Improved process for the preparation of 7-(morpholinyl)-2-(N-piperazinyl)methylthieno[2,3-c]pyridine derivatives

Abstract

The present invention describes an improved second generation process for the synthesis of NRC-1111 (1,5-[2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine) dimethanesulfonate and NRC-1109 (II,5-[3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate. This process is a cost-effective, high-yield and industrially feasible process for the synthesis of high purity compounds of formula I and II. Formula (I) For NRC-1111, formula (I): R = H and for NRC-1109, formula (II): R = CH3. NRC-1111 and NRC-1109 are potential anticancer agents. JPEG2024517127000031.jpg78147

Description

[Technical field]

[0001] Field of the invention: The present invention describes an improved second generation process for the synthesis of NRC-1111 (I, 5-[2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine) dimethanesulfonate and NRC-1109 (II, 5-[3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate. This process is a cost-effective, high-yielding and industrially feasible process for the synthesis of high purity compounds of formula I and II.

[0002] [ka]

[0003] NRC-1111 and NRC-1109 are potential anticancer agents. [Background technology]

[0004] Background of the invention: The present invention relates to an improved process for the preparation of potential anticancer agents NRC-1111 (Formula-I; R=H; 5-[2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine) dimesylate hydrate and NRC-1109 (Formula-II; R=CH3; 5-[3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimesylate hydrate.

[0005] Processes for the preparation of NRC-1111 and NRC-1109 are described in US 2017 / 0320891 published November 9, 2017.

[0006] The process is illustrated in Scheme-I shown below:

[0007] [ka]

[0008] The process illustrated in Scheme-I involves (i) esterification of 3-methylthiophene-2-carboxylic acid with dimethyl sulfate to give methyl 3-methylthiophene-2-carboxylate (Stage-I), which is reacted with N-bromosuccinimide in carbon tetrachloride solvent to give 3-(bromomethyl)-2-thiophenecarboxylic acid methyl ester (Stage-II). The Stage-II compound is cyanated with sodium cyanide in aqueous methanol to give 3-(cyanomethyl)-2-thiophenecarboxylic acid methyl ester (Stage-III), which is hydrolyzed with 1N sodium hydroxide in THF and methanol medium and acidified to give 3-(cyanomethyl)-2-thiophenecarboxylic acid (Stage-IV). Bromination cyclization of the Stage-IV compound with phosphorus tribromide in DMF medium at 120-125° C. gives 5,7-dibromothieno[2,3-c]pyridine (Stage-V), which is condensed with morpholine in a sealed tube at 105-110° C. to give 5-bromo-7-(4-morpholinyl)-thieno[2,3-c]pyridine (Stage-VI). Lithiation of the Stage-VI compound with n-BuLi followed by formylation with dimethylformamide (DMF) gives 5-bromo-7-(4-morpholinyl)-thieno[2,3-c]pyridine-2-carboxaldehyde (Stage-VII). The Stage-VII compound is reductively aminated with 1-methylsulfonyl-piperazine using sodium triacetoxyborohydride (STAB) to give 5-bromo-2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)-thieno[2,3-c]pyridine (Stage-VIII), which undergoes Suzuki coupling with 2-aminopyrimidine-5-boronic acid pinacol ester using bis(triphenylphosphine)palladium(II) dichloride to give 5-[2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine (NRC-1111 base).

[0009] This is a first generation process and has been developed on a small scale with an overall yield of 8%. A second generation process is being developed with the following objectives: 1. To develop pharma-ceutically acceptable salts of NRC-1111 and NRC-1109 and to identify stable polymorphs thereof. 2. Developing simplified processes with fewer operations that are suitable for scale-up. 3. Develop a cost-effective and high-yielding process. 4. Developing safe processes from an environmental perspective. 5. To develop a process that should give a final product of high purity (greater than 99.5%) and does not require further expensive purification. 6. To develop an industrially viable and robust process from the following Stage-V intermediates:

[0010] [ka]

[0011] The NRC-1111 process starts with the above intermediate where R=H as shown below:

[0012] [ka]

[0013] The NRC-1109 process starts with the above intermediate where R=CH3 as shown below:

[0014] [ka]

[0015] Thus, a second generation process that satisfies the above objectives is shown in Scheme-2:

[0016] [ka] Summary of the Invention [Means for solving the problem]

[0017] Summary of the invention: Considering the above mentioned requirements, the objective of the present invention is to develop an improved process which is environmentally friendly, safe, industrially applicable, does not have the drawbacks of the first generation processes and allows to synthesize the desired compound of formula-I in high purity (99.8%) and in high yield (about 22% overall yield).

