Novel process of preparing a trisubstituted pyrazine derivative

Abstract

The present invention relates to a process of preparing a compound of formula (2) or a salt thereof, comprising a one-step reaction converting a compound of formula (1) or a salt thereof into the compound of formula (2) or salt thereof:, wherein Z is chloro, bromo or iodo.

Description

[0001] NOVEL PROCESS OF PREPARING A TRISUBSTITUTED PYRAZINE DERIVATIVE

[0002] Field of the invention

[0003] The present invention relates to a process of preparing a compound of formula (2) or a salt thereof, comprising a one-step reaction converting a compound of formula (1) or a salt thereof into the compound of formula (2) or salt thereof: wherein Z is chloro, bromo or iodo.

[0004] Background of the invention

[0005] Example 125 of WO 2015 / 124932 describes the preparation of a compound of formula (4) :

[0006] In WO 2015 / 124932 the compound formula (4) is prepared by the following route:

[0007] The synthetic strategy in WO 2015 / 124932 for the conversion of compound (la) into compound (2) requires a two-step conversion, firstly a vinylation step to introduce a vinyl group and secondly a hydrogenation step to reduce the vinyl group to an ethyl group. Compound (2) is then converted into the HCI salt (3) which in turn is converted into compound (4).

[0008] Unfortunately, two-step vinylation / hydrogenation conversion from compound (la) to compound (2) produces several by-products that have proven difficult to purge. Moreover, the two-step vinylation / hydrogenation process of WO 2015 / 124932 requires high temperatures (120 °C for the vinylation step), microwave irradiation (for the vinylation step), expensive reagents (2-ethenyl-4,4,5,5-tetramethyl-l,3,2- dioxaborolane for the vinylation step) and long reaction times (3 days for the hydrogenation step), which renders the process unsuitable for industrial scale manufacture.

[0009] Therefore, there is a need for an alternative or improved process of converting the compound of formula (1) or salt thereof into the compound of formula (2) or salt thereof. The present invention provides such an alternative or improved process which is suitable for industrial scale manufacture since it can be carried out quickly (in less than 24 hours), at lower temperatures (at less than 75 °C), without microwave irradiation and using inexpensive reagents (for example EtsB), and which can provide the compound of formula (2) or salt thereof in high purity and / or high yield.

[0010] Summary of the invention

[0011] A first aspect of the invention provides a process of preparing a compound of formula (2) or a salt thereof, comprising a one-step reaction converting a compound of formula (1) or a salt thereof into the compound of formula (2) or salt thereof: wherein Z is chloro, bromo or iodo.

[0012] Z is chloro, bromo or iodo. In a preferred embodiment, Z is bromo.

[0013] In one embodiment, the reaction is performed in the presence of an ethyl nucleophile.

[0014] Preferably the ethyl nucleophile comprises boron, zinc, magnesium, silicon, tin, aluminium or lithium. In one embodiment, the reaction is performed in the presence of Et3B, 9-ethyl-9-borabicyclo[3.3. l]nonane, EtB(OH)2 or an ester thereof (such as EtB(OMe)2, EtB(0Et)2, EtB(OiPr)2 or 2-ethyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane), EtZnCI, EtZnBr, EtZnI, Et2Zn, EtMgCI, EtMgBr, EtMgl, Et2Mg, EtSiF3, an ethyl trialkoxysilane (such as EtSi(OMe)3, EtSi(0Et)3, 2-ethyl-2- methoxybenzo[d][l,3,2]dioxasilole or 2-ethyl-2-ethoxybenzo[d][l,3,2]dioxasilole), Et4Sn, EtsAI or EtLi. In one embodiment, the reaction is performed in the presence of Et3B, EtZnBr or EtMgBr. In a preferred embodiment, the reaction is performed in the presence of Et3B.

[0015] In one embodiment, the reaction is performed in the presence of at least 1 equivalent of ethyl nucleophile per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of less than 10 equivalent of ethyl nucleophile per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of 1 to 10 equivalent of ethyl nucleophile per 1 equivalent of the compound of formula (1) or salt thereof. An "equivalent" is the amount of one substance in moles relative to a given amount of another substance in moles.

