Processes for the preparation of fused pentacyclic imidazoles and intermediates

Abstract

Herein are provided processes of converting a compound of Formula (I) into a compound of Formula (IV). Also provided are processes of preparing the compound of Formula (I), processes of converting the compound of Formula (IV), together with associated intermediate compounds and crystalline forms.

Description

[0001] PROCESSES FOR THE PREPARATION OF FUSED PENTACYCLIC IMIDAZOLES AND

[0002] INTERMEDIATES

[0003] FIELD

[0004] Herein are provided processes of converting a compound of Formula (I) into a compound of Formula (IV).

[0005] Also provided are processes of preparing the compound of Formula (I), processes of converting the compound of Formula (IV), together with associated intermediate compounds and crystalline forms.

[0006] BACKGROUND

[0007] Described herein are processes of preparing a compound of Formula (I) and converting it into a compound of Formula (IV), after which the compound of Formula (IV) can be deprotected at the amino group to provide the compound of Formula (V):

[0008] The compound of Formula (V) 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. The compound of Formula (V) is a pharmacologically active substituted fused pentacyclic benzimidazole derivative which shows pharmacological activity on TNFo signalling and is described in WO 2018 / 197503 as example 6.

[0009] The compounds of Formula (III) and (IVa) herein are intermediates in the preparation of the compound of Formula (V) and are described as intermediates 3 and 17 respectively in WO 2018 / 197503.

[0010] There is a desire to provide processes of preparing the compound of Formula (V) and its intermediates which are suitable for large-scale manufacturing, such as an industrial scale.

[0011] SUMMARY

[0012] A first aspect provides a process of preparing a compound of Formula (IV): wherein R1is an amine protecting group, comprising the steps of:

[0013] (a) converting a compound of Formula (I) to a compound of Formula (II):

[0014] followed by:

[0015] (b) contacting the compound of Formula (II) with a compound of Formula (III) to obtain the compound of Formula (IV):

[0016] A second aspect provides a process of preparing a compound of Formula (I) comprising converting a compound of Formula (VI) to the compound of Formula (I): wherein R1is an amine protecting group.

[0017] A third aspect provides a process of preparing a compound of Formula (V): comprising preparing a compound of Formula (IV) according to a process of the first aspect, followed by a process of deprotection of the amine group of the compound of Formula (IV) to obtain the compound of Formula (V).

[0018] A fourth aspect provides a crystalline form of a compound of Formula (IVa): wherein the crystalline form is of Form 2 having an X-ray powder diffraction pattern comprising characteristic peaks at 7.6° ±0.2° 20, 10.0° ±0.2° 20, and 17.3° ±0.2° 20.

[0019] A fifth aspect provides a process of preparing the crystalline Form 2 of the compound of Formula (IVa) as defined in the fourth aspect, comprising:

[0020] (a) contacting a compound of Formula (IVa) with a solvent comprising 2- methyltetra hydrofuran; and

[0021] (b) obtaining the crystalline Form 2 of the compound of Formula (IVa).

[0022] A sixth aspect provides a compound of Formula (la):

[0023] BRIEF DESCRIPTION OF THE FIGURES

[0024] Figure 1 shows an X-ray powder diffraction pattern of crystalline Form 2 of the compound of Formula (IVa).

[0025] Figure 2 show a differential scanning calorimetry (DSC) plot of crystalline Form 2 of the compound of Formula (IVa). Figure 3 shows an X-ray powder diffraction pattern of crystalline Form 1 of the compound of Formula (la).

[0026] Figure 4 show a differential scanning calorimetry (DSC) plot of crystalline Form 1 of the compound of Formula (la).

[0027] DETAILED DESCRIPTION

[0028] A first aspect provides a process of preparing a compound of Formula (IV): wherein R1is an amine protecting group, comprising the steps of:

[0029] (a) converting a compound of Formula (I) to a compound of Formula (II): followed by:

[0030] (b) contacting the compound of Formula (II) with a compound of Formula (III) to obtain the compound of Formula (IV):

[0031] In one embodiment of the first aspect, the process of step (a) is performed in the presence of a solvent comprising 2 -methyltetra hydrofuran (2-MeTHF). Typically, the solvent comprises a mixture of 2-MeTHF and water.

[0032] In one embodiment of the first aspect, the process of step (b) is performed in the presence of a solvent comprising 2-MeTHF. Typically, the solvent comprises a mixture of 2-MeTHF and water.

[0033] In one embodiment of the first aspect, the process of step (a) and step (b) are performed in the presence of a solvent comprising 2-MeTHF. Typically, the solvent comprises a mixture of 2-MeTHF and water.

[0034] Solvents typically constitute a large percentage of the mass of materials used to prepare active pharmaceutical ingredients and therefore there is a need for the use of more environmentally sustainable solvents. 2 -Methyltetra hydrofuran is reported as a green solvent (see for example the Sigma Aldrich Greener Solvent Alternatives Guide 2015).

[0035] In one embodiment of the first aspect, the process of step (a) is performed in the presence of 6-20 volumes of 2-MeTHF. Typically, the process of step (a) is performed in the presence of 8-12 volumes of 2-MeTHF. Typically, a further 3-10 volumes of 2-MeTHF are added in the process of step (b).

[0036] Unless stated otherwise, in relation to the first aspect, volume (vol) is the amount of solvent in mL per gram of starting compound of Formula (I).

[0037] In one embodiment of the first aspect, at least 50% of the total solvent volume in the process comprises 2-MeTHF (v / v). Typically, at least 60% of the total solvent volume in the process comprises 2-MeTHF (v / v), or 70% or 80%. More typically, at least 90% of the total solvent volume in the process comprises 2-MeTHF (v / v). Most typically, at least 95% of the total solvent volume in the process comprises 2-MeTHF (v / v), or 98% or 99%.

[0038] In one embodiment of the first aspect, the process of step (a) is performed in the presence of 0.02-0.05 volumes of water.

[0039] In one embodiment of the first aspect, in step (a) 0.1 -0.3% of the total solvent volume in the process comprises water (v / v). Typically, in step (a) about 0.2% of the total solvent volume in the process comprises water (v / v).

[0040] In one embodiment of the first aspect, the reaction mixture in step (b) is biphasic.

[0041] In one embodiment of the first aspect, in step (b) 25-40% of the total solvent volume in the process comprises water (v / v). Typically, in step (b) 30-35% of the total solvent volume in the process comprises water (v / v).

[0042] In one embodiment of the first aspect, the process of step (a) is performed in the presence of a catalyst such as a Pd(ll) catalyst. Typically, the process of step (a) is performed in the presence of chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'-biphenyl)[2-(2'-amino- 1 ,1'-biphenyl)]palladium(ll) catalyst (also known as XPhosPdG2).

[0043] In one embodiment of the first aspect, the process of step (b) is performed in the presence of a catalyst such as a Pd(ll) catalyst. Typically, the process of step (b) is performed in the presence of XPhosPdG2 catalyst.

[0044] In one embodiment of the first aspect, the process of step (a) and step (b) are performed in the presence of the same catalyst such as a Pd(ll) catalyst. Typically, the process of step (a) and step (b) are performed in the presence of XPhosPdG2 catalyst.

[0045] In one embodiment of the first aspect, the process comprises the addition of 0.001 -0.03 equivalent of the catalyst in step (a). Typically, 0.001 -0.01 equivalent, 0.001 -0.008 equivalent, or 0.001 -0.005 equivalent. More typically, 0.003-0.005 equivalent. Unless stated otherwise, all equivalents (eq) in the first aspect are molar equivalents relative to the amount of the starting material compound of Formula (I).