[0018] Therefore, the primary objective of the present invention is to develop an improved process for preparation of 5-[2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine dimethanesulfonate hydrate, NRC-1111 dimesylate hydrate having formula-I by selecting Scheme-II as the operating route and designing all five stages of reaction conditions, work-up and purification.

[0019] Yet another object of the present invention is to develop a process for 5-bromo-7-(4-morpholinyl)-thieno[2,3-c]pyridine (Stage-VI) by avoiding sealed tube and excess molar morpholine.

[0020] Another object of the present invention is to develop an improved process for the preparation of 5-bromo-7-(4-morpholinyl)-thieno[2,3-c]pyridine-2-carboxaldehyde (Stage-VII) using tri-n-butyllithium magnesite (0.7M in hexane) reagent for lithiation, which avoids the problems of scale-up and consistently gives high purity product.

[0021] Another object of the present invention is to develop an improved process for the preparation of 5-bromo-2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)-thieno[2,3-c]pyridine (Stage-VIII) by replacing STAB with 2-picoline borane complex and modifying all the process parameters.

[0022] Yet another object of the present invention is to develop an improved process for the preparation of 5-[2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine (Stage-IX; NRC-1111 base) by replacing bis(triphenylphosphine)palladium (II) dichloride with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexed with dichloromethane to obtain high yield and pure product on multi-kilogram scale.

[0023] It is yet another object of the present invention to select the dimesylate salts as the acid addition salts of NRC-1111 and NRC-1109 and to prepare the corresponding hydrates, thus establishing the polymorphic nature of both NRC-1111 dimesylate hydrate and NRC-1109 dimesylate hydrate at the kilogram scale.

[0024] Another object of the present invention is to provide a crystalline form of 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) (NRC-1111 base) characterized by: i) Its powder X-ray diffraction pattern having peaks at about 9.31, 11.06, 18.64 and 20.05 ± 0.2 degrees 2-θ. ii) Powder X-ray diffraction pattern as shown in Figure 1.

[0025] Another object of the present invention is to provide a crystalline form of 5-[3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) (NRC-1109 base) characterized by: i) Its powder X-ray diffraction pattern having peaks at about 8.76, 9.45, 16.87, 18.39 and 19.50 ± 0.2 degrees 2-θ. ii) Powder X-ray diffraction pattern as shown in Figure 3.

[0026] Another object of the present invention is to provide a crystalline form of 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate hydrate (NRC-1111), characterized by: i) Its powder X-ray diffraction pattern having peaks at about 6.19, 15.11, 18.40, 18.65, 21.60, 22.56 and 25.13 ± 0.2 degrees 2-θ. ii) Powder X-ray diffraction pattern as shown in Figure 5.

[0027] Another object of the present invention is to provide a crystalline form of 5-[3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate salt hydrate (NRC-1109) characterized by: i) Its powder X-ray diffraction pattern having peaks at about 7.67, 10.69, 18.39, 19.58, 21.93 and 25.83 ± 0.2 degrees 2-θ. ii) Powder X-ray diffraction pattern as shown in Figure 7.

[0028] Another object of the present invention is to provide a process for the preparation of a crystalline form of 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate hydrate (NRC-1111), comprising the steps of: a) adding DM water to 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine (NRC-1111 base); b) Mix the reaction mixture for 90-100 min. o C. c) cooling the reaction mixture and adding methanol; d) adding methanesulfonic acid diluted in methanol to the reaction mixture; e) Stirring and filtering the mass to obtain the crystalline form of NRC-1111 dimethanesulfonate hydrate.

[0029] In stage-VI for the preparation of 5-bromo-7-(4-morpholinyl)-thieno[2,3-c]pyridine, the moles of morpholine, methacrylic acid relative to 5,7-dibromothieno[2,3-c]pyridine (stage-V) can be in the range of 2.0-3.0, preferably in the range of 2.25-2.50 moles. The moles of potassium carbonate relative to stage-V can be in the range of 2.0-4.0, preferably in the range of 2.0-3.0. The preferred solvent for the reaction is dimethylformamide (DMF).

