of the above mentioned β2 agonist has already been proposed in WO2007/010356. However, this process presents the drawback that the β2 agonist N-[(4'-hydroxybiphenyl-3-yl)methyl]- 2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2- methylpropyl}phenyl)acetamide is obtained with still some impurities present which are very difficult to remove by means of usual purification sequences. However, purity of the pharmaceutical substance, particularly considering the detrimental effect that the presence of certain impurities during the crystallization stage can have on the physical properties of the pharmaceutical substance crystals, is essential to control in order to develop a viable manufacturing process.

It has now been found that the isolation and use of a substantially crystalline form of 2- chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2-oxoethyl)phenyl]-1 , 1 - dimethylethyl}-acetamide of formula (1 ):

in the preparation of said β2 agonist provides purge of critical impurities and their fate products as well as problematic residual reagents which were previously difficult to purge so that the final product is obtained with an acceptable higher purity.

The intermediate 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2- oxoethyl)phenyl]-1 , 1 -di methylethyl}acetam ide of form ula ( 1 ) is already known from WO2007/010356. However, the process described in WO 2007/010356 does not involve th e iso l ati o n of 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2-oxoethyl)- phenyl]-1 , 1 -di methylethyl}acetam ide wh ich was only prepared as an uncrystallized solution. As a consequence, purging impurities and problematic residual reagents at this stage of the process was difficult and resulted in an unacceptably high impurity burden being carried out into the latter steps in the preparation of the above mentioned β2 agonist.

A first object of the present invention is thus a substantially crystalline form of 2-chloro-N- {2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2-oxoethyl)phenyl]-1 , 1 - dimethylethyl}acetamide (also referred as the "intermediate of formula (1 )").

The intermediate of formula (1 ) according to the present invention has an X-ray diffraction pattern characterized by the following 3 unique X-ray diffraction pattern peaks expressed in terms of 2-theta angle (± 0.1 ° 2Θ) when measured using Cu Ka1 radiation (Wavelength = 1 .5406 A):

Angle (°2Θ) Intensity (%)

9.1 7.7

10.5 18.8

1 1 .4 6.7 According to another embodiment, the intermediate of formula (1 ) according to the present invention may also be characterized by a Fourier Transform Infra-red (FT-IR) pattern having the main characteristic peaks at 1535 (s), 1 179 (s), 834 (s) and 769 (s) cm^"1.

According to another embodiment, the intermediate of formula (1 ) according to the present invention may also be characterized by a Fourier Transform Raman pattern having the main characteristic peaks at 1294 (s), 1001 (vs), and 772 (w) cm^"1.

According to another embodiment, the intermediate of formula (1 ) according to the present invention may also be characterized by a solid state ¹³C NMR pattern having the following principal carbon chemical shifts referenced to external sample of solid phase adamantane at 29.5 ppm:

^{a> Defined as peak heights. Intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

For avoidance of doubt, "crystalline" or "substantially crystalline" according to the present invention means that the intermediate of formula (1 ) according to the present invention is at least 50% crystalline, preferably at least 70% crystalline, more preferably at least 80% crystalline, still more preferably at least 85% crystalline, still more preferably at least 90% crystalline and even more preferably at least 95% crystalline.

The intermediate of formula (1 ) according to the present invention may be obtained by reaction of a compound of formula (2):

with chloroacetonitrile in the presence of an acid catalyst such as acetic acid, sulfuric acid, trifluoroacetic acid or mixtures thereof in a suitable solvent such as acetic acid, trifluoroacetic acid, chloroacetonitrile, toluene, or dichloromethane at temperatures of 0°C to 1 10°C followed by removal of the acid and volatile solvents during the reaction work-up and the addition an antisolvent such as 2-butanol, n-butanol, cyclohexane, heptanes, toluene or mixtures thereof, to crystallize the compound of formula (1 ) which is isolated using standard techniques. Typical conditions comprise treating 1 .0 equivalents of the compound of formula (2) with 1 to 1 0 equivalents, preferably 5 to 7 equivalents, of chloroacetonitrile and 1 to 25 equivalents, preferably 14 to 16 equivalents, of trifluoroacetic acid at 20°C to 70°C, preferably 45°C to 55°C, for 1 to 24 hours then crystallizing the compound of formula (1 ) by removing the trifluoroacetic acid by distillation, then adding 10 to 25 equivalents, preferably 15 to 20 equivalents of 2-butanol and 0.005 to 0.1 equivalents, preferably 0.01 to 0.05 equivalents of seed crystals of the compound of formula (1 ) at 35°C to 70°C, preferably 55°C to 65°C, followed by 0 to 20 equivalents, preferably 9 to 1 1 equivalents of cyclohexane then cooling the mixture to 0°C to 30°C, preferably 15°C to 25°C over 0.5 to 3 hours.

Preferably, said compound of formula (2) is prepared by reaction of a compound of formula

in the presence of a suitable amide coupling agent such as 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, 1 ,1 '-carbonyldiimidazole, 2,4,6- tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,5-trioxide (T3P®), pivaloyl chloride or isobutyl chloroformate in a suitable solvent such as tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, toluene, acetonitrile, propionitrile, pyridine or dimethylformamide, optionally in the presence of a base such as triethylamine, 4-methylmorpholine, or diisopropylethylamine, also optionally in the presence of a suitable additive such as 1 -hydroxybenzotriazole, 2-hydroxypyridine or N- hydroxysuccinimide. Typical conditions comprise reacting 1.0 equivalent of the compound of formula (3) with 1.0 equivalents of 1,1 '-carbonyldiimidazole in ethyl acetate at 15°C to 30°C for 0.25 to 4 hours followed by reaction with 1.1 equivalents of the amine of formula (4) at 20°C to 60°C for 1 to 24 hours.

The compound of formula (4) may be prepared as described in WO 2007/010356. Alternatively, the com ound of formula (4) may be prepared according to Scheme 1 below:

SCHEME 1

In Step (a), (3-cyanophenyl)boronic acid is reacted with 4-bromophenol in the presence of a suitable palladium catalyst such as p a 11 a d i u m ( 11 ) acetate, (dibenzylideneacetone)dipalladium(O), palladium(ll) trifluoroacetate, a suitable catalyst ligand such as triphenyl phosphine, tri-o-tolyl phosphine, tri-te/t-butyl phosphine, 1,1'- bis(diphenylphosphino)ferrocene or tris-te/t-butylphosphonium tetrafluoroborate, and a suitable base such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, disodium hydrogen phosphate triethylamine, diisopropylethylamine, or N-methyl morpholine in a suitable solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dichloromethane, toluene, isopropyl acetate, 4-methyl-2-pentanone, butan-2-one, or acetone optionally in the presence of water. Typical conditions comprise reacting 1.0 equivalent of 4-bromophenol with 1.05 equivalents of (3-bromophenyl)boronic acid in the presence of 1 to 3 equivalents of potassium carbonate and a catalytic amount of a palladium catalyst such as 0.01 to 0.05 equivalents of palladium acetate or tn^'s(dibenzylideneacetone)dipalladium(0) and a suitable ligand such as 0.01 to 0.05 equivalents of 1,1'-bis(diphenylphosphino)ferrocene ortris-te/f- butylphosphonium tetrafluoroborate in a suitable solvent such as aqueous 2- methyltetrahydrofuran or aqueous tetrahydrofuran under a nitrogen atmosphere at 20°C- 70°C for 4 to 12 hours.

In Step (b), the compound of formula (5) is reduced by catalytic hydrogenation using a suitable nitrile hydrogenation catalyst such as palladium, rhodium, platinum or nickel optionally on a suitable support such as carbon or alumina, in a suitable solvent such as water, methanol, ethanol, n-butanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran optionally in the presence of either a base such a lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide or ammonia, or an acid such as sulfuric acid, hydrogen chloride, methanesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid. Typical conditions comprise either hydrogenating a solution of 1 .0 equivalent of the compound of formula (5) in methanol containing 1 to 3 equivalents of sodium methoxide over a Raney Nickel catalyst at 20°C to 60°C for 2 to 24 hours, or hydrogenating a solution of 1 equivalent of the compound of formula (5) in a solution of methanol containing 1 -3 equivalents of methanesulfonic acid over a palladium on carbon catalyst at 20°C to 60°C for 2 to 24 hours.

The compound of formula (3) may be prepared as described in WO 2007/010356. Alternativel the compound of formula (3) may be prepared according to Scheme 2 below:

(3) (8)

SCHEME 2

In step (c) a mixture of 1 ,3-bis(chloromethyl)benzene, a palladium catalyst and a base in methanol or ethanol is reacted with carbon monoxide at elevated pressure and elevated temperature. Typical conditions comprise combining a solution of 1 .0 equivalents of 1 ,3- bis(chloromethyl)benzene in methanol or ethanol with 1 to 6 equivalents of N,N- diisopropylethylamine and a 0.005 to 0.05 equivalents of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) and then heating the mixture to 30°C to 100°C for 4-24 hours under 20 to 500 psi pressure of carbon monoxide to give dimethyl 2,2'-(1 ,3- phenylene)diacetate.

In step (d) one of the ester groups in the compound of formula (9), such as one of the methyl ester groups in dimethyl 2,2'-(1 ,3-phenylene)diacetate, is selectively hydrolysed to the compound of formula (8), such as [3-(2-methoxy-2-oxoethyl)phenyl]acetic acid, in the presence of a suitable enzyme known in the art, such as a lipase, esterase or protease, preferably a lipase. Preferred enzymes are Mucor Miehei esterase, Rhizomucor Miehei lipase, Thermomuces Languinosus lipase, Penicllin acylase. More preferably, the reaction is carried out with Lipase® (Thermomuces Languinosus lipase, (EC No 3.1 .1 .3)) at a pH between 5 and 9 and a temperature between 10°C and 40°C in water in the presence of a suitable buffering agent such as calcium acetate, dipotassium hydrogenphosphate or triethanolamine, and optionally in the presence of a suitable base such as sodium hydroxide, potassium hydroxide or lithium hydroxide. Typical conditions comprise 1.0 equivalents of dimethyl 2,2'-benzene-1 ,3-diyldiacetate reacting with 5 to 200 ml of Lipolase® (liquid formulation) in a calcium acetate buffer solution at temperatures between 20°C and 40°C, maintaining the pH between 5.5 and 6.8 by the addition of a base such as sodium hydroxide or potassium hydroxide.

In step (e) the compound of formula (8), such as [3-(2-methoxy-2-oxoethyl)phenyl]acetic acid, is reacted with an "activated" methyl reagent (organometallic methyl such as CH₃MgCI, CH₃MgBr, CH₃Li) to give the compound of formula (3). Typical conditions comprise treating a solution of 1 .0 equivalent of [3-(2-methoxy-2-oxoethyl)phenyl]acetic acid in a suitable solvent such as tetrahydrofuran or a m ixture of toluene and tetrahydrofuran with a solution of 2 to 5 equivalents of methylmagnesium bromide or methylmagnesium chloride in tetrahydrofuran at -20°C to 20°C.

The intermediate of formula (1 ) according to the present invention is useful in the preparation of the β2 agonist A/-[(4'-hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)-2 -hydroxy- 2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2- methylpropyl} henyl)acetamide of formula (14):

Another object of the present invention is thus a process for preparing the β2 agonist Λ/- [(4'-hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)-amino]-2-methylpropyl}phenyl)acetamide of formula (14) involving use of the compound of formula (1 ) according to the present invention.

More precisely, the process for preparing the β2 agonist N-[(4'-hydroxybiphenyl-3- yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}- ethyl)amino]-2-methylpropyl}phenyl)acetamide of formula (14) comprises the step of deprotecting the intermediate of formula (1 ) according to the present invention in order to obtain a compound of formula 1 1 ):

(11)

in the presence of thiourea and an acid such as hydrochloric acid, acetic acid or trifluoroacetic acid in a suitable solvent such as 2-butanol, acetic acid, isopropanol, ethyl acetate, isopropyl acetate, water or a mixture thereof. Typical conditions comprise reacting a mixture of 1 .0 equivalent of the compound of formula (1 ) with 1 to 2 equivalents of thiourea and 1 to 4 equivalents of acetic acid in a mixture of water and 2-butanol and heating at reflux for 2 to 24 hours.

