Novel aminocarbonylation processes

Abstract

Herein are provided processes of converting the compound of Formula (I) to the compound of Formula (II).

Description

[0001] NOVEL AMINOCARBONYLATION PROCESSES

[0002] FIELD

[0003] Herein are provided processes of preparing a compound of Formula (II) from a compound of Formula (I):

[0004] BACKGROUND

[0005] Described herein are processes of preparing a compound of Formula (II). The compound of Formula (II) is a known intermediate in the preparation of the compound of Formula (III):

[0006] The compound of Formula (III) has the chemical name (7R,14R)-11 -[2-(1 - aminocyclobutyl)pyrimidin-5-yl]-1 -(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-5(14H)-one.

[0007] A process of converting a compound of Formula (I) into a compound of Formula (II) is described in WO 2016 / 050975 and a process for converting the compound of Formula (II) into the compound of Formula (III) is described in WO 2018 / 197503.

[0008] The compound of Formula (III) is a pharmacologically active substituted fused pentacyclic benzimidazole derivative which shows pharmacological activity on TNFo signalling. An impurity identified in processes for preparing the compound of Formula (II) is the uncyclized compound of Formula (IV):

[0009] There is a desire to provide processes of preparing the compound of Formula (II) with high yields. There is also a desire to provide processes of preparing the compound of Formula (II) which are suitable for large-scale manufacturing, such as industrial scale. There is also a desire to provide processes of preparing the compound of Formula (II) with high purity, in particular with reduced amounts of the uncyclized compound of Formula (IV).

[0010] SUMMARY

[0011] The processes described herein are based on the unexpected finding of processes that convert the compound of Formula (I) into the compound of Formula (II) in high yield and purity and which are suitable for manufacturing the compound on a large scale.

[0012] In a first aspect, herein is provided a process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II): in the presence of a solvent comprising acetonitrile, toluene or a mixture thereof. In a second aspect, herein is provided a process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II) in the presence of phenol and 1 ,2,2,6,6-pentamethylpiperidine.

[0013] In a third aspect, herein is provided a process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II) in the presence of sodium phenoxide.

[0014] In a fourth aspect, herein is provided the compound of Formula (II) with a HPLC purity of 98% or more.

[0015] In a fifth aspect, herein is provided a process of preparing a compound of Formula (III): which comprises a process according to the first, second or third aspect.

[0016] DETAILED DESCRIPTION

[0017] A first aspect provides a process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II) in the presence of a solvent comprising acetonitrile, toluene or a mixture thereof.

[0018] The compound of Formula (I) has the chemical name (1 R,3R)-1 -[2-bromo-6- (difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1 ,2-a]benzimidazol-3-amine. A process for preparing the compound of Formula (I) is described in WO 2016 / 050975 (see intermediate 40).

[0019] The compound of Formula (II) has the chemical name (7R,14R)-11 -chloro-1 - (difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-5(14H)- one. In one embodiment of the first aspect, the process is performed in the presence of a solvent comprising acetonitrile.

[0020] In one embodiment of the first aspect, the process is performed in the presence of 6-20 volumes of acetonitrile. Typically, the process is performed in the presence of 10-15 volumes of acetonitrile, or 12-14 volumes.

[0021] Unless stated otherwise, volume (vol) is the amount of solvent in mL per gram of starting compound of Formula (I).

[0022] In one embodiment of the first aspect, at least 50% of the total solvent volume in the process comprises acetonitrile (v / v). Typically, at least 60% of the total solvent volume in the process comprises acetonitrile (v / v), or 70% or 80%. More typically, at least 90% of the total solvent volume in the process comprises acetonitrile (v / v). Most typically, at least 95% of the total solvent volume in the process comprises acetonitrile (v / v), or 98% or 100%.

[0023] In one embodiment of the first aspect, the process is performed in the presence of a base, typically an organic base. Typically, the process is performed in the presence of sodium phenoxide or potassium phenoxide. Typically, the process is performed in the presence of sodium phenoxide (also known as PhONa). More typically, the process is performed in the presence of 1 -5 equivalent of sodium phenoxide, or 1 -2 equivalent or 1 .1 -1 .5 equivalent.

