WO2020230037A1 - Alternate process for the preparation of encequidar - Google Patents
Alternate process for the preparation of encequidar Download PDFInfo
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- WO2020230037A1 WO2020230037A1 PCT/IB2020/054507 IB2020054507W WO2020230037A1 WO 2020230037 A1 WO2020230037 A1 WO 2020230037A1 IB 2020054507 W IB2020054507 W IB 2020054507W WO 2020230037 A1 WO2020230037 A1 WO 2020230037A1
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- oxo
- chromene
- carboxylic acid
- chloride
- encequidar
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The aspect of the present application relate to process for the preparation of Encequidar (HM-30181A) and salts thereof. Specific aspects relate to an improved process for the Encequidar and its mesylate salt, comprising the amidation of aniline precursor of Encequidar of formula II using 4-oxo-4H-chromene-2-carboxylic acid in the presence of an activating agent.
Description
ALTERNATE PROCESS FOR THE PREPARATION OF ENCEQUIDAR.
INTRODUCTION
Aspects of the present application relate to the process for preparation of Encequidar (HM-30181A) and salts thereof. Specific aspects relate to the alternate and improved processes for the Encequidar and salts thereof.
Encequidar is the adopted name of compound developed by Hanmi pharma having the chemical name: /V-[2-(2-{4-[2-(6,7-Dimethoxy-3,4-dihydro-2(l//)- isoquino liny ljcthyl] phenyl }-2/7-tctrazol-5-yl)-4,5-dimcthoxyphcnyl]-4-oxo-4/7-chromcnc-2- carboxamide and the structure as below.
Encequidar is P-glycoprotein pump inhibitor, which can facilitate oral absorption of traditional cytotoxics such as Paclitaxel, Topotecan, Irinotecan and Docetaxel with improved oral bio availability, efficacy and for improved patient tolerability, as compared to IV administration of the same cytotoxics.
US 7625926 B2 (the ‘926 patent) first discloses Encequidar, its mesylate salt, preparative process, pharmaceutical composition and their use for inhibiting activity of P- glycoprotein. The process disclosed in the ‘926 patent involves the amidation of amine precursor of Encequidar (2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)- yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxy aniline) with 4-oxo-4H-chromene-2- carboxylic acid in the presence of a condensing agent, as depicted below.
The reported processes for the preparation of Encequidar suffer from drawbacks such as low yield, sluggish reactions or the like. Further, these process involve lengthy steps of first making and quantifying the moisture sensitive S-benzothiazol-2-yl ester derivatives of chromenone carboxylic acid and then using it to effect the amidation reaction to form Encequidar. Also, these procedures involve the use of excess reagents and reactants, ultimately resulting in lack of material balance. Hence, these process are not suitable at commercial scale and there remains a need for an improved process for the preparation of Encequidar and salts thereof, which can overcome the disadvantages of the prior art yet cost effective and industrially viable.
SUMMARY
In an aspect, the present application provides a process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid, in the presence of an activating agent.
In another aspect, the present application provides a process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with an activated form of 4-oxo-4H-chromene-2-carboxylic acid, wherein the activated form of 4-oxo-4H-chromene-2-carboxylic acid is not isolated.
In another aspect, the present application provides a process for the preparation of
Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid in the presence of Propylphosphonic Anhydride (T3P).
In another aspect, the present application provides a process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid in the presence of N- [(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminiumhexafluoro phosphateN-oxide (HATU).
In another aspect, the present application provides a process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid in the presence of an acid chloride.
DETAILED DESCRIPTION
In an aspect, the present application provides a process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid, in the presence of an activating agent.
In embodiments, the compound of formula-II may be obtained according to any of the procedures known in the literature. In embodiments, the 4-oxo-4H-chromene-2- carboxylic acid may be obtained according to the procedures known in the art or is available commercially.
In embodiments, the compound of formula-II or 4-oxo-4H-chromene-2-carboxylic acid may be optionally purified before using, according to any known techniques such as recrystallization, chromatography or the like.