[0030] In stage-VII for the preparation of 5-bromo-7-(4-morpholinyl)-thieno[2,3-c]pyridine-2-carboxaldehyde, the moles of tri-n-butyllithium magnesite in 0.7M hexane can be in the range of 0.9-1.3, preferably in the range of 1.1-1.2 moles. The moles of dimethylformamide can be in the range of 1.8-2.2, preferably in the range of 1.9-2.1 moles. The preferred solvent for the reaction is tetrahydrofuran (THF). Alternatively, stage-VI can be prepared using isopropylmagnesium bromide (1.5M in THF), n-butyllithium (1.6M in hexane) reagents.

[0031] In stage-VIII for the preparation of 5-bromo-2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)-thieno[2,3-c]pyridine, the number of moles of 1-methanesulfonylpiperazine can be in the range of 1.4-1.8, preferably in the range of 1.2-1.6. The number of moles of trimethyl orthoformate can be in the range of 14-18 moles, preferably in the range of 15-17. The number of moles of 2-picoline borane complex can be in the range of 2.5-3.5 moles, preferably in the range of 2.8-3.2.

[0032] In stage-IX for the preparation of 5-[2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine (NRC-1111 base), the mole number of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexed with dichloromethane can be in the range of 0.01 to 0.05 moles, preferably 0.05 moles. The base for the reaction can be selected from potassium phosphate, potassium acetate or potassium carbonate. Preferably it is potassium phosphate.

[0033] In stage-X for the preparation of 5-[2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine dimesylate hydrate, the corresponding base is refluxed with water to give the hydrate, which is subsequently treated with methanesulfonic acid to give the dimesylate hydrate. [Brief description of the drawings]

[0034] Brief description of the drawings: [Figure 1] FIG. 1: Illustrates the characteristic PXRD pattern of the NRC-1111 base crystalline form. [Diagram 2] FIG. 2: Illustrates the DSC thermogram of the NRC-1111 base crystalline form. [Diagram 3] FIG. 3: Illustrates the characteristic PXRD pattern of the NRC-1109 base crystalline form. [Figure 4] FIG. 4: Illustrates the DSC thermogram of the NRC-1109 base crystalline form. [Diagram 5] Figure 5: Illustrates the characteristic PXRD pattern of the NRC-1111 dimesylate hydrate crystal form. [Figure 6] FIG. 6: Illustrates the DSC thermogram of the NRC-1111 dimesylate hydrate crystal form. [Figure 7] Figure 7: Illustrates the characteristic PXRD pattern of the NRC-1109 dimesylate hydrate crystal form. [Figure 8] FIG. 8: Illustrates the DSC thermogram of the NRC-1109 dimesylate hydrate crystal form. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] PXRD Method of Analysis: PXRD analysis of crystalline forms of NRC-1111 and NRC-1109 and their salts was performed using a Panlytical Expert Pro DY3248 X-ray powder diffractometer with 10 wavelengths of Cu-Ka radiation at 1.5406 Å at a continuous scan rate of 0.03° / min.

[0036] Details of the invention are given in the examples provided below, which are provided for illustrative purposes only and therefore should not be construed as limiting the scope of the invention.

[0037] Working Example: Example-1: Process for preparation of stage-VI compound [where R=H]:

[0038] [ka]

[0039] Charge 425 ml of dimethylformamide and 85.0 ml (0.2901 mol) of 5,7-dibromothieno[2,3-c]pyridine at 25-35°C and stir for 5-10 min. Charge 100.22 g (0.7252 mol) of potassium carbonate followed by 63.16 g (0.7252 mol) of morpholine at 25-35°C. Increase the temperature of the mass to 100-110°C in 2 hrs. Cool the reaction mass to RT and filter the reaction mass. Wash the wet cake with methanol and charge the filtrate to 2975 ml of DM water at 20-25°C and stir for 30 min. Filter the solid and wash with methanol to obtain 80.55 g (92.78%) of light brown solid with 98.11% HPLC purity.

[0040] Example-2: Process for preparation of Stage-VI compound [where R=CH3]: Charge N,N-dimethylformamide (625 ml) and 5,7-dibromo 3-methylthieno[2,3-c]pyridine 125g (0.4071 mol) at 25-35°C and stir for 5-10 minutes. Charge potassium carbonate 168.81 g (1.221 mol) followed by morpholine 106.42 g (1.221 mol) at 25-35°C. Increase mass temperature to 110-115°C for 2 hours. Cool reaction mass to RT and filter reaction mass. Wash wet cake with methanol. Charge filtrate to DM water 2975 ml at 20-25°C and stir for 90 minutes. Filter solid and wash with methanol to obtain light brown solid 120.01g (94.11%) with 98.68% HPLC purity.

