Field of invention The present invention relates to a novel chemical process for the synthesis of the compound 2- fluoro-N-methyl-4-[7-quinolin-6-yl-methyl)-imidazo[1 ,2-b][1 ,2,4]triazin-2yl]benzamide.

Background of the invention The present invention provides an improved process to prepare the compound of Formula (I) that is more efficient, shorter and better suited for commercial production scale than processes known in the art.

The compound of Formula (I) is an intermediate for the preparation of 2-fluoro-N-methyl-4-[7- quinolin-6-yl-methyl)-imidazo[1 ,2-b][1 ,2,4]triazin-2yl]benzamide, herein also referred as the compound of Formula (VI): The compound of Formula (VI) is a c-Met inhibitor that is useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways. PCT/US2007/085100 and PCT/US2009/044622 provide processes of making the compound of Formula (VI) and describes the compound of Formula (IV) as being useful in treating diseases, which respond to inhibition of the tyrosine kinase enzymatic activity of the HGF/c-Met kinase signaling pathway.

The compound of Formula (VI), preparation of the compound of Formula (VI), and pharmaceutical compositions of the compound of Formula (VI) are originally described in PCT/US2007/085100 as Example 7.

Nevertheless, there remains a need to provide improved processes for the preparation of intermediates that contribute to the preparation of the compound of Formula (VI), which are economically more efficient, shorter, and better suited for commercial production scale.

Description of the invention

The present invention is directed to a novel chemical process for preparing the compound of Formula (I) and its purification, using less hazardous chemicals and/or reaction conditions, generating less waste and providing a reproducible process that is easier to handle on production scale, more efficient as compared to the methods disclosed in the prior art.

In this regard, the present invention is provided in the following aspects.

In accordance with a first aspect of the present invention, there is provided a process for producing the compound of Formula (I),

(I), or a salt thereof, comprising reacting a salt form thereof, particularly HCI, of a compound of Formula (la); with a compound of Formula (lb) in the presence of a base; wherein Ri and R ₂ are OC C ₁ a _-6 lkyl or halogen.

In accordance with a second aspect of the invention, there is provided a process according to the first aspect, further comprising the step of preparing the compound of Formula (lb) a) reacting a compound of Formula (I la) a reagent selected from R-metal, wherein R is selected from C _1-6 alkyl, aryl or N( C _1-6 alkyl) ₂ and said metal is selected from lithium, MgCI, MgBr, Mgl, CuLi, ZnCI, or ZnBr or salts thereof, preferably with (CH ₃ ) ₂ CHMgCI LiCI, followed by reacting with a compound of Formula (lib) to form a compound of Formula (lb); wherein Ri and R2 are OC _1-6 alkyl or halogen;

H c Cl, N( C _1-6 alkyl) ₂ , OC _1-6 alkyl or OCO( C _1-6 alkyl); wherein when Y is Y can be produced using conditions described in Ayala-Mata et al., Molecules 2012(17), pp. 13864-13878, and X1 is Cl, Br, or I.

Preferably, Ri and R ₂ are Cl, OCH ₃ or OCH ₂ CH ₃ and Y is

In accordance with a third aspect of the invention, there is provided a compound of Formula (lb) wherein Ri and R ₂ are OCi- ₆ alkyl or halogen. In accordance with a fourth aspect of the invention, there is provided a process according to the first aspect, further comprising reacting a compound of Formula (I), or salt thereof, with a compound of Formula (III) at a temperature from about 120°C to about 150°C to form a compound of Formula (IV) or salt thereof; wherein X ₂ is Cl, I, or Br.

In accordance with a fifth aspect of the invention, there is provided a process according to the first aspect and fourth aspect, further comprising reacting the compound of Formula (IV), or salt thereof, with an acid to form a compound of Formula (V) or salt thereof. An acid may be selected from trifluroacetic acid (TFA), methanesulfonic acid (MsOH), and hydrochloric acid (HCI). Preferably, said acid is concentrated hydrochloric acid.

In accordance with a sixth aspect of the invention, there is provided a process according to the first aspect and fifth aspect, further comprising reacting the compound of Formula (V), or salt thereof, with CH ₃ NH ₂ in the presence of a coupling agent to form a compound of Formula (VI) or salt thereof.