The compound of formula (1 1 ) is then reacted with a compound of formula (12):

wherein Bn means benzyl and TBDMS means te/f-butyldimethylsilyl, to initially give the compound of formula 13):

which is then followed by deprotection steps to obtain the final β2 agonist of formula (14).

More precisely, the compound of formula (1 1 ) is reacted with the compound of formula (12) in the presence of a suitable base such as lithium carbonate, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or dipotassium hydrogenphosphate in a suitable solvent such as toluene, 4-methyl-2-pentanone, 2-methyl- 2-butanol, 3-methyl-1 -butanol, n-butyl acetate, n-propyl acetate, isopropyl acetate or propionitrile. Typical conditions comprise treating 1 .0 equivalents of the compound of formula (1 1 ) with 0.5 to 2.0 equivalents of the compound of formula (12) and 1 .0 to 4.0 equivalents of sodium hydrogen carbonate in n-butyl acetate at temperatures up to and including reflux for 10 to 48 hours.

Preferably the compound of formula (13) thus obtained is not isolated and the first deprotection step is carried out directly.

Preferably, two deprotection steps are carried out to remove the TBDMS and benzyl protecting groups and obtain the β2 agonist of formula (14).

Preferably, a first deprotection step is carried out to remove the TBDMS protecting group to obtain a compound of formula (13a):

or a salt thereof, using a fluoride-containing reagent such as tetrabutylammonium fluoride, tetraethylammonium fluoride, tetramethylammonium fluoride, triethylamine trihydrofluoride or pyridine hydrofluoride i n a suitable solvent such as tetrahydrofuran, 2-methyl tetrahydrofuran, methanol, ethanol, 2-butanol, n-butyl acetate, ethyl acetate, isopropyl acetate, water or mixtures thereof and optionally in the presence of an acid such as acetic acid, trifluoroacetic acid, benzoic acid, fumaric acid or citric acid. Typical conditions com prise treati ng th e com po u nd of form u l a ( 1 3) with 1 to 2 eq u ival e nts of tetraethylammonium fluoride and 1 to 4 equivalents of acetic acid in a mixture of n-butyl acetate, ethyl acetate and methanol at 20° to 60°C for 2 to 24 hours.

Preferably a salt of compound of formula (13a) is then prepared and used in the next deprotection step. Possible salts of the compound of formula (13a) include L-tartrate, fumarate, L-ascorbate or xinafoate. A preferred salt of compound of formula (13a) is the hemifumarate salt (13b):

Said salt may be prepared by treating a solution of the compound of formula (13a) as a free base in a suitable solvent such as methanol, ethanol, isopropanol, n-butyl acetate, ethyl acetate, water, 4-methyl-2-pentanone, butan-2-one, tetrahydrofuran, 2-methyl tetrahydrofuran or mixtures thereof with fumaric acid at 20°C to reflux temperature. Typical conditions comprise treating 1 .0 equivalents of the compound of formula (13a) with 0.4 to 0.6 equivalents of fumaric acid and seed crystals of the hemifumarate salt (13b) in a mixture of n-butyl acetate and ethanol at 50°C to 75°C for 0.25 to 2 hours then cooling the mixture to 10°C to 30°C for 1 to 10 hours. Preferably, the hemifumarate salt (13b) is prepared by combining a solution of 1 .0 equivalent of the compound of formula (13a) as a free base in a suitable solvent such as ethanol or a mixture of ethanol and n-butyl acetate with a solution of 0.5 equivalents of fumaric acid in ethanol at 60°C to 70°C together with 0.5 to 5% w/w of seed crystals of the hemifumarate salt (13b) for 0.5 to 10 hours.

Preferably a second deprotection step is then carried out to remove benzyl protecting group and obtain the β2 agonist of formula (14). Practically, the hemifumarate salt (13b) is treated with a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide in a mixture of water and a suitable solvent such as isopropyl acetate, ethyl acetate, n-butyl acetate, dichloromethane, tetrahydrofuran, or 2-methyl tetrahydrofuran to give the free base of the compound of formula (1 3a) which is then debenzylated using standard methodology as described in "Protective Groups in Organic Synthesis" by T. W. Greene and P. Wutz to provide the compound of formula (14). Typical conditions comprise treating 1 .0 equivalents of the hemifumarate salt (13b) in tetrahydrofuran with an excess of an aqueous solution of potassium carbonate then washing the solution with aqueous sodium chloride solution to give a solution of the free base of compound of formula (13a) in a mixture of tetrahydrofuran and water which is reacted with an excess of hydrogen under 40 to 80 psi pressure in the presence of a suitable catalyst such as 5% palladium on carbon at 15 to 30°C for 2 to 48 hours. After removing the catalyst from the reaction mixture, the β2 agonist of formula (14) is crystallized by exchanging the solvent into an antisolvent which may be selected from ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, toluene, butan-2-one, 4-methyl-2-pentanone, methanol, ethanol, or 2-methyltetrahydrofuran using a distillation process and is then isolated. Preferably the antisolvent is acetonitrile.

The β2 agonist of formula (14) thus obtained may then be purified by slurrying the compound of formula (14) in a solvent which may be selected from ethanol, methanol, isopropanol , acetonitrile, water, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, acetone, butan-2-on e , 4-methyl-2-pentanone, ethyl acetate, butyl acetate, isopropyl acetate or solvent mixture thereof. Preferably, the β2 agonist of formula (14) is purified by slurrying in a mixture of 10%v/v to 30%v/v water in methanol at 10 to 60°C for 1 to 24 hours.

The β2 agonist of formula (14) thus obtained may be re-crystallized by dissolving the compound of formula (14) obtained according to the steps described above in a suitable solvent such as a mixture of water and tetrahydrofuran and then exchanging the solvent with an antisolvent which may be selected from ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, toluene, butan-2-one, 4-methyl-2-pentanone, methanol, ethanol, or 2- methyltetrahydrofuran. Preferably, the β2 agonist of formula (14) is re-crystallized by dissolving the compound of formula (14) in a mixture of 10%v/v to 30%v/v water in tetrahydrofuran and exchanging the solvent into mainly acetonitrile using a distillation process during which the β2 agonist of formula (14) crystallizes.

The β2 agonist of formula (14) thus obtained may then be purified by slurrying the compound of formula (14) in a solvent which may be selected from ethanol, methanol, isopropanol, acetonitrile, water, tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, acetone, butan-2-one , 4-methyl-2-pentanone, ethyl acetate, butyl acetate, isopropyl acetate or solvent mixture thereof. Preferably, the β2 agonist of formula (14) is purified by slurrying in a mixture of 10% v/v to 30% v/v water in methanol at 10 to 60°C for 1 to 24 hours.

The compound of formula (12) may be prepared as described in WO 2007/010356. Alternatively, the compound of formula (12) may be prepared as disclosed in scheme 3:

SCHEME 3

Steps (f) and (g) are performed according to the conditions well known from the literature (Step (f): Greene, T. W.; Wuts, P. G. M. (1999). Protective Groups in Organic Synthesis (3^rd ed.), Wiley-lnterscience, p. 266, ISBN 0-471-16019-9.; Step (g): Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. (1989). Vogel's Textbook of Practical Organic Chemistry (5^th ed.), Harlow:Longman, p. 1052, ISBN 0-582-46236-3). The starting materials are all commercially available. Steps (h) to (k) are similar to those described in WO 2007/010356.

The process for preparing the β2 agonist A/-[(4'-hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)- 2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2- methylpropyl}phenyl)acetamide of formula (14) is further summarized below in Scheme 4:

Step (5)

SCHEME 4 Steps (1 ) to (7) in scheme 4 are performed as previously described herein. The present invention is further illustrated by the examples below. FIGURES

Figure 1 : DSC trace of the compound of example 1

Figure 2: PXRD pattern of the compound of example 1

Figure 3: Fourier Transform Infra-red (FT-IR) spectroscopy pattern of example 1

Figure 4: Expanded form of the fingerprint region of the FT-IR spectroscopy pattern of example 1

Figure 5: Fourier Transform Raman spectroscopy pattern of example 1

Figure 6: Expanded form of the fingerprint region of the Fourier Transform Raman spectroscopy pattern of example 1

Figure 7: CPMAS spectrum of example 1

Figure 8: DSC trace of the compound of preparation 6

Figure 9: PXRD pattern of the compound of preparation 6

Figure 10: Fourier Transform Infra-red (FT-IR) spectroscopy pattern of preparation 6

Figure 11 : Expanded form of the fingerprint region of the FT-IR spectroscopy pattern of preparation 6

Figure 12: Fourier Transform Raman spectroscopy pattern of preparation 6

Figure 13: Expanded form of the fingerprint region of the Fourier Transform Raman spectroscopy pattern of preparation 6

Figure 14: CPMAS spectrum of preparation 6

Figure 15: PXRD pattern for the compound of example 2

Figure 16: Fourier Transform Infra-red (FT-IR) spectroscopy pattern of example 2

Figure 17: Expanded form of the fingerprint region of the FT-IR spectroscopy pattern of example 2

Figure 18: Fourier Transform Raman spectroscopy pattern of example 2

Figure 19: Expanded form of the fingerprint region of the Fourier Transform Raman spectroscopy pattern of example 2

Figure 20: CPMAS spectrum of example 2

Figure 21 : ¹H NMR of chloroacetonitrile (performed in DMSO with water present) Figure 22: ¹H NMR of a solution of 2-Chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3- yl)methyl]amino}-2-oxoethyl)phenyl]-1 ,1 -di m eth yl eth yl }aceta m i d e as o bta i n ed i n WO2007/010356

Figure 23: ¹H NMR of the isolated crystalline 2-Chloro-A/-{2-[3-(2-{[(4'-hydroxybiphenyl-3- yl)methyl]amino}-2-oxoethyl)phenyl]-1 ,1 -dimethylethyl}-acetamide according to example 1

EXAMPLES

Example 1 : Preparation of the crystalline form of 2-Chloro-A -{2-f3-(2-{f(4'- hvdroxybiphenyl-3-yl)methyllamino)-2-oxoethyl)phenyl1-1 ,1 -dimethylethyl)- acetamide of formula (1)

a) Preparation 1 : 2-i3-(2-Hvdroxy-2-methylpropyl)phenvnacetic acid of formula (3)

2-[3-(2-Hydroxy-2-methylpropyl)phenyl]acetic acid may be prepared as described in WO 2007/010356. Alternatively, it may be prepared as follows:

Preparation 1 a): Dimethyl 2,2'-(1 ,3-phenylene)diacetate of formula (9) (wherein R is methyl)

(9, R = methyl)

A solution of 1 ,3-bis(chloromethyl)benzene (15g, 85.6 mmol) and N,N- diisopropylethylamine (60 ml, 344 mmol) in methanol (107 ml) was charged to a bomb pressure reactor, which contained a magnetic stirrer bar, tetrakis(triphenylphosphine) palladium(O) (0.99g, 0.85 mmol) was added and the apparatus was purged with carbon monoxide. The apparatus was pressurized to 300psi of carbon monoxide and heated to 80°C and stirred at this temperature for 8 hours. The reaction was allowed to cool to room temperature and the mixture was evaporated under vacuum. The residue was dissolved in toluene (400ml) and washed with aqueous hydrochloric acid {2N, 2 x 300ml). The toluene layer was washed with saturated aqueous sodium hydrogen carbonate solution (300ml) and saturated brine (100ml) then dried (MgS0₄) and evaporated under vacuum to give dimethyl 2,2'-(1 ,3-phenylene)diacetate a yellow mobile oil with a few solids present (17.2g, 90%) that can be used directly in the next step.