[0046] In one embodiment of the first aspect, the process comprises the addition of 0.001 -0.03 equivalent of the catalyst in step (b). Typically, 0.001 -0.01 equivalent, 0.001 -0.008 equivalent, or 0.001 -0.005 equivalent.

[0047] In one embodiment of the first aspect, the process comprises the addition of 0.001 -0.03 equivalent of the catalyst in step (a) and the addition of 0.001 -0.03 equivalent of the catalyst in step (b). Typically, in each step independently, 0.001 -0.01 equivalent, 0.001 - 0.008 equivalent, or 0.001 -0.005 equivalent.

[0048] Compared to similar prior art processes, the processes described herein may be performed with a lower equivalent of catalyst. This may provide advantages in relation to cost efficiency and purification particularly on an industrial scale.

[0049] Compared to similar prior art processes, the processes described herein may be performed with step (a) and step (b) using some of the same reaction conditions (e.g. solvent and / or catalyst) for both steps. This may provide advantages in relation to cost efficiency and purification particularly on an industrial scale.

[0050] In one embodiment of the first aspect, the process of step (a) is performed in the presence of a base. Typically, the process of step (a) is performed in the presence of potassium acetate. More typically, the process of step (a) is performed in the presence of 1 -2 equivalent of potassium acetate.

[0051] In one embodiment of the first aspect, the process of step (b) is performed in the presence of a base. Typically, the process of step (b) is performed in the presence of potassium phosphate. More typically, the process of step (b) is performed in the presence of 1 -2 equivalent of potassium phosphate.

[0052] In one embodiment of the first aspect, the process of step (a) is performed at a temperature of 60-85 °C. Typically, the process is performed at a temperature of 70-83 °C. In one embodiment of the first aspect, the process of step (b) is performed at a temperature of 30-75 °C. Typically, the process is performed at a temperature of 60-75 °C.

[0053] In one embodiment of the first aspect, the process of step (a) is performed for a period of 10 minutes to 10 hours. Typically, the process is performed for a period of 20 minutes to 2 hours.

[0054] In one embodiment of the first aspect, the process of step (b) is performed for a period of 10 minutes to 10 hours. Typically, the process is performed for a period of 20 minutes to 2 hours.

[0055] In one embodiment of the first aspect, the compound of Formula (II) is not isolated between step (a) and step (b).

[0056] In one embodiment of the first aspect, the process of step (a) is performed in the presence of a borylation reagent. Typically, the process of step (a) is performed in the presence bis(pinacolato)diboron.

[0057] In one embodiment of the first aspect, the R1amine protecting group is an ester.

[0058] Typically, R1is tert- butyloxycarbonyl (Boc) or carboxybenzyl (Cbz). More typically, R1is tert- butyloxycarbonyl (Boc).

[0059] In one embodiment of the first aspect, the compound of Formula (I) is prepared by the process of the second aspect.

[0060] In one embodiment of the first aspect, the compound of Formula (IV) obtained is washed with ethylene diamine. Typically, the compound of Formula (IV) obtained is washed with ethylene diamine and water. Typically, the compound of Formula (IV) obtained is washed 1 -5 times, more typically 2-4 times.

[0061] Without wishing to be bound by theory it is believed that washing with ethylene diamine removes residual palladium hence increasing the purity of the compound of Formula (IV). In one embodiment of the first aspect, the process is performed without the use of column chromatography.

[0062] The processes described herein provide the compound of Formula (IV) 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.

[0063] In one embodiment of the first aspect, the process is performed on an industrial scale. Typically, the process is performed providing batches of the compound of Formula (IV) of about 1 Kg or more, 10 Kg or more, 20 Kg or more, or 50 Kg or more, or 100 Kg or more, or 1000 Kg or more.

[0064] 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.

[0065] Therefore, the first aspect described herein also provide the compound of Formula (IV) obtained or obtainable by a process provided herein. Typically, the compound of Formula (IV) is the compound of Formula (IVa).

[0066] In one embodiment of the first aspect, the compound of Formula (IV) 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, or 99.99% or more, or about 100%.

[0067] In one embodiment of the first aspect, the compound of Formula (IV) is obtained from the compound of Formula (I) in a molar yield of 90% or more, or 93% or more.

[0068] In one embodiment of the first aspect, the compound of Formula (IV) is a compound of Formula (IVa):

[0069] Typically, the compound of Formula (IVa) is obtained as a crystalline Form 2 as defined according to the fourth aspect. Typically, the compound of Formula (IVa) obtained from step (b) is then crystallised by a further process step according to the fifth aspect.

[0070] A second aspect provides a process of preparing a compound of Formula (I) comprising converting a compound of Formula (VI) to the compound of Formula (I): wherein R1is an amine protecting group.

[0071] In one embodiment of the second aspect, the R1amine protecting group is an ester. Typically, R1is tert- butyloxycarbonyl (Boc) or carboxybenzyl (Cbz). More typically, R1is tert- butyloxycarbonyl (Boc). Typically, R1is the same in the first and second aspect.

[0072] In one embodiment of the second aspect, the process is performed in the presence of a vinamidinium salt. Typically, the process is performed in the presence of a salt of N-(2- chloro-3-(dimethylamino)allylidene)-N-methylmethanaminium; N-(2-chloro-3- (diethylamino)allylidene)-N-methylmethanaminium; or pyrrolidinium, 1 -[2-chloro-3-(1 - pyrrolidinyl)-2-propen-1 -ylidene]-. For example, a salt may be selected from the group consisting of Cl', I', Br', PF&', and CIOT. Most typically, the process is performed in the presence of N-(2-chloro-3-(dimethylamino)allylidene)-N-methylmethanaminium hexafluorophosphate(V); N-(2-chloro-3-(diethylamino)allylidene)-N-methylmethanaminium hexafluorophosphate(V); or pyrrolidinium, 1 -[2-chloro-3-(1 -pyrrolidinyl)-2-propen-1 - ylidene]-, hexafluorophosphate. Most typically, the process is performed in the presence of N-(2-chloro-3-(dimethylamino)allylidene)-N-methylmethanaminium hexafluorophosphate(V) .

[0073] In one embodiment of the second aspect, the process is performed in the presence of an amine base, typically diisopropylethylamine or triethylamine.

[0074] In one embodiment of the second aspect, the process is performed in the absence of diisopropylethylamine or triethylamine, typically in the absence of any amine base.

[0075] In one embodiment of the second aspect, the process is performed in the presence of a solvent comprising acetonitrile.

[0076] In one embodiment of the second aspect, the process comprises converting a compound of Formula (VI) to the compound of Formula (I) is performed at a temperature in the range of 50-90 °C, more, typically 55-85 °C.

[0077] In one embodiment of the second aspect, the process further comprises preparing a compound of formula (VI), wherein the compound of formula (VI) is prepared by converting a compound of Formula (VII) to the compound of Formula (VI):

[0078] (VII) (VI)

[0079] Typically, the process of preparing the compound of Formula (VI) is performed in the presence of Pd / C catalyst and hydrogen. Typically, the process of preparing the compound of Formula (VI) is performed in the presence of a solvent comprising methanol.

[0080] Typically, the process of preparing the compound of Formula (VI) is performed at a temperature of 20-40 °C.

[0081] In one embodiment of the second aspect, the process further comprises preparing a compound of Formula (VII), wherein the compound of Formula (VII) is prepared by converting a compound of Formula (VIII) to the compound of Formula (VII):

[0082] (VIII) (VII)

[0083] Typically, the process of preparing the compound of Formula (VII) is performed in the presence of hydroxylamine or a salt thereof such as hydroxylamine hydrochloride.

