CYCLOPROPYL BENZAMIDE DERIVATIVES AS INTERMEDIATES FOR

CYTOKINE INHIBITORS

The present invention relates to novel processes for the preparation of intermediate compounds which can be used to prepare therapeutic agents. The present invention also relates to novel intermediate compounds which can be used to prepare therapeutic agents.

Cytokines are produced by a wide variety of cells such as monocytes and macrophages and they give rise to a variety of physiological effects which are believed to be important in disease or medical conditions such as inflammation and immunoregulation. For example, TNFα and IL-I have been implicated in the cell signalling cascade which is believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. It is also known that, in certain cellular systems, TNFα production precedes and mediates the production of other cytokines such as IL-I.

Abnormal levels of cytokines have also been implicated in, for example, the production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes, the stimulation of the release of proteolytic enzymes such as collagenase, the activation of the immune system, for example by stimulation of T-helper cells, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferation and to angiogenesis.

Cytokines are also believed to be implicated in the production and development of disease states such as inflammatory and allergic diseases, for example inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, Crohn's disease and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease and adult respiratory distress syndrome), and in the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart failure, acute heart failure, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular

injury including restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteoperosis and periodontitis, and the abnormal changes in bone 5 metabolism which may accompany rheumatoid arthritis and osteoarthritis. Excessive cytokine production has also been implicated in mediating certain complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in mediating certain complications of CNS surgery or injury such as neurotrauma and ischaemic stroke. Excessive cytokine production has also been io implicated in mediating or exacerbating the development of diseases involving cartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), chronic obstructive pulmonary disease, tumour invasiveness and tumour metastasis and multiple sclerosis. Excessive cytokine production has also been is implicated in pain.

Evidence of the central role played by TNFα in the cell signalling cascade which gives rise to rheumatoid arthritis is provided by the efficacy in clinical studies of antibodies of TNFα (The Lancet. 1994, 344, 1125 and British Journal of Rheumatology. 1995, 34, 20 334).

WO 2005/061465 discloses a series of compounds having the structure (A) below which inhibit the effects of cytokines by virtue of inhibition of the enzyme p38 kinase :-

25 (A) wherein

Q _a is phenyl or heteroaryl, and Q _a may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, amino, (l-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and (1- 6C)alkoxycarbonyl; Ri and R ₂ are each independently selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl; and

Qb is phenyl, heteroaryl or heterocyclyl, and Qb may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(l-6C)alkyl, (l-6C)alkoxy, (3-6C)cycloalkoxy, (3-6C)cycloalkyl-(l-6C)alkoxy, carboxy, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy- (l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, aminosulphonyl, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl and (3-6C)cycloalkylsulphonyl; and wherein any of the substituents on Q _a or Q _b defined hereinbefore which comprise a CH ₂ group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH ₂ or CH ₃ group one or more substituents selected from hydroxy, cyano, amino, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; or a pharmaceutically-acceptable salt thereof.

Methods of synthesising compounds of the type (A) described above are described in WO 2005/061465 and typically involve reacting a benzoic acid (B), or an activated derivative thereof, of formula:

(B)

wherein Q _a , Qb, Ri and R ₂ are as defined for formula (A), with an amine (C):

or reacting an acid (D) or an activated derivative thereof:

(D) wherein Q _a , Qb, Ri and R ₂ are as defined for formula (A), with an aniline:

under standard amide bond forming conditions.

WO 2005/061465 also describes methods of synthesising further intermediate compounds useful in the preparation of compounds of the structure (A). Examples of certain further such methods are described in WO 2005/042502, WO 2005/042537, WO 2004/099156 and Hynes et al, Bioorg. & Med. Chem. Lett., 18 (2008), 1762-1767, but none of these documents describes a process according to the present invention as described herein.

There remains a continuing need for new methods of synthesising compounds of formula (A) and hence for new and efficient methods for preparing intermediates useful in the preparation of such therapeutic compounds.