¹H NMR: when analysed by conventional proton NMR (400MHz, d₆-DMSO), the compound of preparation 1 a) gives the following spectrum: δ 3.62 (s, 6H), 3.67 (s, 4H), 7.16-7.17 (m, 3H) and 7.26-7.28 (m, 1 H).

¹³C NMR: when analysed by conventional carbon NMR (100MHz, d₆-DMSO), the compound of preparation 1 a) gives the following spectrum: δ 40.0, 51 .7, 127.8, 128.4, 130.2, 134.4 and 171.5.

MS: when analysed by mass spectrometry, using positive electrospray ionisation technique, the compound of preparation 1 a) gave a mass of 223.0966 (Ci₂Hi₅0 ), calculated 223.0965.

Preparation 1 b): r3-(2-methoxy-2-oxoethyl)phenyl1acetic acid of formula (8) (wherein R is methyl)

(8, R = methyl)

Lipolase® (Thermomyces lanuginsus lipase solution, 1 .9 g) was added to a solution of calcium acetate in water (23.0 g of a 0.2M solution) and the resultant mixture was stirred at room temperature for 30 minutes. A solution of dimethyl 2,2'-(1 ,3-phenylene)diacetate (5.0 g) in toluene (5 ml) was added and the mixture was stirred at room temperature. The pH of the mixture was maintained at approximately pH 6.5 by the addition of aqueous 1 M sodium hydroxide controlled by a pH stat. The reaction was complete after 27 hours. The pH of the mixture was adjusted to pH 3.6 using 1 M aqueous hydrochloric acid, and ethyl acetate (25 ml) was added. After stirring for 1 hour, the mixture was filtered through filter aid and the solids were washed with ethyl acetate (100 ml). The filtrates were combined and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 25 ml), and the combined organic phases were extracted with sodium hydrogen carbonate solution (3 x 30 ml, 10% aqueous solution). The combined aqueous extracts were acidified to pH 2 using 5M hydrochloric acid, and were extracted with toluene (2 x 50 ml). The combined organic layers were dried (MgSO₄) and concentrated in vacuo to give the title compound (2.81 g) as a mobile oil that can be used directly in the next step.

¹H NMR: when analysed by conventional proton NMR (400MHz, d₆-DMSO), the compound of preparation 1 b) gives the following spectrum: δ 3.55 (s, 2H), 3.62 (s, 3H), 3.67 (s, 2H), 7.14-7.17 (m, 3H), 7.25-7.28 (m, 1 H) and 12.34 (bs, 1 H).

¹³C NMR: when analysed by conventional carbon NMR (100MHz, d₆-DMSO), the compound of preparation 1 b) gives the following spectrum: δ 40.5, 40.6, 51 .7, 127.6, 127.8, 128.3, 130.2, 134.3, 135.0, 171.5 and 172.5.

MS: when analysed by mass spectrometry, using positive electrospray ionisation technique, the compound of preparation 1 b) gave a mass of 209.0806 (CnHi₃O ), calculated 209.0808.

Preparation 1 c): r3-(2-Hvdroxy-2-methylpropyl)phenyl1acetic acid of formula (3)

A solution of crude [3-(2-methoxy-2-oxoethyl)phenyl]acetic acid (20g, net 18.9g; 0.09mole; HPLC purity 94.6% including toluene peak) in dry tetrahydrofuran (170ml) and dry toluene (170ml) was cooled to -15 to -5°C under N₂ purge. A solution of 3M methylmagnesium chloride in tetrahydrofuran (106ml; 0.32 mole, 3.5eq) was added dropwise keeping the temperature below 0°C. On completion of the addition, the cooling was removed and the grey suspension was allowed to warm to ambient temperature. Once the reaction was complete, the slurry was cooled to 0 to 5°C and quenched by the slow addition of water (100ml). The pH of the mixture was then adjusted to between pH 1 and pH 2.5 by adding concentrated hydrochloric acid. The mixture was extracted with isopropyl acetate (100ml) and the isopropyl acetate extracts back washed with water (3 x 50ml). The organic phase was dried (MgS0₄), and the solvent was exchanged into approximately 100 ml of toluene using vacuum distillation. The resultant mixture was heated to 55°C, then cooled to 20°C over 4 hours and stirred for 2 hours. The resultant solid was collected by filtration, washed with toluene (20 ml) and dried at 50°C in vacuo to give the title compound as a yellowish solid (14.2 g).

If necessary [3-(2-hydroxy-2-methylpropyl)phenyl]acetic acid can be purified using the following procedure. A mixture of 3-(2-hydroxy-2-methylpropyl)phenyl]acetic acid (14.2g) and ethyl acetate (55ml) and heptane (52ml) was heated to 50°C to give a clear solution. The solution was cooled to 35°C over 1 hour, and then seed crystals were added and the mixture was stirred at 35°C for 1 hour. The slurry was cooled to 30°C over 1 hour and cooled further to -5°C over 4 hours. The slurry was agitated for 4 hours. The resultant solid was collected by filtration, washed the with a mixture of ethyl acetate (6ml) and heptane (23ml) and dried at 50°C in vacuo t o g i v e p u r i f i e d [ 3-(2-hydroxy-2- methylpropyl)phenyl]acetic acid as a white solid (1 1.4g).

Characterisation data for [3-(2-hydroxy-2-methylpropyl)phenyl]acetic synthesised using preparation 1 c) is identical to that reported in WO 2007/010356.

Alternatively, 2-[3-(2-hydroxy-2-methylpropyl)phenyl]acetic acid may be prepared through the intermediate diethyl 2,2'-(1 ,3-phenylene)diacetate as follows:

Preparation 1 d): diethyl 2, 2'- 1 ,3-phenylene)diacetate

A solution of 1 ,3-bis(chloromethyl)benzene (15g, 85.6 mmol) and N,N- diisopropylethylamine (60 ml, 344 mmol) in ethanol (107 ml) was charged to a bomb pressure reactor, which contained a magnetic stirrer bar, Tetrakis(triphenylphosphine) palladium(O) (0.99g, 0.85 mmol) was added and the apparatus was purged with carbon monoxide. The apparatus was pressurized to 300psi of carbon monoxide and heated to 80°C and stirred at this temperature for 12 hours. The reaction was allowed to cool to room temperature. The mixture was evaporated under vacuum. The residue was dissolved in toluene (400ml) and washed with HCI (2N, 2 x 300ml). The organic phase was washed with saturated sodium hydrogen carbonate solution (300ml) and saturated brine (100ml), dried (MgS0₄) and evaporated under vacuum to give the title compound as a yellow mobile oil with a few solids present (21.4g).

¹H NMR: when analysed by conventional proton NMR (400MHz, d₆-DMSO), the compound of preparation 1 d) gives the following spectrum: δ 1 .19 (t, J 8.0Hz, 6H), 3.64 (s, 4H), 4.08 (q, J 8.0Hz, 4H), 7.16-7.18 (m, 3H) and 7.26-7.28 (m, 1 H).

¹³C NMR: when analysed by conventional carbon NMR (100MHz, d₆-DMSO), the compound of preparation 1 d) gives the following spectrum: δ 14.0, 40.2, 60.2, 127.8, 128.3, 130.1 , 134.5 and 171.0.

MS: when analysed by mass spectrometry, using positive electrospray ionisation technique, the compound of preparation 1 d) gave a mass of 251.1277 (C-| H-|₉0 ), calculated 251.1278.

Subsequent conversion to 2-[3-(2-hydroxy-2-methylpropyl)phenyl]acetic acid are then similar to those described in preparation 1 b) and 1 c), and in WO 2007/010356. b) Preparation 2: 3'-(aminomethyl¾biphenyl-4-ol of formula (4)

3'-(Aminomethyl)biphenyl-4-ol of formula (4) may be prepared using the method described in WO2008/010853. Alternatively, 3'-(aminomethyl)biphenyl-4-ol may be prepared as described below.

Preparation 2a): 4-Hvdroxybiphenyl-3-carbonitrile of formula (5)

To a solution of (3-cyanophenyl)boronic acid (25.0 g, 0.170 mol) in tetrahydrofuran (125 ml) under a nitrogen atmosphere was added 4-bromophenol (28.0 g, 0.162 mol) followed by a second portion of tetrahydrofuran (100 ml). To this mixture was added a solution of sodium carbonate (20.0 g, 0.238 mol) in water (125 ml) and the resultant mixture was stirred at room temperature for 10 minutes whilst being sparged with nitrogen, To the mixture was added tris(dibenzylideneacetone)dipalladium(0) (3.16 g, 0.00324 mol), tris- te/t-butylphosphonium tetrafluoroborate (1.88 g, 0.00648 mol) and tetrahydrofuran (25 ml). The reaction was stirred at room temperature under an atmosphere of nitrogen for 4 hours and filtered. The solids were washed with tetrahydrofuran (50 ml), and the combined filtrates were extracted with te/f-butyl methyl ether (2 x 100 ml). The combined organic phases were filtered through a pad of filter aid, and the solvent in the filtrate was exchanged into 2-propanol (100ml) using distillation. The solution was cooled to 4 to 5°C over 3 hours and the resultant slurry was stirred at 4 to 5°C for 2 hours. The solid was collected by filtration, and was washed with cold 2-propanol (3 x 50 ml) and dried in vacuo to give 4-hydroxybiphenyl-3-carbonitrile (25.4 g) as an off-white solid.

¹H NMR: when analysed by conventional proton NMR (400MHz, de-DMSO), the compound of preparation 2a) gives the following spectrum: δ 6.88 (d, J 8.0Hz, 2H), 7.57-7.63 (m, 3H), 7.73 (d, J 8.0Hz, 1 H), 7.93 (d, J 8.0Hz, 1 H), 8.05 (s, 1 H) and 9.72 (bs, 1 H).

¹³C NMR: when analysed by conventional carbon NMR (100MHz, d₆-DMSO), the compound of preparation 2a) gives the following spectrum: δ 1 12.0, 1 15.9, 1 18.9, 128.1 , 128.6, 129.3, 129.9, 130.0, 130.6, 141.3 and 157.9.

MS: when analysed by mass spectrometry, using positive electrospray ionisation technique, the compound of preparation 2a) gave a mass of 196.0758 (Ci₃Hi₀NO), calculated 196.0757.

Alternative conditions are provided as follows:

A solution of 2-methyltetrahydrofuran (790.5 kg) and purified water (430.9 kg) was heated to reflux under a nitrogen atmosphere for two hours then cooled to 15-25°C. To this solution at 30-30°C was added (3-cyanophenyl)boronic acid (93.0 kg, 632.9 mol) and 4- bromophenol (1 15.0 kg, 664.7 mol). Anhydrous potassium carbonate (174.7 kg, 1264 mol) was then added in 10-12 kg portions every 5-8 minutes. After purging the reactor with nitrogen, 1 ,1 '-bis(diphenylphosphino)ferrocene (7.02 kg, 12.7 mol) was added and the mixture was stirred for 10 minutes, and then palladium(ll) acetate (2.84 kg, 12.7 mol) was added. The resultant mixture was heated at 65-70°C under nitrogen with stirring for 8 hours. The mixture was cooled to 15-25°C, and n-hexane (613.8 kg) was added. The resultant slurry was filtered, and the filter cake was washed with 2-methyltetrahydrofuran (79.0 kg). The filtrate and wash were collected and the lower aqueous phase was removed. To the organic phase was added n-hexane (202.6 kg) and the mixture was stirred for 3.5 hours then filtered through a pad of silica gel (60 kg) held in a filter. The filter cake was washed with a solution of 2-methyltetrahydrofuran (79 kg) and n-hexane (82 kg). The combined filtrate and wash were concentrated by distillation at atmospheric pressure until the volume of the residue was 250-300 L, and then distillation was continued at reduced pressure (<0.08MPa) until the volume of the residue was 150-160 L. The mixture was then cooled to 30-35°C, n-hexane (429.6 kg) was added, and the mixture was cooled to 15-25°C. After stirring for 2 hours, the solid was collected by filtration and, washed with n-hexane (61 .4 kg) and then dried at 50°C in vacuo to give 4-hydroxybiphenyl-3- carbonitrile (1 13.4 kg) as a pale yellow solid.

