An improved process for preparation of zastaprazan

Abstract

The present invention relates to an improved process for preparation of Zastaprazan or its pharmaceutically acceptable salts, which comprises: a) reaction of methyl 5,6- diaminonicotinate and 3-bromobutan-2-one to obtain methyl 8-amino-2,3-dimethyl imidazo[1,2-a]pyridine-6-carboxylate hydrobromide salt, b) reaction of obtained compound in step a) with 2,6-dimethylbenzyl chloride in presence of base in solvent, in absence of catalyst to obtain methyl 8-((2,6-dimethylbenzyl)amino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate, c) hydrolysis of the obtained compound in step b) in presence of base in a solvent to obtain 8-((2,6-dimethylbenzyl)amino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid d) condensation of obtained compound in step c) with azetidine or its salts in presence of condensing agent, base and solvent to obtain Zastaprazan, wherein condensing agent is selected from PyBOP or T3P.

Description

[0001] AN IMPROVED PROCESS FOR PREPARATION OF ZASTAPRAZAN

[0002] FIELD OF INVENTION

[0003] The present invention relates to an improved process for preparation of Zastaprazan or its pharmaceutically acceptable salts.

[0004] BACKGROUND OF THE INVENTION

[0005] Zastaprazan (coded as OCN-101 / JP-1366) is chemically known as azetidin-l-yl-[8-[(2,6- dimethyl phenyl)methylamino]-2,3-dimethylimidazo[l,2-a]pyridin-6-yl]methanone represented by structural Formula I as below:

[0006] Formula I

[0007] Onconic Therapeutics, a subsidiary of Jeil Pharmaceutical has completed the phase 3 clinical trial of Zastaprazan in Korea. Zastaprazan is used for treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases, such as peptic ulcer, gastric / duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD), are the most common diseases suffered by most of the world's population, including Korea. It is a digestive disease.

[0008] Zastaprazan and its pharmaceutically acceptable salts are disclosed in U.S. Patent No. US

[0009] 10,696,671 B2 (herein after referred as ‘671). US ‘671 describes a process for preparation of

[0010] Zastaprazan, the synthetic process is represented schematically as shown below in scheme I:

[0011] Scheme I

[0012] The process disclosed in US ‘671 involves the use of EDCI, which is hygroscopic as well as genotoxic, and not suitable for commercial use. Further the disclosed process involves column purification of Zastaprazan, which tedious and not suitable for industrial preparations.

[0013] W02002020523 Al discloses the preparation methyl 8-((2,6-dimethylbenzyl) amino)-2,3- dimethylimidazo[l,2-a]pyridine-6-carboxylate, which an intermediate useful in the synthesis of Zastaprazan, the synthetic process is represented schematically as shown below in scheme II:

[0014] Scheme II The process disclosed in WO ‘523 involves the use of methyl tert-butyl ether for isolating Methyl 8-amino-2,3-dimethyl imidazo[l,2-a]pyridine-6-carboxylate. Further the disclosed process involves column purification, which tedious and not suitable for industrial preparations.

[0015] In view of the above, there is a need to provide a process for preparation of Zastaprazan, which avoids the use of condensing agent which are not stable and column chromatographic purification and use of expensive reagents which leads to simple, reproducible and is well suited for industrial scale preparation.

[0016] OBJECTIVES OF THE INVENTION

[0017] One objective of the present invention is to provide a process for preparation of Zastaprazan, which avoids column chromatographic purification.

[0018] Another objective of the present invention is to provide a process for preparation of Zastaprazan, which resulted in high yield and purities.

[0019] Another objective of the present invention is to provide a process for preparation of Zastaprazan, which avoids condensing agents that are genotoxic and hygroscopic in nature.

[0020] Another objective of the present invention is to provide a process for preparation of Zastaprazan, which is commercially and industrially feasible.

[0021] SUMMARY OF THE INVENTION

[0022] In one embodiment, the present invention provides an improved process for preparation of Zastaprazan or its pharmaceutically acceptable salts of compound of formula I: Formula I which comprises: a) reaction of methyl 5,6-diaminonicotinate compound of Formula II Formula II and 3-Bromobutan-2-one to obtain methyl 8-amino-2,3-dimethyl imidazo[l,2-a]pyridine-6- carboxylate hydrobromide salt compound of Formula III,

[0023] Formula III b) reaction of compound of Formula III with 2,6-dimethylbenzyl chloride in presence of base in solvent, in absence of catalyst to obtain methyl 8-((2,6-dimethylbenzyl)amino)-2,3- dimethylimidazo[l,2-a]pyridine-6-carboxylate compound of Formula IV, c) hydrolysis of compound of Formula IV in presence of base in a solvent to obtain 8-((2,6- dimethylbenzyl)amino)-2,3-dimethylimidazo[l,2-a]pyridine-6-carboxylic acid compound of Formula V,

[0024] d) condensation of compound of Formula V with azetidine or its sats in presence of condensing agent, base and solvent to obtain Zastaprazan compound of formula I, wherein condensing agent is selected from PyBOP or T3P. e) optionally converting the compound of Formula I into its pharmaceutically acceptable salts.