[0024] In one embodiment of the first aspect, the process is performed in the presence of phenoxide ions.

[0025] In one embodiment of the first aspect, the process is performed in the presence of phenoxide ions and the phenoxide ions may be in salt form with a suitable counterion, for example sodium or potassium. Alternatively, the phenoxide ions may be generated in situ in the process, typically, by deprotonation of phenol with a suitable base.

[0026] In one embodiment of the first aspect, the process is performed in the presence of phenoxide ions and the phenoxide ions are prepared in situ by treatment of phenol with a suitable base. The combination of phenol and a suitable base may be referred to herein as a base system. Typically, the base or base system are in the liquid state. Typically, in the liquid state the base or base system is dissolved in the solvent. Typically, the base is a tertiary amine base, for example, a base selected from 1 , 2, 2,6,6- pentamethylpiperidine (PMP), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), A / ,A / - diisopropylethylamine or triethylamine. More typically, the base is PMP. A base system comprising PMP may provide particularly favourable conversion from the compound of Formula (I) to the compound of Formula (II). It was observed that when the base system comprises N-methyl-imidazole (NMI), then comparatively more compound of Formula (I) remained at the end of the process. More typically, the phenoxide ions are prepared in situ by treatment of 1 .5-2.5 equivalent of phenol with 1 -2 equivalent of PMP. Even more typically, the phenoxide ions are prepared in situ by treatment of 1 .8-2.2 equivalent of phenol with 1 .2-1 .8 equivalent of PMP. In situ preparation of phenoxide ions from a process performed in the presence of phenol and PMP is a process which may provide particularly reduced amounts of the uncyclized compound of Formula (IV). Typically, phenol and 1 ,2,2,6,6-pentamethylpiperidine (PMP) are present in the process in liquid state.

[0027] Unless stated otherwise, all equivalents (eq) are molar equivalents relative to the amount of the starting material compound of Formula (I).

[0028] A second aspect provides a process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II) in the presence of in the presence of phenol and 1 ,2,2,6,6-pentamethylpiperidine.

[0029] Performing the process in the presence of phenol and PMP is a process which may provide particularly reduced amounts of the uncyclized compound of Formula (IV).

[0030] In one embodiment of the second aspect, the process is performed in the presence of 1 .5- 2.5 equivalent of phenol. Typically, 1 .8-2.2 equivalent of phenol.

[0031] In one embodiment of the second aspect, the process is performed in the presence of 1 -2 equivalent of PMP. Typically, 1 .2-1 .8 equivalent of PMP.

[0032] In one embodiment of the second aspect, the process is performed in the presence of 1 .5- 2.5 equivalent of phenol and 1 -2 equivalent of PMP. Typically, the process is performed in the presence of 1 .8-2.2 equivalent of phenol and 1 .2-1 .8 equivalent of PMP. In one embodiment of the second aspect, phenol and 1 ,2,2,6,6-pentamethylpiperidine (PMP) are present in the process in liquid state. Typically, the phenol and 1 , 2, 2,6,6- pentamethylpiperidine (PMP) are dissolved in a solvent, typically a solvent comprising acetonitrile.

[0033] In one embodiment of the second aspect, the process comprises a first step treatment with carbon monoxide, in the presence of phenol and 1 ,2,2,6,6-pentamethylpiperidine (PMP). The process may or may not be followed by a second step treatment with an amide coupling agent. As described herein performing the process in the presence of phenol and PMP is a process which may provide particularly reduced amounts of the uncyclized compound of Formula (IV). Hence, typically, the process is not followed by a second step treatment with an amide coupling agent.

[0034] A third aspect provides a process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II) in the presence of sodium phenoxide.

[0035] In one embodiment of the third aspect, the process is performed in the presence of 1-5 equivalent of sodium phenoxide, or 1 -2 equivalent, or 1 .1 -1 .5 equivalent.