Preparation 2b): 3'-(Aminomethyl)biphenyl-4-ol of formula (4)

3'-(Aminomethyl)biphenyl-4-ol may be prepared using the method described i n WO 2008/010853. Alternatively, 3'-(aminomethyl)biphenyl-4-ol may be prepared as described below:

To a solution of 4-hydroxybiphenyl-3-carbonitrile (18.0 g, 0.0922 mol) in methanol (270 ml) was added methanesulfonic acid (17.7 g, 0.184 mol) and 10% palladium on carbon (1.8 g). The resultant mixture was hydrogenated under 145 psi pressure of hydrogen at 40°C for 4 hours. The reaction mixture was filtered through filter aid, and the solvent in the filtrate was exchanged into predominantly water by distillation to give an aqueous solution having a total volume of approximately 180 ml. The solution was cooled to room temperature, and the pH was adjusted to between pH 9.3 and 9.7 by the addition of 2M aqueous sodium hydroxide. The resultant slurry was filtered. The solid was washed with water (2 x 50 ml) and dried at 45°C in vacuo to give the title compound (16.5 g) as a colourless solid. If necessary, 3'-(aminomethyl)biphenyl-4-ol may be purified as follows. A suspension of 3'- (aminomethyl)biphenyl-4-ol (1 .0 g) and absolute ethanol (20 ml) was heated to reflux for 2 hours then cooled to room temperature over 2 hours and stirred at this temperature for 4 hours. The solid was collected by filtration, washed with ethanol (2 x 5 ml) and dried at 45°C in vacuo to give purified 3'-(aminomethyl)biphenyl-4-ol (0.85 g) as an off-white solid.

¹H NMR: when analysed by conventional proton NMR (400MHz, d₆-DMSO), the compound of preparation 2b) gives the following spectrum: δ 3.75 (s, 2H), 6.85 (d, J 8.0Hz, 2H), 7.23 (d, J 8.0Hz, 1 H), 7.33 (t, J 8.0Hz, 1 H), 7.40 (t, J 8.0Hz, 1 H), 7.48 (d, J 8.0Hz, 2H) and 7.55 (s, 1 H).

¹³C NMR: when analysed by conventional carbon NMR (100MHz, d₆-DMSO), the compound of preparation 2b) gives the following spectrum: δ 45.7, 1 15.6, 123.8, 124.7, 125.1 , 127.7, 128.5, 131 .1 , 140.0, 144.8 and 157.0.

MS: when analysed by mass spectrometry, using positive electrospray ionisation technique, the compound of preparation 2B) gave a mass of 200.1072 (C-|₃H-|₄N0), calculated 200.1070.

Alternative conditions for the synthesis of 3'-(aminomethyl)biphenyl-4-ol are provided as follows:

To a suspension of freshly prepared Raney Nickel (prepared from nickel-aluminium alloy (86 kg)) in methanol (925.2 kg) was added 4-hydroxybiphenyl-3-carbonitrile (88.0 kg, 450.8 mol). To this mixture was added a solution of sodium methoxide in methanol (162.8 kg of a 30% solution, 904.4 mol) over 1 hour. After purging the reactor with nitrogen, it was purged and pressurised to 0.3MPa with hydrogen and then heated to 38-45°C and hydrogenated at this temperature for 6 hours. The hydrogen was vented and the catalyst was removed by filtration. The spent catalyst was washed with purified water (88 kg), and the combined filtrates were concentrated at a temperature of 55°C and pressure of <- 0.08MPa until no further distillate was produced. Purified water (1936 kg) was added to the residue and the mixture was concentrated under the same conditions until no further distillate was produced. The mixture was cooled to 20-30°C, activated carbon (17.6 kg) was added and the suspension was stirred at this temperature for 4-6 hours after which time it was filtered through celite (40 kg). The filter cake was washed with purified water (88 kg) and the combined filtrates were neutralised to pH 6-7 with acetic acid (80 kg) at 15- 25°C. The mixture was washed with a mixture of isopropyl acetate (224.4 kg) and tetrahydrofuran (78.4 kg) and then twice with isopropyl acetate (224.4 kg each wash). To the product-containing aqueous phase was added activated carbon (17.6 kg). The suspension was stirred at 20-30°C for 2-4 hours, and then filtered. The filter cake was washed with purified water (88 kg) and the combined filtrates were treated with 20% aqueous sodium hydroxide (84 kg) until the pH of the mixture was pH 9-10. The mixture was stirred at 15-25°C for 1 hour, and the solids were collected by filtration then washed with water (470.4 kg) until the pH of the filtrate was pH 7-8. To a suspension of the crude solid in purified water (1080 kg) was added acetic acid (18 kg) until the pH was 6-7. The mixture was filtered to remove particulate material, and the pH of the filtrate was adjusted to pH 9-10 by the addition of 20% aqueous sodium hydroxide. After stirring for 1 hour, the solid was collected by filtration and washed with purified water (600 kg). The damp cake was combined with 95% ethanol (800 kg) and purified water (50 kg) and mixture was heated at reflux for 8 hours after which time it cooled to 15-20°C, filtered and washed with 95 % eth a n o l (60 kg ) . Th e d a m p ca ke was d ri ed at 50 to 60 ° C to g i ve 3 '- (aminomethyl)biphenyl-4-ol (47.2 kg) as a colourless solid.

If necessary, further purification may be carried out using one or both of the procedures described as follows:

- Purification method 1 : Purified water (360 kg) and 3'-(aminomethyl)biphenyl-4-ol (34.2 kg) were combined and a solution of sodium hydroxide (43 kg of a 20% solution) was added until the mixture became a clear solution. The solution was filtered through a bed of celite (4 kg) and the cake was washed with purified water (10 kg). The pH of the filtrate was adjusted to pH 6-7 using acetic acid (22 kg), and purified water (100 kg) was then added. The mixture was then filtered. The pH of the filtrate was adjusted to pH 9-10 using 20% aqueous sodium hydroxide to give a slurry that was stirred for 1 hour then filtered. The filter cake was washed with purified water (140 kg). The damp cake was suspended in 95% ethanol (320 kg) and the slurry was heated at reflux for 3 hours. The mixture was the cooled to 25-30°C and stirred for 30 mins before the solid was collected by filtration. The filter cake was washed with 95% ethanol (40 kg), and then dried to give purified 3'- (aminomethyl)biphenyl-4-ol (17.0 kg). - Purification method 2: Purified water (680 kg) and 3'-(aminomethyl)biphenyl-4-ol (32.4 kg) were combined and acetic acid (1 1 .3 kg) was added at 15-25°C to adjust the pH to pH 6-7. The mixture was filtered through a pad of celite (204 kg) and the cake was washed twice with purified water (68.4 kg and 157.3 kg) then with methanol (326.4 kg) then three times with purified water (306 kg each wash). The combined filtrates were basified to pH 9-10 using 20% aqueous sodium hydroxide (51 kg), and the mixture was stirred at 15- 25°C for 1 hour. The solid was collected by filtration, and the filter cake was washed with purified water (681 kg then three times using 100 kg each wash). The damp cake was suspended in a mixture of 95% ethanol (438.3 kg) and purified water (28.3 kg) and the mixture was heated at reflux for 3 hours. After cooling to 15-20°C, the suspension was stirred for 2 hours and the solid was collected by filtration. The filter cake was washed with 95% ethanol (26.9 kg) and was then dried to give purified 3'-(aminomethyl)biphenyl-4-ol (29.4 kg). c) Preparation of the crystalline form of 2-chloro-A -(2-r3-(2-(r(4'-hvdroxybiphenyl-3- yl)methyl1amino}-2-oxoethyl)phenyl1-1 ,1 -dimethylethyl}-acetamide of formula (1)

[3-(2-Hydroxy-2-methylpropyl)phenyl]acetic acid according to preparation 1 (30 kg, 144 mol) was dissolved in ethyl acetate (150 L) at 25°C. 1 ,1 '-Carbonyldiimidazole (24.1 Kg, 144 mol) was added to the sol ution and the reaction left to proceed for 1 hour. 3'- (Aminomethyl)biphenyl-4-ol according to preparation 2 (31.6 Kg, 159 mol) was added and the resulting slurry was heated to 50°C. After 3 hours the reaction mixture was cooled 20°C and was washed with 2M aqueous citric acid (158 L) and 1 M aqueous sodium bicarbonate solution (150 L). The organic layer was diluted with chloroacetonitrile (56.1 L) and the solution distilled at atmospheric pressure, the end point was when the internal temperature reached 1 10°C. The chloroacetonitrile solution was cooled to 50°C and trifluoroacetic acid (168 L) was charged over 90 minutes. The reaction was allowed to proceed at this temperature for a further 2 hours. The solution was subjected to a reduced pressure (-0.950 barg) to allow the distillation of trifluoroacetic acid maintaining a temperature of 50°C. Upon completion of the distillation 2-butanol (225 L) was added to the reaction and the solution was warmed to 60°C. Seed crystals of 2-chloro-N-{2-[3-(2- {[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2-oxoethyl)phenyl]-1 ,1 -dimethylethyl}acetamide (0.67Kg, 1 %w/w based on 100% conversion) were added and the slurry was held at 60°C for i hour. Cyclohexane (150 L) was added whilst maintaining the 60°C temperature. The slurry was allowed to cool from 60°C to 20°C at a rate of 0.5°C/min) and stirred at 20°C for 4 hours. The solid was collected by filtration, washed with cyclohexane (2 x 90 L), and dried in vacuo at 45°C to give 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}- 2-oxoethyl)phenyl]-1 ,1 -dimethylethyl}acetamide (58.7kg, 87.6% yield) a colourless solid.

Seed crystals of 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2- oxoethyl)phenyl]-1 ,1 -dimethylethyl}acetamide were prepared as follows:

[3-(2-Hydroxy-2-methylpropyl)phenyl]acetic acid according to preparation 1 (40 g, 0.192 mol) was dissolved in ethyl acetate (200 ml) at 25°C. 1 ,1 '-Carbonyldiimidazole (33.02g, 0.192mol) was added to the solution and the reaction left to proceed for 1 hour. 3'- (Aminomethyl)biphenyl-4-ol according to preparation 2 (42.1 g, 0.21 1 mol) was added and the resulting slurry was heated to 50°C. After 3 hours the reaction mixture was cooled to 20°C and was washed with 2M aqueous citric acid (21 1 ml) and 1 M aqueous sodium bicarbonate solution (200 ml). The organic layer was diluted with chloroacetonitrile (74.8 ml) and the solution was distilled at atmospheric pressure, the end point was when the internal temperature reached 1 10°C. The chloroacetonitrile solution was cooled to 50°C and trifluoroacetic acid (224 ml) was added over 90 minutes. The reaction was allowed to proceed at this temperature for a further 2.5 hours. The solution was subjected to a reduced pressure (1 13 mbar) to allow the distillation of trifluoroacetic acid maintaining a temperature of 50°C. Upon completion of the distillation, 2-butanol (300 ml) was added to the reaction and the solution was warmed to 60°C and held under a positive pressure of nitrogen overnight. The solution was transferred to a larger reactor also maintained at 60°C whereupon crystallisation occurred within 10 minutes. Cyclohexane (748 ml) was added whilst maintaining the 60°C temperature. The slurry was allowed to cool from 60°C to 20°C and stirred at 20°C for 3 hours. The solid was collected by filtration and was dried in vacuo at 45 °C to give 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2- oxoethyl)phenyl]-1 ,1 -dimethylethyl}acetamide (81. Og, 90.7% yield) as an off-white solid.