[0084] Typically, the process of preparing the compound of Formula (VII) is performed in the presence of a solvent comprising isopropanol.

[0085] Typically, the process of preparing the compound of Formula (VII) is performed at a temperature of 30-50 °C.

[0086] In one embodiment of the second aspect, the process further comprises preparing a compound of Formula (VIII), wherein the compound of Formula (VIII) is prepared by converting a compound of Formula (IX) to the compound of Formula (VIII): N ,H2 NHR1

[0087] “"CN - >- '-'CN

[0088] (IX) (VIII)

[0089] Typically, R1is tert- butyloxycarbonyl (Boc) and the process of preparing the compound of Formula (VIII) is performed in the presence of di-tert-butyl dicarbonate. Typically, the process of preparing the compound of Formula (VIII) is performed in the presence of a solvent comprising 2-MeTHF.

[0090] Typically, the process of preparing the compound of Formula (VIII) is performed at a temperature of 20-40 °C.

[0091] In one embodiment of the second aspect, the process further comprises preparing a compound of Formula (IX), wherein the compound of Formula (IX) is prepared by converting a compound of Formula (X) to the compound of Formula (IX):

[0092] (X) (IX) Typically, the process of preparing the compound of Formula (IX) is performed in the presence of sodium cyanide. Typically, the process of preparing the compound of Formula (IX) is performed in the presence of a solvent comprising aqueous ammonia.

[0093] Typically, the process of preparing the compound of Formula (IX) is performed at a temperature of 15-35 °C, more typically 20-30 °C.

[0094] In one embodiment of the second aspect, the process comprises one or more precursor step of:

[0095] (i) converting the compound of Formula (X) to the compound of Formula (IX);

[0096] (ii) converting the compound of Formula (IX) to the compound of Formula (VIII);

[0097] (iii) converting the compound of Formula (VIII) to the compound of Formula (VII); and / or

[0098] (iv) converting the compound of Formula (VII) to the compound of Formula (VI); followed by the step of converting the compound of Formula (VI) to the compound of Formula (I). Typically, the process comprises steps (i), (ii), (iii) and (iv).

[0099] In one embodiment of the second aspect, the process of converting a compound of Formula (VI) to the compound of Formula (I) and precursor steps (i), (ii), (iii) and (iv) are all performed at a temperature of 15-90 °C, more typically at a temperature of 20-85 °C.

[0100] In one embodiment of the second aspect, the process of converting a compound of Formula (VI) to the compound of Formula (I) and precursor steps (i), (ii), (iii) and (iv) are all performed at a temperature above -50 °C, more typically above 0 °C. Hence, typically none of the steps require refrigerated conditions, let alone cryogenic conditions.

[0101] WO 2018 / 197503 describes an intermediate 16 which is the bromo analog of the compound of Formula (I) as described herein. WO 2017 / 167995 also describes the same bromo analog which is referred to therein as intermediate 39.

[0102] WO 2018 / 197503 intermediate 16 is prepared from cyclobutanone (via intermediates 13, 14 and 15) and the described preparation of intermediate 14 uses a reaction temperature of -70 °C. WO 2017 / 167995 intermediate 39 is prepared from cyclobutanone (via intermediates 36, 37 and 38) and the described preparation of intermediate 37 uses a reaction temperature of -78 °C. Advantageously, the process described in the present application may provide the compound of Formula (I) from the compound of Formula (X) (cyclobutanone) without the use of such cold conditions. This may provide advantages in relation to cost efficiency and manufacturability particularly on an industrial scale.

[0103] In one embodiment of the second aspect, the process of converting a compound of Formula

[0104] (VI) to the compound of Formula (I) and precursor steps (i), (ii), (iii) and (iv) are all performed in the absence of chlorinated solvents. Typically, in the presence of a solvent comprising acetonitrile, methanol, isopropanol, 2-MeTHF, aqueous ammonia or a mixture thereof.

[0105] Solvents constitute a large percentage of the mass of materials used to prepare active pharmaceutical ingredients and therefore there is a need for the use more environmentally sustainable solvents, in particular unchlorinated solvents, because chlorinated solvents pose environmental and health concerns.

[0106] WO 2018 / 197503 intermediate 16 is prepared from cyclobutanone (via intermediates 13, 14 and 15) and the described preparation of intermediate 14 uses dichloromethane solvent. WO 2017 / 167995 intermediate 39 is prepared from cyclobutanone (via intermediates 36, 37 and 38) and the described preparation of intermediate 37 uses dichloromethane solvent.

[0107] In one embodiment of the second aspect, the process of converting the compound of Formula (VI) to compound of Formula (I) is performed without the use of column chromatography. Typically, the processes to prepare the compounds of Formula (IX), (VIII),

[0108] (VII) and (VI) are also performed without the use of column chromatography. Typically, the process of converting a compound of Formula (VI) to the compound of Formula (I) and precursor steps (i), (ii), (iii) and (iv) are all performed without the use of column chromatography.

[0109] WO 2018 / 197503 intermediate 16 is prepared from cyclobutanone (via intermediates 13, 14 and 15) in a process comprising column chromatography. WO 2017 / 167995 intermediate 39 is prepared from cyclobutanone (via intermediates 36, 37 and 38) in a process comprising column chromatography. Advantageously, the process described in the present application may provide the compound of Formula (I) from the compound of Formula (X)(cyclobutanone) without the use of column chromatography.

[0110] In one embodiment of the second aspect, the process of converting the compound of Formula (VI) to compound of Formula (I) is performed on an industrial scale. Typically, the process is performed providing batches of the compound of Formula (I) of about 1 Kg or more, 10 Kg or more, 20 Kg or more, or 50 Kg or more, or 100 Kg or more, or 1000 Kg or more. Typically, the processes to prepare the compounds of Formula (IX), (VIII), (VII) and (VI) are also performed on an industrial scale.

[0111] The second aspect described herein also provides the compound of Formula (I) obtained or obtainable by a process provided herein. Typically, the compound of Formula (I) is the compound of Formula (la).

[0112] In one embodiment of the second aspect, the compound of Formula (I) 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, or 99.99% or more, or about 100%.

[0113] In one embodiment of the second aspect, the compound of Formula (I) is obtained from the compound of Formula (VI) in a molar yield of 80% or more, or 90% or more.

[0114] In one embodiment of the second aspect, the compound of Formula (I) is obtained from the compound of Formula (X) in a molar yield of 30% or more, or 40% or more, or 50% or more, or 60% or more.

[0115] WO 2018 / 197503 intermediate 16 is prepared from cyclobutanone (via intermediates 13, 14 and 15) in a yield of 20%. WO 2017 / 167995 intermediate 39 is prepared from cyclobutanone (via intermediate 36, 37 and 38) in a yield of 13%. Advantageously, the process described in the present application may provide the compound of Formula (I) from the compound of Formula (X) (cyclobutanone) in improved yield compared to the processes described in WO 2018 / 197503 and WO 2017 / 167995. This may provide advantages in relation to cost efficiency and manufacturability particularly on an industrial scale. A third aspect provides a process of preparing a compound of Formula (V): comprising preparing a compound of Formula (IV) according to a process of the first aspect, followed by a process of deprotection of the amine group of the compound of Formula (IV) to obtain the compound of Formula (V).

[0116] In one embodiment of the third aspect, the compound of Formula (IV) is the compound of Formula (IVa).

[0117] In one embodiment of the third aspect, the deprotection is performed in the presence of hydrochloric acid.

