[go: up one dir, main page]

WO2025215593A1 - Procédé amélioré pour la préparation de zastaprazan - Google Patents

Procédé amélioré pour la préparation de zastaprazan

Info

Publication number
WO2025215593A1
WO2025215593A1 PCT/IB2025/053808 IB2025053808W WO2025215593A1 WO 2025215593 A1 WO2025215593 A1 WO 2025215593A1 IB 2025053808 W IB2025053808 W IB 2025053808W WO 2025215593 A1 WO2025215593 A1 WO 2025215593A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
solvent
zastaprazan
base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/053808
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Bandi Vamsi Krishna
Ray Uttam Kumar
Boju Sreenivasulu
Nethinti CHANDRASEKHARA RAO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hetero Labs Ltd
Original Assignee
Hetero Labs Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hetero Labs Ltd filed Critical Hetero Labs Ltd
Publication of WO2025215593A1 publication Critical patent/WO2025215593A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to an improved process for preparation of Zastaprazan or its pharmaceutically acceptable salts.
  • 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:
  • 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.
  • 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)
  • 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:
  • One objective of the present invention is to provide a process for preparation of Zastaprazan, which avoids column chromatographic purification.
  • Another objective of the present invention is to provide a process for preparation of Zastaprazan, which resulted in high yield and purities.
  • 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.
  • Another objective of the present invention is to provide a process for preparation of Zastaprazan, which is commercially and industrially feasible.
  • 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,
  • 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
  • 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.
  • 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.
  • 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.
  • Figure 1 shows powder X-ray diffractogram pattern of Zastaprazan crystalline Form H.
  • 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.
  • 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.
  • ketone solvent is selected from group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclopentanone or cyclohexanone.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol or butanol.
  • 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.
  • step d condensation of compound of Formula V with azetidine or its salts in presence of condensing agent, base and solvent.
  • Condensing agent is selected from PyBOP or T3P, base is organic base; solvent is selected from group consisting of dimethylformamide, dimethylacetamide, dimethylsulphoxide or methanol.
  • 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.
  • Zastaprazan crystalline form designated as Form H having 20 characteristic peaks at 7.4, 9.3 and 13.8 ⁇ 0.2 degrees.
  • Zastaprazan crystalline Form H 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.
  • the alcoholic solvent is selected from methanol, ethanol, isopropanol or propanol.
  • Zastaprazan is converted into Zastaprazan citrate using citric acid in acetone.
  • PyBOP Benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate EDO/ EDC.
  • HC1 l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide chloride
  • HATU Hexafluorophosphate azabenzotriazole tetramethyl uranium
  • T3P Propylphosphonic anhydride
  • 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.
  • 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.
  • 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 %.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation de zastaprazan ou de ses sels pharmaceutiquement acceptables, qui consiste à : a) faire réagir du 5,6-diaminonicotinate de méthyle et du 3-bromobutan-2-one pour obtenir du 8-amino-2,3-diméthyl imidazo[1,2-a]pyridine-6-carboxylate de méthyle, b) faire réagir le composé obtenu à l'étape a) avec du chlorure de 2,6-diméthylbenzyle en présence d'une base dans un solvant, en l'absence de catalyseur pour obtenir du 8-((2,6-diméthylbenzyl)amino)-2,3-diméthylimidazo[1,2-a]pyridine-6-carboxylate de méthyle, c) hydrolyser le composé obtenu à l'étape b) en présence d'une base dans un solvant pour obtenir de l'acide 8-((2,6-diméthylbenzyl)amino)-2,3-diméthylimidazo[1,2-a]pyridine-6-carboxylique d) condenser le composé obtenu à l'étape c) avec de l'azétidine ou ses sels en présence d'agent de condensation, de base et de solvant pour obtenir du zastaprazan, l'agent de condensation étant choisi parmi PyBOP ou T3P.
PCT/IB2025/053808 2024-04-12 2025-04-11 Procédé amélioré pour la préparation de zastaprazan Pending WO2025215593A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202441029757 2024-04-12
IN202441029757 2024-04-12

Publications (1)

Publication Number Publication Date
WO2025215593A1 true WO2025215593A1 (fr) 2025-10-16

Family

ID=97350003

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2025/053808 Pending WO2025215593A1 (fr) 2024-04-12 2025-04-11 Procédé amélioré pour la préparation de zastaprazan

Country Status (1)

Country Link
WO (1) WO2025215593A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999055706A1 (fr) * 1998-04-29 1999-11-04 Astrazeneca Ab Derives d'imidazo pyridine qui inhibent la secretion d'acide gastrique
WO2013022458A1 (fr) * 2011-08-05 2013-02-14 Boston Scientific Scimed, Inc. Procédés de conversion d'une substance médicamenteuse amorphe en une forme cristalline
WO2018008929A1 (fr) * 2016-07-05 2018-01-11 Jeil Pharmaceutical Co.,Ltd. Dérivés d'imidazo[1,2-a]pyridine, leurs procédés de préparation et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999055706A1 (fr) * 1998-04-29 1999-11-04 Astrazeneca Ab Derives d'imidazo pyridine qui inhibent la secretion d'acide gastrique
WO2013022458A1 (fr) * 2011-08-05 2013-02-14 Boston Scientific Scimed, Inc. Procédés de conversion d'une substance médicamenteuse amorphe en une forme cristalline
WO2018008929A1 (fr) * 2016-07-05 2018-01-11 Jeil Pharmaceutical Co.,Ltd. Dérivés d'imidazo[1,2-a]pyridine, leurs procédés de préparation et leur utilisation

Similar Documents

Publication Publication Date Title
KR101539561B1 (ko) 목시플록사신 염산염의 합성방법
NZ575780A (en) Process for preparing trityl olmesartan medoxomil and olmesartan medoxomil
AU2018354972A1 (en) An improved process for the preparation of ribociclib and its salts
EP2794610B1 (fr) Procédés et intermédiaires de préparation du pralatrexate
JP2021119142A (ja) キサンチンをベースとする化合物の調製方法
US8324381B2 (en) Preparation of ester of purine derivatives
US20110105751A1 (en) Conversion of tryptophan into beta-carboline derivatives
WO2007010555A2 (fr) Nouvelles formes cristallines d'hydrochlorure de moxifloxacine et procede de preparation associe
US20190284197A1 (en) Pharmaceutically acceptable salts and polymorphic forms of hydrocodone benzoic acid enol ester and processes for making same
WO2007100387A2 (fr) Procédé de préparation de tadalafil
WO2025215593A1 (fr) Procédé amélioré pour la préparation de zastaprazan
US6562975B1 (en) Process for preparing zolpidem
JP7379381B2 (ja) リナグリプチンおよびその塩の製造のための中間体およびプロセス
US9499491B2 (en) One pot process for the preparation of telmisartan
JP4315815B2 (ja) ジェミフロキサシン酸性塩類の製造方法
US20030088094A1 (en) Novel synthesis and crystallization of piperazine ring-containing compounds
EP1590353B1 (fr) Procede pour preparer du cefpodoxime proxetil
WO2006070379A1 (fr) Procede de synthese de la 4-amino-1-isobutyl-1h-imidazo[4,5-c]-quinoleine (imiquimod)
US20120259116A1 (en) Novel Process for the Preparation of Paliperidone
WO2008053324A1 (fr) Procédé perfectionné pour la préparation de mésylate de gémifloxacine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25786048

Country of ref document: EP

Kind code of ref document: A1