[0041] Example-3: Process for preparation of stage-VII compound [where R=H]:

[0042] [ka]

[0043] Charge 440 ml of dry tetrahydrofuran and 44.0 g (0.147 mol) of 4-(5-bromothieno[2,3-c]pyridin-7-yl)morpholine at 25-35°C. Cool the temperature of the mass to -60° to -70°C and charge 234.34 ml (0.1617 mol) of tri-n-butyllithium magnesite (0.7M in hexane). Stir the reaction mass for 90 minutes, charge 21.48 g (0.294 mol) of dry dimethylformamide and stir for 90 minutes. Increase the temperature of the mass to 0-5°C and stir for 45 minutes. Charge 2N HCl to the reaction mass at 0-5°C and stir for 15 minutes. Extract with ethyl acetate and wash with 10% sodium chloride solution. Evaporate the organic layer and charge the residue with a mixture of isopropyl ether and tetrahydrofuran. Increase the temperature of the mass to 55-60° C., bring the mass to RT and charge hexane to the reaction mass. Filter the solid and wash with hexane to give 25.42 g (52.48%) of a yellow solid with 99% HPLC purity.

[0044] Example-4: Alternative process for the preparation of stage-VII compound [where R=H]: Charge 200 ml of dry tetrahydrofuran and 20 g (0.0668 mol) of 4-(5-bromothieno[2,3-c]pyridin-7-yl)morpholine at 25-35°C. Cool the temperature of the mass to -60° to -70°C and charge 24.96 ml (0.0367 mol) of isopropylmagnesium bromide (1.5M in THF) followed by 45.95 ml (0.0735 mol) of n-butyllithium (1.6M in hexane). Stir the reaction mass for 90 minutes, charge 9.76 g (0.1336 mol) of dry dimethylformamide and stir for 90 minutes. Raise the temperature of the mass to 0-10°C and stir for 45 minutes. Add 2N Charge HCl to the reaction mass at 0-10°C and stir for 15 min. Extract with ethyl acetate and wash with 10% sodium chloride solution. Distill off the organic layer and charge isopropyl ether and tetrahydrofuran mixture to the residue. Increase the mass temperature to 55-60°C, bring the mass to RT and charge hexane to the reaction mass. Filter the solid and wash with hexane to obtain 16.02 g (73.25%) of yellow solid with 98.8% HPLC purity.

[0045] Example-5: Process for preparation of stage-VII compound [where R=CH3]: Charge 2200 ml of dry tetrahydrofuran and 110 g (0.3512 mol) of 4-(5-bromo-3-methylthieno-[2,3-c]pyridin-7-yl)-morpholine at 25-35°C. Cool the temperature of the mass to -65° to -71°C and slowly charge 451.52 ml (0.3161 mol) of tri-n-butyllithium magnesite (0.7M in hexane). Stir the reaction mass for 30 minutes, slowly charge 54.62 ml (0.7024 mol) of dry N,N-dimethylformamide and stir for 120 minutes. Increase the temperature of the mass to -15 to -25°C and quench the reaction mass with 2200 ml of 2N HCl at -15 to -25°C and stir for 15 minutes. Extract with dichloromethane and wash the organic layer with DM water. Evaporate the organic layer, charge the residue with methanol and filter the yellow solid. Yield: 75.6 g (63%) with 97.8% HPLC purity.

[0046] Example-6: Alternative process for preparation of stage-VII compound [R=CH3]: Charge 500 ml of dry tetrahydrofuran and 50 g (0.159 mol) of 4-(5-bromothieno[2,3-c]pyridin-7-yl)morpholine at 25-35°C. Cool the temperature of the mass to -60° to -70°C and charge 70.69 g (0.087 mol) of isopropylmagnesium bromide (1.5M in THF) followed by 52.5 g (0.175 mol) of n-butyllithium (1.6M in hexane). Stir the reaction mass for 90 minutes, charge 23.3 g (0.319 mol) of dry dimethylformamide and stir for 90 minutes. Increase the temperature of the mass to 0-10°C and stir for 45 minutes. Charge 2N HCl to the reaction mass at 0-10°C and stir for 15 minutes. Extract with ethyl acetate and wash with 10% sodium chloride solution. Evaporate off the organic layer and charge the residue with isopropyl ether and tetrahydrofuran mixture. Increase the mass temperature to 55-60°C, bring the mass to RT and charge hexane to the reaction mass. Filter the solid and wash with hexane to obtain 35.4 g (65%) of yellow solid with 98.10% HPLC purity.