[0025] In another embodiment, the present invention provides methyl 8-((2,6-dimethylbenzyl)amino)- 2,3-dimethylimidazo[l,2-a]pyridine-6-carboxylate compound of Formula IV, which comprises reaction of compound of Formula III

[0026] Formula III with 2,6-dimethylbenzyl chloride in presence of base in solvent, in absence of catalyst to obtain compound of Formula IV. In another embodiment, the present invention provides an improved process for preparation of Zastaprazan or its pharmaceutically acceptable salts compound of Formula I: which comprises condensation of 8-((2,6-dimethylbenzyl)amino)-2,3-dimethyl imidazo[l,2- a]pyridine-6-carboxylic acid compound of Formula V : with azetidine or its salts in presence of condensing agent, base and solvent to obtain compound of formula I, wherein condensing agent is selected from PyBOP or T3P.

[0027] In another embodiment, the present invention provides Zastaprazan crystalline form designated as Form H which is characterized by Powder X-Ray Diffraction, having the 20 characteristic peaks at 7.4, 9.3 and 13.8 ± 0.2 degrees.

[0028] In another embodiment, the present invention provides a process for the preparation of Zastaprazan crystalline Form H, which comprises: a. dissolving Zastaprazan in an alcoholic solvent; b. removing the solvent from the solution; and c. isolating Zastaprazan crystalline Form H. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 shows powder X-ray diffractogram pattern of Zastaprazan crystalline Form H.

[0030] X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-a radiation. Adequate sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 increment and scan speed of 0.2 sec / step. The sample was placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] In one aspect of the present invention provides an improved process for preparation of Zastaprazan or its pharmaceutically acceptable salts of compound of Formula I: which comprises: a) reaction of methyl 5,6-diaminonicotinate compound of Formula II and 3- bromobutan-2-one to obtain methyl 8-amino-2,3-dimethyl imidazo[l,2-a]pyridine-6- carboxylate hydrobromide salt compound of Formula III, b) reaction of compound of Formula III with 2,6-dimethylbenzyl chloride in presence of base in solvent, in absence of catalyst to obtain Methyl 8-((2,6-dimethylbenzyl)amino)-2,3-dimethylimidazo[ 1 ,2-a]pyridine-6- carboxylate compound of Formula IV, c) hydrolysis of compound of Formula IV in presence of base in a solvent to obtain 8-((2,6-dimethylbenzyl)amino)-2,3-dimethylimidazo[l,2-a]pyridine- 6-carboxylic acid compound of Formula V, d) condensation of compound of Formula V with azetidine or its salts in presence of condensing agent, base and solvent to obtain compound of formula I, wherein condensing agent selected from PyBOP or T3P, e) optionally converting the compound of Formula I into its pharmaceutically acceptable salts.

[0033] The above process is outlined below in scheme III:

[0034]

[0035] Scheme III

[0036] In step a), reaction of compound of Formula II and 3-Bromobutan-2-one is carried out in ketone solvent, wherein ketone solvent is selected from group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclopentanone or cyclohexanone.

[0037] The reaction temperature may range from 70-110 °C and preferably at a temperature in the range from 95-105 °C. The duration of the reaction may range from 1-5 hours, preferably for a period of 2 hours.

[0038] Use of acetone for isolation of compound of Formula III is advantageous when compare to W02002020523 Al, wherein discloses the use of Methyl tert-butyl ether for isolation of compound of Formula III, which is expensive and highly flammable and not suitable for commercial purpose.

[0039] In step b), reaction of compound of Formula III with 2,6-dimethylbenzyl chloride is carried out in presence of base in solvent, wherein base is inorganic base, solvent is alcoholic solvent.

[0040] Inorganic base is selected from the groups consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or cesium bicarbonate. Alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol or butanol.

[0041] The reaction is carried out in absence of catalyst, which is advantageous when compared to prior art such W02002020523A1 and US10696671B2, wherein involves use of sodium iodide or potassium iodide.

[0042] The reaction temperature may range from 60-90 °C and preferably at a temperature in the range from 70-75 °C. The duration of the reaction may range from 1-5 hours, preferably for a period of 3 hours.

[0043] In step c), hydrolysis of compound of Formula IV is carried out in presence of base in solvent, wherein base is inorganic base, solvent is alcoholic solvent.

[0044] Inorganic base is selected from the groups consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or cesium bicarbonate, preferably sodium hydroxide.