[0016] In a preferred embodiment, the reaction is performed in the presence of Et3B. In one embodiment, the reaction is performed in the presence of at least 0.33, 0.4 or 0.5 equivalent of Et3B per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of at least 0.6 equivalent of Et3B per 1 equivalent of the compound of formula (1) or salt thereof.

[0017] In one embodiment, the reaction is performed in the presence of less than 6, 5, 4 or 3 equivalent of Et3B per 1 equivalent of the compound of formula (1) or salt thereof.

[0018] In one embodiment, the reaction is performed in the presence of 0.33 to 6 equivalent of EtsB per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of 0.4 to 5 equivalent of Et3B per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of 0.5 to 4 equivalent of Et3B per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of 0.6 to 3 equivalent of Et3B per 1 equivalent of the compound of formula (1) or salt thereof.

[0019] In one embodiment, the reaction is performed in the presence of a catalyst. In one embodiment, the catalyst is a complex comprising Pd or Ni and one or more phosphine ligands. Such catalysts can be used in the reaction as preformed Pd- or Ni- phosphine complexes or they can be generated in situ from Pd or Ni pre-catalyst compounds and phosphine ligands. The Pd and Ni catalysts can be used with the metal in either the "0" or "+2" oxidation state. The phosphine ligands can be monodentate or bidentate.

[0020] In one embodiment, the catalyst is PdCl2(PPh3)2, Pd(dppf)Cl2 or an analogue thereof (such as an analogue with a different substitution on the ferrocenyl phosphines), NiCl2(PPh3)2, or N i(dppf)Ch or an analogue thereof (such as an analogue with a different substitution on the ferrocenyl phosphines). In a preferred embodiment, the catalyst is Pd(dppf)Cl2.

[0021] In one embodiment, the pre-catalyst compound is Pd(OAc)2, PdCk, allyl palladium (II) chloride dimer, bis(dibenzylideneacetone)palladium (0), tris(dibenzylideneacetone)dipalladium (0), NiCh, nickel (II) acetylacetonate, or bis(l,5-cyclooctadiene)nickel (0).

[0022] In one embodiment, the phosphine ligand is a triaryl- or trialkyl-phosphine, or a mixed aryl-alkyl phosphine. In one embodiment, the phosphine ligand is PPh3, tri-o-tolyl- phosphine, P('Pr)3, P(lBu)3, SPhos, n-BuAd2P, l,l'-bis(diphenylphosphino)ferrocene, l,l'-bis(di-tert-butylphosphino)ferrocene or BiNAP. In a preferred embodiment, the phosphine ligand is l,l'-bis(diphenylphosphino)ferrocene.

[0023] In one embodiment, the reaction is performed in the presence of a catalyst. In one embodiment, the reaction is performed in the presence of 0.0001 to 0.1 equivalent of catalyst per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of 0.001 to 0.1 equivalent of catalyst per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of 0.001 to 0.05 equivalent of catalyst per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of 0.001 to 0.03 equivalent of catalyst per 1 equivalent of the compound of formula (1) or salt thereof.

[0024] The degree of conversion in the ethylation reaction of the present invention is improved in the presence of a base. Typical bases that can be used include alkali and alkaline earth metal carbonate, bicarbonate and phosphate salts. The salts can be used in an anhydrous form, as a hydrate, or as an aqueous solution. Alkali metal alkoxides, such as sodium methoxide or potassium t-butoxide, can also be used, preferably in an anhydrous form or as an alcohol (or other solvent) solution. In addition, tetraalkylammonium fluorides and amine derivatives can also be used.

[0025] In one embodiment, the reaction is performed in the presence of a base. In one embodiment, the reaction is performed in the presence of a base selected from CS2CO3, K2CO3, Na2CO3, K3PO4 or tetra-n-butylammonium fluoride. In one embodiment, the reaction is performed in the presence of a base selected from CS2CO3, K2CO3, Na2CO3 or tetra-n-butylammonium fluoride. In a preferred embodiment, the reaction is performed in the presence of CS2CO3 or tetra-n- butylammonium fluoride, preferably in the presence of CS2CO3.