Preferably, said coupling agent is selected from carbonylimidazole, 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide, N-hydroxybenzotriazole, (benzotriazol-1-yl oxyl)tripyrrolidinophosphonium hexafluorophosphate, 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4- methyl-morpholinium chloride, n-propanephosphonic acid anhydride or 2 , 4 ,6-trich lo ro- 1 ,3,5- triazine and salts thereof. In accordance with a seventh aspect of the invention, there is provided a compound of Formula (VI) or salts thereof, prepared by the process according to the first aspect and sixth aspect. In accordance with a eighth aspect of the invention, there is provided a process according to the first aspect, further comprising the preparation of compound of Formula (I) by a process comprising: a) reacting a compound of Formula (la) and Formula (lb) in the presence of acid to form a compound of (2E,2'E)-2,2'-(1-(4-cyano-3-fluorophenyl)ethane-1 ,2-diylidene)bis(hydrazine-1- carboximidamide) or (2Z,2'E)-2,2'-(1-(4-cyano-3-fluorophenyl)ethane-1 ,2- diylidene)bis(hydrazine-1 -carboximidamide); and b) after the reacting in step a), reacting the compound of (2E,2'E)-2,2'-(1-(4-cyano-3- fluorophenyl)ethane-1 ,2-diylidene)bis(hydrazine-1 -carboximidamide) or (2Z,2'E)-2,2'-(1-(4- cyano-3-fluorophenyl)ethane-1 ,2-diylidene)bis(hydrazine-1 -carboximidamide); with a base to form the compound of Formula (I).

Preferred bases include NaOH, KOH, K ₂ C0 ₃ and NaHC0 ₃ . Preferably, said base is NaOH.

In accordance with an ninth aspect of the invention, there are provided intermediate compounds selected from (2E,2'E)-2,2'-(1-(4-cyano-3-fluorophenyl)ethane-1 ,2-diylidene)bis(hydrazine-1- carboximidamide) or (2Z,2'E)-2,2'-(1-(4-cyano-3-fluorophenyl)ethane-1 ,2- diylidene)bis(hydrazine-l-carboximidamide).

General terms:

C alkyl is meant to refer to a saturated hydocarbon group, which is straight -chained or branched. Examples include methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g., n- butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

Aryl being a radical or part of a radical is an aromatic hydrocarbon group, for example, C _6-10 aryl, and is preferably a mono- or polycyclic, especially monocyclic, bicyclic or tricyclic aryl moiety with 6 to 14 carbon atoms for example 6 to 10 carbon atoms, preferably phenyl, indenyl, indanyl or naphthyl and the like.

Salts or salt forms are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds or any of the intermediates mentioned herein with a basic nitrogen atom (e.g. imino or amino), especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane-1 ,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1 ,5-naphthalene-disulfonic acid, N- cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo and iodo.

General Process Conditions: The following, in accordance with the knowledge of a person skilled in the art about possible limitations in the case of single reactions, applies in general to all processes mentioned hereinbefore and hereinafter, while reaction conditions specifically mentioned above or below are preferred.

The following Examples serve to illustrate the invention without limiting the scope thereof, while they on the other hand represent preferred embodiments of the reaction steps, intermediates and/or the process of manufacture of the product in free base form or as a pharmaceutically acceptable salt thereof.

The process(es) according to the present invention are summarized in Scheme 1.

Scheme lPreparation of compounds:

Example 1: 2,2-dimethoxy-1-morpholinoethan-1-one

Chemical Formula: C ₈ H ₁₅ N0 ₄ Molecular Weight: 189.21 A mixture of methyl 2,2-dimethoxyacetate (1 .50 kg, 1 .0 eq.) and morpholine (1 .27 kg, 1 .3 eq.) is heated to 120°C and stirred for 16 hours. After complete conversion, the reaction mixture is cooled to room temperature and acetic anhydride (0.544 kg, 0.48 eq.) is added. The crude mixture is pre-purified by fractionated distillation. Fractions with a HPLC purity <99% are combined and distilled again to yield 2,2-dimethoxy-1-morpholinoethan-1-one (1 .28 kg, 60%) as a colorless liquid.