[0036] In one embodiment of the second or third aspect, the process is performed in the presence of an aprotic solvent. Typically, the process is performed in the presence of a solvent comprising acetonitrile, N-methyl-pyrrolidone, toluene, dimethylformamide or a mixture thereof. More typically, the process is performed in the presence of a solvent comprising acetonitrile, toluene or a mixture thereof. Most typically, the process is performed in the presence of a solvent comprising acetonitrile.

[0037] In one embodiment of the first, second or third aspect, the compound of Formula (I) is treated with carbon monoxide. Typically, the compound of Formula (I) is treated with carbon monoxide for 0.5-8 hours. Typically, the compound of Formula (I) is treated with carbon monoxide for 2-8 hours. More typically, the compound of Formula (I) is treated with carbon monoxide, then the reaction mixture is filtered and washed with solvent. Typically, the reaction mixture is washed with tetra hydrofuran. In one embodiment of the first, second or third aspect, the process is performed in the presence of a catalyst. Typically, the catalyst is a palladium catalyst such as Pd ( 11 ) acetate or (1 ,3-bis(diphenylphosphino)propane)palladium(ll) chloride (also known as Pd (I I )Cl?(dppp) ) . Typically, the catalyst is Pd (I I) acetate. Typically, the process is performed in the presence of O.OO5-O.O5 equivalent of a catalyst, or 0.005-0.02 equivalent, or 0.009-0.011 equivalent, or about 0.01 equivalent. More typically, the process is performed in the presence of O.OO5-O.O5 equivalent of Pd(ll) acetate catalyst, or 0.005- 0.02 equivalent, or 0.009-0.011 equivalent, or about 0.01 equivalent.

[0038] In one embodiment of the first, second or third aspect, the process is performed in the presence of a catalyst and a ligand. Typically, the catalyst is Pd (I I ) acetate and the ligand is 1 ,3-bis(diphenylphosphino)propane (dppp).

[0039] In one embodiment of the first, second or third aspect, the process is performed at a pressure of 125-350 kilopascals (kPa), or 275-345 kilopascal, or about 310 kilopascal.

[0040] In one embodiment of the first, second or third aspect, the process is performed at a pressure of 2-8 megapascals (MPa), or 4-6 MPa.

[0041] In one embodiment of the first, second or third aspect, the process is performed at a temperature of 90-110 °C. Typically, the process is performed at a temperature of 95-105 °C. Typically, the process is performed at a temperature of 95-105 °C for 2-8 hours. More typically, the process is performed at a temperature of 95-105 °C followed by cooling to 15-25 °C.

[0042] In one embodiment of the first, second or third aspect, the process is performed at a temperature of 90-200 °C. Typically, the process is performed at a temperature of 110-190 °C. Typically, the process is performed at a temperature of 120-180 °C.

[0043] In one embodiment of the first, second or third aspect, the process comprises a first step treatment with carbon monoxide, followed by a second step treatment with an amide coupling agent. Typically, the process comprises a first step treatment with carbon monoxide, then the reaction mixture is filtered, followed by a second step treatment with the amide coupling agent. Typically, the amide coupling reagent is (1 -cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU). Typically, the second step treatment is performed in the presence of 0.1 -1 .2 equivalent of COMU, or 0.1 -1 equivalent or 0.2-0.7 equivalent. Typically, the second step treatment is performed in the presence of COMU at 45-55 °C for 6-10 hours. Typically, the process is performed in the presence of COMU, then the reaction mixture is filtered and washed with solvent. Typically, the reaction mixture is washed with acetonitrile.

[0044] Without wishing to be bound by theory, it is believed that amide coupling agents such as COMU assist conversion of the ring opened impurity (IV) into the cyclised product compound of Formula (II). Therefore, such treatment increases the yield and purity of the compound of Formula (II) obtained.

[0045] In one embodiment of the first, second or third aspect, the process comprises treatment with sodium bicarbonate. Typically, the process comprises treatment with aqueous sodium bicarbonate.

