SYNTHESIS OF COPANLISIB AND ITS DIHYDROCHLORIDE SALT

Abstract

The present invention relates to a novel method of preparing copanlisib, and copanlisib dihydrochloride, to novel intermediate compounds, and to the use of said novel intermediate compounds for the preparation of said copanlisib.

Claims

1: A method of preparing copanlisib (7): ##STR00060## comprising the following steps: step A6: reacting a compound of formula (6): ##STR00061## with a compound of formula (6b): ##STR00062## wherein the compound of formula (6) is reacted with the compound of formula (6b) optionally in the presence of a catalyst, optionally in the presence of a coupling agent, optionally in a solvent, thereby providing copanlisib (7): ##STR00063## said compound of formula (6): ##STR00064## being prepared by the following step A5: reacting a compound of formula (5): ##STR00065## with an annelating agent, wherein the compound of formula (5) is reacted with the annelating agent optionally in the presence of a base, optionally in a solvent, thereby providing a compound of formula (6); said compound of formula (5): ##STR00066## being prepared by the following step A4: reacting a compound of formula (4): ##STR00067## with hydrogen in the presence of a 5% palladium/1% iron catalyst on carbon which is water-wetted, in a solvent, thereby providing a compound of formula (5).

2: The method according to claim 1, wherein said compound of formula (4): ##STR00068## is prepared by the following step A3: reacting a compound of formula (3): ##STR00069## with ethylenediamine, optionally in the presence of N-bromosuccinimide, optionally in a solvent, thereby providing a compound of formula (4).

3: The method according to claim 2, wherein said compound of formula (3): ##STR00070## is prepared by the following step A2: reacting a compound of formula (2): ##STR00071## with a compound of formula (2a): ##STR00072## wherein the compound of formula (2) is reacted with the compound of formula (2a) optionally in a solvent, optionally in the presence of a base, optionally with heating, thereby providing a compound of formula (3).

4: The method according to claim 3, wherein said compound of formula (2): ##STR00073## is prepared by the following step A1: a) reacting a compound of formula (1): ##STR00074## with nitric acid and sulphuric acid, wherein the compound of formula (1) is reacted with nitric acid and sulphuric acid optionally in solution in a solvent, and then b) adding a base, optionally in a solvent, thereby providing a compound of formula (2).

5: The method according to claim 1, wherein said compound of formula (6b): ##STR00075## is prepared by the following step A7: a) reacting a compound of formula (6a): ##STR00076## with a base, wherein the compound of formula (6a) is reacted with the base optionally in a solvent, with heating, then, b) after cooling, adding methyl formate, then c) adding guanidine hydrochloride, followed by heating, then, d) adding water and an aqueous solution of a base, followed by heating, then, e) adding an aqueous solution of a mineral acid, f) adding an amine, and filter, then g) adding an aqueous solution of a strong base, then h) adding an aqueous solution of a mineral acid, thereby providing a compound of formula (6b): ##STR00077## which is optionally purified before the next step.

6: The method according to claim 1, which further comprises the following step A8: reacting copanlisib, of formula (7): ##STR00078## with hydrogen chloride, optionally hydrochloric acid, thereby providing copanlisib dihydrochloride (8): ##STR00079##

7: The method according to claim 1, wherein copanlisib is prepared via the following steps shown in Reaction Scheme 3, infra: ##STR00080##

8: A compound selected from: ##STR00081##

9: Use of a compound selected from: ##STR00082## for preparing copanlisib (7): ##STR00083## or copanlisib dihydrochloride (8): ##STR00084##

10: The method of claim 1, wherein the compound of formula (6) is reacted with the compound of formula (6b) in the presence of a catalyst, wherein the catalyst is N,N-dimethyl-4-aminopyridine.

11: The method of claim 1, wherein the compound of formula (6) is reacted with the compound of formula (6b) in the presence of a coupling agent, wherein the coupling agent is N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride.

12: The method of claim 1, wherein the compound of formula (5) is reacted with an annelating agent, wherein the annelating agent is cyanogen bromide.