[0045] Alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol or butanol.

[0046] The reaction temperature may range from 45-85 °C and preferably at a temperature in the range from 60-70 °C. The duration of the reaction may range from 1-5 hours, preferably for a period of 1 hour.

[0047] In step d), condensation of compound of Formula V with azetidine or its salts in presence of condensing agent, base and solvent.

[0048] Condensing agent is selected from PyBOP or T3P, base is organic base; solvent is selected from group consisting of dimethylformamide, dimethylacetamide, dimethylsulphoxide or methanol.

[0049] Organic base is selected from triethylamine or diisopropylethylamine. The reaction temperature may range from 25-70 °C and preferably at a temperature in the range from 45-55 °C. The duration of the reaction may range from 1-5 hours, preferably for a period of 2 hours.

[0050] In another aspect of the present invention provides Zastaprazan crystalline form designated as Form H having 20 characteristic peaks at 7.4, 9.3 and 13.8 ± 0.2 degrees.

[0051] In another aspect of the present invention provides a process for the preparation of Zastaprazan crystalline Form H, which comprises: dissolving Zastaprazan in an alcoholic solvent; removing the solvents from the solution; and isolating Zastaprazan crystalline Form H.

[0052] In another aspect of the present invention, the alcoholic solvent is selected from methanol, ethanol, isopropanol or propanol.

[0053] Zastaprazan is converted into Zastaprazan citrate using citric acid in acetone.

[0054] In the present invention abbreviations used have the meanings as below:

[0055] PyBOP : Benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate EDO / EDC. HC1: l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide chloride HATU: Hexafluorophosphate azabenzotriazole tetramethyl uranium T3P: Propylphosphonic anhydride

[0056] In the following section embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilled in the art.

[0057] Examples:

[0058] Example 1: Preparation of Methyl 8-amino-2,3-dimethyl imidazo[l,2-a]pyridine-6- carboxylate hydrobromide compound of Formula III

[0059] 3-Bromobutan-2-one (99 grams) was added to a mixture of Methyl 5,6-diaminonicotinate (100 grams) and cyclohexanone (1000 mL). Heated the reaction mixture to 95-105 °C and stirred for 2 hours. After completion of the reaction, the reaction mixture was washed with acetone to get title compound. Yield: 135 grams; purity by HPLC: 91.23 %.

[0060] Example 2: Preparation of Methyl 8-((2,6-dimethylbenzyl)amino)-2,3- dimethylimidazo[l,2-a]pyridine-6-carboxylate compound of Formula IV

[0061] 2,6-dimethylbenzyl chloride (38 grams) and sodium carbonate (88 grams) were added to a mixture of compound of Formula III (50 grams) and isopropyl alcohol (500 mL) at 25 -35 °C. Heated the reaction mixture to 70-75° C and stirred for 3 hours. After completion of reaction, the reaction mixture was cooled to 25-35 °C. Isopropyl alcohol (500 mL) was added to reaction mixture, heated the reaction mixture to 60-70 °C and then cooled to 0-10 °C. Filtered the reaction mixture and then dried to get title compound.

[0062] Yield: 50 grams; purity by HPLC: 99.63 %.

[0063] Example 3: Preparation of 8-((2,6-dimethylbenzyl)amino)-2,3-dimethyl imidazo[l,2- a]pyridine-6-carboxylic acid compound of Formula V

[0064] A mixture of Compound of Formula IV (100 grams), sodium hydroxide (47 grams) and methanol (1000 mL) was heated to 60-70 °C and stirred for 1 hour. After completion of reaction, distilled off the solvent from reaction mixture. Water was added to the obtained residue and acidified with hydrochloric acid followed by acetic acid. Filtered the compound and then dried to get title compound.

[0065] Yield: 90 grams; purity by HPLC: 99.68 %

[0066] Example 4: Preparation of Zastaprazan using HATU

[0067] HATU (1.71 grams), azetidine (0.32 grams), diisopropylethylamine (1.16 grams) were added to a mixture of 8-((2,6-dimethylbenzyl)amino)-2,3-dimethylimidazo [l,2-a]pyridine-6-carboxylic acid (1 grams) and dimethylformamide (10 mL) at 15-20 °C and stirred for 3hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. Distilled off the solvent to get title compound.

[0068] Yield: 0.5 grams; % yield: 44.6 %; purity: 43.64 %.

[0069] Example 5: Preparation of Zastaprazan using EDC. HC1 EDC.HC1 (4.41 grams), azetidine (1.65 g), triethylamine (6.2 grams) were added to a mixture of 8-((2,6-dimethylbenzyl)amino)-2,3-dimethylimidazo[l,2-a] pyridine-6-carboxylic acid (5 grams) and dimethylformamide (10 mL) at 0-5 °C and stirred for 4 hours. After completion of the reaction, the reaction mixture was quenched with aq. Sodium bicarbonate and extracted with dichloromethane. Distilled off the solvent to get title compound. Yield: 4 grams; % yield: 71 %; purity: 79.94 %.