[0046] The processes described herein may typically be performed in a reactor. The nature of the reactor used in the present processes are not particularly limited, and can be of essentially any feasible shape or size, and made of any suitable material. A reactor may be operated in a batch set-up, i.e. a reactor in which starting material, reagent(s) and solvent(s) are added at a time point, and the reaction is allowed to proceed to completion. Alternatively, a reactor may be operated in a continuous (flow) set-up, i.e. a reactor in which starting material, reagent(s) and solvent(s) are added either continuously or periodically over time, and product is continuously or periodically removed from the reactor as it is produced.

[0047] A continuous reactor for a continuous set-up typically comprises one or more inlets for starting material, one or more inlets for CO gas, one or more inlets for other reagent(s), one or more inlets for solvent(s) and / or one or more outlets for product. Further equipment such a pressure controls, temperature controls, mixing apparatus, flow controls, etc may be incorporated.

[0048] In one embodiment of the first, second or third aspect, the process is performed in a batch set-up. In one embodiment of the first, second or third aspect, the process is performed in a continuous set-up. Such a process may be particularly suitable for large scale manufacture. Typically, the base or base system are in the liquid state.

[0049] In one embodiment of the first, second or third aspect, the process is performed in a continuous set-up and at a pressure of 2-8 megapascals (MPa), or 4-6 MPa.

[0050] In one embodiment of the first, second or third aspect, the process is performed in a continuous set-up and at a temperature of 90-200 °C. Typically, the process is performed at a temperature of 110-190 °C. Typically, the process is performed at a temperature of 120-180 °C.

[0051] In one embodiment of the second aspect, the process is performed in a continuous set-up in the presence of phenol and 1 ,2,2,6,6-pentamethylpiperidine. Typically, the phenol and 1 ,2,2,6,6-pentamethylpiperidine are in liquid state.

[0052] In one embodiment of the first, second or third aspect, the compound of Formula (II) is isolated by filtration. Typically, the compound of Formula (II) is isolated by filtration and washed with solvent such as water. Typically, the compound of Formula (II) is isolated by filtration, washed with solvent such as water and dried.

[0053] In one embodiment of the first, second or third aspect, the process is performed without the use of column chromatography.

[0054] The processes described herein provide the compound of Formula (II) in sufficiently high purity without the need for column chromatography to purify the product. Given that column chromatography cannot be practically used for industrial processing the present processes allow for a highly purified product to be produced on a large scale using industrially applicable methods.

[0055] In one embodiment of the first, second or third aspect, the process is performed on an industrial scale. Typically, the process is performed providing batches of the compound of Formula (II) of about 1 Kg or more, 10 Kg or more, 20 Kg or more, or 50 Kg or more. Compared to similar prior art processes, the processes described herein have a reproducibly high yield, are conducted using mild non-toxic solvent to provide product with excellent HPLC purity and therefore are suitable for large scale manufacture.

[0056] Therefore, the first, second or third aspects described herein also provide the compound of Formula (II) obtained or obtainable by a process provided herein.

[0057] In one embodiment of the first, second or third aspect, the compound of Formula (II) obtained has a HPLC purity of 98% or more, 98.5% or more, 99% or more, 99.5% or more, 99.8% or more or 99.9% or more.

[0058] In one embodiment of the first, second or third aspect, the compound of Formula (II) obtained comprises 2% or less of the impurity of Formula (IV), or 1% or less, or 0.5% or less, or 0.1% or less as measured by HPLC.

[0059] In one embodiment of the first, second or third aspect, the compound of Formula (II) is obtained from the compound of Formula (I) in a molar yield of 60% or more, or 70% or more or 75% or more.

[0060] A fourth aspect provides the compound of Formula (II) with a HPLC purity of 98% or more. Typically, with a HPLC purity of 98.5% or more, 99% or more, 99.5% or more, 99.8% or more. More typically, with a HPLC purity or 99.9% or more.

