WO2023139125A1

WO2023139125A1 - Improved process for preparation of copanlisib

Info

Publication number: WO2023139125A1
Application number: PCT/EP2023/051132
Authority: WO
Inventors: Kristyna DRAGOUNOVA; Petr Benovsky
Original assignee: Synthon B.V.
Priority date: 2022-01-18
Filing date: 2023-01-18
Publication date: 2023-07-27

Abstract

The presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof comprising:.

Description

IMPROVED PROCESS FOR PREPARATION OF COPANLISIB

BACKGROUND OF THE PRESENT INVENTION The presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof:

Copanlisib, 2-Amino-N-[7-methoxy-8-[3-(4-morpholinyl)propoxy]-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, is a phosphatidylinositol 3- kinase (PI3K) inhibitor, launched as dihydrochloride salt for the treatment for adults with relapsed follicular lymphoma who have received at least two prior therapy regimens.

Copanlisib was first disclosed in W02008070150 by Bayer. Processes for preparation of Copanlisib are disclosed in W02008070150 or WO2016071435 by Bayer. The disadvantages of the processes described in prior art is use of hazardous, toxic and explosive reagents in processes for Copanlisib preparation. W02008070150 describes a process that uses I2/NH3 that yield explosive I3N. Process described in WO2016071435 uses highly toxic BrCN for Copanlisib production.

There is still a need for improved process for preparation of Copanlisib that uses no explosive or toxic reagents. SUMMARY OF THE INVENTION

The presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof,

, comprising: a. Reacting compound of formula (2) with cyanamide (NH2CN) in methanol in a presence of a base to provide compound of formula (3);

,CN

Prot means a protective group;

Reacting compound of formula (3) with compound of formula (4) or a salt thereof in a presence of a base to provide compound of formula (5):

c. Transforming compound of formula (5) into compound of formula (1). DETAILED DESCRIPTION OF THE INVENTION

,CN

(2) (3)

Prot means a protective group;

c. Transforming compound of formula (5) into compound of formula (1).

The reaction step a. is preferably performed under a protecting atmosphere, for example under argon or nitrogen atmosphere. The protective group, Prot, can be a suitable hydroxyl protective group, for example a hydroxyl protective group disclosed in Protective groups in organic synthesis, Theodora W. Greene and Petr G.M.Wuts, 3rd Ed., John Wiley & Sons Inc. The protective group is preferably benzylic group. The base in step a. can be for example an alkali metal alkoxide such as sodium or potassium methoxide or sodium or potassium ethoxide or sodium or potassium butoxide sodium or potassium tert-butoxide. The concentration of compound of formula (2) in the solvent can be between 0.010 and 0.020 g/ml. The concentration of cyanamide (NH2CN) in the solvent can be between 0.005 g/ml and 0.015 g/ml. The molar ratio between compound of formula (2) and the cyanamide (NH2CN) can be between 1:3 and 1:6, preferably it is between 1:4 and 1:5. The molar ratio between the compound of formula (2) and the base can be between 1:3 and 1:6, preferably it is between 1:4 and 1:5. The reaction step a. is performed in a presence ofN-bromo- succinimide. The molar ratio between compound of formula (2) and N-bromosuccinimide 1:3 and 1:6, preferably it is between 1:4 and 1:5.