[0026] In one embodiment, the reaction is performed in the presence of a base. In one embodiment, the reaction is performed in the presence of 1 to 5 equivalent of base per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of 2 to 4 equivalent of base per 1 equivalent of the compound of formula (1) or salt thereof. In one embodiment, the reaction is performed in the presence of about 3 equivalent of base per 1 equivalent of the compound of formula (1) or salt thereof.

[0027] The ethylation reaction is usually carried out in an aprotic solvent, although small amounts of protic solvents (such as water) can be tolerated. Typical solvents for the reaction include ethers (such as tetra hydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, tert-butyl methyl ether, 1,4-dioxane, or methyl cyclopentyl ether), amides (such as dimethylformamide, dimethylacetamide, or N-methyl-2-pyrrolidone), aromatics (such as toluene), nitriles (such as acetonitrile), and sulfoxides (such as dimethylsulfoxide).

[0028] In one embodiment, the reaction is performed in the presence of a solvent selected from tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, tert-butyl methyl ether, 1,4-dioxane, methyl cyclopentyl ether, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, toluene, acetonitrile, dimethylsulfoxide or a mixture thereof. In one embodiment, the reaction is performed in the presence of a solvent selected from tetra hydrofuran, 2-methyl-tetrahydrofuran or a mixture thereof. In a preferred embodiment, the reaction is performed in the presence of tetra hydrofuran.

[0029] In one embodiment, the reaction is heated to a temperature of between 30 °C to 80 °C. In one embodiment, the reaction is heated to a temperature of between 50 °C to 75 °C. In one embodiment, the reaction is heated to a temperature of between 60 °C to 75 °C. In one embodiment, the reaction is heated to a temperature of between 65 °C to 70 °C.

[0030] In one embodiment, the reaction is performed for 1 to 24 hours. In one embodiment, the reaction is performed for 1 to 12 hours. In one embodiment, the reaction is performed for 1 to 8 hours. In one embodiment, the reaction is performed for 1 to 4 hours.

[0031] In one embodiment, after the reaction is complete the reaction mixture is washed with water, an aqueous solution of HCI or an aqueous solution of NaOH. In one embodiment, after the reaction is complete the reaction mixture is washed with an aqueous solution of NaOH. In one embodiment, after the reaction is complete the reaction mixture is washed with a 0.1 M to 10 M aqueous solution of NaOH. In one embodiment, after the reaction is complete the reaction mixture is washed with a 0.5 M to 5 M aqueous solution of NaOH. "M" refers to the molar concentration which is the amount of solute (in moles) per volume of solution (in litres).

[0032] In one embodiment, the compound of formula (1) is used in its non-salt form.

[0033] In one embodiment, the compound of formula (1) is used in the form of a salt.

[0034] The compounds used in and provided by the process of the present invention can be in their free base form or their acid addition salt form. Acid addition salts are addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, toluene-p-sulfonic, naphthalene-2-sulfonic or camphorsulfonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid). The acid addition salt may be a mono-, di-, tri- or multi-acid addition salt. A preferred salt is a hydrohalogenic, sulfuric, phosphoric or organic acid addition salt. A preferred salt is a hydrochloric acid addition salt or a camphorsulfonic acid addition salt. The compounds used in and provided by the process of the present invention can also be salts formed with a cation. Suitable cations include, but are not limited to lithium, sodium, potassium, magnesium, calcium and ammonium. The salt may be a mono-, di- or tri-salt. A preferred salt is a mono- or di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. A preferred salt is a mono- or di-sodium salt.

[0035] Preferably any salt is a pharmaceutically acceptable, non-toxic salt. However, in addition to pharmaceutically acceptable salts, other salts are included in the present invention, since they have potential to serve as intermediates in the purification or preparation of other, for example, pharmaceutically acceptable salts, or are useful for identification, characterisation or purification of a compound provided by the process of the present invention.