[0118] In one embodiment of the third aspect, the process is performed at a temperature of 60-90 °C.

[0119] In one embodiment of the third aspect, the deprotection is performed in the presence of a solvent comprising 2 -methyltetra hydrofuran. Typically, the process is performed in the presence of a solvent comprising a mixture of 2-MeTHF and water.

[0120] In one embodiment of the third aspect, the process is performed without the use of column chromatography.

[0121] In one embodiment of the third aspect, the compound of Formula (V) 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, or about 100%.

[0122] In one embodiment of the third aspect, the compound of Formula (V) is obtained from the compound of Formula (IV) in a molar yield of 90% or more, or 95% or more. In one embodiment of the third aspect, the process is performed on an industrial scale. Typically, the process is performed providing batches of the compound of Formula (V) of about 1 Kg or more, 10 Kg or more, 20 Kg or more, or 50 Kg or more, or 100 Kg or more, or 1000 Kg or more.

[0123] A fourth aspect provides a crystalline form of a compound of Formula (IVa): wherein the crystalline form is of Form 2 having an X-ray powder diffraction pattern comprising characteristic peaks at 7.6° ±0.2° 20, 10.0° ±0.2° 20, and 17.3° ±0.2° 20.

[0124] Another crystalline form of the compound of Formula (IVa) is described in WO 2025 / 068505 (that crystalline form is referred to in the present application as Form 1 ). Advantageously, Form 2 is more stable at room temperature than Form 1 . With its increased stability at room temperature, Form 2 is less soluble than Form 1 and, hence, after a crystallization process, Form 2 may be isolated in a higher yield than Form 1 .

[0125] As used herein X-ray powder diffraction patterns are typically those which can be obtained using CuKo radiation.

[0126] In one embodiment of the fourth aspect, the X-ray powder diffraction pattern further comprises a peak at 20.0° ±0.2° 20.

[0127] In one embodiment of the fourth aspect, the X-ray powder diffraction pattern further comprises a peak at 5.8° ±0.2° 20.

[0128] In one embodiment of the fourth aspect, the X-ray powder diffraction pattern further comprises a peak at 15.3° ±0.2° 20.

[0129] In one embodiment of the fourth aspect the comprises peaks at 5.8° ±0.2° 20, 7.6° ±0.2° 20, 10.0°±0.2° 20, 15.3° ±0.2° 20, 17.3°±0.2° 20 and 20.0°±0.2° 20. In one embodiment of the fourth aspect, the X-ray powder diffraction pattern may comprise peaks corresponding to 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 of the peaks listed in the table below ±0.2° 20:

[0130] In one embodiment of the fourth aspect, the X-ray powder diffraction pattern is substantially as illustrated in Figure 1 . In one embodiment of the fourth aspect, the crystalline form has a melting temperature of

[0131] 204° C ±2°C. Typically, melting temperatures are measured by DSC.

[0132] In one embodiment of the fourth aspect, the DSC is substantially as illustrated in Figure 2. In one embodiment of the fourth aspect, the crystalline form is an anhydrate. A fifth aspect provides a process of preparing the crystalline Form 2 of the compound of Formula (IVa) as defined in the fourth aspect, comprising:

[0133] (a) contacting a compound of Formula (IVa) with a solvent comprising 2- methyltetrahydrofuran; and

[0134] (b) obtaining the crystalline Form 2 of the compound of Formula (IVa).

[0135] In one embodiment of the fifth aspect, step (a) comprises contacting a compound of Formula (IVa) with a solvent comprising 2-methyltetrahydrofuran to form a solution.

[0136] In one embodiment of the fifth aspect, the compound of Formula (IVa) used in step (a) can be provided in any crystalline form.

[0137] In one embodiment of the fifth aspect, step (a) is carried out at a temperature in the range of 5-100 °C. Typically, step (a) is carried out at a temperature in the range of IQ- 40 °C.

[0138] In one embodiment of the fifth aspect, the step (b) comprises adding Form 2 seed crystals.

[0139] In one embodiment of the fifth aspect, in step (b) Form 2 may be obtained by addition of a suitable antisolvent. Typically, in step (b) Form 2 may be obtained by addition of a suitable antisolvent and Form 2 seed crystals. Typically, the antisolvent comprises cyclopentyl methyl ether, methylcyclohexane and mixtures thereof. Most typically, the antisolvent comprises methylcyclohexane. Typically, the volume ratio of solvent to antisolvent is from 10:1 to 1 :10, more typically from 5:1 to 1 :5, such as 1 :1 .

[0140] In one embodiment of the fifth aspect, step (b) is carried out at a temperature in the range of 10-40°C. Typically, step (b) is carried out at a temperature in the range of 20- 30 °C, such as about 25 °C.

[0141] A sixth aspect provides a compound of Formula (la):

[0142] In one embodiment of the sixth aspect, the compound of Formula (la) is provided in a crystalline form, Form 1 , having an X-ray powder diffraction pattern comprising characteristic peaks at 9.4°±0.2° 20, 12.8°±0.2° 20, and 22.2°±0.2° 20. Typically, the X- ray powder diffraction pattern further comprises a peak at 19.2 °±0.2° 20. Typically, the X-ray powder diffraction pattern further comprises a peak at 17.5 °±0.2° 20. Typically, the X-ray powder diffraction pattern further comprises a peak at 19.5 °±0.2° 20. In one embodiment of the sixth aspect, the compound of Formula (la) is provided in a crystalline form, Form 1 , having an X-ray powder diffraction pattern comprising characteristic peaks at 9.4° ±0.2° 20, 12.8°±0.2° 20, 17.5 °±0.2° 20, 19.2 °±0.2° 20, 19.5 °±0.2° 20 and 22.2°±0.2° 20. In one embodiment of the sixth aspect, the compound of Formula (la) is provided in a crystalline form, Form 1 , having an X-ray powder diffraction pattern comprising peaks corresponding to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22 or 23 of the peaks listed in the table below ±0.2° 20:

[0143] In one embodiment of the sixth aspect, the compound of Formula (la) is provided in a crystalline form, Form 1 , having an X-ray powder diffraction pattern is substantially as illustrated in Figure 3.

[0144] In one embodiment of the sixth aspect, the compound of Formula (la) is provided in a crystalline form, Form 1 , wherein the crystalline form has a melting temperature of 108° C ±2°C.

[0145] In one embodiment of the sixth aspect, the compound of Formula (la) is provided in a crystalline form, Form 1 , wherein the crystalline form has a DSC is substantially as illustrated in Figure 4.

[0146] In one embodiment of the sixth aspect, the compound of Formula (la) is provided in a crystalline form, Form 1 , wherein the crystalline form is an anhydrate.

[0147] In one embodiment of the sixth aspect, the compound of Formula (la) 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, or 99.99% or more, or about 100%. For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect 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 preferred, typical or optional embodiment of any aspect herein described should also be considered as a preferred, typical or optional embodiment of any other aspect.

[0148] EXAMPLES

[0149] Example 1 : Preparation of tert-butyl (1-(5-chloropyrimidin-2-yl)cyclobutyl)carbamate (compound of Formula (la))

[0150] Step 1 : Preparation of 1 -aminocyclobutane-1 -carbonitrile

[0151] To a reactor was charged aqueous ammonia (30% w / w, 900 kg), ammonium chloride (273 kg) and water (50 kg). The resulting mixture was then stirred at 25 °C. In a second reactor, sodium cyanide (150 kg) was charged, followed by the addition of the mixture from the first reactor (NH4CI, NH3, H2O). The line from the first reactor was rinsed with aqueous ammonia (30% w / w, 122 kg) to ensure complete transfer of ammonium chloride, and finally, water (50 kg) was charged to the second reactor. The resulting mixture was stirred for at least 15 min at 25 °C followed by cyclobutanone (204 kg) addition over at least 1 h, maintaining 25 °C. The reaction was aged for at least 7 h under stirring.