The present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein Q _a is phenyl or heteroaryl, and Q _a may optionally bear one or two substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, amino, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and (l-6C)alkoxycarbonyl; and wherein any of the substituents on Q _a defined hereinbefore which comprise a CH ₂ group which is attached to 2 carbon atoms or a CH ₃ group which is attached to a carbon atom may optionally bear on each said CH ₂ or CH ₃ group one or more substituents selected from hydroxy, cyano, amino, (l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylamino and di-[(l-6C)alkyl]amino; which process comprises reacting a compound of formula (II) or a pharmaceutically acceptable salt thereof:

with an acid of formula (III), or an activated derivative thereof:

(III) wherein Q _a is as defined for formula (I) and any functional group is optionally protected, and wherein the reaction is carried out in the presence of a base, and provided that when Q _a in formula (I) and formula (III) is heteroaryl, it is not a pyridyl or pyrazinyl group, and thereafter if necessary or desired, carrying out one or more of the following steps:

(i) removing any protecting groups;

(ii) forming a pharmaceutically acceptable salt.

A suitable activated derivative of an acid of the formula (III) is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloro formate such as isobutyl chloro formate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an alcohol such as N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide.

In one embodiment of the process of the invention, the compound of formula (III) is an acyl halide, preferably an acyl chloride.

The reaction is carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl-lithium, for example n-butyl-lithium, or a

dialkylamino -lithium, for example lithium di-isopropylamide, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene.

In one embodiment of the process of the invention, the base is an organic amine base, preferably triethylamine.

The process of the invention is typically conveniently conducted in the presence of a suitable base only and does not require the use of a coupling agent such as HATU (i.e. 2- (1 H-9-azabenzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate) .

The reaction is also preferably carried out in a suitable inert solvent or diluent, for example tetrahydrofuran, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a temperature in the range, for example, -78 to 15O ⁰ C, conveniently at or near ambient temperature of about 20 to 25°C.

In one embodiment of the process of the invention, the solvent is dichloromethane.

Advantageously, the process of the invention provides a convergent synthesis for the preparation of compounds of formula (I) whereby large fragments are coupled together in a final step, the fragments themselves being individually elaborated at an earlier stage. This process therefore provides a practical and efficient route for the manufacture on a commercial scale of compounds which are useful as intermediates in the preparation of therapeutic compounds.

Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods

being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1 to 4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.

A carboxy protecting group may be the residue of an ester- forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, tert-butyl); lower alkoxy lower alkyl groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (for example 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (for example benzyl, p_-methoxybenzyl, o-nitrobenzyl, p_-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (for example trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl and vinylethyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.

Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for example benzoyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p_-nitrobenzyloxycarbonyl); tri lower alkylsilyl groups (for

example trimethylsilyl, tert-butyldimethylsilyl) and aryl lower alkyl groups (for example benzyl).

Examples of amino protecting groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, p_-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p_-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for example benzyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p_-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene); benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as p_-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as o-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents. The reader is referred to Protective Groups in Organic Synthesis, 3rd Edition, by Green and Wuts, published by John Wiley & Sons for general guidance on protecting groups.

In one embodiment of the process of the invention, no protecting group(s) are used, thereby obviating the need for protection and deprotection steps and so leading to a more efficient and economical synthesis.

Suitable pharmaceutically-acceptable salts include acid-addition salts with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric, maleic, tartaric, fumaric, hemifumaric, succinic, hemisuccinic, mandelic, methanesulphonic, dimethanesulphonic, ethane- 1 ,2-sulphonic, benzenesulphonic, salicylic or 4-toluenesulphonic acid.

Unless otherwise indicated, the term 'alkyl' when used alone or in combination, refers to a straight chain or branched chain alkyl moiety. A 1-6C alkyl group has from one to six carbon atoms including methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, n- hexyl and the like.