Compound of formula (2) and cyanamide (NH2CN) are mixed with the solvent. The mixture is cooled to 0-5°C. To the mixture the base is added. The base can be added in solid form or can be added in form of a solution, for example as a solution in the solvent used in step a. The base can be added portion wise, for example in 2 or 3 or 4 or 5 or 6 or 8 or 10 or 12 or 14 or 16 portions. The mixture is heated to room temperature (between 20°C and 25°C) and stirred at this temperature for between 25 and 60 minutes. The mixture is cooled to 0-5°C and to the mixture N-bromosuccinimide is added in the course of 30-180 minutes. The mixture is heated to a temperature between 45°C and 55°C and stirred at this temperature for between 15-60 minutes. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the mixture is cooled to room temperature (20-25°C) and stirred at this temperature for between 1 and 6 hours. The mixture can be optionally cooled to a temperature between 0-5°C and stirred at this temperature for between 1 and 10 hours. Obtained solid compound of formula (3) can be isolated by any suitable technique, for example using filtration and optionally dried. In the step b. compound of formula (3) is reacted with compound of formula (4) or a salt thereof in a presence of a base to provide compound of formula (5). The reaction step b. is preferably performed under a protecting atmosphere, for example under argon or nitrogen atmosphere. The reaction is performed in a suitable solvent selected for example from an alcohol such as methanol or ethanol or propanol or isopropanol, preferably methanol is used. The concentration of compound of formula (3) in the solvent can be between 0.08 and 0.2 g/ml. Compound of formula (4) can be used in a form of a salt, for example HC1 salt. The molar ratio between compound of formula (3) and compound of formula (4) or a salt thereof can be between 1:0.9 and 1:1, preferably it is 1:0.95. As a base an organic amine for example N,N-diisopropylethyl amine or triethyl amine or dimethyl amine or diethyl amine, preferably N,N-diisopropylethyl amine is used. The molar ratio between compound of formula (3) and the base can be between 1:2.5 and 1:5, preferably it is between 1:3 and 1:3.5. Compound of formula (3) and compound of formula (4) or a salt thereof are mixed with the solvent. To the mixture the base is added and the mixture is heated to a temperature between 50°C and the reflux temperature of used solvent and stirred at this temperature for between 2 and 10 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the mixture is then cooled to room temperature (20°C- 25°C) and stirred at this temperature for between 30-180 minutes to obtain a suspension. Obtained solid compound of formula (5) can be isolated by any suitable technique, for example using filtration and optionally dried. As a result of use of an alcohol, preferably methanol, as a solvent in reaction step b. the compound of formula (5) can be isolated directly from reaction mixture in good yield and purity. There is no need for work-up of the reaction mixture that is often time consuming, can decrease the yield of the isolated compound and produce by product waste and significant amount of solvents. In the step c. the compound of formula (5) can be transformed into compound of formula (1) for example by a process comprising: a. Reductive cyclization of the compound of formula (5) to obtain compound of formula (6A) and deprotecting compound of formula (6A) to obtain compound of formula (6),

b. Reacting compound of formula (6) with compound of formula (7) to obtain compound of formula (8),

c. Reacting compound of formula (8) with compound of formula (9) to obtain compound of formula (1),

The reductive cyclization step a. can be done for example by H2 (hydrogen) in a solvent selected from for example tetrahydrofurane or dimethylformamide or an alcohol such as methanol or ethanol. The reductive cyclization step is done in a presence of a catalyst selected for example from Pt or Pd or SnCL, preferably it is Pt on carbon (Pt/C) or Pd on carbon (Pd/C), more preferably it is Pt/C dopped by Fe is used. The reductive cyclization is done in a presence of organic base selected for example from an amine such as N,N- diisopropylethyl amine or triethylamine. The concentration of compound (5) in the solvent can be between 0.015 g/ml and 0.05 g/ml. Molar ratio between compound of formula (5) and the catalyst can be between 90: 1 and 110:1. Compound of formula (5) is mixed with the solvent and the catalyst is added. The mixture is reduced by H2 at a temperature between 35°C - 50°C for between 15 and 30 hours at for example between 3-80 bars. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the mixture is filtered and the filtrate is evaporated to provide compound of formula (6A). Compound of formula (6A) is deprotected to obtain compound of formula (6). Conditions for deprotection of compound of formula (6 A) depend on the protective group Prot and are described in prior art (Protective groups in organic synthesis, Theodora W.