[0047] Example-7: Process for preparation of compound of Stage-VIII [R=H]:

[0048] [ka]

[0049] Charge 650 ml of methanol and 65 g (0.1986 mol) of 5-bromo-7-morpholino-thieno[2,3-c]pyridine-2-carbaldehyde at 25-35°C. Charge 52.19 g (0.3178) of 1-methanesulfonylpiperazine followed by 316.07 g (2.979 mol) of trimethyl orthoformate and 11.90 g (0.1986 mol) of acetic acid and stir at 55-60°C for 4 hours. Dissolve 63.72 g (0.5958) of 2-picoline borane complex in 130 ml of THF and charge the reaction mass at 55-60°C and stir for 3 hours. Cool the mass to RT and filter the reaction mass and wash with methanol. Charge 975.0 ml dichloromethane and the crude solid followed by 39.65 ml concentrated HCl at 25-30° C. Raise temperature to reflux and maintain for 30 min, bring to RT and filter. Charge wet compound in DM water and purify with aqueous ammonia at 25-30° C. H Neutralize to 9-10. Filter the solid and wash with DM water, dry at 55-60° C. to give 77.24 g (81.8%) of a yellow compound with 99.4% HPLC purity.

[0050] Example-8: Process for preparation of compound of Stage-VIII [R=CH3]: Charge 1200 ml of methanol and 60 g (0.1758 mol) of 5-bromo-3-methyl-7-morpholino-thieno[2,3-c]pyridine at 25-35°C. Charge 46.20 g (0.281 mol) of 1-methanesulfonylpiperazine followed by 279.87 g (2.637 mol) of trimethyl orthoformate and 10.55 g (0.1758 mol) of acetic acid and stir at 60-65°C for 4 hours. Dissolve 56.43 g (0.528) of 2-picoline borane complex in 120 ml of THF and slowly charge the reaction mass at 60-65°C and stir for 3 hours. Cool the mass to RT and filter the reaction mass and wash with methanol. Charge 975 ml dichloromethane and the crude solid followed by 39.65 ml concentrated HCl at 25-30° C. Raise temperature to reflux and maintain for 30 min, bring to RT and filter. Charge the wet compound in DM water and purify with aqueous ammonia at 25-30° C. H Neutralize to 9-10. Filter the solid and wash with DM water, dry at 55-60° C. to give 63.84 g (74.2%) of a yellow compound with 98.5% HPLC purity.

[0051] Example-9: Process for the preparation of stage-IX compound [where R=H]:

[0052] [ka]

[0053] Charge 64.31 g (0.303 mol) of potassium phosphate, 86.4 ml of DM water and 720 ml of tetrahydrofuran and degas under nitrogen atmosphere for 60 minutes at 25-30° C. Charge 72 g (0.1515) of 4-[5-bromo-2[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[2,3-c]pyridin-7-yl]morpholine and 40.18 g (0.1818 mol) of 2-aminopyrimidine-5-boronic acid pinacol ester and degas under nitrogen atmosphere for 45 minutes at 25-30° C. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexed with 6.186 (0.00757 mol) dichloromethane is charged to the reaction mass and degassed at 25-30°C for 10 min under nitrogen atmosphere. The temperature of the mass is raised to 60-65°C for 5 h under nitrogen atmosphere. The reaction mixture is cooled to RT and charged with 720 ml DM water and the solid is filtered and washed with DM water. The crude solid is purified by acid-base purification method to obtain 53.09g (71.5%) with 99.8% HPLC purity. XRD and DSC are shown in Figures 1 and 2.