13: The method of claim 1, wherein the compound of formula (5) is reacted with the annelating agent in the presence of a base, wherein the base is triethylamine.

14: The method of claim 3, wherein the compound of formula (2) is reacted with the compound of formula (2a) in the presence of a base, wherein the base is potassium carbonate.

15: The method of claim 4, wherein the base of step A1 b) is potassium carbonate.

16: The method of claim 5, wherein the compound of formula (6a) is reacted with a base, wherein the base is sodium methoxide.

17: The method of claim 5, wherein the base of step A7 d) is sodium hydroxide.

18: The method of claim 5, wherein the mineral acid of step A7 e) is hydrochloric acid.

19: The method of claim 5, the amine of step A7 f) is dicyclohexylamine.

20: The method of claim 5, wherein the strong base of step A7 g) is sodium hydroxide.

21: The method of claim 5, wherein the mineral acid of step A7 h) is hydrochloric acid.

Description

EXAMPLES

Example 1: Step A1: Preparation of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (2-nitro-vanillin) (2)

[0124] 2-Nitrovanilin (2) was synthesized via a flow nitration of vanillin acetate (1) in a micro reactor. 3.94 kg of nitric acid (65 w %) were added to 5.87 kg of concentrated sulfuric acid at 0° C. (nitrating acid). 1.5 kg of vanillin acetate were dissolved in 2.9 kg of dichloromethane (vanillin acetate solution). Both solutions reacted in a micro reactor with flow rates of app. 8.0 mL/min (nitrating acid) and app. 4.0 mL/min (vanillin acetate solution) at 5° C. The reaction mixture was directly dosed into 8 kg of water at 3° C. After 3 h flow rates were increased to 10 mL/min (nitrating acid) and 5.0 mL/min (vanillin acetate solution). After additional 9 h the flow reaction was completed. The layers were separated at r.t., and the aqueous phase was extracted with 2 L of dichloromethane. The combined organic phases were washed with 2 L of saturated sodium bicarbonate, and then 0.8 L of water. The dichloromethane solution was concentrated in vacuum to app. 3 L, 3.9 L of methanol were added and app. the same volume was removed by distillation again. Additional 3.9 L of methanol were added, and the solution concentrated to a volume of app. 3.5 L. 1.25 kg of methanol were added, followed by 2.26 kg of potassium carbonate. The mixture was stirred at 30° C. for 3 h. 7.3 kg of dichloromethane and 12.8 kg of aqueous hydrochloric acid (10 w %) were added at <30° C. (pH 0.5-1). The mixture was stirred for 15 min, and the layers were separated. The organic layer was filtered, and the filter cake washed with 0.5 L of dichloromethane. The aqueous layer was extracted twice with 4.1 kg of dichloromethane. The combined organic layers were concentrated in vacuum to app. 4 L. 3.41 kg of toluene were added, and the mixture concentrated to a final volume of app. 4 L. The mixture was cooled to 0° C. After 90 min the suspension was filtered. The collected solids were washed with cold toluene and dried to give 0.95 kg (62%).

[0125] .sup.1H-NMR (400 MHz, d.sub.6-DMSO): δ=3.84 (s, 3H), 7.23 (d, 1H), 7.73 (d, 1H), 9.74 (s, 1H), 11.82 (brs, 1H).

[0126] NMR spectrum also contains signals of regioisomer 6-nitrovanillin (app. 10%): δ=3.95 (s, 3H), 7.37 (s, 1H), 7.51 (s, 1H), 10.16 (s, 1H), 11.11 (brs, 1H).

Example 2: Step A2: Preparation of 3-methoxy-4-[3-(morpholin-4-yl)propoxy]-2-nitrobenzaldehyde (3)

[0127] 854 g of 4-(3-chloropropyl)morpholine hydrochloride were suspended in 19.4 L of acetonitrile and the mixture was stirred for 50 min. at r.t. The mixture was filtered, and the residue was washed with 0.7 L of acetonitrile. The filtrate was dosed to a suspension of 700 g of 2-nitrovanilline and 1.96 kg of potassium carbonate in 7 L of acetonitrile at r.t. over a period of ca. 2 h. The reaction mixture was heated to reflux, and stirred at reflux for 3 h. The mixture was cooled to r.t., and filtered. The residue was washed twice with acetonitrile. The filtrate was concentrated under vacuum and the residue dissolved in 5.6 L of ethyl acetate. This solution is washed with 7 L of aqueous 10 w % sodium chloride solution, then 7.7 L of aqueous 1% sodium chloride solution. After removal of the solvent, the viscous residue of ca. 1.14 kg was dissolved in 2.3 L of dichloromethane, the solvent of the next step.