Greene and Petr G.M.Wuts, 3rd Ed., John Wiley & Sons Inc.). Compound of formula (6A), wherein Prot group can be cleaved by an acid, can be deprotected for example using trifluoroacetic acid. The reaction is preferably performed under a protective atmosphere, for example argon or nitrogen atmosphere. The molar ratio between compound of formula (6A) and trifluoroacetic acid can be between 1:100 and 1:200. Reaction is preferably done in trifluoroacetic acid used also as a solvent. Compound of formula (6A) is added to trifluoroacetic acid, preferably at a temperature between 0-5°C. Compound of formula (6A) is added preferably in portions, for example in 2 or 3 or 4 or 5 or 6 or 7 or 8 portions. The mixture is heated to a temperature between 55°C and 65°C and stirred at this temperature for between 10 and 24 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is completed the mixture is cooled to room temperature (20-25°C). Trifluoroacetic acid is removed by co-evaporation with solvents (di chloromethane or heptane or methanol) and obtained solid is dried under vacuum (100 mbar, 30 °C, overnight).

Compound of formula (6) is reacted with compound (7) in a presence of a base in a suitable solvent. Compound of formula (7) can be used in a form of a salt, for example HC1 salt. The solvent can be selected from an alcohol such as methanol or ethanol or propanol or butanol or isopropanol or isobutanol or N,N-dimethylformamide or the mixture of the solvents with water. The molar ratio between compound of formula (6) and compound of formula (7) or a salt thereof can be between 1:1.5 and 1:2. The molar ratio between compound of formula (6) and the base can be between 1 :2 and 1:6. Compound of formula (6) is mixed with the solvent or solvent mixture, the base and compound of formula (7). The mixture is heated to a temperature between 80°C and 100°C and stirred at this temperature for between 3 and 8 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the mixture is cooled to room temperature (20°C-25°C). To the mixture water is added. The volume ratio between the solvent used in step a. and the added water can be between 1:0.3 and 1:0.7. The mixture is stirred at room temperature for between 10 and 60 minutes. The phases are separated and water phase is extracted with n-butanol. The volume ratio between n-butanol and water added previously can be between 1.2:1 and 1.7:1. Phases are separated and the mixed organic phases are concentrated to approximately 40% of the original volume. The mixture is heated to 50°C. To the mixture tert-butylmethyl ether is added. The volume ratio between added tertbutylmethyl ether and the solvent to which tert-butylmethyl ether is added is approximately 1:1. The mixture is cooled to a temperature between -5°C and 5°C and stirred at this temperature for between 30 and 180 minutes. Obtained suspension was filtered off to provide compound (8). Compound of formula (8) is reacted with compound of formula (9) to provide compound of formula (1),

The reaction is performed in a suitable solvent, for example N,N-dimethylformamide in a presence of coupling agent, for example N,N-dimethylaminopyridine and N-[l-(dimethyl- amino)propyl]-N’ -ethylcarbodiimine. Concentration of compound of formula (8) in the solvent can be between 0.03 g/ml and 0.08 g/ml. The molar ratio between compound of formula (8) and compound of formula (9) can be between 1:0.7 and 1:1.3. Concentration of the coupling agent and molar ratio between compound of formula (8) and the coupling agent depends on used coupling agent. The compound of formula (8) is mixed with the solvent, compound of formula (9) and the coupling agent. The mixture is stirred at room temperature (20°C-25°C) for between 15 and 24 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, obtained suspension is filtered off and obtained solid compound of formula (1) is washed and optionally dried. It can be converted into a salt, for example 2.HC1 salt or a hydrate thereof, by contacting compound of formula (1) with corresponding acid.

Obtained Copanlisib or a salt thereof can be used for preparation of a pharmaceutically acceptable composition and can be used for the treatment of conditions treatable by Copanlisib or a salt thereof.

The invention will be further illustrated by the following examples. EXAMPLES

Example 1: Preparation of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde

50 g of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde and 52.6 g of potassium carbonate were mixed with 350 ml of anhydrous DMF under argon. To the mixture 36.2 ml of benzyl bromide was added and the mixture was stirred for 12 hours. The reaction mixture was poured into 3500 ml of water to obtain a suspension. Solid product was filtered off and dried under vacuum (100 mbar, overnight, 35 - 50 °C) to provide 4-(benzyloxy)-3-methoxy-2- nitrobenzaldehyde in almost 100% yield.