[0152] MeTHF (872 kg) was charged and the mixture was stirred for 30 min, then allowed to settle. The bottom phase was transferred to a reactor, in which MeTHF (436 kg) was charged afterwards. The mixture was stirred, and the bottom phase was cut. The process was repeated once more. The three organic phases were combined and concentrated under vacuum to a volume of approximately 613 L, maintaining temperature below 40 °C

[0153] MeTHF (436 kg) was charged, and the stream was concentrated to 613 L. The process was repeated once more until the resulting stream reached adequate water content (not more than 0.5% w / w), thereafter the stream was cooled to 0 °C and maintained at that temperature for at least 30 min. The slurry was then filtered and sent to the next reactor. The filter was rinsed with two portions of MeTHF (131 kg). The filtered solution and the washes were combined and assayed at 25 °C. The concentration of 1 -aminocyclobutane-1 - carbonitrile was adjusted to 25% w / w either by charging more MeTHF or by distilling off some. The 1 -aminocyclobutane-1 -carbonitrile was not isolated but used directly in step 2.

[0154] Step 2: Preparation of tert-butyl (l -cyanocyclobutyl)carbamate

[0155] In a separate reactor, MeTHF (114 kg) and di-tert-butyl dicarbonate (B0C2O) were charged and mixed. This solution was charged over at least 10 h to the previous reactor (Step 1 ). The B0C2O line was rinsed with MeTHF (50 kg). The reaction was aged for at least 6 h longer, then at 30±3 °C for at least 30 min, and then filtered. The filter was rinsed twice with MeTHF (195 kg). The filtrate and the washes were combined and distilled to 912 L, maintaining temperature below 40 °C.

[0156] The stream was maintained at 25 °C and heptane (1085 kg) was charged over at least 2 h. Once the addition was completed, the stream was cooled to -10 °C over at least 2 h and maintained at that temperature for at least 1 h. Tert-butyl (1 -cyanocyclobutyl)carbamate was then isolated by filtration. The wet cake was rinsed with two portions of a mixture of heptane (272 kg) and MeTHF (146 kg), pre-cooled to -10 °C. The rinsed solid was dried at 25-30 °C to provide tert-butyl (1 - cyanocyclobutyl)carbamate (77.6% yield over two steps; 443 Kg; GC purity: 99.2%).

[0157] GC method:

[0158] Diluent: DCM (dichloromethane). Column: MEGA-SE52 30m long and 0.32 mm internal diameter, film thickness 0.5um or equivalent. Helium as carrier gas (constant flow; 1 .8 mL / min). Injector temperature 240°C in split mode with a split ratio 20:1 and injection volume 1 uL. Detector FID at 250° C with air flow 400 mL / min. H2 flow 40 mL / min. Make up flow 15 mL / min.

[0159] Run time 27 min.

[0160] RT (retention time) tert-butyl (l -cyanocyclobutyl)carbamate: 17.503 min.

[0161] Step 3: Preparation of tert-butyl (1 -(N'-hydroxycarbamimidoyl)cyclobutyl)carbamate

[0162] Hydroxylamine hydrochloride (125 kg), 2-propanol (2100 kg) and tert-butyl (1 - cyanocyclobutyl)carbamate (the compound from step 2) (282 kg) were charged in this order in a reactor. The reactor was rinsed with 2-propanol (117 kg). The mixture was stirred at 25 °C, then heated to 43 °C and maintained at that temperature for at least 15 min. Triethylamine (197 kg) was charged over at least 6 h, maintaining 43 °C. After complete addition of EtsN, the reaction was stirred at 43°C during 14 h The reaction mixture was transferred to another reactor, rinsing the line with 2-propanol (100 kg), then concentrated to 2373 L, maintaining T < 50 °C. Water (791 kg) was charged and the mixture was distilled to 1412 L. The operation was repeated once more. The slurry was cooled to 6 °C over at least 1 h, then aged at that temperature for at least 2 h. Tert-butyl (1 -(N'-hydroxycarbamimidoyl)cyclobutyl)carbamate was isolated by centrifugation. The wet cake was washed with water (1694 kg) pre-cooled to 6 °C. Finally, the washed cake was discharged, transferred to a biconical dryer and dried at a temperature below 50 °C (296 kg, 89.8% yield, purity 99.9%).

[0163] HPLC method:

[0164] Diluent: MeOH

[0165] The chromatographic procedure may be carried out using: Detector: UV 200 nm

[0166] Column: Kinetex XB-C18, 250 mm x 4.6 mm, 5.0 pm;

[0167] Column temperature: 35° C

[0168] Mobile phase:

[0169] Mobile phase A: 10mM Ammonium formate pH 7 with diluted NH3. For example, 0.63g of ammonium formate in 1 L of mQ water pH 7 using 1% diluted ammonium hydroxide.

[0170] Mobile phase B: MeOH

[0171] Injection volume: 5.0 pL Flow rate: 1 .0 mL / min Total run time: 39 minutes

[0172] RT Tert-butyl (1 -(N'-hydroxycarbamimidoyl)cyclobutyl)carbamate: 13.966 min. Step 4: Preparation of tert- butyl (l -carbamimidoylcyclobutyl)carbamate

[0173] Tert-butyl (1 -(N'-hydroxycarbamimidoyl)cyclobutyl)carbamate (the compound from step 3) (118 kg), methanol (342 kg) and glacial acetic acid (34.0 kg) were charged in a reactor. The acetic acid charge line was rinsed with methanol (50 kg). In the meanwhile, palladium on charcoal (2.4 kg, 10% w / w, 50% w / w wet) was charged in an autoclave, then rinsed with water (0.8 kg). The tert-butyl (1 -(N'-hydroxycarbamimidoyl)cyclobutyl)carbamate suspension was transferred into the autoclave and the reactor and transfer line were rinsed with methanol (93 kg). Raney nickel (0.47 kg) was suspended in methanol (25 kg) and charged to the autoclave. The charge system was rinsed with two portions of methanol (25 kg each).

[0174] After vacuum / nitrogen cycle, hydrogen was charged to the autoclave at 1 .3 bar. Stirring was turned on and the reaction was aged at 30 °C and 1 .3 bar for at least 7 h. The autoclave was then vented and inerted with nitrogen. The reaction mixture was then transferred through a filter to a reactor. The filter was rinsed with two portions of MeOH (140 kg). The combined streams were concentrated to 354 L, maintaining T < 45 °C.

[0175] Toluene (512 kg) was charged, and the resulting stream was concentrated to 354 L. The process was repeated once more. The stream was aged for at least 2h at 5 °C, then tertbutyl (l -carbamimidoylcyclobutyl)carbamate was isolated by centrifugation. The wet cake was washed twice with toluene (102 kg). The washed cake was discharged and transferred to a biconical dryer, then dried at 40 °C (134.7 kg, 97.7% yield, Purity: 99.9%).

[0176] HPLC method: Diluent: MeOH. Chromatographic conditions: Detector: UV 210 nm. Column: Zorbax Eclipse XDB-C18, 150 mm x 4.6 mm, 5.0 um. Column temperature: 30° C.

[0177] Mobile phase A: 1 .3 g / L ammonium phosphate dibasic pH 7.0 with HCIO4. Mobile phase B: MeOH. Injection volume: 5.0 uL. Flow rate: 1.0 mL / min Flow rate: 1 .0 mL / min.