[0036] The compounds and / or salts used in and provided by the process of the present invention may be anhydrous or in the form of a hydrate (e.g. a hemihydrate, monohydrate, dihydrate or trihydrate) or other solvate. Such other solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.

[0037] In one embodiment, the compound of formula (2) or salt thereof is obtained in its non-salt form.

[0038] In one embodiment, the compound of formula (2) or salt thereof is obtained in the form of a salt.

[0039] In one embodiment, the compound of formula (2) or salt thereof is obtained from the reaction in a yield of at least 60%, 70%, 80%, 90%, 95% or 97%.

[0040] In one embodiment, the compound of formula (2) or salt thereof is obtained from the reaction with a purity of at least 97%, 98%, 99%, 99.5% or 99.7% as measured by HPLC or Q-NMR.

[0041] In one embodiment, the reaction is suitable for industrial scale manufacture. In one embodiment, the reaction is suitable for preparing the compound of formula (2) or salt thereof in batches of at least 10 g, 100 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, or 100 kg.

[0042] In a preferred embodiment, Z is bromo and the reaction is performed in the presence of 0.6 to 3 equivalent of EtsB, 0.001 to 0.03 equivalent of Pd(dppf)Cl2, and 2 to 4 equivalent of CS2CO3 (all per 1 equivalent of the compound of formula (1) or salt thereof), and preferably in the presence of tetra hydrofuran.

[0043] In one embodiment, the process further comprises the step of converting the compound of formula (2) or salt thereof into a compound of formula (3) or a salt thereof: In one embodiment, the process further comprises the step of converting the compound of formula (2) or salt thereof into a (lS)-(+)-camphor-

[0044] 10-sulfonic acid salt or hydrochloric acid salt of the compound of formula (3).

[0045] In one embodiment, the compound of formula (3) or salt thereof is obtained from the reaction in a yield of at least 60%, 70%, 80% or 90%.

[0046] In one embodiment, the compound of formula (3) or salt thereof is obtained from the reaction with a purity of at least 97%, 98%, 99%, 99.5%, 99.7%, 99.8% or 99.9% as measured by HPLC or Q-NMR.

[0047] In one embodiment, the reaction is suitable for industrial scale manufacture. In one embodiment, the reaction is suitable for preparing the compound of formula (3) or salt thereof in batches of at least 10 g, 100 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, or 100 kg.

[0048] In one embodiment, the process further comprises the step of converting the compound of formula (3) or salt thereof into a compound of formula (4) or a salt thereof:

[0049] In one embodiment, the compound of formula (4) or salt thereof is obtained from the reaction in a yield of at least 60%, 70%, 80% or 90%. In one embodiment, the compound of formula (4) or salt thereof is obtained from the reaction with a purity of at least 97%, 98%, 99%, 99.5%, 99.7%, 99.8% or 99.9% as measured by HPLC or Q-NMR.

[0050] In one embodiment, the reaction is suitable for industrial scale manufacture. In one embodiment, the reaction is suitable for preparing the compound of formula (4) or salt thereof in batches of at least 10 g, 100 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, or 100 kg.

[0051] In one embodiment, the process further comprises the step of preparing a pharmaceutical composition comprising the compound of formula (4) or salt thereof.

[0052] A second aspect of the invention provides a compound of formula (2) or a salt thereof, prepared by or preparable by a process of the first aspect of the invention.

[0053] A third aspect of the invention provides a compound of formula (3) or a salt thereof, prepared by or preparable by a process of the first aspect of the invention.

[0054] A fourth aspect of the invention provides a compound of formula (4) or a salt thereof, prepared by or preparable by a process of the first aspect of the invention.