[0054] Example-10: Process for preparation of Stage-IX compound [R=CH3]: Charge 47.71 g (0.2247 mol) of potassium phosphate, 66 ml of DM water and 550 ml of tetrahydrofuran and degas under nitrogen atmosphere for 60 minutes at 25-30° C. Charge 55 g (0.1123) of 4-[5-bromo 3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[2,3-c]pyridin-7-yl]morpholine and 29.81 g (0.1348 mol) of 2-aminopyrimidine-5-boronic acid pinacol ester and degas under nitrogen atmosphere for 45 minutes at 25-30° C. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexed with 4.59 g (0.00562 mol) of dichloromethane is charged to the reaction mass and degassed at 25-30° C. for 10 min under nitrogen atmosphere. The temperature of the mass is raised to 60-65° C. for 5 h under nitrogen atmosphere. The reaction mixture is cooled to RT and filtered. The crude solid is purified by acid-base purification method to obtain 43.1 g (76.2%) with 99.81% HPLC purity. XRD and DSC are shown in Figures 3 and 4.

[0055] Example-11: Process for the preparation of stage-X compound [where R=H]:

[0056] [ka]

[0057] Charge 350 ml DM water and 140 g (0.285 mol) 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine at 25-30°C and stir for 5-10 min. Increase temperature of reaction mass to 90-100°C in 1 h. Cool reaction mass to RT and stir for 2 h. Charge 2800 ml methanol at 25-30°C and stir for 5-10 min. Charge 109.92 (1.143 mol) methanesulfonic acid diluted in 420 ml methanol to reaction mass at 25-30°C. The reaction mass is stirred for 2 hours and the reaction mass is filtered and washed with 140 ml of methanol to obtain 208.87g (1.5% w / w) of 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine dimesylate hydrate with 99.9% HPLC purity and assay by HPLC is 101.4% w / w. Water content by Karl Fischer: 10%; XRD and DSC are shown in Figures 5 and 6.

[0058] Example-12: Process for preparation of stage-X compound [R=CH3]: Charge 750 ml of methanol and 30 g (0.0595 mol) of 5-[3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7 morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine and 2.41 g (0.119 mol) of DM water at 25-30° C. and stir for 5-10 minutes. Charge 14.31 g (0.1489 mol) of methanesulfonic acid diluted in 150 ml of methanol to the reaction mass at 25-30° C. Increase the temperature of the reaction mass to 60-65° C. for 1 hour. The reaction mass is filtered at 45° C. and washed with 300 ml of methanol to obtain 37.93 g (1.26% w / w) of 5-[3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine dimesylate hydrate with 99.8% HPLC purity; Assay by HPLC is 100.0% w / w. Water content by Karl Fischer: 5%; XRD and DSC are shown in Figures 7 and 8.

[0059] Advantages of this invention: 1. Stabilization at multi-kilogram scale levels. 2. High yield (approximately ~20% overall yield) process. 3. High purity (99.8%) NRC-1111 dimesylate hydrate and NRC-1109 dimesylate hydrate can be obtained. 4. Simple and industrially applicable process.

Claims

1. The method comprises the steps of: 【Chemistry 1】 Improved process for the preparation of 5-[3-substituted-2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine) dimethanesulfonate compound: a) Formula-(V) 【Chemistry 2】 is reacted with morpholine in the presence of a suitable base and solvent to obtain a compound of formula-(VI) 【Chemistry 3】 providing a compound of formula (I); b) treating the compound of formula-(VI) with a suitable base in a solvent followed by formylation with dimethylformamide to provide a compound of formula-(VII); (or) The compound of formula-(VI) is treated with a Grignard reagent and a suitable base in a solvent, followed by formylation with dimethylformamide to give the compound of formula-(VII). 【Chemistry 4】 providing a compound of formula (I); c) The compound of formula-(VII) is reacted with 1-methylsulfonyl-piperazine in the presence of 2-picoline borane complex and trimethyl orthoformate in a solvent to obtain the compound of formula-(VIII). 【Chemistry 5】 providing a compound of formula (I); d) Reaction of the compound of formula-(VIII) with 2-aminopyrimidine-5-boronic acid pinacol ester in the presence of PdCl2(dppf)DCM complex, a suitable base and a solvent to give the compound of formula-(IX) 【Chemistry 6】 providing a compound of formula (I); e) treating the compound of formula-(IX) with methanesulfonic acid in a solvent to provide the compound of formula-(I).