Purity by HPLC: 99.4%.

¹ H NMR (400 MHz, DMSO-c/6): d = 3.34 (s, 6 H), 3.39-3.50 (m, 2 H), 3.50-3.59 (m, 6 H), 4.89 (s, 1 H) ppm. MS (ESI): m/z = 212.089 [M+Na],

Example 2: 2,2-diethoxy-1-morpholinoethan-1-one

Chemical Formula: O ₁₀ H ₁₉ NO ₄ Molecular Weight: 217.27 To a solution of morpholine (12.7 mL, 12.8 g, 147 mmol) in dry tetrahydrofuran (160 mL) at 0°C, /PrMgCI.LiCI (96.0 mL, 125 mmol, 1.3 M in THF) is added slowly in five portions and then stirred for ~15 min until a gray suspension formed. Ethyl 2,2-diethoxyacetate (20 g, 114 mmol) is added at the same temperature until a clear yellowish solution is obtained. The resulting reaction mixture is stirred for 1 hour. The reaction mixture is quenched with saturated aqueous NH ₄ CI solution (40 mL) resulting in an intense pale yellow solids precipitation. The solid is filtered off before transferring the reaction mixture in a separatory funnel. Ethyl acetate (200 mL) is added, and the organic phase is washed with water (2 x 100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure (4 mbar) to get a yellow oil (11.6 g, 47%). The aqueous phase and solids are extracted again with ethylacetate (2 x 200 mL) to yield after concentration under reduced pressure (4 mbar) to a pale yellow oil (8.6 g, 35%). Overall 20.2 g (82%) of the desired product are obtained.

Purity by NMR: >95 %. ¹ H NMR (400 MHz, DMSO-c/6): d = 1.13-1.16 (m, 6 H), 3.42-3.67 (m, 12 H), 5.00 (s, 1 H) ppm.

Example 3: 4-(2,2-dimethoxyacetyl)-2-fluorobenzonitrile

Chemical Formula: C11H10 FNO3 Molecular Weight: 223.20 A solution of 4-bromo-2-fluorobenzonitrile (20 g, 1 .0 eq.) in Methyl-THF (100 ml_) is cooled to - 10 °C. Isopropylmagnesium chloride lithium chloride complex solution (1.3 M, 100 ml_, 1.3 eq.) is added at -10 °C within 1 hour. After complete addition, the reaction mixture is stirred for 1 h at -10 °C. Afterwards, a solution of 2,2-dimethoxy-1-morpholinoethan-1-one (22.7 g, 1.2 eq.) in THF (60 ml_) is added within 1 h, and the reaction mixture is stirred for another 2 hours. The reaction mixture is warmed to 5 °C and quenched by addition of aqueous citric acid monohydrate solution (10%, 100 ml_). The biphasic mixture is stirred at 25 °C for at least 30 min. The aqueous layer is removed and the organic layer is used in the subsequent step without any purification.

Analytical data of isolated sample of 4-(2,2-dimethoxyacetyl)-2-fluorobenzonitrile: ¹ H NMR (400 MHz, DMSO-d6): δ = 3.23-3.52 (m, 6 H), 5.43 (s, 1 H), 7.90-8.04 (m, 2 H), 8.12 (dd, J = 8.3, 6.5 Hz, 1 H) ppm.

MS (ESI): m/z = 207.034 [M-CH ₄ ].

Example 4: 4-(2,2-diethoxyacetyl)-2-fluorobenzonitrile

Chemical Formula: C ₁₃ H ₁₄ FN0 ₃ Molecular Weight: 251.26

Procedure: See 4-(2,2-dimethoxyacetyl)-2-fluorobenzonitrile.

Analytical data of isolated sample of 4-(2,2-diethoxyacetyl)-2-fluorobenzonitrile: ¹ H NMR (400 MHz, DMSO-d6): δ = 1.13 (t, J = 7.0 Hz, 6 H), 3.65 (ddq, J = 32.0, 9.7, 7.0 Hz, 4 H), 5.48 (s, 1 H), 7-96-8.02 (m, 2 H), 8.13 (dd, J = 8.3, 6.5 Hz, 1 H) ppm.