[0055] Abbreviations ([l,l'-binaphthalene]-2,2'-diyl)bis(diphenylphosphine) (lS)-(+)-camphor-10-sulfonic acid equivalents ethyl high performance liquid chromatography in-process control iso-propyl methyl acetonitrile tert-butyl methyl ether n-butyl-di-l-adamantylphosphine N-bromosuccinimide

[0056] N-chlorosuccinimide bis(triphenylphosphine)nickel (II) dichloride Ni(dppf)Cl2 [l,l'-bis(diphenylphosphino)ferrocene]dichloronickel (II) PdCI2(PPh3)2 bis(triphenylphosphine)palladium (II) dichloride Pd(dppf)CI2[l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)

[0057] Pd(OAc)2palladium (II) acetate PPh3triphenylphosphine SPhos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBAF tetra-n-butylammonium fluoride lBu tert-butyl

[0058] THF tetra hydrofuran

[0059] V volumes (L / kg, ml / g)

[0060] Examples

[0061] IPC HPLC screening process conditions for the analysis of compound (2)

[0062] The conversion to compound (2) in the examples described herein was analysed using an in-process control (IPC) HPLC screening assay under the following conditions.

[0063] IPC HPLC screening process conditions Example 1 : Study of conditions for the one-step conversion of compound (la) to compound (2)

[0064] Compound (la), which is a compound of formula (1) wherein Z is bromo, can be prepared as described in WO 2015 / 124932 (pages 93-95) :

[0065] Compound (la) (0.2 g, 1.0 eq) was treated under the conditions described in Table 1.

[0066] After 4 hours, the conversion to compound (2) was analysed using an in-process control (IPC) assay using HPLC under the conditions as described hereinabove.

[0067] The IPC data in Table 1 shows that all reactions provide compound (2) but that the conditions in example 1A provide a higher yielding conversion of compound (la) into compound (2) than obtained in the other examples.

[0068] Example 2: Study of catalysts for the one-step conversion of compound ( la) to compound (2)

[0069] Compound (la) (0.2-0.3 g, 1.0 eq) was contacted with 0.02 eq of the catalyst identified in Table 2, CS2CO3 (3.0 eq) and EtsB (3.0 eq) in THF (10 V) at 70±5 °C. After 4 hours, the conversion to compound (2) was analysed using an in-process control (IPC) assay using HPLC under the conditions as described hereinabove.

[0070] The IPC data in Table 2 shows that both catalysts provide compound (2) but that Pd(dppf)Cl2 catalysis provides a higher yielding conversion of compound (la) into compound (2).

[0071] Example 3: Study of number of equivalents of EtsB for the one-step conversion of compound (la) to compound (2)

[0072] Compound (la) (0.3-0.5 g, 1.0 eq) was contacted with Pd(dppf)Ch (0.02 eq), CS2CO3 (3.0 eq) and Et3B (number of equivalents specified in Table 3) in THF (10 V) at 70±5 °C. After 4 hours, the conversion to compound (2) was analysed using an in-process control (IPC) assay using HPLC under the conditions as described hereinabove.

[0073] The IPC data in Table 3 shows that all reactions provide compound (2) but that using 0.6 eq of Et3B provides a higher yielding conversion of compound (la) into compound (2) than when fewer equivalents are used.

[0074] Example 4: Study of base for the one-step conversion of compound (la) to compound £2)

[0075] Compound (la) (0.3 g, 1.0 eq) was contacted with Pd(dppf)Ch (0.02 eq), a base as specified in Table 4 (3.0 eq) and Et3B (3.0 eq) in THF (10 V) at 70±5 °C. After 4 hours, the conversion to compound (2) was analysed using an in-process control (IPC) assay using HPLC under the conditions as described hereinabove. The IPC data in Table 4 shows that K2CO3, K3PO4 and tetra-n-butylammonium fluoride can be used as base instead of CS2CO3.

[0076] Example 5: Temperature study for the one-step conversion of compound ( la) to compound (2)

[0077] Compound (la) (0.2-0.3 g, 1.0 eq) was contacted with Pd(dppf)Ch (0.02 eq), CS2CO3 (3.0 eq) and EtsB (3.0 eq) in THF (10 V) at the temperature specified in Table 5. After 4-18 hours, the conversion to compound (2) was analysed using an in-process control (IPC) assay using HPLC under the conditions as described hereinabove.