[0128] .sup.1H-NMR (500 MHz, d.sub.6-DMSO): d=1.97 (m, 2H); 2.36 (m, 4H); 2.45 (t, 2H); 3.56 (m, 4H); 3.85 (s, 3H); 4.27 (t, 2H); 7.51 (d, 1H); 7.87 (d, 1H); 9.80 (s, 1H).

Example 3: Step A3: Preparation of 4-{3-[4-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-nitrophenoxy]propyl}morpholine (4)

[0129] 6.1 kg of the dichoromethane solution from the previous reaction (containing 5.25 mol of 3-methoxy-4-[3-(morpholin-4-yl)propoxy]-2-nitrobenzaldehyde; example 2) was diluted with 25.7 L of dichloromethane. Over a period of 10 min. 836 g of ethylenediamine were added, and the reaction mixture was stirred for 1 h at r.t. After cooling to 00, 2.476 kg of N-bromosuccinimide were added in three portions. The reaction mixture was warmed to 25° C. within 30 m in. and then cooled again to 0° C. The reaction mixture was stirred at 0° C. for 10 5 min. 2.3 L of saturated aqueous sodium bicarbonate solution were added, followed by 5.4 L of aqueous sodium hydroxide solution (20 w %) to adjust the solution to pH 14. 5.8 L of water were added, and the mixture was warmed to r.t. The organic phase was separated, washed with 12.9 L of water and dried over 1 kg of sodium sulfate. The filtrate was evaporated (1.87 kg residue).

[0130] This residue was combined with a second batch (1.83 kg), and suspended in 16 L of acetone. 13 L of n-heptane were added at r.t. within 30 min. The mixture was stirred at r.t. for 1 h, then cooled to 0° C. and stirred for 2 h at 0° C. The suspension was filtered. The collected solids were washed with n-heptane and dried to yield 2.9 kg (76%).

[0131] .sup.1H-NMR (400 MHz, d.sub.6-DMSO): δ=1.94 (m, 2H); 2.37 (bs, 4H); 2.45 (t, 2H); 3.52 (m, 4H); 3.57 (m, 4H); 3.82 (s, 3H); 4.18 (t, 2H); 7.07 (bs, 1H); 7.33 (d, 1H); 7.48 (d, 1H).

Example 4: Step A4: Preparation of 6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-[3-(morpholin-4-yl)propoxy]aniline (5)

[0132] A mixture of 625 g of 4-{3-[4-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-nitrophenoxy]propyl}morpholine (4) in 5 kg of methanol (saturated with potassium carbonate) and 63 g of catalyst (5% Pd/1% Fe on carbon, water-wetted) was stirred for 24 h under 100 bar hydrogen pressure at 40 t. The catalyst is filtered off under inert gas atmosphere, and washed with methanol to yield 6.1 kg of product solution. For work-up several batches of product solutions were combined. The solvent was switched to toluene by distillation in vacuum. The toluene product solution was filtered at 75° C., and then concentrated in vacuum until the product precipitates. The mixture was filtered, the solids washed with cold toluene and dried. Hydrogenation of 5 kg of 4-{3-[4-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-nitrophenoxy]propyl}-morpholine (4) yielded 3.3 kg (71%).

[0133] .sup.1H-NMR (400 MHz, d.sub.6-DMSO): δ=1.88 (m, 2H); 2.36 (bs, 4H); 2.44 (t, 2H); 3.26 (t, 2H); 3.57 (m, 4H); 3.66 (s, 3H); 3.82 (t, 2H); 4.02 (t, 2H); 6.25 (d, 1H); 6.70 (s, 1H); 6.90 (bs, 2H), 7.16 (d, 1H).