[0178] Total run time: 15 min.

[0179] RT tert-butyl (1 -carbamimidoylcyclobutyl)carbamate: 5.252 min.

[0180] Step 5: Preparation of tert- butyl (1 -(5-chloropyrimidin-2-yl)cyclobutyl)carbamate (the compound of Formula (la)

[0181] In a reactor, acetonitrile (1000 kg), tert-butyl (l -carbamimidoylcyclobutyl)carbamate (the compound from step 4) (189 kg) and N-(2-chloro-3-(dimethylamino)allylidene)-N- methylmethanaminium hexafluorophosphate(V) (244 kg) were charged in this order. The reactor walls were rinsed with acetonitrile (148 kg). Stirring was turned on followed by the addition of diisopropylethylamine (DIPEA) (112 kg). The line was rinsed with acetonitrile (50 kg).

[0182] The reaction mixture was then heated to 60 °C for at least 3 h. The stream was then concentrated to 568 L, maintaining temperature below 45 °C. Once the distillation was finished, the stream was heated to 70 °C to solubilize the mass. The mixture was then cooled to 52 °C and maintained at that temperature for at least 30 min. Water (947 kg) was then charged over at least 2 h. The resulting stream was cooled to 3 °C over at least 2 h, then aged under these conditions for at least 1 h.

[0183] Crude compound of Formula (la) was then isolated in a filter dryer. The wet cake was washed with five portions of a water (237 kg) and acetonitrile (112 kg) mixture pre-cooled to 3 °C.

[0184] Acetonitrile (595 kg) was then charged in the filter dryer, the stirring was turned on and the mixture was stirred at 50 °C until complete dissolution was observed. The solution was then transferred to a reactor. The filter dryer was rinsed with acetonitrile (396 kg) and the two streams were combined and aged at 40 °C for at least 15 min and finally passed through an activated charcoal filter at approximately 15 kg / min. The filtrates were collected in a dedicated reactor. The line connecting the crystallization reactor, the filter dryer and the filter were rinsed with acetonitrile (199 kg). Finally, the filter dryer was rinsed once more with acetonitrile (297 kg). All the collected solutions were concentrated to 568 L.

[0185] Once the distillation was completed, the stream was heated to 70 °C to solubilize the mass. The mixture was then cooled to 52 °C and maintained at that temperature for at least 30 min. Water (947 kg) was then charged over at least 2 h. The resulting stream was cooled to 3°C over at least 2 h, then aged under these conditions for at least 1 h. The compound of Formula (la) was isolated by centrifugation. The wet cake was washed with a mixture of water (296 kg) and acetonitrile (139 kg) pre-cooled to 3 °C. The washed cake was discharged and transferred to a biconical dryer and dried at 50 °C to provide the compound of Formula (la) (88% yield, 173.4 Kg). HPLC purity: 99.98%

[0186] The total yield for the obtention of the ch loro -pyrimidine compound of Formula (la), in these 5 steps starting from cyclobutanone, is hence 60% in these experiments.

[0187] The obtained solid was identified as a crystalline form, Form 1 . XRPD of Form 1 is shown in Figure 3. Apparatus / conditions: X-Ray analysis was carried out at room temperature on a D8 Advance from Bruker, configured in PHI-SPINNER with a sealed copper anode X-ray tube (A CuKo average = 1 .54178 A) (45kV and 40mA). An acquisition time of 0.2s per step in an angular range from few 2-Theta degrees to 40° degrees with a 0.02° step size in 20 was used for each sample analysis.

[0188] DSC of Form 1 is shown in Figure 3. Melting temperature is 108°C, with an enthalpy of 108 J / g. Method: DSC was carried out on a Diamond apparatus from Perkin Elmer. The samples were prepared in Aluminum 50pl crucibles with perforated lids crimped not tightly.

[0189] Analyses were carried out with a scanning rate of 10 °C / min, from 30 to 130°C.

[0190] No water was detected in a Karl-Fisher analysis or in a GC headspace (Gas Chromatography apparatus) indicating that Form 1 is an anhydrate.

[0191] HPLC method:

[0192] Diluent: MeOH.

[0193] Chromatographic conditions:

[0194] Detector: UV 265 nm. Column: Zorbax Eclipse XDB-C18, 150 mm x 4.6 mm x 5.0 um.

[0195] Column temperature: 30° C.

[0196] Mobile phase:

[0197] Mobile phase A: 1 .3 g / L ammonium phosphate dibasic pH 7.0 with HCIO4.

[0198] Mobile phase B: ACN.

[0199] Injection volume: 15 uL. Flow rate: 1.0 mL / min. Total run time: 24 minutes.

[0200] RT: 5.956 min.

[0201] Identification by NMR:

[0202] Sample preparation: 30 mg of the product dissolved in about 0.75 mL of CDCL. Proton NMR acquired with a Bruker AV400 instrument in CDCL: 6 8.67 (s, 2H), 5.70 (s, 1 H), 2.70 (m, 2H), 2.58 (m, 2H), 2.10 (m, 2H), 1.40 (s, 9H).

[0203] Alternative Step 5: Preparation of (1 -(5-chloropyrimidin-2-yl)cyclobutyl)carbamate (the compound of Formula (la)

[0204] In a reactor, tert-butyl (l -carbamimidoylcyclobutyl)carbamate (the compound from step 4) (29.4 kg) was charged and acetonitrile (147 L) was added. The white suspension was stirred at 20 °C for 10 minutes and then heated up to reflux (internal temperature 80 °C).

[0205] Meanwhile, a solution of N-(2-chloro-3-(dimethylamino)allylidene)-N- methylmethanaminium hexafluorophosphate(V) (39.4 kg) in acetonitrile (73.5 L) was prepared. This solution was stirred for minimum 15 min at 25 °C. This solution was added into the reactor at 80 °C over 30 min keeping the internal temperature not below than 75 °C. The reactor walls and lines were rinsed with acetonitrile (14.7 L). The suspension was stirred at 80 °C for 4 hours.

[0206] The stream was then concentrated to 102.9 L under vacuum at a temperature close to 70 °C. Once the distillation was finished, the mixture was then cooled (-10 °C / h) to 50 °C where a crystallization started to occur. The suspension was stirred at 50 °C for about one hour. Water (147 L) was then added over at least 2 h keeping the internal temperature at 50 °C. The suspension was then stirred for an extra one hour at 50 °C prior to cooling down (-10 °C / h) to 22 °C. The suspension was then stirred again for one hour at 22 °C.

[0207] Crude compound of Formula (la) was then isolated in a filter dryer. The wet cake was washed with five portions of a water (35.3 L) and acetonitrile (25.3 L) mixture. The washings consisted of an alternance of washings, trituration (x2) and a last washing.

[0208] The washed cake was discharged and transferred to a biconical dryer and dried at 40 °C for 24 hours to provide the compound of Formula (la) (88.5% yield, 27 Kg).

[0209] The total yield obtained for the obtention of the ch loro -pyrimidine compound of Formula (la), in these 5 steps starting from cyclobutanone, is hence of 60% in these experiments. Example 2: Preparation of tert-butyl (1-{5[7R,14R)-1-(difluoromethoxy)-6-methyl-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b]benzodiazocin-11- yl]pyrimidin-2-yl}cyclobutyl)-carbamate (compound of Formula (IVa))

[0210] A reactor was charged with KOAc (9.5 kg), bis(pinacolato)diboron (B2Piri2) (13.76 kg), the compound of Formula (la) (14.63 kg) followed by 2-methyltetrahydrofuran (MeTHF) (146.3 L) and H2O (285 mL). The reaction mixture was then stirred 15 min at 20 ± 5 °C and vacuum / argon were applied to get an oxygen free atmosphere. Chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'-biphenyl)[2-(2'-amino-1 ,T- biphenyl)]palladium(ll) (XPhosPdG2) (0.228 kg) was then added to the reactor, followed again by vacuum / argon to get an oxygen free atmosphere. The mixture was heated to 80±3°C and kept under stirring for 1 hour until full conversion of starting material was observed. The reaction mixture was cooled to 20±5°C.