[0078] The IPC data in Table 5 shows that all reactions provide compound (2) but that the reaction rate increases with increasing temperature. At 40-70 °C similar results were obtained.

[0079] Example 6: Study of work-up procedures for the one-step conversion of compound (la) to compound (2)

[0080] Compound (la) (1 g, 1.0 eq) was contacted with Pd(dppf)Cl2 (0.02 eq), CS2CO3 (3.0 eq) and EtsB (0.6 eq) in THF (10 V) at 65-70 °C. After 3 hours, the reaction mixture was worked-up using the procedures described in Table 6. The amount of residual boron was assessed using B-NMR and the purity of the compound (2) obtained was assessed with Q-NMR.

[0081] The data shows that all work-up conditions used provide compound (2) but that when washing with an aqueous solution of NaOH, compound (2) is obtained with the lowest amount of residual boron and the highest purity.

[0082] Example 7: Preparation of alternative compound (lb)

[0083] Compound (lb), which is a compound of formula (1) wherein Z is chloro, can be prepared as follows.

[0084] To a solution of tert-butyl / V-[(lS / 2S)-2-{[5-(trifluoromethyl)pyrazin-2- yl]amino}cyclopentyl]carbamate (0.8 g, 2.3 mmol, 1.0 eq) in DMF (2.4 ml, 3 V) was added a solution of NCS (370 mg, 2.8 mmol, 1.2 eq) in MeCN (1.6 ml, 2 V). The reaction was stirred for 2 hours at 25 °C, concentrated in vacuo and then purified by column chromatography to afford the compound (lb) (508 mg, yield 58%, purity 100%).

[0085] Example 8: Large scale one-step process of preparing compound (2)

[0086] Compound (la) (10.0 g, 1.0 eq), CS2CO3 (23.0 g, 3.0 eq), Pd(dppf)Cl2 (341.3 mg, 0.02 eq) and THF (100 mL, 10 V) were charged to a reactor under N2 protection. EtsB (IM in THF, 14.1 mL, 0.6 eq) was added dropwise at 20-25 °C. The reaction mixture was heated to 65-70 °C, stirred for 2 hours and then cooled to 20-25 °C. The reaction was quenched with IM aq. NaOH (4 V) and MTBE (5 V), stirred for 30 mins, and the two phases (aqueous and organic) were separated. The aqueous phase was extracted with MTBE (5 V) and the extract combined with the organic phase. The organic phase was washed twice with IM aq. NaOH (2 V x 2) and then with H2O (2 V), concentrated to 3-3.5 V and exchanged with n-heptane (5 V) three times. On GC sample analysis the residual MTBE was 0.09%. The mixture was stirred for at least 1 hour at -5±2 °C, filtered, washed with cold n-heptane (1 V x 2), and dried under vacuum to obtain compound (2) (7.79 g) with a purity of 98.41% and a yield of 80.6%.

[0087] Example 9: Preparation of the compound (3) CSA salt

[0088] Compound (2) (7.6 g, 1.0 eq), 6N HCI (7.6 mL, 1 V) and MeCN (38 mL, 5 V) were charged to a reactor under N2protection. The reaction mixture was heated to 50-55 °C, stirred for 6 hours and then cooled to 20-25 °C. The mixture was charged with 20% w / w aq. NaCI (4 V) while keeping the temperature at < 40 °C, before concentration to 6 V. The mixture was charged with MTBE (8 V) and 2M aq. NaOH (3 V) at 20-25 °C, stirred for 30 mins, and the two phases (aqueous and organic) were separated. The aqueous phase was extracted with MTBE (5 V) and the extract combined with the organic phase. The organic phase was washed with H2O (5 V), concentrated to 4.5-5 V and exchanged with MeCN (5 V) twice. The mixture was charged with activated carbon (5% w / w) and stirred for 1 hour, before filtration and washing the filter cake with MeCN (1 V x 2). The filtrate was charged with CSA (0.911 eq) at 40-45 °C, stirred for 0.5 hour at 40-45 °C, before cooling to 20-25 °C and stirring for 1 hour. The mixture was filtered, washed with MeCN (1.5 V x 2), and dried under vacuum to obtain the CSA salt of compound (3) (8.66 g) with a purity of 99.73% and a yield of 84.2%.