In embodiments, the acylation of compound of formula-II with 4-oxo-4H-
chromene-2-carboxylic acid may be carried out in the presence of an inert solvent. Inert solvent may be selected from the group consisting of hydrocarbon solvents, halogenated hydrocarbon solvents, ether solvents, ketone solvents, nitrile solvents, ester solvents, polar aprotic solvent or mixtures thereof. Hydrocarbon solvents may include, but not limited to toluene, xylene; halogenated hydrocarbons may include, but not limited to dichloromethane, chloroform; ether solvents may include, but not limited to diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 1 , 4-dioxane; ketone solvents may include, but not limited to acetone, methyl ethyl ketone and methyl isobutyl ketone; nitrile solvents may include, but not limited to acetonitrile and propionitrile; ester solvents may include, but not limited to ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate and ethyl butanoate; polar aprotic solvents may include, but not limited to N,N-dimethylformamide, dimethyl sulfoxide and N,N-dimethylacetamide; or mixtures thereof.
In embodiments, the reaction between the compound of formula-II and 4-oxo-4H- chromene-2-carboxylic acid may be carried in the presence of an activating agent. Activating agent is a reagent that can be used to activate the 4-oxo-4H-chromene-2- carboxylic acid to accelerate the acylation of compound of formula-II.
Activating agent may be selected from the group consisting of oxalyl chloride, thionyl chloride, phosphorus oxychloride, I , G-carbonyldiimidazole (CDI), N,N'- disuccinimidyl carbonate, pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, trichlorobenzoyl chloride, 4-nitobenzoyl chloride, diethyl cyanophosphonate (DEPC), (1- Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), Benzotriazole- l-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), /V,/V,/V', /V'-Tctramcthyl-0-( 1 /7-bcnzotnazo l- 1 -yljuroniu m hexafluorophosphate (HBTU), A-[(Dimethylamino)- l - l,2,3-triazolo-[4,5-h]pyridin- l- y 1 m c t h y 1 c n c ] - A- m c t h y 1 m c t h a n a m i n i u m hexafluorophosphate A-oxidc (HATU) and Propylphosphonic anhydride (T3P).
In embodiments, the acylation of compound of formula-II and 4-oxo-4H- chromene-2-carboxylic acid may be carried in the presence of a base. Base may include, but not limited to triethylamine, diisopropyl ethyl amine, pyridine, lutidine, collidine, alkali metal hydroxides, alkali metal carbonate or bicarbonates.
In embodiments, the acylation of compound of formula-II, may be carried out either by in situ activation of 4-oxo-4H-chromene-2-carboxylic acid in the presence of
activating agent or by reacting the compound of formula-II with an activated form of 4- oxo-4H-chromene-2-carboxylic acid, prepared before. In embodiments, the step of acylating a compound of formula-II with an activated form of 4-oxo-4H-chromene-2- carboxylic acid is carried out without isolating the activated form of of 4-oxo-4H- chromene-2-carboxylic acid.
In alternate embodiments, the acylation may be carried out by reacting the compound of formula-II with an activated form of 4-oxo-4H-chromene-2-carboxylic acid. The activated forms of 4-oxo-4H-chromene-2-carboxylic acid may be its derivatives such as anhydrides, acid chloride or esters thereof. Such activated anhydrides may include, but not limited to: mixed anhydrides with pivaloyl chloride, trichlorobenzoyl chloride, 4- nitrobenzoyl chloride, ethyl chloroformate, isobutyl chloroformate or any other suitable acid derivatives.
In embodiments, activated form of 4-oxo-4H-chromene-2-carboxylic acid may be corresponding derivative formed when combined with reagents such as HATU, T3P or the like.
In embodiments, activated anhydrides may be prepared by reacting 4-oxo-4H- chromene-2-carboxylic acid with acid chlorides in the presence of suitable base such as triethylamine, diisopropyl ethyl amine, pyridine, lutidine and collidine under suitable reaction conditions.