[0211] A solution of K3PO4 (54.53 kg) in water (102.6 L) was then added at 20±5 °C to the reactor under stirring and hydrogen atmosphere. The addition was followed by vacuum / argon to get an oxygen free atmosphere. XPhosPdG2 (0.228 kg) was then added to the reactor, followed by vacuum / argon. The mixture was then heated to 70±5 °C followed by the addition of a solution of the compound of Formula (III) (19 kg) in MeTHF (62.7 kg) and water (2.7 L). The reactor used to prepare the solution of the compound of Formula (III) was rinsed with a solution of 7 L MeTHF and 0.38 L of H2O before being added to the reaction mixture. The reaction was stirred at 70±5 °C for 1 hour and then cooled to 20±5 °C.

[0212] The biphasic reaction mixture was then filtered at 20±5 °C and the cartridge filter was rinsed with 14.6 L of MeTHF The reaction mixture was left to settle for 30 min to allow phase separation, then the aqueous layer was removed (palladium content of the organic layer was 104 ppm). A mixture of NaCl (10.3 kg), H?O (103 L) and ethylene diamine (3.0 kg) was added to the remaining organic layer and stirred during 2h at 30±10 °C. The reaction mixture was left to settle for 30 min to allow phase separation, then the aqueous layer was removed. This sequence was repeated 3 times (palladium content of the organic layer after ethylene diamine wash was 4 ppm). Thereafter 2 other liquid-liquid extractions were performed using a solution of NaCl (10.3 kg) and water (103 L) under stirring at 30±10 °C and allow to settle for phase separation.

[0213] The isolation of the compound of Formula (IVa) was then conducted via the distillation of the reaction mixture until water content reached < 1%, followed by the addition of MeTHF until a final volume of 116 L. At this stage, 95 g of seeds of crystalline Form 2 crystals were added to the reaction mixture at 25 °C and the stirring was maintained for 3 hours. Methylcyclohexane (116 L) was then added to the reactor over 1 hour at 25 °C and the reaction mixture was kept under stirring during 8 to 12 hours.

[0214] The isolation of the desired compound of Formula (IVa) was completed via a filtration and the cake was rinsed 2 times with a 1 / 1 ratio of MeTHF / methylcyclohexane (15 L : 15 L) at 25 °C. After drying, 27.3 kg of the compound of Formula (IVa) were isolated (yield = 93%).

[0215] Example 3: Preparation of crystalline Form 1 of tert-butyl (1-{5[7R,14R)-1- (difluoromethoxy)-6-methyl-5-oxo-5, 6,7,14-tetrahydro-7,14-methanobenzi mi dazo[ 1,2- b] benzodiazoci n-11-yl]pyrimidin-2-yl}cyclobutyl)-carbamate (compound of Formula (IVa)

[0216] Intermediate 17 of WO 2018 / 197503 is solubilized in 1 ,4-dioxane and heated at 45-55 °C.

[0217] To the heated solution, 3-6 volumes of n-heptane was added at 45-55°C, and the temperature was cooled to 15-25 °C. The suspension was stirred for 1 -3 h and filtered. A second crop was obtained by adding filtrate on a mixture of 2.6 vol 1 ,4-dioxane and 17 vol n-heptane at 50-65 °C. The mixture was stirred for 1 -3 h, cooled to 15-25 °C, stirred for 3- 4 h and filtered. The combined cake was washed with 3.6 vol of n-heptane and then dried under vacuo at 45-55 °C for 10-20 h to provide the crystalline Form 1 of the compound of Formula (IVa).

[0218] Example 4: Preparation of seed crystals of crystalline Form 2 of tert-butyl (1- {5[7R, 14R)- 1 -(difluoromethoxy)-6-methyl-5-oxo-5,6,7, 14-tetrahydro-7, 14- methanobenzimidazof 1 ,2-b]benzodiazocin-11-yl]pyrimidin-2-yl}cyclobutyl)-carbamate (compound of Formula (IVa)

[0219] 2.4g of Form 1 of the compound of Formula (IVa) were partially dissolved in 16 mL Me-THF at 60° C. The suspension was cooled down to 50° C and stirred overnight. The suspension was then cooled down to 20° C at a 20K / h cooling rate, stirred 2.5h, then cooled down to 0°C at 20K / h cooling rate. After overnight stirring at 0°C, the suspension was heated up to 20° C, and part of the suspension was filtered off on a glass filter. The obtained solid was identified as a new crystalline form according to XRPD and DSC measurements. XRPD of Form 2 is shown in Figure 1 . Apparatus / conditions: X-Ray analysis was carried out at room temperature on a D8 Advance from Bruker, configured in PHI-SPINNER with a sealed copper anode X-ray tube (A CuKo average = 1 .54178 A) (45kV and 40mA). An acquisition time of 0.2s per step in an angular range from few 2-Theta degrees to 40° degrees with a 0.02° step size in 20 was used for each sample analysis.

[0220] DSC of Form 2 is shown in Figure 2. Melting temperature = 204.01 °C; melting enthalpy = 52.7 J / g; melting of Form 2 followed by the crystallization of Form 1 , melting point of Form 1 observed upon further heating. Apparatus / conditions: DSC analysis was carried out on a Diamond apparatus from Perkin Elmer. The samples were prepared in Aluminum 50pl crucibles with perforated lids crimped not tightly. Analyses were carried out, with a scanning rate of 5 °C / min up to 240° C.

[0221] Thermogravi metric analysis (TGA) analysis showed no significant loss weight, indicating Form 2 being an anhydrate crystalline form.

[0222] Example 5: Preparation of crystalline of Form 2 of tert-butyl (1-{5[7R,14R)-1- (difluoromethoxy)-6-methyl-5-oxo-5, 6,7,14-tetrahydro-7,14-methanobenzi mi dazo[ 1,2- b] benzodiazoci n-11-yl]pyrimidin-2-yl}cyclobutyl)-carbamate (compound of Formula (IVa) using seed crystals

[0223] Using a Dean-Stark apparatus, water was removed from a 33.7g of a solution containing 3.5g of the compound of Formula (IVa) dissolved in Me-THF saturated with water in a reactor thermostated at 55 °C under vacuum. After 15 min, the water content in the solution was 620ppm. The solution was then concentrated to 16 mL at 55 °C under vacuum. The solution was cooled down to 25 °C, then the solution was seeded with 40 mg of Form 2 seed crystals of the compound of Formula (IVa). The suspension was stirred 2.5h at 25°C, then 16 mL of methyl -cyclohexane was added in 50 min. After 2.5h of stirring, the suspension was filtered on a glass filter, and washed twice with 8mL of a 50 / 50 mixture of Me-THF and methyl-cyclohexane. The obtained solid was dried overnight at 50° C under vacuum. 3.2g of Form 2 of the compound of Formula (IVa).

[0224] Example 6: Preparation of (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-

[0225] (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one (compound of Formula (V))

[0226] A reactor was charged with the compound of Formula (IVa) (24.5 kg), MeTHF (62 L) and water (49 L). The biphasic reaction mixture was stirred at 20± 5 °C during 15 min and then heated to 70± 3 °C.