¹H NMR

When analysed by conventional proton NMR (600MHz, d6-DMSO), the material obtained in example 1 gave the following spectrum: δ 1.22 (s, 6H), 2.96 (s, 2H), 3.48 (s, 2H), 4.00 (s, 2H), 4.34 (d, J 5.9 Hz, 2H), 6.87 (m, 2H), 7.00 (dt, J 7.5 & 1 .5 Hz, 1 H), 7.06 (t, J 1.5 Hz, 1 H), 7.15 (d, J 7.7 Hz, 3H), 7.17 (d, J 7.5 Hz, 1 H), 7.21 (t, J 7.5 Hz, 1 H), 7.34 (t, J 7.7 Hz, 1 H), 7.42 (m, 4H), 7.60 (s, 1 H), 8.58 (t, J 5.9 Hz, 1 H) and 9.56 (br s, 1 H).

DSC Data

The melting point of the material obtained in example 1 was determined by Differential Scanning Calorimetry (DSC) using a TA instruments Q1000 differential scanning calorimeter. The sample was heated at 20°C/minute, from 20°C to 300°C, in a closed aluminium pan under nitrogen purge gas. 1.635 mg of the material obtained in example 1 shows a sharp endothermic melt with onset of 157°C ± 2°C and peak at 159°C ± 2°C. The DSC trace obtained is shown in Figure 1.

Elemental analysis for the material obtained in example 1

Found: C, 69.64%; H, 6.31 % and N, 5.99%. C27H29CIN2O3 requires C, 69.74%; H, 6.29% and N, 6.02%.

Powder X-Rav Diffraction Data

The powder X-ray diffraction pattern of the material obtained in example 1 was determined using a Bruker-AXS Ltd. D4 EN DEAVOR powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer geometry, automatic beam divergence slit and a PSD Vantec-1 detector. The sample was prepared for analysis by mounting onto a low background silicon wafer specimen mount with a 0.5 mm cavity. The specimen was rotated whilst being irradiated with copper KCH X-rays (wavelength = 1.5406 Angstroms) with the X-ray tube operated at 35kV/40mA. The analysis was in continuous mode set for data acquisition at 0.2 second count per 0.018° step size over a two theta range of 2° to 55° at room temperature. The instrument calibration was verified using a corundum reference standard (NIST: SRM 1976 XRD flat plate intensity standard).

The peaks obtained were aligned against a silicon reference standard. Peak search was carried out using the threshold and width parameters set to 1 and 0.15, respectively, within the Eva software released by Bruker-AXS. Characteristic diffraction angles and their intensities are given in Table 1 and Figure 2 shows the experimentally measured pattern. The unique diffraction peaks of this material are given in Table 2. Table 1 : Characteristic diffraction peaks of example 1 (± 0.1 ° 2Θ)

Table 2: Unique characteristic diffraction peaks of example 1 (± 0.1 ° 2Θ)

As will be appreciated by the skilled person, the relative intensities of the various peaks within Tables 1 and 2 may vary due to a number of factors such as for example orientation effects of crystals in the X-ray beam or the purity of the material being analysed or the degree of crystallinity of the sample. The peak positions may also shift for variations in sample height but the peak positions will remain substantially as defined in given Tables 1 and 2. The skilled person will also appreciate that measurements using a different wavelength will result in different shifts according to the Bragg equation - ηλ = 2d sinB. Such alternative PXRD patterns generated by use of alternative wavelengths are nevertheless representations of the same material.

Fourier Transform Infra-red (FT-IR) spectrum

When characterised by Fourier Transform Infra-red (FT-IR) spectroscopy, the compound of example 1 gives the pattern shown in Figure 3. The fingerprint region is shown in expanded form in Figure 4. The characteristic peaks are given in Table 3 below (w = weak, s = strong, m = medium). The main characteristic peaks are 1535 (s), 1 179 (s), 834 (s), and 769 (s) cm^"1.

Table 3: characteristic FT-IR peaks of example 1 (cm^"1)

Wavenumber (cm ¹)

3367m 1643s 1350m 947w

3332m 1615m 1316m 929w

3157m 1603s 1292m 906w

3053w 1596s 1268s 886w

3017w 1535s 1240s 834s

3002w 1522s 1207m 817m

2986w 1481s 1179s 805m

2972m 1466m 1 145m 787s

2945w 1444m 1 109w 781s

2912w 1431s 1094m 769s

2851w 1422s 1064w 732s

2703w 1412m 1025m 704s

2617w 1391 m 1000m 688s

2482w 1367m 972w 663s The IR spectrum was acquired using a ThermoNicolet Nexus FTIR spectrometer equipped with a 'DurasampllR' single reflection ATR accessory (diamond surface on zinc selenide substrate) and d-TGS KBr detector. The spectrum was collected at 2 cm^"1 resolution and a co-addition of 512 scans. Happ-Genzel apodization was used. Because the FT-IR spectrum was recorded using single reflection ATR, no sample preparation was required. Using ATR FT-IR will cause the relative intensities of infrared bands to differ from those seen in a transmission FT-IR spectrum using KBr disc or nujol mull sample preparations. Due to the nature of ATR FT-IR, the bands at lower wavenumber are more intense than those at higher wavenumber. Experimental error, unless otherwise noted, was ± 2 cm^"1. Peaks were picked using ThermoNicolet Omnic 6.1 a software. Intensity assignments are relative to the major band in the spectrum so they are not based on absolute values measured from the baseline.

Fourier Transform Raman spectrum

When characterised by Fourier Transform Raman spectroscopy, the compound of example 1 gives the pattern shown in Figure 5. The fingerprint region is shown in greater detail in Figure 6. The characteristic peaks are given in Table 4 below (w = weak, s = strong, m = medium, vs = very strong). The main characteristic peaks are 1294 (s), 1001 (vs), and 772 (w) cm^"1.

Table 4: characteristic Raman peaks of example Kcm^"1)

Wavenumber (cm ¹)

3370w 2600w 1090w 440w

3336w 1644w 1027m 418w

3168w 1616s 1001vs 373w

3055m 1606vs 888w 315w

3035w 1523w 870w 295w

3019w 1460w 817m 263m

3003w 1443w 806w 240w

2988w 1423w 789w 220m 2974w 1352w 772w 182w

2941 m 1308s 736w 108vs

2925w 1294s 705w 92vs

2914w 1263m 644w 61 vs

2859w 1242w 604w

2772w 1209w 540w

2721w 1 181 m 516w

The Raman spectra were collected using a Bruker Vertex70 FT-IR spectrometer with Ramll Raman module equipped with a 1064nm NdYAG laser and LN-Germanium detector. All spectra were recorded using 2cm^"1 resolution and Blackman-Harris 4-term apodization. The laser power was 250mW and 1 024 scans for PF-3653478 or 1300 scans for PF2434029-42 were co-added. Each sample was placed in a glass vial and exposed to the laser radiation. The data is presented as intensity as a function of Raman shift. Experimental error, unless otherwise noted, was ± 2 cm^"1. Peaks were picked using ThermoNicolet Omnic 6.1 a software. Intensity assignments are relative to the major band in the spectrum so they are not based on absolute values measured from the baseline.

Solid state NMR data for the material obtained in example 1

Approximately 15 mg of sample were tightly packed into a 2.5 mm Zr02 rotor. Spectra were collected at ambient temperature and pressure on a Bruker-Biospin 2.5 mm CPMAS probe positioned into a wide-bore Bruker-Biospin Avance 600 MHz (¹H frequency) NMR spectrometer. The packed rotor was oriented at the magic angle and spun at 15.0 kHz. The ¹³C solid state spectra were collected using a proton decoupled cross-polarization magic angle spinning (CPMAS) experiment. The cross-polarization contact time was set to 2.0 ms. A proton decoupling field of approximately 100 kHz was applied during acquisition. The carbon spectrum of the compound of example 1 was acquired for 16,384 scans with a 3.5 second recycle delay. Carbon spectra were referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm. Automatic peak picking was performed using Bruker-BioSpin TopSpin version 3.0 software. The output of the automated peak picking was visually checked to ensure validity and adjustments manually made if necessary. The carbon chemical shifts observed for example 1 are as follows in Table 5.

Table 5

^{a> Referenced to external sample of solid phase adamantane at 29.5 ppm.

<^b) Defined as peak heights. Intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

The unique carbon chemical shifts observed for example 1 are as follows in Table 6:

Table 6

3C Chemical Shifts [ppm + 0.2 ppm] ^(a) Intensity ^(b)

173.2 42.2

158.5 50.2

55.5 60.4 ^<a) Referenced to external sample of solid phase adamantane at 29.5 ppm. <^b) Defined as peak heights. Intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

The corresponding carbon CPMAS spectrum for example 1 is illustrated in Fig. 7.

Example 2: preparation of the β2 agonist A -r(4'-Hvdroxybiphenyl-3-yl)methvn-2-(3-{2- f((2/?)-2-hvdroxy-2-(4-hvdroxy-3-f(methylsulfonyl)aminolphenyl)ethyl)amino1-2- methylpropyl) phenvDacetamide of formula (14). a) Preparation 3: A -(2-(Benzyloxy)-5-r(1/?)-2-bromo-1 -hvdroxyethvn phenyl) methane sulfonamide

N-{2-(Benzyloxy)-5-[(1 f?)-2-bromo-1 -hydroxyethyl] phenyl} methane sulfonamide is prepared according to the methods described in WO 2008/010356. b) Preparation 4: A -r2-(Benzyloxy)-5-((1 /?)-2-bromo-1 -(rterf-butyl(dimethyl)-silvnoxy) ethvDphenyllmethanesulfonamide of formula (12)

N-[2-(Benzyloxy)-5-((1 f?)-2-bromo-1 -{[te/f-butyl(dimethyl)silyl]oxy} ethyl)phenyl] methane sulfonamide may be prepared the methods described in WO 2008/010356. Alternatively, the following conditions may be used:

To a solution of N-{2-(benzyloxy)-5-[(1 f?)-2-bromo-1 -hydroxyethyl] phenyl} methane sulfonamide according to Preparation 3 (1.0 kg, 2.50 mol) in dichloromethane (2.0 L),_was added imidazole (0.255 kg, 3.74 mol) followed by te/t-butyldimethylsilyl chloride (0.527 kg, 3.50 mol). The resultant mixture was heated to reflux for 1 -2 hours. The reaction was cooled to 20-25°C and was washed with demineralised water (3 x 5.0 L). The organic layer was dried (Na₂S0₄) then filtered into a reactor. The solvent was then exchanged into ethanol by distillation under vacuum at <30°C to give a slurry in approximately 2 L of ethanol. The solid was collected by filtration, washed with ethanol (2.0 L) and dried at 40- 45°C in vacuo to give the title compound (1.0 to 1 .15 kg typically obtained) as a colourless solid.