A suitable value for Q _a when it is heteroaryl is, for example, an aromatic 5- or 6- membered monocyclic ring, a 9- or 10-membered bicyclic ring or a 13- or 14-membered tricyclic ring each with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, and provided that when Q _a is heteroaryl, it is not a pyridyl or pyrazinyl group. For example, a suitable value for Q _a when it is heteroaryl is furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl, S,Si-dioxodibenzothiophenyl, xanthenyl, dibenzo-1,4- dioxinyl, phenoxathiinyl, phenoxazinyl, dibenzothiinyl, phenothiazinyl, thianthrenyl, benzofuropyridyl, pyridoindolyl, acridinyl or phenanthridinyl, preferably furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrido[l,2-a]imidazolyl, pyrazolyl, thiadiazolyl, isothiazolyl, pyridazinyl or pyrimidinyl, more preferably furyl, isoxazolyl, thiazolyl, pyrido[l,2-a]imidazolyl, thiadiazolyl or pyridazinyl or pyrimidinyl. In one embodiment, when Q _a is heteroaryl, it is not a pyridyl, pyrazinyl or pyrimidinyl group.

In one embodiment of the process of the invention, Q _a in formula (I) and formula (III) is phenyl, optionally substituted by 1 or 2 substituents as hereinbefore defined.

Suitable values for various substituents on Q _a include :- for halogeno: fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-6C)alkenyl: vinyl and allyl; for (2-6C)alkynyl: ethynyl and 2-propynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;

for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert- butoxycarbonyl; for (l-6C)alkylamino: methylamino, ethylamino and propylamino; for di-[(l-6C)alkyl] amino: dimethylamino, diethylamino and N-ethyl-N-methylamino; for halogeno-(l-6C)alkyl: fluoromethyl, chloromethyl, bromomethyl,difluoromethyl, dichloromethyl, dibromomethyl,

2-fluoroethyl, 2-chloroethyl and 2-bromoethyl; for hydroxy-(l-6C)alkyl: hydroxymethyl, 2-hydroxy ethyl, 1 -hydroxy ethyl and 3- hydroxypropyl; for (l-6C)alkoxy-(l-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxy ethyl, 2- methoxy ethyl, 2-ethoxy ethyl and 3-methoxypropyl; for cyano-(l-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 3-cyanopropyl; for amino-(l-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-aminopropyl; for (l-6C)alkylamino-(l-6C)alkyl:methylaminomethyl, ethylaminomethyl,l- methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl; for di-[(l-6C)alkyl]amino-(l-6C)alkyl: dimethylaminomethyl, diethylaminomethyl, 1- dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl. for carboxy-(l-6C)alkyl: carboxymethyl, 1-carboxy ethyl, 2-carboxyethyl,3-carboxypropyl and 4-carboxybutyl; for (l-6C)alkoxycarbonyl-(l-6C)alkyl: methoxycarbonylmethyl, ethoxycarbonylmethyl,tert-butoxycarbonylmethyl, 1 -methoxycarbonylethyl, 1 - ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3- methoxycarbonylpropyl and 3-ethoxycarbonylpropyl.

In an embodiment of the process of the present invention, Q _a in formula (I) and in formula (III) is phenyl, and Q _a may optionally bear one or two substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, amino, (l-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and (1- 6C)alkoxycarbonyl; and wherein any of the substituents on Q _a defined hereinbefore which comprise a CH ₂ group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH ₂ or CH ₃ group one or more

substituents selected from hydroxy, cyano, amino, (l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylamino and di-[(l-6C)alkyl] amino.

In a further embodiment of the process of the present invention, Q _a in formula (I) and in formula (III) is phenyl, and Q _a may optionally bear one or two halogeno (especially fluoro) substituents.

In a further embodiment of the process of the invention, Q _a in formula (I) and formula (III) is phenyl substituted by one or two halogen substituents, preferably two halogen, especially fluoro, substituents. In a particular embodiment, the compound of formula (III) is a compound of formula (III A):

or an activated derivative thereof, suitably an acyl chloride of formula (IIIB):

(IIIB)

A further process of the present invention is for preparing a compound of formula (IA) or a pharmaceutically acceptable salt thereof:

which process comprises reacting a compound of formula (II) or a pharmaceutically acceptable salt thereof:

with an compound of formula (IIIA), or an activated derivative thereof (suitably an acyl chloride of formula (IIIB) above):

(IIIA) wherein any functional group is optionally protected, and wherein the reaction is carried out in the presence of a base, and thereafter if necessary or desired, carrying out one or more of the following steps:

(i) removing any protecting groups; (ii) forming a pharmaceutically acceptable salt.