[0061] In one embodiment of the fourth aspect, the compound of Formula (II) comprises 2% or less of the impurity of Formula (IV), or 1% or less, or 0.5% or less, or 0.1% or less as measured by HPLC.

[0062] A fifth aspect provides a process of preparing a compound of Formula (III), which comprises a process of according to the first, second or third aspect. A process for converting the compound of Formula (II) to the compound of Formula (III) is described in WO 2018 / 197503 (e.g. example 6).

[0063] For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the processes herein described may occur in combination with any other embodiment of the same aspect. In addition, insofar as is practicable it is to be understood that any typical or optional embodiment of any aspect of the processes herein described should also be considered as a typical or optional embodiment of any other aspect.

[0064] EXAMPLES

[0065] Having been generally described herein, the following non-limiting examples are provided to further illustrate the disclosure.

[0066] Analytical method

[0067] Identification, assay and impurity determination (by HPLC) was performed for the examples using the following method:

[0068] Example 1 : Comparison of the stability of the compound of Formula (I) in several solvents

[0069] Example 1a:

[0070] Stability of the starting material compound of Formula (I) was compared in several solvents using the following conditions:

[0071] 10 volumes of solvent for 24 hours at 100 °C (80 °C for acetonitrile due to boiling point (b.p.) of 81.6 °C);

[0072] Stability assessed by assay wt%.

[0073] The results of example 1a show that the starting material had the best stability when using acetonitrile as the solvent, at the temperatures tested. Example 1b:

[0074] Stability of the starting material of formula (I) was compared in acetonitrile and in toluene, at 80° C, after 24 and 48 hours (conditions: 10 volumes of solvents at 80° C; stress test followed by HPLC purity):

[0075] The results of example 1b show that the starting material demonstrates similar stability in acetonitrile and in toluene at 80° C.

[0076] Example 2: Solvent comparison for the conversion of the compound of Formula (I) to the compound of Formula (II)

[0077] Several solvents were tested using the following conditions: The compound of Formula (I) (300 mg), Pd(dppp) (0.05 eq), PhONa (2.0 eq); 1 .2 x SM 4A sieves; Solvent (13 V); CO 40 psi (276 kPa); 100 °C (80 °C for acetonitrile due to b.p. of 81.6 °C); 16 hours; 250 rpm. Equipment - Endeavor catalyst screening equipment.

[0078] The results of example 2 show that use of acetonitrile as a solvent in the process provides the highest proportion of the desired product of Formula (II). Acetonitrile also provides a low proportion of the ring opened impurity of Formula (IV) and the lowest combined amount of the remaining starting material and impurity of Formula (IV) (2.8 %area).

[0079] Example 3: Base comparison for the conversion of the compound of Formula (I) to the compound of Formula (II) Several bases were tested using the following conditions:

[0080] The compound of Formula (I) (300 mg); Pd(ll) acetate (Pd(OAc)?) (0.05 eq); dppp (0.05 eq); Toluene 13 V; CO 20 psi (138 kPa); 100°C; 16 hours. Unless otherwise stated, for the organic bases, which are liquids miscible with the solvent, a slight excess of 1 .2 eq was used. For the other bases which are mineral bases and are crystalline solids with low or no solubility in the organic medium, a larger excess of 2 eq was used to improve the phase transfer (availability of the base). The results of example 3 show that use of PhONa as a base in the process provides the highest proportion of the desired product of Formula (II) and a low proportion of remaining starting material and ring opened impurity of Formula (IV).

[0081] Example 4: Large scale conversion of the compound of Formula (I) to the compound of Formula (II)

[0082] Under nitrogen protection, acetonitrile (12.4-13.7 vol), the compound of Formula (I) (73.2 Kg; 1 eq), sodium phenoxide (1.29-1.44 eq), bis diphenylphosphino propane (0.018- 0.021 eq) and palladium (II) acetate (0.009-0.011 eq) were charged in a high-pressure reactor.