If necessary, A/-{2-(benzyloxy)-5-[(1 f?)-2-bromo-1 -hydroxyethyl] phenyl} methane sulfonamide may be purified as follows:

A stirred suspension of A/-{2-(benzyloxy)-5-[(1 f?)-2-bromo-1 -hydroxyethyl] phenyl} methane sulfonamide (84.6 g) in ethanol (846 ml) under an atmosphere of nitrogen was heated at reflux until a clear solution was formed. The mixture was then slowly cooled to 25°C, and the suspension is stirred for 18 hours. The solid was collected by filtration, washed with ethanol (170 ml) and dried at 40°C in vacuo to give purified A/-{2-(benzyloxy)-5-[(1 f?)-2- bromo-1 -hydroxyethyl] phenyl} methane sulfonamide (72.5 g) as an off-white solid. c) Preparation 5: 2-r3-(2-Amino-2-methylpropyl)-phenvn-A -r(4'-hvdroxybiphenyl-3- vDmethyllacetamide of formula (11)

The compound of example 1 (55.0 kg, 1 18mol) was added to a stirred solution of 2-butanol (248 L) and water (275 ml) at 20°C forming a slurry. Acetic acid (14.9 L) and thiourea (10.8 g, 142 mol) were added and the reaction was heated at reflux. After 5 hours the solution was cooled to 40°C. The pH was adjusted to 10.8 ± 0.2 (at 25°C) using 2M NaOH and the layers were then separated. The organic layer was diluted with additional 2-butanol (165 L) before washing with water (2 x 248 L) and brine (248 L). The organic layer was distilled down to a volume of 143 L at atmospheric pressure. Acetonitrile (242 L) was then added and the solution was distilled down to a volume of 180 L. Acetonitrile (198 L) was then added. The solution was cooled to 70°C at which point seed crystals of the title compound were added (0.4 Kg, 1 % based on 100% yield of the title compound) and the resulting slurry was stirred at 70°C for 1 hour. The slurry was diluted with additional acetonitrile (275 L) before cooling to 20°C at 0.3°C/min where it was left to stir for 4 hours. The slurry was diluted by the addition of acetonitrile (121 L). The solid was collected by filtration, washed with acetonitrile (2 x 121 L) and dried in vacuo at 50 °C to give the title compound (39.8 kg, 86.7% yield) as a colourless solid. d) Preparation 6: (/?)-2-(3-(2-r2-(4-Benzyloxy-3-methanesulfonamidophenyl)-2- hvdroxy-ethylamino1-2-methylpropyl)phenyl)-A -r(4'-hvdroxybiphenyl-3-yl)methvn- acetamide hemifumarate of formula (13b)

(2-[3-(2-Amino-2-methylpropyl)phenyl]-A/-[(4'-hydroxybiphenyl-3-yl)methyl]acetamide according to preparation 5 (50.0 kg, 129 mol), ((f?)-A/-{2-benzyloxy-5-[2-bromo-1 -(te/f- butyldimethylsiloxy)ethyl]phenyl}methanesulfonamide according to preparation 4 (69.5 kg, 135 mol) and sodium bicarbonate (21.7 kg, 258 mol) were added to a reactor containing n- butyl acetate (500 L). The resulting slurry was heated to reflux temperature and n-butyl acetate (350 L) was removed from the mixture by distillation at atmospheric pressure. The concentrated reaction mixture was heated at reflux for 35 hours. The reaction was cooled to 20-25°C, diluted with ethyl acetate (500 L) and washed with water (500 L). The n-butyl acetate/ethyl acetate solution was diluted with methanol (150 L). Acetic acid (14.8 L, 258 mol) was added in one portion at 22°C followed by tetraethylammonium fluoride hydrate (28.8 kg, 142 mol). The reaction mixture was heated to 50°C and was maintained at this temperature for 5 hours. The reaction was cooled to 20°C, quenched by the addition of aqueous 1 M potassium carbonate solution (450 L) at 20°C and the resulting biphasic mixture was stirred for 15 min. The phases were separated and the organic phase was washed with water (200 L). To the organic phase was added absolute ethanol (200 L) and the solution was distilled under reduced pressure to a volume of approximately 400 L. The concentrated solution was diluted with absolute ethanol (350 L). The solution was concentrated under reduced pressure to a volume of approximately 250 L. The concentrate was diluted with absolute ethanol (450 L) and the mixture was heated to 65°C. Seed crystals of the title compound (0.5 kg, 1 % w/w) were added to the mixture and a solution of fumaric acid (7.5 kg, 65 mol) in absolute ethanol (250 L) was added whilst maintaining a temperature of 65°C. After 1 hour the resulting slurry was cooled to 20°C at 0.23°C/min and stirring at this temperature was continued for 3 hours. The slurry was filtered and the solid was washed with absolute ethanol (300 L). The wet filter-cake was suspended in ethyl acetate (600 L), and the slurry was heated to 50°C and agitated for 1 hour. The slurry was cooled to 20°C and the solid was collected by filtration, washed with ethyl acetate (50 L) and dried at 45°C under vacuum to obtain the title compound as a colourless solid (82.3 kg, 83.5% yield) which contained 0.79% w/w water by Karl-Fischer analysis (equivalent to 0.34 moles of water per mole of title compound).

¹H NMR

When analysed by conventional proton NMR (600MHz, d₆-DMSO), the compound of preparation 6 gave the following spectrum: δ 1.03 (s, 6H), 2.73 (s, 2H), 2.78 (dd, J 1 1 .5 & 9.3 Hz, 1 H), 2.89 (m, 4H), 3.46 (m, 2H), 4.31 (d, J 6 Hz, 2H), 4.68 (dd, J 9.3 & 3.1 Hz, 1 H), 5.17 (s, 2H), 6.51 (s, 1 H), 6.84 (m, 2H), 7.04 (d, J 7.7 Hz, 1 H), 7.1 1 (m, 3H), 7.17 (d, J 7.6 Hz, 1 H), 7.21 (m, 2H), 7.32 (m, 3H), 7.39 (m, 6H), 7.54 (d, J 7.2 Hz, 2H) and 8.56 (t, J 6.0 Hz, 1 H).

Elemental Analysis for the compound of preparation 6

Found: C, 66.85%; H, 6.23% and N, 5.42%. C^H^NsOsS. 0.34 H₂0 requires C, 66.90%;

H, 6.22% and N, 5.44%.

Differential Scanning Calorimetry

Differential Scanning Calorimetry was undertaken using a DSC Q1000 instrument to heat

I .974mg of the title compound from 25 to 250°C at 20°C per minute in a closed aluminium pan under nitrogen purge gas. The material obtained from preparation 6 shows a sharp endothermic melt with onset of 157°C ± 2°C and peak at 159°C ± 2°C. The DSC trace is shown in Figure 8.

Powder X-Rav Diffraction

The powder X-ray diffraction pattern of the compound of preparation 6 was determined using a Bruker-AXS Ltd. D4 EN DEAVOR powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer geometry, automatic beam divergence slit and a PSD Vantec-1 detector. The sample was prepared for analysis by mounting onto a low background silicon wafer specimen mount with a 0.5mm cavity. The specimen was rotated whilst being irradiated with copper KCH X-rays (wavelength = 1 .5406 Angstroms) with the X-ray tube operated at 35kV/40mA. The analysis was in continuous mode set for data acquisition at 0.2 second count per 0.018° step size over a two theta range of 2° to 55° at room temperature. The instrument calibration was verified using a corundum reference standard (NIST: SRM 1976 XRD flat plate intensity standard). The peaks obtained were aligned against a silicon reference standard. Peak search was carried out using the threshold and width parameters set to 1 and 0.3, respectively, within the Eva software released by Bruker-AXS. Characteristic diffraction angles and their intensities are given in Table 7 and Figure 9 shows the experimentally measured pattern. The unique diffraction peaks of this material are given in Table 8.

Table 7: Characteristic diffraction peaks of compound of preparation 6 (± 0.1 ° 2Θ)

Angle (°2Θ) Intensity % Angle (°2Θ) Intensity %

5.8 5.1 22.6 75.6

6.7 5.9 23.1 86.7

9.9 23.1 23.9 50.0

1 1.5 37.2 24.4 31.5

13.3 19.6 25.4 32.0

15.0 34.5 26.0 69.0

16.1 24.2 26.7 31.7

16.4 21.3 27.8 34.3

17.5 94.1 28.6 27.2 18.1 39.6 29.4 45.5

19.3 100.0 30.3 25.9

20.3 87.7 30.8 26.9

21.1 76.3 31 .0 28.7

21.7 76.3 31 .2 26.0

21.9 75.5 31 .8 21.7

22.3 97.2 32.3 26.9

Table 8: Unique characteristic diffraction peaks of the compound of

preparation 6 (± 0.1 ° 2Θ)

Fourier Transform Infra-red (FT-IR) spectrum

When characterised by Fourier Transform Infra-red (FT-IR) spectroscopy, the compound of preparation 6 gives the pattern shown in Figure 10. The fingerprint region is shown in expanded form in Figure 1 1 . The characteristic peaks are given in Table 9 below (w = weak, s = strong, m = medium). The main characteristic peaks are 1 1 18 (s), 837 (m), and 766 (m).

Table 9: characteristic FT-IR peaks of the compound of preparation 6 (cm^"1)

Wavenumber (cm ¹)

3029m 1396m 1005m 785m

1627m 1363s 977m 766m

1608s 1329s 961 m 754m 1547s 1266s 934w 731 m

1517s 1202m 906w 705s

1508s 1 151s 885w 697s

1481 m 1118s 859w 669s

1470m 1083m 837m

1449m 1045w 818m

1417m 1020w 793m

The IR spectrum was acquired using a ThermoNicolet Nexus FT-IR spectrometer equipped with a 'DurasampllR' single reflection ATR accessory (diamond surface on zinc selenide substrate) and d-TGS KBr detector. The spectrum was collected at 2cm^"1 resolution and a co-addition of 512 scans. Happ-Genzel apodization was used. Because the FT-IR spectrum was recorded using single reflection ATR, no sample preparation was required. Using ATR FT-IR will cause the relative intensities of infrared bands to differ from those seen in a transmission FT-IR spectrum using KBr disc or nujol mull sample preparations. Due to the nature of ATR FT-IR, the bands at lower wavenumber are more intense than those at higher wavenumber. Experimental error, unless otherwise noted, was ± 2 cm^"1. Peaks were picked using ThermoNicolet Omnic 6.1 a software. Intensity assignments are relative to the major band in the spectrum so they are not based on absolute values measured from the baseline.

Fourier Transform Raman spectrum

When characterised by Fourier Transform Raman spectroscopy, the compound of preparation 6 gives the pattern shown in Figure 12. The fingerprint region is shown in greater detail in Figure 13. The characteristic peaks are given in Table 10 below (w = weak, s = strong, m = medium, vs = very strong). The main characteristic peaks are 1298 (s), 1002 (vs), and 819 (m).

Table 10: characteristic FT-Raman peaks of the compound of preparation 6

Wavenumber (cm ¹)

3064m 1589m 1094w 621w 3043m 1519w 1047w 591w

3019w 1472w 1028w 523w

3007w 1445w 1002vs 431w

2969w 1408m 904w 369w

2951 m 1333w 859w 304w

2928m 1298s 819m 259w

2887w 1272m 802w 226m

2718w 1221w 749w 205m

2594w 1 174w 729w 96vs

1657m 1 157w 699w 78vs

1610vs 1 120w 644w

The Raman spectra were collected using a Bruker Vertex70 FT-IR spectrometer with Ramll Raman module equipped with a 1064nm NdYAG laser and LN-Germanium detector. All spectra were recorded using 2cm^"1 resolution and Blackman-Harris 4-term apodization. The laser power was 250mW and 1024 scans for the compound of example 1 or 1300 scans for the title compound were co-added. Each sample was placed in a glass vial and exposed to the laser radiation. The data is presented as intensity as a function of Raman shift. Experimental error, unless otherwise noted, was ± 2 cm^"1. Peaks were picked using ThermoNicolet Omnic 6.1 a software. Intensity assignments are relative to the major band in the spectrum so they are not based on absolute values measured from the baseline.

Solid state NMR data for the compound of preparation 6

Approximately 15 mg of sample were tightly packed into a 2.5 mm Zr02 rotor. Spectra were collected at ambient temperature and pressure on a Bruker-Biospin 2.5 mm CPMAS probe positioned into a wide-bore Bruker-Biospin Avance 600 MHz (¹H frequency) NMR spectrometer. The packed rotor was oriented at the magic angle and spun at 15.0 kHz. The ¹³C solid state spectra were collected using a proton decoupled cross-polarization magic angle spinning (CPMAS) experiment. The cross-polarization contact time was set to 2.0 ms. A proton decoupling field of approximately 100 kHz was applied during acquisition. The carbon spectrum of the title compound was acquired for 16,384 scans with a 2.5 second recycle delay and is shown in Figure 14. Carbon spectra were referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm.

Automatic peak picking was performed using Bruker-BioSpin TopSpin version 3.0 software. The output of the automated peak picking was visually checked to ensure validity and adjustments manually made if necessary. The carbon chemical shifts observed are as follows in Table 1 1 and the characteristic peaks are as follows in Table 12.