In embodiments, activated form of 4-oxo-4H-chromene-2-carboxylic acid is 4- oxo-4H-chromene-2-carboxylic acid chloride. In embodiments, 4-oxo-4H-chromene-2- carboxylic acid chloride may be obtained by reacting 4-oxo-4H-chromene-2-carboxylic acid with a chlorinating agent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride or the like.
In embodiments, the acylation of compound of formula-II may be carried out at suitable temperature of about 0 °C to reflux temperature of the solvent used. In embodiments, the acylation may be carried out for sufficient time to complete the acylation of the compound of formula-II for about one hour or more.
In embodiments, Encequidar obtained from the acylation of compound of formula- II may be recovered from the reaction mixture according to any of the suitable wok-up procedures as described in the instant application or according to any other suitable procedures known in the art.
Encequidar obtained according to the procedures of this aspect may be optionally purified employing methods such as recrystallization or acid-base treatment under
suitable conditions. Encequidar may be separated from the reaction mixture using separation techniques known in the art such as filtration, centrifugation and decantation or evaporation of solvent. Encequidar may be dried at controlled temperature, optionally under reduced pressure.
The process of this aspect bypasses the requirement to prepare and isolate the activated thioester derivative of 4-oxo-4H-chromene-2-carboxylic acid described in the prior art, which even requires its purification before using it for acylation of compound of formula-II. The moisture sensitive activated thioester derivative inevitably requires very specific procedures for its handling and quantification before proceeding to acylation. Use of such activated thioester derivatives can also result in contamination of the product with unwanted by-products / impurities that need to be removed in additional purification steps. Furthermore, such thioesters are associated with other drawbacks such as unpleasant odour and formation of mercapto related impurities and color imparted due to thiol moiety. The present process avoids all such drawbacks, additional and tedious steps of even making and purifying such activated thioester derivatives before the acylation step.
As alluded to above, the synthesis of Encequidar disclosed in US 8680277 B2 therefore proceeds in two steps. Step 1: preparation of S-benzothiazol-2-yl ester of 4-oxo- 4H-chromene-2-carbothionic acid via reaction of 4-oxo-4H-chromene-2-carboxylic acid with the sulfur containing reagent 2,2'-dithiobis-benzothiazol. Step 2: Reaction of the S- benzothiazol-2-yl ester of 4-oxo-4H-chromene-2-carbothionic acid with the compound of formula II to effect the desired amidation.
Though US 8680277 B2 states that Step 2 proceeds with 95% yield and affords Encequidar with about 98% purity through re-crystallization alone, it needs to be conceded that the yield of the preceding Step 1, reported in this art, is 80%. The inventors of the present application have found during their scale-up efforts that the isolated yield of the purified product at Step 1 is only 68%. Hence, even if one were to assume that subsequent Step 2 as stated in US 8680277 B2 can be performed with equimolar quantities of the S-benzothiazol-2-yl ester of 4-oxo-4H-chromene-2-carbothionic acid and compound of formula II, the overall yield of Encequidar from the 4-oxo-4H-chromene-2- carboxylic acid is only 76%.
Hence, the process of present application has a clear advantage of a direct conversion of the 4-oxo-4H-chromene-2-carboxylic acid and compound of formula II to Encequidar without the need to isolate and quantify any reactive intermediate. Further, we
have observed in the presence of activating agents such as Propylphosphonic Anhydride (T3P), the amidation with 4-oxo-4H-chromene-2-carboxylic acid proceeds cleanly to completion and affords Encequidar with 94% yield (as against the 76% yield of US 8680277 B2).
In another aspect, the present application provides a process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid in the presence of Propylphosphonic Anhydride (T3P).
In another aspect, the present application provides a process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid in the presence of N- [(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminiumhexafluoro phosphate N-oxide (HATU).