Example 5: Step A5: Preparation of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (6)

[0134] 375 ml of triethylamine were added to 300 g of 6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-[3-(morpholin-4-yl)propoxy]aniline (5) in 3 L of dichloromethane. The solution was cooled to 0° C., and a solution of 98 g of bromocyanide in 300 mL of dichloromethane was added within ap. 0.5 h. The resulting suspension was stirred for 1 h at −5 to 0° C., and then 2 h at 10° C. The reaction mixture was washed three times with 675 mL saturated aqueous sodium bicarbonate solution. The organic phase was concentrated in vacuum. 1.1 L of isopropanol was added and the mixture was heated to ap. 75° C. ° C. The resulting solution was cooled to r.t. overnight, and then cooled to 5° C. and stirred for 2 h. The product was filtered off, washed twice with cold isopropanol, and dried, yielding 230 g (70%).

[0135] .sup.1H-NMR (500 MHz, d.sub.6-DMSO): d=1.88 (m, 2H); 2.36 (bs, 4H); 2.44 (t, 2H); 3.57 (m, 4H); 3.70 (s, 3H); 3.86 (m, 4H); 4.04 (t, 2H); 6.65 (bs, 2H); 6.69 (d, 1H); 7.40 (d, 1H).

Example 6: Step A7: Preparation of 2-aminopyrimidine-5-carboxylic acid (6b)

[0136] 1 kg of methyl 3,3-dimethoxypropanoate was dissolved in 7 L of 1,4-dioxane. 1.58 kg of sodium methoxide solution (30 w % in methanol) were added. The mixture was heated to reflux, and ap. 4.9 kg of distillate were removed. The resulting suspension was cooled to r.t., and 0.5 kg of methyl formate was added. The reaction mixture was stirred overnight, then 0.71 kg of guanidine hydrochloride was added, and the reaction mixture was stirred at r.t. for 2 h. The reaction mixture was then heated to reflux, and stirred for 2 h. 13.5 L of water were added, followed by 0.72 kg of aqueous sodium hydroxide solution (45 w %). The reaction mixture was heated at reflux for additional 0.5 h, and then cooled to 50° C. 0.92 kg of aqueous hydrochloric acid (25 w %) were added until pH 6 was reached. Seeding crystals were added, and additional 0.84 kg of aqueous hydrochloric acid (25 w %) were added at 50° C. until pH 2 was reached. The mixture was cooled to 20° C. and stirred overnight. The suspension was filtered, the collected solids washed twice with water, then twice with methanol, yielding 0.61 kg (65%).

[0137] Four batches produced according to the above procedure were combined (total 2.42 kg). 12 L of ethanol were added, and the resulting suspension was stirred at r.t. for 2.5 h. The mixture was filtered. The collected solids were washed with ethanol and dried in vacuum to yield 2.38 kg.

[0138] To 800 g of this material 2.5 L of dichloromethane and 4 L of water were added, followed by 1375 mL of dicyclohexylamine. The mixture was stirred for 30 min. at r.t. and filtered. The collected solids are discarded. The phases of the filtrate are separated, and the organic phase was discarded. 345 mL of aqueous sodium hydroxide solution (45 w %) were added to the aqueous phase. The aqueous phase was extracted with 2.5 L of ethyl acetate. The phases were separated and the organic phase discarded. The pH value of the aqueous phase was adjusted to pH 2 using app. 500 mL of hydrochloric acid (37 w %). The mixture was filtered, and the collected solids were washed with water and dried, yielding 405 g.

[0139] The 405 g were combined with a second batch of comparable quality (152 g). 2 L of ethyl acetate and 6 L of water were added, followed by 480 mL of aqueous sodium hydroxide solution (45 w %). The mixture was stirred at r.t. for 30 min. The phases were separated. The pH of the aqueous phase was adjusted to pH 2 with ap. 770 mL of aqueous hydrochloric acid (37 w %). The mixture was filtered, and the collected solids washed with water and dried to yield 535 g.