Certain compounds of formula (I) are novel and these, and their pharmaceutically acceptable salts, form a further aspect of the invention.

The present invention further provides a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

Compounds of formula (II) and (III) above are known compounds or they can be prepared from known compounds by conventional methods such as those illustrated in the Examples. The compound of formula (II) is described in US 2005/0215795 and a method

for its preparation from commercially available 4-methyl-3-nitrobenzoyl chloride is disclosed in US 2006/0235020.

Compounds of formula (I) are suitably used in the production of pharmaceutical compounds and in particular, compounds with cytokine inhibitory activity as described in WO 2005/061465.

The invention will now be illustrated in the following non-limiting Example:

Unless otherwise specified, all starting materials & reagents were purchased from standard suppliers and were used without further purification. Reactions were carried out on a pilot plant under a nitrogen atmosphere and at ambient temperature, i.e. in the range 17 to 25 ⁰ C, unless otherwise stated. Yields are given for illustration only and are not necessarily the maximum attainable.

When given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using perdeuterio dimethyl sulfoxide (DMSO-d _δ ) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; bs, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; at, apparent triplet; q, quartet; m, multiplet; br, broad.

Mass spectra were run by electrospray (ESP); unless otherwise stated, the mass ion quoted is (MH) ⁺ which refers to the protonated mass ion.

HPLC was performed using the following conditions:- Column, 15 cm ACE 3, C18, 4.6 mm, 3μ, Eluent A:100% Water, 1% Formic Acid. Eluent B:100% MeCN, 1% Formic Acid. Timetable

Flow: 1.5 niL/min, Stop time: 20.00 min, Post time: 5.00 min, Injection: 2.5 μL,Wavelength:254 nm, Temperature: 40 ⁰ C

Example 1 Preparation of 7V-cvclopropyl-3-( 3 ,4-difluorobenzamido)-4-methylbenzamide

(i) 3 -Nitro-N-cyclopropyl-4-methyl-benzamide

4-Methyl-3-nitrobenzoic acid (MNBA, 6 kg), dimethylaminopyridine (DMAP, 0.12 kg) and thionyl chloride (30.7 L) was charged to a reactor, heated to 70 to75°C and stirred for 1 hour. The reaction was sampled to check conversion and excess thionyl chloride removed by vacuum distillation. Toluene (28.9 L) was added and the reaction mixture further concentrated under reduced pressure. This procedure was repeated four times. Dichloromethane (36.4 L) was added and the mixture stirred to homogenise. Isopropanol (68.8 L), Triethylamine (9.2 L) and Cyclopropylamine (2.43 L) was charged to a second reactor vessel and cooled with stirring to 0 to 5 ⁰ C. 4-Methyl-3-nitrobenzoyl chloride solution was added to the mixture maintaining a batch temperature 0 to 5 ⁰ C. The mixture was heated to 2O ⁰ C and sampled to check conversion. The volatiles were removed by atmospheric distillation and the solution volume adjusted to approximately 40 L. The mixture was cooled to 12 to 17 ⁰ C. Water (112.5 L) and concentrated hydrochloric acid (3.4 L, 30% w/w) was added to adjust pH 5 to 6. The mixture was stirred for 1 hour and product isolated by filtration and used as a solvent wet solid in the subsequent stage.

(ii) 3 - Amino-N-cyclopropyl-4-methyl-benzamide

10% Pd/C (1.5 kg, 50% water wet) was added to an inerted reactor vessel. The product of stage (i) (15 kg) was charged and the reactor inerted with nitrogen. Isopropanol (163 L) was added, the reaction contents adjusted to 25 to 3O ⁰ C and vessel pressurised with hydrogen. The mixture was heated to 30 to 4O ⁰ C, stirred for 1 hour and sampled to check conversion. The vessel was purged with nitrogen and the mixture concentrated by distillation to adjust volume to approximately 80 L. Isopropanol (38.2 L) was added and the mixture heated to reflux to reduce batch volume to approximately 80L (Distillate 38.2 L). The mixture was diluted with isopropanol (38.2 L) and sampled for water content (<0.05 % w/w). A solution of the product, 3-amino-N-cyclopropyl-4-methyl-benzamide, was used directly in the subsequent step although the product can be isolated as a white, crystalline solid by adjustment of isopropylalcohol volumes and addition of methyl tert- Butyl Ether (MTBE).