In another aspect, the present application provides a process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid in the presence of acid chloride. Acid chloride is selected from the group consisting of pivaloyl chloride, trichlorobenzoyl chloride and 4-nitrobenzoyl chloride.
In embodiments, the step of acylating the compound of formula-II with 4-oxo-4H- chromene-2-carboxylic acid may be carried according to the embodiments described in previous aspect of the instant application.
In another aspect, the present application provides a process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with an activated form of 4-oxo-4H-chromene-2-carboxylic acid. In embodiments, the step of acylating the compound of formula-II with an activated form of 4-oxo-4H-chromene-2-carboxylic acid may be carried according to the embodiments described in previous aspect of the instant application. In embodiments, activated form of 4-oxo-4H-chromene-2-carboxylic acid may include, but not limited to derivatives such as anhydrides, acid chlorides, esters of 4-oxo-4H-chromene-2-carboxylic acid. Such activated anhydrides may be selected from the mixed anhydrides with pivaloyl chloride^ trichlorobenzoyl chloride, 4-nitrobenzoyl chloride, ethyl chloroformate, isobutyl chloroformate or any other suitable acid derivatives. In embodiments, activated form of 4- oxo-4H-chromene-2-carboxylic acid may be also include derivatives of 4-oxo-4H-
chromene-2-carboxylic acid formed when it is combined with reagents such as HATU, T3P or the like.
In another aspect, the present application provides Encequidar produced according to aspects of instant application and pharmaceutical compositions thereof, wherein the chemical purity of Encequidar or a salt thereof may be more than 95% by HPLC or more than 99% by HPLC.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. The term“inert solvent” when used in the present application is a solvent that does not react with the reactants or reagents under conditions that cause the chemical reaction indicated to take place.
EXAMPLES
Example- 1: Preparation of Encequidar using activated thioester derivative of 4-oxo- 4H-chromene-2-carboxylic acid
Preparation of Thioester derivative: To a mixture of 4-oxo-4H-chromene-2-carboxylic acid (115 g), 2,2'dithiobis-benzothiazole (241.3 g), Triphenylphosphine (TPP) (190.3 g) in dichloromethane (2.4 L) at 26°C, a solution of triethylamine (102 mL) in dichloromethane (345 mL) was added slowly for 1 hour. The reaction mixture was stirred for 3.5 hours at the same temperature. The reaction mixture was filtered and the wet solid was washed with acetone (2 x 340 mL) to obtain 140 g of 4-oxo-4H-chromene-2-carbothionic acid S- benzothiazol-2-yl ester.
A mixture of 4-oxo-4H-chromene-2-carbothionic acid 5- be n zo t h i azo 1 - 2 - y 1 ester (15.9 g) and 2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-
4,5-dimethoxy aniline (22.0 g) in dichloromethane (440 mL) was stirred at 26 °C for 3.5 hours. Methanol (28.6 mL) and 95% aqueous acetone (924 mL) were added to the reaction mixture at 26°C and stirred at the same temperature for 18.5 hours. The solid was filtered and washed with acetone (110 mL) to obtain the title compound as yellowish solid. Yield: 30 g (wet weight); Purity by HPLC: 97.49%
Example-2: Preparation of Encequidar using Pivaloyl chloride and 4-oxo-4H- chromene-2-carboxylic acid
To a mixture of 4-oxo-4H-chromene-2-carboxylic acid (200 mg) in dichloromethane (5 mL) at 30 °C, triethylamine (0.22 mL) was added, followed by the addition of pivaloyl chloride (0.15 mL). The reaction mixture was stirred for 30 minutes and 2-(2-(4-(2-(6,7-dimethoxy- 3,4-dihydroisoquinolin-2(lH)-yl)ethyl) phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxy aniline (0.542 g) was added. The reaction mixture was further stirred for 3 hours at 30 °C and chloroform (5 mL) was added. The reaction mixture was heated to 48 °C and stirred for 16 hours at same temperature. The reaction mixture was allowed to cool to 32 °C and water (10 mL) was added. The mixture was stirred and separated the organic layer. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to remove the solvent completely. The product obtained was slurried in ethyl acetate (10 mL) and the solid was filtered. The solid was dissolved in dichloromethane (5 mL) and ethyl acetate (15 mL) was added. The mixture was stirred for 4 hours at 33 °C and the solid was filtered. The solid was dissolved in 10% MeOH/ chloroform mixture and washed with 1% sodium bicarbonate solution (3 mL). The organic layer was separated and the solvent was removed by evaporation under reduced pressure. The product was slurried in ethyl acetate (5 mL) and the solid was filtered to obtain the title compound as yellow solid. Yield: 105 mg; Purity by HPLC: 87.8%
Example-3: Preparation of Encequidar using HATU and 4-oxo-4H-chromene-2- carboxylic acid
To a mixture of 4-oxo-4H-chromene-2-carboxylic acid (101 mg), 2-(2-(4-(2-(6,7-dimethoxy- 3,4-dihydroisoquinolin-2(lH)-yl)ethyl) phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxy aniline (200 mg) in dichloromethane (5 mL) at 29°C, triethylamine (0.1 mL) was added, followed by the addition of HATU (N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide) (0.146 mg). The reaction mixture was stirred for 24 hours at 30 °C. Further lots of HATU (220 mg), triethylamine (0.1 mL) and
dichloromethane (5 mL) were added to the reaction mixture. The reaction mixture was stirred for 2 hours at 32 °C. Water was added and the reaction mixture was extracted with 10% MeOH/ dichloromethane (10 mL). The organic layer was separated and the solvent was removed by evaporation under reduced pressure. The product was purified by through column chromatography on 100-200 mesh silica gel using MeOH/chloroform. The separated fractions were combined and the solvent was removed by evaporation under reduced pressure. The product was triturated with ethyl acetate (5 mL) and the solid obtained was filtered and dried to obtain the title compound as a yellow solid. Yield: 100 mg and Purity by HPLC: 97.81%
Example-4: Preparation of Encequidar using Propylphosphonic Anhydride (T3P) and 4-oxo-4H-chromene-2-carboxylic acid
To a mixture of 4-oxo-4H-chromene-2-carboxylic acid (1.1 g), 2-(2-(4-(2-(6,7-dimethoxy- 3,4-dihydroisoquinolin-2(lH)-yl)ethyl) phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxy aniline (2.0 g) in dichloromethane (40 mL) at 31 °C, diisopropylethylamine (2.0 mL) was added, followed by the addition of 50% propylphosphonic anhydride (T3P) in ethyl acetate (7.4 mL). The reaction mixture was stirred for 16 hours at 30 °C. Water (20 mL) was added to the reaction and the mixture stirred for 15 minutes. The aqueous layer was separated and extracted with 5% MeOH/ dichloromethane (2 x 20 mL). The combined organic layer was washed with saturated sodium bicarbonate solution (2 x 30 mL), followed by washing with brine (20 mL). The organic layer was dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure at 45 °C. The product was slurried in ethyl acetate (40 mL) for 1 hour at 32 °C and the solid obtained was filtered and dried under reduced pressure at 40 °C for 1 hour to obtain the title compound as yellow solid. Yield: 2.5 g and purity by HPLC: 95.94%
Claims
1. A process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid, in the presence of an activating agent.
2. The process of claim 1, wherein the activating agent is selected from the group consisting of oxalyl chloride, thionyl chloride, phosphorus oxychloride, 1,1'- carbonyldiimidazole (CDI), N,N'-disuccinimidyl carbonate, pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, trichlorobenzoyl chloride, 4-nitobenzoyl chloride, diethylcyanophosphonate(DEPC), (l-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethyl amino-morpholino-carbenium hexafluorophosphate (COMU), Benzotriazole-l-yl-oxy- tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), N,N,N',N'-Tetramethyl-0- (lH-benzotriazol-l-yl)uronium hexafluorophosphate (HBTU), N-[(Dimethylamino)-lH- l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminiumhexafluoro phosphateN-oxide (HATU) and Propylphosphonic anhydride (T3P).