[0089] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

Claims1. A process of preparing a compound of formula (2) or a salt thereof, comprising a one-step reaction converting a compound of formula (1) or a salt thereof into the compound of formula (2) or salt thereof:wherein Z is chloro, bromo or iodo.

2. The process according to claim 1, wherein Z is bromo.

3. The process according to claim 1 or 2, wherein the reaction is performed in the presence of EtsB, 9-ethyl-9-borabicyclo[3.3.1]nonane, EtB(OH)2 or an ester thereof (such as EtB(OMe)2, EtB(OEt)2, EtB(OiPr)2 or 2-ethyl-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane), EtZnCI, EtZnBr, EtZnI, Et2Zn, EtMgCI, EtMgBr, EtMgl, Et2Mg, EtSiFs, an ethyl trialkoxysilane (such as EtSi(OMe)3, EtSi(OEt)3, 2-ethyl-2-methoxybenzo[d][l,3,2]dioxasilole or 2-ethyl-2- ethoxybenzo[d][l,3,2]dioxasilole), Et4Sn, EtsAI or EtLi.

4. The process according to any one of claims 1 to 3, wherein the reaction is performed in the presence of a catalyst, optionally wherein the catalyst is selected from PdCl2(PPh3)2, Pd(dppf)Cl2 or an analogue thereof, NiCl2(PPh3)2, or Ni(dppf)Cl2 or an analogue thereof.

5. The process according to any one of claims 1 to 3, wherein the reaction is performed in the presence of:(i) a pre-catalyst compound, optionally wherein the pre-catalyst compound is selected from Pd(OAc)2, PdCh, allyl palladium (II) chloride dimer, bis(dibenzylideneacetone)palladium (0), tris(dibenzylideneacetone)dipalladium (0), NiCk, nickel (II) acetylacetonate, or bis(l,5-cyclooctadiene)nickel (0); and(ii) a phosphine ligand, optionally wherein the phosphine ligand is selected from PPhs, tri-o-tolyl-phosphine, P('Pr)3, P(lBu)3, SPhos, n-BuAd2P, 1,1'- bis(diphenylphosphino)ferrocene, l,l'-bis(di-tert-butylphosphino)ferrocene or BiNAP.

6. The process according to any one of the preceding claims, wherein the reaction is performed in the presence of a base, optionally wherein the base is selected from CS2CO3, K2CO3, Na2CO3, K3PO4 or tetra-n-butylammonium fluoride.

7. The process according to any one of the preceding claims, wherein the reaction is performed in the presence of a solvent, optionally wherein the solvent is selected from tetra hydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, tertbutyl methyl ether, 1,4-dioxane, methyl cyclopentyl ether, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, toluene, acetonitrile, dimethylsulfoxide or a mixture thereof.

8. The process according to any one of the preceding claims, wherein the reaction is heated to a temperature of between 30 °C to 80 °C, optionally wherein the reaction is heated to a temperature of between 60 °C to 75 °C.

9. The process according to any one of the preceding claims, wherein the reaction is performed for 1 to 24 hours, optionally wherein the reaction is performed for 1 to 4 hours.

10. The process according to any one of the preceding claims, wherein after the reaction is complete the reaction mixture is washed with an aqueous solution of NaOH.

11. The process according to any one of the preceding claims, further comprising the step of converting the compound of formula (2) or salt thereof into a compound of formula (3) or a salt thereof:

12. The process according to claim 11, wherein the compound of formula (3) is obtained in the form of a (lS)-(+)-camphor-10-sulfonic acid salt or hydrochloric acid salt.

13. The process according to claim 11 or 12, further comprising the step of converting the compound of formula (3) or salt thereof into a compound of formula (4) or a salt thereof:

14. The process according to claim 13, further comprising the step of preparing a pharmaceutical composition comprising the compound of formula (4) or salt thereof.

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