(iii) JV-cyclopropyl-3 -(3 ,4-difluorobenzamido)-4-methylbenzamide

3,4-Difluorobenzoic acid (2.5 kg, DFBA) and DMAP (0.015 kg) was charged to reactor 1 and inerted with nitrogen. Dichloromethane (9.4 L) and thionyl chloride (1.16 L) was added followed by dichloromethane (0.8 L). The mixture was heated to reflux, stirred for 4 hours and cooled to 20 to 25 ⁰ C.

3-Amino-N-cyclopropyl-4-methyl-benzamide (2.69 Kg @ 100 % strength; [18.57 kg, 14.5 % w/w, 14.14 mol as solution in isopropanol]), triethylamine (4.4 L) and dichloromethane (3.8 L) was charged to reactor 2 and cooled to 0 to 5 ⁰ C. A solution of difluorobenzoylchloride (reactor 1) was added to the mixture maintaining a batch temperature 0 to 5 ⁰ C. Dichloromethane (3.8 L) was added, the mixture heated to 20 to 25 ⁰ C and stirred for 2 hours. The volatiles were removed by atmospheric distillation to adjust to target solution concentration of iV-cyclopropyl-3-(3,4-difluorobenzamido)-4- methylbenzamide (28 to 32% w/w). The batch was cooled to 20 to 25 ⁰ C, stirred for 1 hour and demineralised water (47 L) added over 30 minutes. The batch was stirred for 1 hour and isolated by filtration. The product was sequentially washed with demineralised water (10 L), aqueous KOH solution (10.06 Kg, 5.57 % w/w) and demineralised water (10 L). Equipment train was cleaned and λ/-cyclopropyl-3-(3,4-difluorobenzamido)-4- methylbenzamide and toluene (50.6 L) was charged to reactor 2. The mixture was heated to reflux to azeotropically dry solution (water content <0.2 % w/w). The mixture was cooled to 20 to 25 ⁰ C, stirred for 1 hour and isolated by filtration. The product was washed with toluene (9 L) and discharged as a toluene wet solid (3.74 Kg). After correction for loss on drying [3.59 kg dry weight (10.77 mol)], JV-cyclopropyl-3-(3,4- difluorobenzamido)-4-methylbenzamide was isolated in overall 76.1 % yield; NMR spectrum: ¹ H-NMR [δ (ppm), 400 MHz, dg-DMSO]: 0.57 (2H, m), 0.66 (2H, m), 2.27 (3H,

s), 2.86 (IH, m), 7.36 (IH, d, J = 8.0 Hz), 7.64 (IH, m), 7.67 (IH, m), 7.81 (IH, d, J = 1.6 Hz), 7.90 (IH, m), 8.05 (IH, m), 8.41 (IH, d, J = 4.0 Hz), 10.12 (lH,s); ¹³ C NMR [δ (ppm), 100.6 MHz, d ₆ -DMSO]: 5.7, 17.9, 23.0, 117.1 (d, ² J _C -F = 18 Hz), 117.7 (d, ² J _C -F = 18 Hz), 125.0, 125.2 (m), 125.8, 130.2, 131.6 (m), 132.5, 135.9, 137.4, 149.2 (dd, ¹ J ₀ -F = 5 227 Hz, ² Jc-F = 12 Hz), 151.7 (dd, ¹ J ₀ -F = 231 Hz, ² J _C - _F = 13 Hz), 163.2, and 166.8; Mass spectrum: M+H ⁺ 331.1254 (theory 331.1258); HPLC: Rt 8.7 mins