[0070] Example 6: Preparation of Zastaprazan using PyBOP

[0071] PyBOP (120.5 grams), azetidine hydrochloride (20.2 grams), diisopropylethylamine (39.8 grams) were added to a mixture of 8-((2,6-dimethylbenzyl)amino)-2,3-dimethylimidazo[l,2- a]pyridine-6-carboxylic acid (50 grams) and dimethylformamide (500 mL) at 0-5 °C. Heated the reaction mixture and stirred for 1 hour. After completion of the reaction, the reaction mixture was quenched with water and extracted with dichloromethane. Distilled off the solvent to get title compound.

[0072] Yield: 55 grams; Yield %: 98.2%; purity by HPLC: 99.88%.

[0073] Example 7: Preparation of Zastaprazan using T3P

[0074] T3P (60 grams), azetidine hydrochloride (4 grams), diisopropylethylamine (7 grams) were added to a mixture of compound of Formula V (10 grams) and dimethylformamide (100 mL) at 25-35 °C and stirred for overnight. After completion of the reaction, the reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried to get title compound.

[0075] Yield: 7.8 grams.

[0076] Example 4: Preparation of Zastaprazan crystalline Form H

[0077] Methanol (400 mL) was added to Zastaprazan (55 grams) at 25-30 °C. Heated the reaction mixture to 60-65 °C and stirred for 1 hour. Cooled the reaction mixture to 0-5 °C and filtered the compound and dried to get Zastaprazan crystalline Form H.

[0078] Yield: 41 grams.

[0079] PXRD of the obtained compound is represented in Figure 1.

Claims

We claim:

1. An improved process for preparation of Zastaprazan or its pharmaceutically acceptable salts of compound of formula I:Formula I which comprises: a) reaction of methyl 5,6-diaminonicotinate compound of Formula IIFormula II and 3-bromobutan-2-one to obtain methyl 8-amino-2,3-dimethyl imidazo[l,2-a]pyridine-6- carboxylate hydrobromide salt compound of Formula III,b) reaction of compound of Formula III with 2,6-dimethylbenzyl chloride in presence of base in solvent, in absence of catalyst to obtain methyl 8-((2,6-dimethylbenzyl)amino)-2,3- dimethylimidazo[l,2-a]pyridine-6-carboxylate compound of Formula IV,c) hydrolysis of compound of Formula IV in presence of base in a solvent to obtain 8-((2,6- dimethylbenzyl)amino)-2,3-dimethylimidazo[l,2-a]pyridine-6-carboxylic acid compound of Formula V,d) condensation of compound of Formula V with azetidine or its salts in presence of condensing agent, base and solvent to obtain Zastaprazan compound of formula I, wherein condensing agent selected from PyBOP or T3P, e) optionally converting the compound of Formula I into its pharmaceutically acceptable salts.

2. An improved process for preparation of Methyl 8-((2,6-dimethylbenzyl)amino)-2,3- dimethylimidazo[l,2-a]pyridine-6-carboxylate compound of Formula IV,which comprises of reaction of compound of Formula IIIFormula III with 2,6-dimethylbenzyl chloride in presence of base in solvent, in absence of catalyst to obtain compound of Formula IV.

3. The process as claimed in claims 1 and 2, wherein the base in inorganic base selected from the groups consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, or cesium bicarbonate.

4. The process as claimed in claims 1 and 2, wherein the solvent is alcoholic solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol or butanol.

5. An improved process for preparation of Zastaprazan or its pharmaceutically acceptable salts compound of Formula I:which comprises of condensation of 8-((2,6-dimethylbenzyl)amino)-2,3- dimethylimidazo[l,2-a]pyridine-6-carboxylic acid compound of Formula V :with azetidine or its salts in presence of condensing agent, base and solvent to obtain compound of formula I, wherein condensing agent selected from PyBOP or T3P.

6. The process as claimed in claims 1 and 5, wherein the base is organic base selected from the group consisting of triethylamine or diisopropylethylamine.

7. The process as claimed in claims 1 and 5, wherein the solvent is selected from group consisting of dimethylformamide, dimethylacetamide, dimethylsulphoxide or methanol8. Zastaprazan crystalline form designated as Form H which is characterized by Powder X-Ray Diffraction, having the °29 characteristic peaks at 7.4, 9.3 and 13.8 ± 0.2 degrees.

9. A process for the preparation of Zastaprazan crystalline Form H, which comprises: a. dissolving Zastaprazan in an alcoholic solvent; b. removing the solvent from the solution; and c. isolating Zastaprazan crystalline Form H.

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