Table 1 1 : ¹³C chemical shifts for the compound of preparation 6 expressed in parts per million (± 0.2 ppm)

Referenced to external sample of solid phase adamantane at 29.5 ppm. ^<b) Defined as peak heights. Intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

Table 12: ¹³C characteristic chemical shifts for the compound of preparation 6 expressed in parts per million (± 0.2 ppm)

^(a> Referenced to external sample of solid phase adamantane at 29.5 ppm. <^b) Defined as peak heights. Intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative. e) Preparation of the B2 agonist A -r(4'-Hvdroxybiphenyl-3-vnmethvn-2-(3-(2-r((2/?)-2- hvdroxy-2-(4-hvdroxy-3-f(methylsulfonyl)aminolphenyl)ethyl)amino1-2- methylpropyDphenvDacetamide of formula (14)

To a suspension of (f?)-2-(3-{2-[2-(4-benzyloxy-3-methanesulfonamidophenyl)-2- hydroxyethylamino]-2-methylpropyl}phenyl)-N-[(4'-hydroxybiphenyl-3-yl)methyl]-acetamide hemifumarate according to preparation 6 (10.0 kg, 13.0 mol) in tetrahydrofuran (89.6 kg) under an atmosphere of nitrogen was added as solution of potassium carbonate (4.1 kg, 30 mol) in water (30 L) and the mixture was stirred at 20°C for 35 minutes. The phases were separated, and the organic phase was washed with a solution of sodium chloride (5.0 kg, 85.6 mol) in water (30 L). The phases were separated and the organic phase was diluted with tetrahydrofuran (67.2 kg) and water (12 L). To the solution was added 5% palladium on carbon (1.0 kg) followed by a rinse of a mixture of tetrahydrofuran (16 kg) and water (2 L) and the mixture was hydrogenated under 50 psi pressure of hydrogen at 20-25°C for 13 hours. The catalyst was removed by filtration and solid washed with a mixture of tetrahydrofuran (77 kg) and water (10 L). To the combined filtrates was added Quadrapure TU® resin (2.5 kg) and the suspension was stirred at 20°C for 9.5 hours. The mixture was filtered, and the solid was washed with a mixture of tetrahydrofuran (20 kg) and water (4 L). The combined filtrates were concentrated by removal 233 L of solvent by distillation under vacuum. To the concentrated solution was added acetonitrile (39 kg) and the solution was concentrated by removing 55 L of solvent by distillation under vacuum. To the concentrated solution was added acetonitrile (40 kg) and the solution was concentrated by removing approximately 50 L of solvent by distillation at atmospheric pressure. The concentrated solution was diluted with acetonitrile (39 kg). Concentration of the mixture by removal of approximately 50 L of solvent by distillation at atmospheric pressure followed by dilution with approximately 39 kg of acetonitrile was repeated 6 times until the solvent composition was predominantly acetonitrile and the temperature of the mixture reached 81 °C. The resultant slurry was cooled to 20 to 25°C over 2.5 hours and stirred at this temperature for 5.5 hours. The solid was collected by filtration, washed with acetonitrile (2 x 39 kg) and dried at 50°C under vacuum to give a solid (6.80 kg). A suspension of this solid (6.80 kg) in a mixture of methanol (61 L) and water (7 L) under an atmosphere of nitrogen was heated at 50°C for 1 hour, then cooled to 20°C and stirred for 0.5 hours at this temperature. The solid was collected by filtration, washed with a mixture of methanol (31 L) and water (3 L), then with methanol (34 L) and dried at 50°C in vacuo to give the compound of formula (14) ( 6.40 kg) as a colourless solid.

The title compound of formula (14) so prepared may be recrystallised using the following procedure. A stirred suspension of the compound of formula 14 (9.42 kg) in a mixture of tetrahydrofuran (81 .4 kg) and water (20.3 L) under an atmosphere of nitrogen was heated to reflux to give a clear solution. The mixture was then distilled at a rate of approximately 27 L/hour atmospheric pressure for 13 hours using a fixed temperature difference between the reactor contents and the reactor's heated jacket (for the reactor used, this temperature difference was 30°C). Over the whole course of the distillation, acetonitrile (a total of approximately 350 L) was continuously added to the mixture at a rate of approximately 27 L/hour. The resultant slurry was cooled to 20°C, stirred at this temperature for 4 hours and the solid was collected by filtration. The filter cake was washed with acetonitrile (2 x 37 kg) and dried at 40°C under vacuum to give a solid (8.86 kg). A stirred suspension of this solid (8.86 kg) in a mixture of methanol (80 L) and water (9 L) under an atmosphere of nitrogen was heated at 50°C for 70 min. The mixture was cooled to 20°C and stirred for 140 min. The solid was collected by filtration, washed firstly with a mixture of methanol (41 L) and water (4 L), secondly with methanol (45 L) then dried at 50°C under vacuum to give a solid (8.38 kg) that was milled on a hammer mill to give the compound of formula (14) as a colourless solid (8.20 kg) which contained 0.48%w/w water by Karl-Fischer analysis (equivalent to 0.17 moles of water per mole of the compound of formula (14)).

Characterisation data for the compound of formula (14) so prepared is provided below.

¹H NMR

When analysed by conventional proton NMR (600MHz, d6-DMSO), the compound of formula (14) gives the following spectrum: δ 0.89 (s, 3H), 0.91 (s, 3H), 2.54 (s, 2H), 2.59- 2.68 (m, 2H), 2.89 (s, 3H), 3.44 (s, 2H), 4.31 (d, 2H), 4.42 (dd, 1 H), 6.80-8.83 (m, 3H), 6.97-7.02 (m, 2H), 7.08-7.12 (m, 3H), 7.16 (t, 1 H), 7.19 (d, 1 H), 7.30 (t, 1 H), 7.37-7.41 (m, 4H), and 8.50 (t, 1 H).

¹³C NMR

When analysed by conventional carbon NMR (151 MHz, d6-DMSO), the compound of formula (14) gives the following spectrum: δ 26.39, 26.64, 39.85, 42.22, 42.48, 46.36, 50.15, 52.71 , 72.00, 1 15.14, 1 15.70, 1 15.70, 123.76, 124.02, 124.29, 124.38, 124.76, 125.23, 126.49, 127.57, 127.63, 128.40, 128.71 , 130.82, 131 .13, 135.38, 135.73, 138.43, 139.94, 140.20, 149.76, 157.1 1 and 170.28.

Elemental Analysis for the compound of formula (14)

Found: C, 65.70%; H, 6.33%, N, 6.71% and S, 5.24%.

H₂0 requires C, 65.78%; H, 6.39%, N, 6.77% and S, 5.16%.

Powder X-Rav Diffraction

The powder X-ray diffraction pattern of the compound of formula (14) was determined using a Bruker-AXS Ltd. D4 ENDEAVOR powder X-ray diffracto meter fitted with an automatic sam ple changer, a theta-theta goniometer geometry, automatic beam divergence slit and a PSD Vantec-1 detector. The sample was prepared for analysis by mounting onto a low background silicon wafer specimen mount with a 0.5mm cavity. The specimen was rotated whilst being irradiated with copper Kcd X-rays (wavelength = 1 .5406 Angstroms) with the X-ray tube operated at 35kV/40mA. The analysis was in continuous mode set for data acquisition at 0.2 second count per 0.018° step size over a two theta range of 2° to 55° at room temperature. The instrument calibration was verified using a corundum reference standard (NIST: SRM 1976 XRD flat plate intensity standard). The peaks obtained were aligned against a silicon reference standard. The peaks obtained were aligned against a silicon reference standard. Peak search was carried out using the threshold and width parameters set to 1 and 0.3, respectively, within the Eva software released by Bruker-AXS (2009). Characteristic diffraction angles and their intensities are given in Table 13 and Figure 15 shows the experimentally measured pattern for the compound of formula (14). The unique diffraction peaks of this material are given in Table 14.

Table 13: Characteristic diffraction peaks of the compound of

formula (14) (± 0.1 ° 2Θ)

Angle (°2Θ) Intensity % Angle (°2Θ) Intensity %

4.2 8.3 23.5 19.2

8.4 7.0 23.9 18.7

10.3 3.1 24.7 8.3

10.9 7.6 25.2 10.5

1 1.3 6.0 25.8 17.9

12.9 14.9 26.4 7.6

13.6 3.7 26.6 7.9

14.4 2.5 27.1 6.1

15.0 19.5 27.4 6.2

15.6 28.0 28.6 6.5

16.7 20.0 29.4 14.4 17.2 27.6 30.5 7.3

18.0 25.2 31.2 7.7

19.1 4.9 31.8 7.0

19.6 14.3 32.2 7.5

20.2 8.0 32.8 6.1

20.8 24.2 33.9 8.0

21.3 9.7 34.7 6.3

21.8 14.6 36.0 7.2

22.8 100.0 36.7 6.0

Table 14: Unique characteristic diffraction peaks of the compound

of formula (14) (± 0.1 ° 2Θ)

As will be appreciated by the skilled person, the relative intensities of the various peaks within Tables 1 3 and 14 may vary due to a number of factors such as for example orientation effects of crystals in the X-ray beam or the purity of the material being analysed or the degree of crystallinity of the sample. The peak positions may also shift for variations in sample height but the peak positions will remain substantially as defined in given Tables 13 and 14. The skilled person will also appreciate that measurements using a different wavelength will result in different shifts according to the Bragg equation - ηλ = 2d sinB. Such alternative PXRD patterns generated by use of alternative wavelengths are nevertheless representations of the same material.

Fourier Transform Infra-red (FT-IR) spectrum

When characterised by Fourier Transform Infra-red (FT-IR) spectroscopy, the compound of formula (14) gives the pattern shown in Figure 16. The fingerprint region is shown in expanded form in Figure 17. The characteristic peaks are given in Table 15 below (w = weak, s = strong, m = medium). The main characteristic peaks are 1498 (m), 1284 (s), 913 (s) and 801 (s).

Table 15: characteristic FT-IR peaks of the compound of formula (14) (cm^"1)

The IR spectrum was acquired using a ThermoNicolet Nexus FT-IR spectrometer equipped with a 'DurasampllR' single reflection ATR accessory (diamond surface on zinc selenide substrate) and d-TGS KBr detector. The spectrum was collected at 2cm^"1 resolution and a co-addition of 512 scans. Happ-Genzel apodization was used. Because the FT-IR spectrum was recorded using single reflection ATR, no sample preparation was required. Using ATR FT-IR will cause the relative intensities of infrared bands to differ from those seen in a transmission FT-IR spectrum using KBr disc or nujol mull sample preparations. Due to the nature of ATR FT-IR, the bands at lower wavenumber are more intense than those at higher wavenumber. Experimental error, unless otherwise noted, was ± 2 cm^"1 (^* error may be larger). Peaks were picked using ThermoNicolet Omnic 6.1 a software. Intensity assignments are relative to the major band in the spectrum so they are not based on absolute values measured from the baseline.

Fourier Transform Raman spectrum

When characterised by Fourier Transform Raman spectroscopy, the compound of formula (14) gives the pattern shown in Figure 18. The fingerprint region is shown in greater detail in Figure 19. The characteristic peaks are given in Table 16 below (w = weak, s = strong, m = medium, vs = very strong). The main characteristic peaks are 1297 (vs), 1000 (vs), 819 (m) and 731 (m).

Table 16: characteristic FT-Raman peaks of the compound of formula (14)

Solid state NMR data for the compound of formula (14)

Approximately 80 mg of sample were tightly packed into a 4.0 mm Zr02 rotor. Spectra were collected at ambient temperature and pressure on a Bruker-Biospin 4.0 mm CPMAS probe positioned into a wide-bore Bruker-Biospin Avance III 500 MHz (¹H frequency) NMR spectrometer. The packed rotor was oriented at the magic angle and spun at 15.0 kHz. The ¹³C solid state spectra were collected using a proton decoupled cross-polarization magic angle spinning (CPMAS) experiment. The cross-polarization contact time was set to 2.0 ms. A proton decoupling field of approximately 100 kHz was applied during acquisition. The carbon spectrum of the compound of formula (14) was acquired for 8,192 scans with a 7.0 second recycle delay and is shown in Figure 20. Carbon spectra were referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm.