[0083] The reactor was degassed by 3 successive vacuum / nitrogen cycles and then pressure was adjusted with carbon monoxide to 310 kPa (275-345 kPa). After heating at 100 °C (95- 105 °C) during 2-8 hours, the mixture was cooled at 20 °C (15-25 °C). The reactor was swapped 3 times with nitrogen, tetra hydrofuran (9-11.2 vol) was added and the mixture was stirred for 2 hours (1 -3 hours) at 20 °C (15-25 °C).

[0084] After filtration on diatomite, the cake was washed with tetra hydrofuran (1 .1 -2.2 vol). The combined mother liquors were concentrated below 50° C under vacuum to 3-6 vol.

[0085] Acetonitrile (4.8-5.3 vol) was added, and the solution was concentrated below 50 °C under vacuum to 3-6 vol. The operation was repeated once, and the concentration was stopped at 5-8 vol.

[0086] (1 -cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino carbeniumhexafluorophospate (COMU; 0.2-0.7 eq) was added and the mixture was stirred at 20 °C (15-25 °C) during 0.5-1 hours and finally heated to 50 °C (45-5 5°C) during 6-10 hours. The mixture was cooled at 0 °C (-5 °C / 5 °C) and stirred for 2 hours.

[0087] After filtration, the cake was washed with acetonitrile (0.9-1 .9 vol) and then stirred in a 4% aqueous solution of carbonate sodium (7-11 vol) for 10 hours (7-15 hours) at 20 °C (15- 25 °C). The suspension was filtered, and the cake was washed with water (1 -2 vol). The wet cake was dried at 40-50 °C under vacuo for 18-24 hours to yield 49.9 Kg of the compound of Formula (II) (78% yield; 99.9% HPLC Purity).

[0088] Example 5: Large scale conversion of the compound of Formula (I) to the compound of Formula (II) in a continuous mode

[0089] Under nitrogen protection, in first feed vessel, nitrogen degassed acetonitrile (5.0-15.0 vol), the compound of Formula (I) (2000 g, assay 92.4 w / w%) and phenol (2 eq) were mixed until complete dissolution. In a second feed vessel, PMP (1.2-1.8 eq) and bis diphenylphosphino propane (0.03 eq) were mixed until complete dissolution. In a third feed vessel, nitrogen degassed acetonitrile (4.0-8.0 vol) and palladium (II) acetate (0.01 - 0.05 eq) were mixed until complete dissolution.

[0090] The continuous reactor installation was purged with nitrogen, followed by pure acetonitrile. The reactor installation was pressurized to 4-6 MPa. Once the system pressure reached the set point, the heat transfer fluid was set to heat the reactor to 120-180 °C.

[0091] The three feed s solutions were then introduced at the adjusted flowrate to reach a 73 min residence time and equivalence ratio for compound of formula (l) / PMP / Pd(OAc)2 of

[0092] 1 / 1 .5 / 0.02. In the current example, in a 1640 mL tubular reactor, the flow rates for feed vessel 1 / feed vessel 2, feed vessel 3 were 11.38 mL / min, 5.85 mL / min, 5.23 mL / min respectively. The CO gas was then introduced at 3.5-7.0 eq (260 mL / min).

[0093] The effluent of the continuous reactor was diluted continuously with THF (total 5 vol) and collected between 1 .5 and 27.5 h run time. After filtration on diatomite, and wash of the cake with tetra hydrofuran (10 vol), the combined effluents were concentrated below 50°C under vacuum to 3-6 vol. Acetonitrile (4 vol) was added, and the solution was concentrated below 50 °C under vacuum to 3-6 vol. The operation was repeated once, and the concentration was stopped at 5-8 vol.

[0094] The resulting solution was stirred for 2 hours at 50 °C, cooled at 0°C and stirred for 2 hours at 0 °C. The suspension was filtered, and the cake was washed with cold acetonitrile (1 -2 vol). The wet cake was dried at 40-60 °C under vacuo for 36-48 hours to yield 1 .2 Kg of the compound of Formula (II) (69% yield; 99.6% HPLC Purity, enantiomeric excess 100%).