Example 5: 4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzonitrile

Chemical Formula: C10H6FN5 Molecular Weight: 215.19

Propionic acid (61 .1 g, 8.3 eq.) and 2-propanol (78 ml_) are added to the organic layer obtained in the previous step. An acidic solution of aminoguanidine hydrochloride (prepared by dissolving aminoguanidine hydrochloride (27.6 g, 2.5 eq.) in water (40 g) and HCI, 37% (15 g) at room tempperature) is added The reaction mixture is heated to an inner temperature of ca. 70 °C and stirred at this temperature for 4 hours until most of the E, E-isomer of the bishydrazone has been converted to the corresponding E,Z-isomer. Afterwards sodium hydroxide solution (15%, 120 g, 4.5 eq.) is added and the reaction mixture is heated at an inner temperature of 70-90 °C for 20 h to cyclize the bishydrazone to the desired triazine. Increase in temperature is achieved by distilling off a part of the solvent mixture. The distillate is afterwards transferred back to the reaction mixture at an inner temperature of 60 °C. The reaction suspension is cooled down to 5 °C and stirred for 2 h at 5 °C. The yellow solid is filtered off and washed with Me0H/H ₂ 0 1 :1 and dried to yield a yellow solid (17.6 g, 81% over two steps).

Purity by HPLC: 99.7% ¹ H NMR (400 MHz, DMSO- d6): δ = 7.70 (s, 2 H), 8.11-8.01 (m, 2 H), 8.14 (dd, J = 11.1 , 1.5 Hz, 1 H), 8.95 (s, 1 H) ppm.

MS (ESI): m/z = 216.068 [M+H],

Example 6: (2Z,2'E)-2,2'-(1-(4-cyano-3-fluorophenyl)ethane-1,2-diyliden e)bis(hydrazine-1- carboximidamide)

Chemical Formula: C11H12FN9 Molecular Weight: 289.28

Analytical data of isolated sample of (2Z,2'E)-2,2'-(1-(4-cyano-3-fluorophenyl)ethane-1 ,2- diylidene)bis(hydrazine-l-carboximidamide): ¹ H NMR (600 MHz, DMSO-c/6) d = 7.86 (dd, J = 8.4, 1 .5 Hz, 1 H) 7.99-8.07 (m, 2 H) 8.09 (br s, 2 H) 8.12-8.19 (m, 2 H) 8.37 (s, 2 H), 12.08 (br s, 1 H) 12.34 (br s, 1 H) 12.31-12.36 (m, 1 H) ppm.

Example 7: (2E,2 ^, E)-2,2'-(1-(4-cyano-3-fluorophenyl)ethane-1,2-diyliden e)bis(hydrazine-1- carboximidamide)

Chemical Formula: C11H12FN9 Molecular Weight: 289.28

Analytical data of isolated sample of (2E,2'E)-2,2'-(1-(4-cyano-3-fluorophenyl)ethane-1 ,2- diylidene)bis(hydrazine-l-carboximidamide): ¹ H NMR (600 MHz, DMSO-c/6): d = 7.31-7.42 (m, 1 H) 7.62 (br dd, J = 9.5, 1.1 Hz, 1 H) 7.83- 7.98 (m, 1 H), 8.01-8.08 (m, 2 H) 8.09 (s, 1 H) 8.13-8.27 (m, 4 H), 10.96 (br s, 1 H), 12.87 (br s, 1 H) ppm.