Automatic peak picking was performed using Bruker-BioSpin TopSpin version 3.0 software. The output of the automated peak picking was visually checked to ensure validity and adjustments manually made if necessary. The carbon chemical shifts observed are as follows in Table 17 and the characteristic peaks of the compound of formula (14) are as follows in Table 18.

Table 17: ¹³C chemical shifts for the compound of formula (14) expressed in parts per million (± 0.2 ppm)

3C Chemical Relative ³C Chemical Relative Shifts [ppm] ^<a) Intensity ^(b) Shifts [ppm] ^<a) Intensity ^(b)

172.6 36 126.4 45

158.5 49 124.6 40

151.1 53 122.7 41

142.6 35 120.0 43 139.3 48 1 19.2 48

136.1 74 1 17.6 53

133.8 40 1 16.3 46

132.9 60 1 13.2 39

132.0 78 71 .2 67

131 .7 67 59.9 66

131 .2 61 50.2 53

130.5 72 45.2 46

130.0 60 43.2 100

129.4 71 37.9 67

129.1 85 23.6 72

128.5 62 21 .1 62

^(a> Referenced to external sample of solid phase adamantane at 29.5 ppm. <^b) Defined as peak heights. Intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

Table 18: ¹³C characteristic chemical shifts of the compound of formula (14) expressed in parts per million (± 0.2 ppm)

Example 3: Absence of residual reagents in the compound of example 1

The data provided below show that the use of a substantially crystalline form of 2-chloro-N- {2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2-oxoethyl)phenyl]-1 , 1 - dimethylethyl}acetamide according to example 1 allows purging problematic residual reagents which were previously difficult to purge as compared with the same intermediate previously used in solution, i.e. in a non-crystalline non-isolated form.

Figure 21 represents the ¹H NMR of chloroacetonitrile (performed in DMSO with water present). Figure 22 represents the ¹H NMR of solution of 2-chloro-A/-{2-[3-(2-{[(4'- hydroxybiphenyl-3-yl)methyl]amino}-2-oxoethyl)phenyl]-1 ,1 -dimethylethyl}acetamide as obtained in WO 2007/010356. As can be seen from this pattern, chloroacetonitrile and also residual ethyl acetate (see peaks at δ 1 .21 (t, 3H), 2.02 (s, 3H) and 4.08 (q, 2H)) are present in the solution. On the contrary no chloroacetonitrile is detected in the ¹H NMR of isolated crystalline 2-chloro-A/-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2- oxoethyl)phenyl]-1 ,1 -dimethylethyl}-aceta m i d e a cco rd i n g to exa m p l e 1 wh i ch i s represented in Figure 23.

The absence of residual chloroacetonitrile is particularly advantageous since it would otherwise react with the thiourea used in the next step of the route to the β2 agonist Λ/-[(4'- Hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)- amino]phenyl}ethyl)amino]-2-methylpropyl} phenyl)acetamide to give 1 ,3-thiazole-2,4- diamine, which is problematic to remove. Because of chloroacetonitrile consuming part of the thiourea, it was also previously necessary to use large amounts of thiourea (about 4 to 5 equivalents) which is toxic and potentially carcinogenic. The absence of residual chloroacetonitrile now allows using a lower amount of thiourea (about 1.2 equivalents).

Example 4: Absence of impurities in the compound of preparation 5

Low level impurities structurally related to the starting materials can be present in the starting materials used in the first steps of the process for preparing the β2 agonist Λ/-[(4'- hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-m ethyl propyl} phenyl )acetam ide . Also, additional impurities can be generated during the reactions involved in these first steps. These impurities can be transformed into new impurities in the downstream synthesis, and some can be difficult to purge. The use of the compound according to the present invention, i.e. in isolated crystalline form, offers a solution to these issues as demonstrated by the data provided below.

To quantify the impurity purge provided by the crystalline compound of example 1 , a direct co m p a ri s o n of t h e p ro ce ss w h e re b y 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3- yl)methyl]amino}-2-oxoethyl)phenyl]-1 ,1 -dimethylethyl}-acetamide is not isolated as a solid but is carried through as a solution and the process involving the isolation was performed. The compound of preparation 5 was synthesised using the same starting material batch responsible for the introduction of impurities which fate to the final β2 agonist.

First, the intermediate of preparation 5 was prepared in a pilot plant trial with 2-chloro-N-{2- [3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2-oxoethyl)phenyl]-1 , 1 - dimethylethyl}acetamide not isolated as a solid form. To that effect, in the process followed to prepare the compound of example 1 , the trifluoroacetic acid was removed by distillation and replaced by 2-butanol, however, rather than crystallising the compound according to the present invention, the deprotection reagents used in Preparation 5 were added to the solution to synthesise the compound of Preparation 5.

Additionally, in a laboratory trial, the compound according to the present invention was crystallised as the form identified in example 1 following the standard protocol as described in example 1 and this isolated material was then converted to the compound of preparation 5 as previously described in example 2.

Both processes involved the crystallisation of the compound of preparation 5 from the same solvent system of acetonitrile and 2-butanol. The purity data shown in Table 19 below is that of the compound of preparation 5 and illustrates the impact of the crystallisation of 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2- oxoethyl)phenyl]-1 ,1 -dimethylethyl}acetamide according to the present invention on the level of impurity in the downstream synthesis of the next intermediate.

Table 19: Comparison of the HPLC purity of the intermediate of Preparation 5 where 2-

Chloro-A/-{2-r3-(2-{r(4'-hvdroxybiphenyl-3-yl)methyl1amino)-2-oxoethyl)phenyl1-1 ,1 - dimethylethyl!acetamide has not been isolated as a solid form (pilot plant trial) and where it has been isolated as a solid form (lab trial).

RRT = Relative Retention Time (by HPLC)

(^2> ND = Not Detected

<³⁾ NMT = Not More Than

The above data clearly demonstrates that the compound of preparation 5 is essentially free of most of the impurities previously generated. The isolation of the compound according to the present invention thus provides a significant purge point for a number of impurities so that the next downstream isolated intermediate according to preparation 5 in the route to the final β2 agonist is of vastly improved purity.

Moreover, these two samples of the compound of preparation 5 were separately converted to the β2 agonist of formula (14) using the protocols described in example 2 and the purity of the two samples were compared by HPLC. Specifically, the levels of the impurities in the β2 agonist of formula (14) that were derived from impurities that were present in the solutions of 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2- oxoethyl)phenyl]-1 ,1 -dimethylethyl}acetamide prior to isolation were measured. The results are shown in Table 20, and they demonstrate that the sample prepared with isolation of a solid form of 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2- oxoethyl)phenyl]-1 ,1 -dimethylethyl}acetamide has superior purity compared to the sample that was derived from 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2- oxoethyl)phenyl]-1 ,1 -dimethylethyl}acetamide that was not isolated as a solid form. It will be appreciated by those skilled in the art that prevention of impurities such as these from being present in pharmaceutical substances is critically important to ensure regulatory acceptability and patient safety. For pharmaceutical substances that can be formulated as dry powders for inhalation, such as the β2 agonist of formula (14), it is additionally important to limit the presence of impurities such as those in Table 20 from the stage that the pharmaceutical substance is crystallised since such impurities have the potential to adversely affect the critical physical properties of the pharmaceutical substance by changing the growth and agglomeration of the pharmaceutical substance crystals during the crystallisation process. Hence such impurities, if not limited prior to the stage that the pharmaceutical substance is crystallised, have the potential to ultimately impact the performance and safety of the drug product.

Table 20: Comparison of the HPLC purities of the compound of formula (14) where 2- Chloro-A/-{2-r3-(2-{r(4'-hvdroxybiphenyl-3-yl)methyl1amino)-2-oxoethyl)phenyl1-1 ,1 - dimethylethvDacetamide has not been isolated as a solid form (pilot plant trial) and where it has been isolated as a solid form (lab trial)

RRT = Relative Retention Time (by HPLC)

<²⁾ NMT = Not More Than

Claims

1. A crystalline form of 2-chloro-N-{2-[3-(2-{[(4'-hydroxybiphenyl-3-yl)methyl]amino}-2- oxoethyl)phenyl -1 ,1 -dimethylethyl}acetamide of formula (1 ):

having an X-ray diffraction pattern characterized by the following principal X-ray diffraction pattern peaks expressed in terms of 2-theta angle (± 0.1 ° 2Θ) when measured using Cu Ka1 radiation Wavelength = 1 .5406 A): 9.1 , 10.5 and 1 1.4.

2. The compound according to claim 1 having a Fourier Transform Infra-red pattern characterized by the main characteristic peaks at 1535, 1 179, 834 and 769 cm^"1.

3. The compound according to claim 1 or 2 having a Fourier Transform Raman pattern characterized by the main characteristic peaks at 1294, 1001 and 772 cm^"1.

4. The compound according to claim 1 , 2 or 3 having a solid state ¹³C nuclear magnetic resonance characterized by the following principal chemical shifts expressed in parts per million (± 0.2 ppm) referenced to an external standard of solid phase adamantane at 29.5 ppm: 173.2, 158.5 and 55.5.

5. A process for preparing a compound according to any one of claims 1 to 4 characterised by the reaction of a compound of formula (2):

with chloroacetonitrile in the presence of an acid catalyst in a suitable solvent at temperatures of 0°C to 1 10°C followed by removal of the acid and volatile solvents during the reaction work-up and the addition an antisolvent to crystallize the compound of formula (1 ) according to any one of claims 1 to 4.

6. A process according to claim 5 wherein the acid catalyst is selected from acetic acid, sulfuric acid, trifluoroacetic acid or mixtures thereof.

7. A process according to claim 6 wherein the acid catalyst is trifluoroacetic acid.

8. A process according to claim 5 wherein the antisolvent is selected from 2-butanol, n- butanol, cyclohexane, heptanes, toluene or mixtures thereof.

9. A process according to claim 8 wherein the antisolvent is cyclohexane.

10. A process according to claim 5 characterized in that the compound of formula (2) is prepared by reaction of a compound of formula (3):

in the presence of a suitable amide coupling agent.

1 1 . A process according to claim 10 wherein the amide coupling agent is selected from 1 - (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, 1 ,1 '- carbonyldiimidazole, 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,5-trioxide, pivaloyl chloride or isobutyl chloroformate.

12. A process accordi ng to claim 10 wherein the amide coupling agent is 1 ,1 '- carbonyldiimidazole.

13. Use of a compound according to any one of claims 1 to 4 in a process for the preparation of the β2 agonist formula (14):

or, if appropriate, its pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof, said process comprising the steps of:

1/ deprotecting the compound according to any one of claims 1 to 4 to obtain a compound of formula (1 1 ):

in the presence of thiourea and an acid;

21 reacting said compound of formula (1 1 ) with a compound of formula (12):

wherein Bn means benzyl and TBDMS means te/t-butyldimethylsilyl, to give the compound of formula (13):

and

3/ deprotecting said compound of formula (13) to give the β2 agonist of formula (14).

14. Use according to claim 13 characterised in that the acid of step 1 / is selected from hydrochloric acid, acetic acid or trifluoroacetic acid.

15. Use according to claim 13 characterized in that step 3/ involves a first deprotection step to remove the TBDMS protecting group to obtain a compound of formula (13a):

or a salt thereof, which is then further deprotected to remove the benzyl protecting group and obtain the β2 agonist of formula (14).

16. Use according to claim 15 characterised in that the compound of formula (13a) is prepared as a salt which is selected from L-tartrate, fumarate, L-ascorbate or xinafoate.

17. Use according to claim 16 characterised in that the compound of formula (13a) is prepared as the hemifumarate salt of formula 13b):