2. In step (a), the base is an inorganic base, wherein the inorganic base is selected from alkali and alkaline earth metal carbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, or any other equivalent base; In step (b), the base is selected from n-butyllithium and tri-n-butyllithium magnesite; and the Grignard reagent is an alkylmagnesium halide, preferably isopropylmagnesium bromide; In step (d), the base is an inorganic base selected from potassium phosphate, potassium acetate or potassium carbonate, preferably potassium phosphate; 2. The process according to claim 1, wherein in steps-a, b, c, d and e), the suitable solvent is selected from alcohol solvents, polar aprotic solvents, ether solvents, hydrocarbon solvents, nitrile solvents, and polar solvents such as water, or mixtures thereof.

3. 2. The process according to claim 1, wherein in step-a), the mole number of morpholine relative to formula-(V) is in the range of 2.0-3.0, preferably in the range of 2.25-2.50 moles, and the mole number of potassium carbonate relative to formula-(V) is in the range of 2.0-4.0, preferably in the range of 2.0-3.0 moles.

4. The process according to claim 1, wherein in step-b), the molar number of formula-(VI) relative to tri-n-butyllithium magnesite in hexane is in the range of 0.9-1.3, preferably in the range of 1.1-1.2 moles, and the molar number of dimethylformamide relative to formula-(VI) is in the range of 1.8-2.2, preferably in the range of 1.9-2.1 moles.

5. 2. The process according to claim 1, wherein in step-c), the molar number of formula-(VII) relative to 1-methanesulfonylpiperazine is in the range of 1.4-1.8, preferably in the range of 1.2-1.6, and the molar number of formula-(VII) relative to trimethyl orthoformate is in the range of 14-18, preferably in the range of 15-17, and the molar number of formula-(VII) relative to 2-picoline borane complex is in the range of 2.5-3.5, preferably in the range of 2.8-3.

2.

6. The process according to claim 1, wherein in step-d), the molar number of formula-(VIII) relative to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexed with dichloromethane is in the range of 0.01 to 0.05 moles, preferably 0.05 moles.

7. 2. The process according to claim 1, wherein the compound of formula-(VI) is prepared by reacting the compound of formula-(V) with morpholine in the presence of a suitable inorganic base selected from alkali and alkaline earth metal carbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, and the solvent is a polar aprotic solvent such as dimethylformamide.

8. The process according to claim 1, wherein the compound of formula-(VII) is prepared by treating the compound of formula-(VI) with tri-n-butyllithium magnesite in tetrahydrofuran, followed by formylation with dimethylformamide to provide the compound of formula-(VII).

9. The process according to claim 1, wherein the compound of formula-(VII) is prepared by treating the compound of formula-(VI) with isopropylmagnesium bromide and n-butyllithium in tetrahydrofuran, followed by formylation with dimethylformamide to provide the compound of formula-(VII).

10. The process according to claim 1, wherein the compound of formula-(VIII) is prepared by reacting the compound of formula-(VII) with 1-methylsulfonyl-piperazine in the presence of 2-picoline borane complex, trimethyl orthoformate and acetic acid in methanol to provide the compound of formula-(VIII).

11. The process according to claim 1, wherein the compound of formula-(IX) is prepared by reacting the compound of formula-(VIII) with 2-aminopyrimidine-5-boronic acid pinacol ester in the presence of PdCl2(dppf)DCM complex, potassium phosphate in tetrahydrofuran to provide the compound of formula-(IX).

12. 2. The process according to claim 1, wherein the compound of formula-(I) (NRC-1111) is prepared by treating the compound of formula-(IX) with methanesulfonic acid in aqueous methanol to provide the (NRC-1111) dimethanesulfonate compound of formula-(I).

13. 5-[2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine) dimethanesulfonate (NRC-1111), comprising the steps of: 【Chemistry 7】 2. The process according to claim 1 for the preparation of a) Formula-(V) 【Chemistry 8】 The compound of formula (VI) is reacted with morpholine in the presence of potassium carbonate base in dimethylformamide solvent to obtain a compound of formula (VI) 【Chemistry 9】 providing a compound of formula (I), b) treating the compound of formula-(VI) with tri-n-butyllithium magnesite reagent in tetrahydrofuran solvent followed by formylation with dimethylformamide to provide compound of formula-(VII); (or) The compound of formula-(VI) is treated with the reagents isopropylmagnesium bromide and n-butyllithium in tetrahydrofuran solvent, followed by formylation with dimethylformamide to give the compound of formula-(VII). 【Chemistry 10】 providing a compound of formula (I), c) The compound of formula-(VII) is reacted with 1-methylsulfonyl-piperazine in the presence of reagents 2-picoline borane complex, trimethyl orthoformate and acetic acid in methanol solvent to obtain the compound of formula-(VIII). 【Chemistry 11】 providing a compound of formula (I), d) The compound of formula-(VIII) is reacted with 2-aminopyrimidine-5-boronic acid pinacol ester in the presence of catalytic PdCl2(dppf)DCM complex and potassium phosphate base in tetrahydrofuran solvent to obtain the compound of formula-(IX): 【Chemistry 12】 providing a compound of formula (I), e) treating the compound of formula-(IX) with methanesulfonic acid in aqueous methanol to provide the compound of formula-(I) (NRC-1111).