[0140] .sup.1H-NMR (400 MHz, d.sub.6-DMSO): δ=7.46 (bs, 2H); 8.66 (s, 2H), 12.72 (bs, 1H).

Example 7: Step A6: Preparation of Copanlisib (7)

[0141] A mixture of 600 g of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydro-imidazo[1,2-c]quinazolin-5-amine, 306 g of 2-aminopyrimidine-5-carboxylic acid, 204 g of N,N-dimethyl-4-aminopyridine, 480 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 1500 g of N,N-dimethylformamide was stirred at room temperature for 15 h. The mixture was filtered, the filter cake was washed with N,N-dimethylformamide then ethanol. The collected solids were dried in vacuum to yield 769 g of copansilib (96%).

Example 8: Step A8: Preparation of Copanlisib Dihydrochloride (8)

[0142] To a suspension of 366 g of copanlisib in 1015 g water, 183 g of an aqueous hydrochloric acid solution (32%) were added while maintaining the temperature at 20° C. (±2° C.) until a pH of 3 to 4 was reached. The resulting mixture was stirred at room temperature for more than 10 min., filtered and the filtercake washed with additional 82 g of water. The filtrate was adjusted to pH 1.8 to 2.0 using aqueous hydrochloric acid solution (32%). The mixture was stirred for 10 min. at room temperature, 146 g of ethanol (100%) were added and stirred for another 10 min. 1 g of seed crystals were added, followed by 1592 g ethanol within 5 h. The resulting substance was removed by filtration, washed with a water-ethanol mixture and dried in vacuum to give 410 g (97%) of the copanlisib dihydrochloride.

[0143] .sup.1H-NMR (500 MHz, d.sub.6-DMSO): δ=2.32 (m, 2H); 3.11 (m, 2H); 3.29 (m, 2H); 3.48 (m, 2H); 3.83 (m, 2H), 3.98 (m, 2H); 4.00 (s, 3H); 4.19 (t, 2H); 4.37 (t, 2H); 4.47 (t, 2H); 7.39 (d, 1H); 7.54 (s, 2H); 8.21 (d, 1H); 8.97 (s; 2H); 11.1 (bs, 1H); 12.6 (bs, 1H); 13.4 (bs, 1H).

[0144] HPLC: stationary phase: XBridge Shield (150 mm, 3.0 mm ID, 3.5 μm particle size): mobile phase A: 20 mmol sodiumdodecylsulphate and 4.0 mL phosphoric acid (85%)/1 L water; mobile phase B: 20 mmol sodiumdodecylsulphate and 4.0 mL phosphoric acid (85%)/L acetonitrile/water (8:2 V/V); UV detection at 250 and 210 nm; oven temperature: 25° C.; injection volume: 3.0 μL; flow 0.5 mL/min; linear gradient in 3 steps: 40% B->50% B (5 min), 50% B->65% B (25 min), 65% B->100% B (5 min), 10 minutes holding time at 100% B; purity: >99.7% 99.75 (Rt=27.1 min), relevant potential by-products: 2-Aminopyrimidine-5-carboxylic acid at RRT (relative retention time) of 0.09 (2.4 min) typically <0.10%, 4-dimethylaminopyrimidine RRT 0.28 (7.6 min): typically <0.03%, by-product 1 RRT 1.03 (27.8 min): typically <0.03%, 7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine RRT 1.14 (31.0 min): typically <0.03%, by-product 6 RRT 1.24 (33.6 min): typically <0.15%,

[0145] Additional HPLC method to determine 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide pyramide: stationary phase: XBridge Shield (150 mm, 3.0 mm ID, 3.5 μm particle size): mobile phase A:: 2.0 mL trifluoro acetic acid/1 L water; mobile phase B: 2.0 mL trifluoro acetic acid/L acetonitrile; UV detection at 250 nm; oven temperature: 20° C.; injection volume: 1.0 μL; flow 0.5 mL/min; li near gradient in 2 steps: 0% B->25% B (20 min), 25% B->35% B (5 min), 5 minutes holding time at 35% B; BAY 80-6946 Rt=15.0 min, 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide RRT 1.07 (16.5 min): typically <0.10%.