Example 8: 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzonitrile

Chemical Formula: C22H13FN6 Molecular Weight: 380.39

1-(2-chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine -2,5-dione (162 kg, 1.0 eq.) and 4-(3- amino-1 ,2,4-triazin-6-yl)-2-fluorobenzonitrile (289 kg, 1.2 eq.) are suspended in ethylene glycol (920 kg) at 20 °C. The suspension is heated to an internal temperature of ca. 110 °C and stirred at that temperature until in solution (for up to 2 hours). Seeding with 2-fluoro-4-(7-(quinolin-6- ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzonitrile (0.089 kg, 0.045% m/m) in ethylene glycol (4 kg) at an internal temperature of ca. 115 °C. Then the mixture is stirred for another 1 hour at an internal temperature of ca. 115 °C and re-seeded with 2-fluoro-4-(7-(quinolin-6- ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzonitrile (0.089 kg, 0.045% m/m) in 4 kg ethylene glycol and stirred at internal temperature of ca. 115 °C for 5 hours. Using an internal temperature ramp, the reaction mass is cooled down to an internal temperature of ca. 70 °C in a period of 3 hours. A mixture of ethanol/ethyl acetate (1/1 vol./vol.) is then dosed over a period of 4 hours at an internal temperature of ca. 70 °C; the mixture is then stirred for 1 hour and, using an internal temperature ramp, cooled down to an internal temperature of ca. 0 °C in a period of 4 hours. Stirring is continued for a minimum of 4 hours at an internal temperature of ca. 0 °C. Then the suspension is heated to an internal temperature of ca. 20 °C, centrifuged and washed with ethanol. Drying takes place at jacket temperature 70 °C / < 20mbar / ca. 24 h until vacuum is constant. 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzonitrile is obtained as yellow solid (207 kg, 72 %) with an assay of 89 % by titration.

¹ H NMR (400 MHz, DMSO-c/6): d = 4.76 (s, 2 H), 8.01-8.10 (m, 4 H), 8.11 (s, 1 H), 8.18 (d, J = 8.9 Hz, 1 H), 8.31 (s, 1 H), 8.36 (d, J = 8.8 Hz, 1 H) 9.07 (d, J = 8.4 Hz, 1 H) 9.23 (s, 1 H), 9.32 (s, 1 H) ppm.

MS (ESI): m/z = 381 .126 [M+H],

Example 9: 2-fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzoic acid

Chemical Formula: C22H16CI2FN5O2 Molecular Weight: 472.30

2-Fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzonitrile (233 kg) and 37% hydrochloric add (901 kg) are charged, the mixture is heated to an inner temperature of ca. 100 °C (reflux) and stirring is continued for 20 hours. The resulting yellow viscous suspension is cooled to an inner temperature of 85°C and an in-process sample is taken. If the control point is satisfied, water (1478 kg) is metered keeping the reaction mixture at 80-110 ^° C. The batch is stirred at an inner temperature >95 ^° C until an orange solution is present. The batch is cooled to about 0 °G and is filtered and washed first with acetone / water (748 kg, 95/5 vol./vol.) and then with acetone (738 kg). An optional in-process control determines residual ammonium chloride content. Drying at 60°C, <20 mbar (in-process control: acetone and water content) gives 2- fluoro-4-(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzoic acid dihydrochloride (248 kg, 86%) as a yellow solid with an assay by titration of >77% (based on free base), ¹ H NMR (500 MHz, DMSO-c/6): d = 4.77 (s, 2 H), 4.84-4.86 (m, 1 H), 8.03-8.10 (m, 4 H), 8.15 (s, 1 H), 8.20 (dd, J = 8.8, 1.9 Hz, 1 H), 8.33 (d, J = 1.3 Hz, 1 H), 8.41 (d, J = 8.9 Hz, 1 H), 9.11

(d, J = 8.3 Hz, 1 H), 9.25 (dd, J = 5.2, 1 .5 Hz, 1 H), 9.37 (s, 1 H) ppm.

MS (ESI): m/z = 400.120 [M+H],

Example 10: 2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1 ,2,4]triazin-2- yl)benzamide