[0095] Aspects

[0096] The following represent aspects of the invention:

[0097] 1 . A process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II): in the presence of a solvent comprising acetonitrile, toluene or a mixture thereof.

[0098] 2. The process of aspect 1 , wherein the process is performed in the presence of sodium phenoxide.

[0099] 3. A process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II): in the presence of sodium phenoxide.

[0100] 4. The process of aspect 2 or aspect 3, wherein the process is performed in the presence of 1 -5 equivalent of sodium phenoxide. 5. The process of any preceding aspect, wherein the compound of Formula (I) is treated with carbon monoxide.

[0101] 6. The process of aspect 5, wherein the compound of Formula (I) is treated with carbon monoxide for 2-8 hours.

[0102] 7. The process of any preceding aspect, wherein the process is performed in the presence of a Pd(ll) acetate catalyst.

[0103] 8. The process of aspect 7, comprising O.OO5-O.O5 equivalent of Pd(ll) acetate catalyst.

[0104] 9. The process of aspect 7 or aspect 8, wherein the process is performed in the presence of the ligand 1 ,3-bis(diphenylphosphino)propane.

[0105] 10. The process of any one of aspects 5-9, comprising a first step treatment with carbon monoxide, and followed by a second step treatment with an amide coupling agent.

[0106] 11 . The process of aspect 10, wherein the amide coupling agent is COMU.

[0107] 12. The process of aspect 11 , comprising 0.1 -1 .2 equivalent of COMU.

[0108] 13. A compound of Formula (II) obtainable or obtained by a process of any one of aspects 1 -12.

[0109] 14. A compound of Formula (II) having a HPLC purity of 98% or more, 98.5% or more, 99% or more, 99.5% or more, 99.8% or more or 99.9% or more.

[0110] 15. A process of preparing a compound of Formula (III): which comprises a process of any one of aspects 1 -12.

Claims

CLAIMS1 . A process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II):in the presence of a solvent comprising acetonitrile, toluene or a mixture thereof.

2. The process of claim 1 , wherein the process is performed in the presence of phenoxide ions.

3. The process of claim 2, wherein the process is performed in the presence of phenol and 1 ,2,2,6,6-pentamethylpiperidine.

4. The process of claim 2, wherein the process is performed in the presence of sodium phenoxide.

5. A process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II):in the presence of phenol and 1 ,2,2,6,6-pentamethylpiperidine.

6. A process of preparing a compound of Formula (II), comprising converting a compound of Formula (I) to the compound of Formula (II):in the presence of sodium phenoxide.

7. The process of claim 4 or claim 6, wherein the process is performed in the presence of 1 -5 equivalent of sodium phenoxide.

8. The process of any preceding claim, wherein the compound of Formula (I) is treated with carbon monoxide.

9. The process of claim 8, wherein the compound of Formula (I) is treated with carbon monoxide for 2-8 hours.

10. The process of any preceding claim, wherein the process is performed in the presence of a Pd(ll) acetate catalyst.11 . The process of claim 10, comprising O.OO5-O.O5 equivalent of Pd(ll) acetate catalyst.

12. The process of claim 10 or claim 11 , wherein the process is performed in the presence of the ligand 1 ,3-bis(diphenylphosphino)propane.

13. The process of any one of claims 8-12, comprising a first step treatment with carbon monoxide, and followed by a second step treatment with an amide coupling agent.

14. The process of claim 13, wherein the amide coupling agent is COMU.

15. The process of claim 14, comprising 0.1 -1.2 equivalent of COMU.

16. The process of any preceding claim, wherein the process is performed in a continuous set-up.

17. A compound of Formula (II) obtainable or obtained by a process of any one of claims 1 -16.

18. A compound of Formula (II) having a HPLC purity of 98% or more, 98.5% or more, 99% or more, 99.5% or more, 99.8% or more or 99.9% or more.

19. A process of preparing a compound of Formula (III):which comprises a process of any one of claims 1 -16.

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