[0227] Under stirring, an aqueous solution of HCl (12.3 kg in 39 L of water) was added in the reactor at 70° C over 1 h ± 30 min. The reaction was maintained during 2 hours at 70± 3 °C and then cooled down to 20± 5 °C.

[0228] The reaction mixture was left to settle for 30 min at 20± 5 °C to allow phase separation, then the organic layer was removed. The aqueous layer was washed two times with MeTHF (2 x 62 L) and the organic layers were discarded.

[0229] The aqueous layer was then added under stirring and over 1 hours ± 30 min to another reactor containing a solution of K3PO4 (54.5 kg), water (91 L) and MeTHF (147 L). After the addition was completed, the stirring was maintained for 1 hour at 20± 5 °C.

[0230] The reaction mixture was left to settle for 30 min at 20± 5 °C to allow phase separation, then the aqueous layer was removed. The organic layer was then washed 2 times with water (2 x 98 L) at 35± 5 °C and the 2 aqueous layers were counter-extracted with MeTHF (50 L). The organic layers were combined and mixed with Siliamet (2.45 kg) under stirring at 50± 3 °C for 4 hours. The suspension was then filtered under cartage and rinsed with MeTHF (7.4 L) / H2O (265 mL) to end-up with a solution of the compound of Formula (V) (8.0% mass) estimated after analysis at 96.2% assay yield (19.64 kg) with an organic purity of 99.7%.

[0231] Solvent swap and crystallization:

[0232] A solution of the compound of Formula (V) (19.08 kg, 8.0% mass) with an organic purity of 99.7% was charged in a reactor followed by the addition of MeTHF (20 L). The solution was concentrated under vacuum to 77 L (TDE below 50 °C; TMtxture below 50° C) followed by the addition of acetonitrile (MeCN) (11 L) to end up with a total volume of 88 L. The distillation was then conducted at constant volume to remove all traces of MeTHF by addition of MeCN. The mixture was then heated to 82 °C for 15 min until solubilization and the solution was then cooled to 70± 3°C at which point 100 g of seed crystals of Form A of the compound of Formula (V) were added under smooth stirring. The mixture was maintained at 70 ± 3 °C for 2 hours and then cooled at 0°C (-5 °C / h). Once at 0± 3 °C, the mixture was maintained during 2 hours under stirring and then filtered. The cake was washed with 39 L of methyl tert- butylether (MTBE) pre-cooled to 0°C and the remaining cake was dried under vacuum without stirring during 4 hours at 49° C. Additional stirring under vacuum allowed to reach complete drying.

[0233] The compound of Formula (V) was obtained (16.92 Kg, crystallization yield: 88.2%, organic purity: 99.9%, only observed impurity: 0.07%).

[0234] Example 7: Preparation of crystals of crystalline Form A of (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 (compound of Formula (V)) A solution at 300 g / l of amorphous form of the compound of Formula (V) in acetonitrile was prepared at 50 °C. Natural cooling at ambient temperature led to obtention of crystalline Form A by spontaneous nucleation.

Claims

CLAIMS1 .A process of preparing a compound of Formula (IV):wherein R1is an amine protecting group, comprising the steps of:(a) converting a compound of Formula (I) to a compound of Formula (II):followed by:(b) contacting the compound of Formula (II) with a compound of Formula (III) to obtain the compound of Formula (IV):

2. The process of claim 1 , wherein the process of step (a) and step (b) are performed in the presence of a solvent comprising 2-methyltetrahydrofuran.

3. The process of claim 1 or claim 2, wherein the process of step (a) and step (b) are performed in the presence of chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1 ,1'-biphenyl)[2-(2'-amino-1 ,1'-biphenyl)]palladium(ll) catalyst.

4. The process of claim 3, comprising the addition of 0.001 -0.01 equivalent of the catalyst in step (a) and the addition of 0.001 -0.01 equivalent of the catalyst in step (b).

5. The process of claim any preceding claim, wherein the compound of Formula (II) is not isolated between step (a) and step (b).

6. The process of any preceding claim, wherein the process is performed without the use of column chromatography.

7. The process of any preceding claim, wherein the compound of Formula (IV) is obtained from the compound of Formula (I) in a molar yield of 90% or more.

8. The process of any preceding claim, wherein R1is tert-butyloxycarbonyl.

9. The process of claim 8, wherein the compound of Formula (IV) is a compound ofFormula (IVa):and is obtained as a crystalline Form 2 having an X-ray powder diffraction pattern comprising characteristic peaks at 7.6° ±0.2° 20, 10.0° ±0.2° 20, and 17.3° ±0.2° 20.

10. A process of preparing a compound of Formula (I) comprising converting a compound of Formula (VI) to the compound of Formula (I):wherein R1is an amine protecting group.11 . The process of claim 10, further comprising the precursor steps of:(i) preparing a compound of Formula (IX) by converting a compound of Formula (X) to the compound of Formula (IX):(X) (IX)(ii) preparing a compound of Formula (VIII) by converting the compound of Formula(IX) to the compound of Formula (VIII):(IX) (VIII)(iii) preparing a compound of Formula (VII) by converting the compound of Formula(VIII) to the compound of Formula (VII):(VIII) (VII) ; and(iv) preparing the compound of formula (VI) by converting the compound of Formula(VII) to the compound of Formula (VI):(VII) (VI)12. The process of claim 11 , wherein the process of converting a compound of Formula (VI) to the compound of Formula (I) and precursor steps (i), (ii), (iii) and (iv) are all performed at a temperature of 15-90°C.

13. The process of claim 11 or claim 12, wherein the process of converting a compound of Formula (VI) to the compound of Formula (I) and precursor steps (i), (ii), (iii) and (iv) are all performed in the absence of chlorinated solvent.

14. The process of any one of claims 11 -13, wherein the process of converting a compound of Formula (VI) to the compound of Formula (I) and precursor steps (i), (ii), (iii) and (iv) are all performed without the use of column chromatography.

15. The process of any one of claims 11 -14, wherein the compound of Formula (I) is obtained from the compound of Formula (X) in a molar yield of 30% or more.

16. The process of any one of claims 1 -9, wherein the compound of Formula (I) is prepared by the process of any one of claims 10-15.

17. A process of preparing a compound of Formula (V):comprising preparing a compound of Formula (IV) according to a process of any one of claims 1 -9 or 16, followed by a process of deprotection of the amine group of the compound of Formula (IV) to obtain the compound of Formula (V).

18. The process of claim 17, wherein the deprotection is performed in the presence of a solvent comprising 2 -methyltetra hydrofuran.

19. A crystalline form of a compound of Formula (IVa):wherein the crystalline form is of Form 2 having an X-ray powder diffraction pattern comprising characteristic peaks at 7.6° ±0.2° 20, 10.0°±0.2° 20, and 17.3°±0.2° 20.

20. A process of preparing the crystalline Form 2 of the compound of Formula (IVa) as defined in claim 19, comprising:(a) contacting a compound of Formula (IVa) with a solvent comprising 2- methyltetrahydrofuran; and(b) obtaining the crystalline Form 2 of the compound of Formula (IVa).21 . A compound of Formula (la):optionally, wherein the compound of Formula (la) is a crystalline form, Form 1 , having (i) an X-ray powder diffraction pattern comprising characteristic peaks at 9.4° ±0.2° 20, 12.8° ±0.2° 20, and 22.2° ±0.2° 20 and / or (ii) a melting temperature of 108°C ±2°C.

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