Example 2: Preparation of methyl (Z)-4-(benzyloxy)-N-cyano-3-methoxy-2- nitrobenzi midate

40 g of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde and 23.42 g of cyanamide (NH2CN) were mixed with 3000 ml of methanol under argon atmosphere. The mixture was cooled to 0-5°C and to the mixture 53.5 g of sodium tert-butoxide was added in the course of 30 minutes portion wise (in 10 portions). The mixture was heated to room temperature (20- 25°C) and stirred at this temperature for 30 minutes. The mixture was cooled to 0-5°C and to the mixture 99 g of N-bromosuccinimide was added slowly, in the course of 60 minutes. The mixture was heated to 50°C. The mixture was cooled to room temperature (20-25°C) and stirred at this temperature for 3 hours. The mixture was then left at 0-5°C for 10 hours. Obtained suspension was filtered off and obtained solid was dried under vacuum (30°C, 100 mbar, 1 hour) to provide methyl (Z)-4-(benzyloxy)-N-cyano-3-methoxy-2-nitrobenzimidate in 65% yield and 99.6% purity (HPLC IN).

Example 3: Preparation of 2-(4-(benzyloxy)-3-methoxy-2-nitrophenyl)-lH-imidazole-

1 -carbonitrile

5 g of methyl (Z)-4-(benzyloxy)-N-cyano-3-methoxy-2-nitrobenzimidate and 1.614 g of 2-chloroethylamine hydrochloride was mixed with 50 ml of methanol under argon atmosphere. To the mixture 7.65 ml of N,N-diisopropylethylamine was added and the mixture was heated to reflux (65°C) and stirred at this temperature for 3 hours. The mixture was cooled to room temperature (20-25°C) and filtered. Obtained solid was dried under vacuum at room temperature for 12 hours to obtain 2-(4-(benzyloxy)-3-methoxy-2- nitrophenyl)-lH-imidazole-l -carbonitrile in 73% yield and 98.4% purity (HPLC IN).

Example 4: Preparation of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1.2-

250 mg of 2-(4-(benzyloxy)-3-methoxy-2-nitrophenyl)-lH-imidazole-l-carbonitrile was mixed with 9 ml of tetrahydrofurane and 66.9 mg of 5% platinum on activated carbon, paste, type 163, 0.1% Fe doped. To the mixture 0.989 ml of N,N-diisopropylethylamine was added. Mixture was placed in miniclave under nitrogen and heated to 40°C. Nitrogen was replaced by H2 (5 bars). Reaction was carried over for 24 hours, then the mixture was filtered and the filtrate was evaporated under reduced pressure (300 mbar, 40°C). The residue was dissolved in 4 ml of acetone and sonicated until white suspension appeared. The solid was collected by filtration to produce essentially pure (98%, HPLC IN) 2-(2-amino-4- (benzyloxy)-3-methoxyphenyl)-lH-imidazole-l -carbonitrile.

Example 5: Preparation of 5-amino-7-methoxy-2.3-dihydroimidazo[1.2-clquinazolin-

8-ol

2 g of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-amine was mixed with 0.2 g of 5% Pd/C and 33.7 ml of N,N-dimethylformamide. The mixture was heated to 60°C. The mixture was hydrogenated under 3 bars of H2 for 18 hours. The mixture was filtered and the filtrate was concentrated to approximately 30-35% of original volume. The rest was cooled to room temperature (20-25°C) and 14 ml of water was added during 10 minutes to obtain a suspension. The mixture was stirred at room temperature and filtered to provide 5-amino-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-8-ol in yield 58%.

Example 6: Preparation of 5-amino-7-methoxy-2.3-dihydroimidazo|T.2-c]quinazohn-

8-0I

Reaction was performed under argon.