3. The process of claim 1, wherein the step of acylating a compound of formula II is carried out in the presence of a base.
4. The process of claim 3, wherein the base is selected from the group consisting of triethylamine, diisopropyl ethyl amine, pyridine, lutidine, collidine, alkali metal hydroxides, alkali metal carbonate and alkali metal bicarbonates.
5. A process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with an activated form of 4-oxo-4H- chromene-2-carboxylic acid, wherein the activated form of 4-oxo-4H-chromene-2- carboxylic acid is not isolated.
6. The process of claim 5, wherein the activated form of 4-oxo-4H-chromene-2- carboxylic acid is a mixed anhydride of an acid chloride, selected from the group consisting of pivaloyl chloride, trichlorobenzoyl chloride and 4-nitrobenzoyl chloride.
7. The process of claim 5, wherein the activated form of 4-oxo-4H-chromene-2- carboxylic acid is 4-oxo-4H-chromene-2-carboxylic acid chloride.
8. The process of claim 5, wherein the activated form is the derivative of 4-oxo-4H- chromene-2-carboxylic acid formed when combined with N-activating agents selected from the group consisting of [(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l- ylmethylene]-N-methylmethanaminiumhexafluorophosphateN-oxide (HATU) and Propylphosphonic anhydride (T3P).
9. A process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid in the presence of Propylphosphonic Anhydride (T3P).
10. A process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid in the presence of [(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l- ylmethylene] -N-methylmethanaminiumhexafluoropho sphateN -oxide (HATU) .
11. A process for the preparation of Encequidar or salts thereof, the process comprising the step of acylating a compound of formula-II with 4-oxo-4H-chromene-2-carboxylic acid in the presence of acid chloride.
12. The process of claim 11, wherein the acid chloride is selected from the group consisting of pivaloyl chloride, trichlorobenzoyl chloride and 4-nitrobenzoyl chloride.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| IN201941018966 | 2019-05-13 | ||
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7625926B2 (en) * | 2003-10-07 | 2009-12-01 | Hanmi Pharm. Co., Ltd | P-glycoprotein inhibitor, method for preparing the same and pharmaceutical composition comprising the same |
| US8680277B2 (en) * | 2010-01-15 | 2014-03-25 | Hanmi Science Co., Ltd | Method for preparing tetrazole methanesulfonic acid salts, and novel compound used in same |
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2020
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7625926B2 (en) * | 2003-10-07 | 2009-12-01 | Hanmi Pharm. Co., Ltd | P-glycoprotein inhibitor, method for preparing the same and pharmaceutical composition comprising the same |
| US8680277B2 (en) * | 2010-01-15 | 2014-03-25 | Hanmi Science Co., Ltd | Method for preparing tetrazole methanesulfonic acid salts, and novel compound used in same |
Non-Patent Citations (3)
| Title |
|---|
| DUNETZ, J. R. ET AL.: "Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 20, no. 2, 2016, pages 140 - 177, XP055321730, DOI: 10.1021/op500305s * |
| MARIA E. DUE-HANSEN, PANDEY SUNIL K., CHRISTIANSEN ELISABETH, ANDERSEN RIKKE, HANSEN STEFFEN V. F., ULVEN TROND: "A protocol for amide bond formation with electron deficient amines and sterically hindered substrates.", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 14, no. 2, 5 November 2015 (2015-11-05) - 2016, pages 430 - 433, XP055759879, DOI: 10.1039/c5ob02129d * |
| WAGHMARE, A. A. ET AL.: "Propylphosphonic anhydride (T3P): An expedient reagent for organic synthesis", REVIEW JOURNAL OF CHEMISTRY, vol. 4, no. 2, 2014, pages 53 - 131, XP035316187, DOI: 10.1134/s2079978014020034 * |
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