Chemical Formula: C ₂₃ H ₁₇ FN ₆ 0 Molecular Weight: 412.43 A suitable vessel is charged with 1-Methyl-2-pyrrolidone (NMP, 1470 kg). 2-Fluoro-4-(7- (quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzoic acid dihydrochloride (188 kg of unpurified material from previous step, corresponding to 151 kg of free base) is charged followed by an NMP rinse (344 kg). The mixture is homogenized at 30°C, cooled to inner temperature 0 °C and carbonyldiimidazole (CDI, 125 kg, 2.05 eq.) is added portionwise. The mixture is stirred at inner temperature 0 °C until conversion of 2-fluoro-4-(7-(quinolin-6- ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzoic acid is completed as confirmed by in-process control check. The reaction mixture is evacuated to remove the liberated C0 ₂ . Methylamine (29.4 kg, 2.5 eq.) is charged to the reactor, keeping the inner temperature <15 °C (target 0-5 °C). The reaction mixture is heated to an inner temperature of 25 °C and is stirred for a minimum of 8 hours until in-process check determines that 2-fluoro-N-methyl-4-(7-(quinolin-6- ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzamide has been formed. Some 2-fluoro-N-methyl- 4-(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzamide will precipitate during this stirring period. Water (1114 kg) is added completing the precipitation. The resulting suspension is stirred for a minimum of 10 hours, is filtered and washed with water (3 x 371 kg). Pre-drying at 20°C and drying at 70°C under reduced pressure gives 2-fluoro-N-methyl-4-(7-(quinolin-6- ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzamide as yellow solid (146 kg, 94%). ¹ H NMR (500 MHz, DMSO-c/6): d = 2.81 (d, J = 4.6 Hz, 3 H), 4.64 (s, 2 H), 7.50 (dd, J = 8.3, 4.2 Hz, 1 H), 7.77-7.82 (m, 2 H), 7.96-7.99 (m, 2 H), 8.00 (s, 1 H), 8.02-8.06 (m, 2 H), 8.30 (dd, J = 8.3, 1 .8 Hz, 1 H), 8.41 (br. dd, J = 4.6, 1 .7 Hz, 1 H), 8.84 (dd, J = 4.2, 1 .7 Hz, 1 H), 9.22 (s, 1 H) ppm.

MS (ESI): m/z = 413.152 [M+H]

Example 11 : 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2- yl)benzamide dihydrochloride hydrate

Chemical Formula: C23H21CI2FN6O2 Molecular Weight: 503.36 A mixture of 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2- yl)benzamide (139 kg) and activated charcoal (3.5 kg) in 37% HCI (115 kg, 4.0 eq.) and water (754 kg) is heated to 60 °C. The suspension is stirred at 55 to 60 °C for 20 min. The crystallizer reactor is pre-heated to a jacket temperature of 55 °C to receive the solution after filtration via charcoal/clarifying filtration media. The filtrate, obtained as a clear yellowish solution, is then cooled via a temperature ramp from 55 to 30 °C. At 30 °C and at high agitation speed crystal seeds (0.75 kg), suspended in acetone (30 kg) are charged to the crystallizer and the emerging suspension is stirred for some time to allow de-supersaturation. The suspension is then cooled via a temperature ramp from 30 to 25 °C. Anti-solvent acetone (2370 kg) is dosed slowly and with effective agitation into the suspension. The suspension is then cooled from 25 to 0 °C and stirred at medium agitator speed. The product is filtered off, washed at 0 °C with cold acetone/water (395 kg, 3:1 m/m) and afterwards with cold acetone (2 x 395 kg). The filter cake is blown dry by means of nitrogen. The damp product is pre-dried with agitation at 20 to 25 °C under vacuum not below 20 mbar, and then dried with intermittent agitation at a jacket temperature ramped up to 40 °C under vacuum not below 10 mbar. After cooling and venting, the product is sampled for analysis of water and acetone content. 2-fluoro-N-methyl-4-(7- (quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)benzamide dihydrochloride hydrate (156 kg, 92%) is obtained as a light yellow, fluffy solid. ¹ H NMR (500 MHz, DMSO-d6): δ = 2.79 (d, J = 4.6 Hz, 3 H), 4.79 (s, 2 H), 7.80 (t, J = 7.6 Hz, 1 H), 7.96-8.10 (m, 3 H), 8.22 (s, 1 H), 8.23 (d, J = 9.0 Hz, 1 H), 8.35 (d, J = 1.5 Hz, 1 H), 8.45-8.51 (m, 2 H), 9.13 (d, J = 8.3 Hz, 1 H), 9.26 (d, J = 5.4 Hz, 1 H), 9.44 (s, 1 H) ppm.

MS (ESI): m/z = 413.152 [M+H].