0.322 g of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-amine was added portion wise (in 3 portions) in the course of 10 minutes to 10.03 ml of trifluoroacetic acid precooled with an ice bath to 0-5°C. The reaction mixture was heated to 60 °C, stirred at this temperature for 17 hours and then cooled to 20-25°C. The mixture was evaporated to approximately 60% of original volume. To the rest 4 ml of a mixture dichloromethane/ heptane (1:1, vol: vol) was added. The mixture was evaporated to approximately 60% of original volume. To the rest 4 ml of a mixture dichloromethane/methanol (1:1, vol:vol) was added. The mixture was evaporated and the rest was dried under vacuum (100 mbar, 30 °C, overnight).

Product 5-amino-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-8-ol.( trifluoroacetic acid)2 was prepared in 87% of yield.

Example 7: Preparation of Copanlisib

1.4 g of 5-amino-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-8-ol was mixed with 14 ml of butanol, 1.4 ml of N,N-dimethylformamide and 1.4 ml of water. To the mixture 2.5 g of K2CO3 was added. To the mixture 1.57 g of 4-(3-chloropropyl)morpholine hydrochloride was added. The resulting mixture was heated to 90°C and stirred for 5 hours. The mixture was cooled to room temperature (20-25°C). To the mixture 8.4 g of water was added and the mixture was stirred for 15 minutes. The phases were separated and the water phase was extracted with 12 ml of butanol. The organic phases were mixed and evaporated to approximately 50-55% of original volume. The mixture was heated to 45°C. To the mixture 11 ml of tert-butyl methyl ether was added. The mixture was cooled to -5°C and stirred at this temperature for 30 minutes. The mixture was filtered off to provide 7-methoxy-8-[3- (morphohn-4-yl)-propoxy]-2,3-dihydroimidazo[l,2-c]quinazolin-5-amine in yield 80%.

1.3 g of 7-methoxy-8-[3-(morpholin-4-yl)-propoxy]-2,3-dihydroimidazo[l,2- c]quinazolin-5-amine was mixed with 21.5 ml of N,N, -dimethylformamide, 0.5 g of 2- aminopyrimidine-5 -carboxylic acid, 0.4 g of N,N-dimethylaminopyridine and 1 g of N-[3- (dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride. The mixture was stirred at 20- 25°C for 15 hours. The mixture was filtered. Obtained solid was dried to provide Copanlisib in 95% yield.

Claims

A process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof,

, comprising:

Reacting compound of formula (2) with cyanamide (NH2CN) in methanol in a presence of a base to provide compound of formula (3);

,CN

(2) (3)

Prot means a protective group b. Reacting compound of formula (3) with compound of formula (4) or a salt thereof in a presence of a base to provide compound of formula (5);

Transforming compound of formula (5) into compound of formula (1).

2. The process according to claim 1 wherein the Prot is benzyl.

The process according to claim 1 or 2 wherein the base in step a. is an alkoxide.

4. The process according to claim 3 wherein the base is selected from sodium or potassium methoxide or sodium or potassium ethoxide or sodium or potassium butoxide sodium or potassium tert-butoxide.

5. The process according to any one of claims 1 to 4 wherein the base in step b. is selected from an organic amine.

6. The process according to claim 5 wherein the base is selected from N,N- diisopropylethyl amine or triethyl amine or dimethyl amine or diethyl amine.

7. The process according to any one of claims 1 to 6 wherein the step b. is performed in an alcohol solvent.

8. The process according to claim 7 wherein the solvent is selected from methanol or ethanol or propanol or isopropanol.

9. The process according to step 8 wherein the solvent is methanol.

10. The process according to any one of claims 7 to 9 wherein the compound of formula (5) is isolated directly from reaction mixture.

11. The process according to anyone of previous claims wherein the step c. comprises: a. Reductive cyclization of compound of formula (5) to obtain compound of formula (6A) and deprotecting compound of formula (6A) to obtain compound of formula (6),

The process according to claim 11 wherein the compound of formula 1 is transformed into a salt or a solvate.