14. 5-[3-methyl-2-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-7-(4-morpholinyl)thieno[2,3-c]pyridin-5-yl]-2-pyrimidinamine) dimethanesulfonate (NRC-1109), comprising the steps of: 【Chemistry 13】 2. The process according to claim 1 for the preparation of a) Formula-(V) 【Chemistry 14】 The compound of formula (VI) is reacted with morpholine in the presence of potassium carbonate base in dimethylformamide solvent to obtain a compound of formula (VI) 【Chemistry 15】 providing a compound of formula (I), b) treating the compound of formula-(VI) with tri-n-butyllithium magnesite reagent in tetrahydrofuran solvent followed by formylation with dimethylformamide to provide compound of formula-(VII); (or) The compound of formula-(VI) is treated with the reagents isopropylmagnesium bromide and n-butyllithium in tetrahydrofuran solvent, followed by formylation with dimethylformamide to give the compound of formula-(VII). 【Chemistry 16】 providing a compound of formula (I), c) The compound of formula-(VII) is reacted with 1-methylsulfonyl-piperazine in the presence of reagents 2-picoline borane complex, trimethyl orthoformate and acetic acid in methanol solvent to obtain the compound of formula-(VIII). 【Chemistry 17】 providing a compound of formula (I), d) The compound of formula-(VIII) is reacted with 2-aminopyrimidine-5-boronic acid pinacol ester in the presence of catalytic PdCl2(dppf)DCM complex and potassium phosphate base in tetrahydrofuran solvent to obtain the compound of formula-(IX). 【Chemistry 18】 providing a compound of formula (I), e) treating the compound of formula-(IX) with methanesulfonic acid in aqueous methanol to provide the compound of formula-(II) (NRC-1109).

15. 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate (NRC-1111).

16. The compound of claim 15 which is a hydrate.

17. A crystalline form of 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) (NRC-1111 base) characterized by: i) its powder X-ray diffraction pattern having peaks at about 9.31, 11.06, 18.64 and 20.05 ± 0.2 degrees 2-θ; ii) Powder X-ray diffraction pattern as shown in Figure 1.

18. 16. The compound of claim 15, which is a crystalline form of 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate hydrate (NRC-1111), characterized by: i) its powder X-ray diffraction pattern having peaks at about 6.19, 15.11, 18.40, 18.65, 21.60, 22.56 and 25.13 ± 0.2 degrees 2-θ; ii) Powder X-ray diffraction pattern as shown in Figure 5.

19. 5-[3-Methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate hydrate (NRC-1109).

20. A crystalline form of 5-[3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) (NRC-1109 base) characterized by: i) its powder X-ray diffraction pattern having peaks at about 8.76, 9.45, 16.87, 18.39 and 19.50 ± 0.2 degrees 2-θ; ii) Powder X-ray diffraction pattern as shown in Figure 3.

21. 20. The compound of claim 19, which is a crystalline form of 5-[3-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate hydrate (NRC-1109), characterized by: i) its powder X-ray diffraction pattern having peaks at about 7.67, 10.69, 18.39, 19.58, 21.93 and 25.83 ± 0.2 degrees 2-θ; ii) Powder X-ray diffraction pattern as shown in Figure 7.

22. A process for the preparation of the crystalline form of 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine) dimethanesulfonate hydrate (NRC-1111) according to claim 18, comprising the steps of: a) adding DM water to 5-[2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-morpholino-thieno[2,3-c]pyridin-5-yl]pyrimidin-2-amine (NRC-1111 base); b) heating the reaction mixture to 90-100° C.; c) cooling the reaction mixture and adding methanol; d) adding methanesulfonic acid diluted in methanol to the reaction mixture; e) stirring and filtering the mass to obtain NRC-1111 dimethanesulfonate hydrate crystal form.

Images