WO2018163212A1 - A process for the preparation of umeclidinium bromide and intermediates thereof - Google Patents
A process for the preparation of umeclidinium bromide and intermediates thereof Download PDFInfo
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- WO2018163212A1 WO2018163212A1 PCT/IN2018/050130 IN2018050130W WO2018163212A1 WO 2018163212 A1 WO2018163212 A1 WO 2018163212A1 IN 2018050130 W IN2018050130 W IN 2018050130W WO 2018163212 A1 WO2018163212 A1 WO 2018163212A1
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- solvent
- mixture
- umeclidinium bromide
- preparation
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- 238000000034 method Methods 0.000 title claims abstract description 29
- 230000008569 process Effects 0.000 title claims abstract description 28
- 229960004541 umeclidinium bromide Drugs 0.000 title claims abstract description 19
- PEJHHXHHNGORMP-AVADPIKZSA-M umeclidinium bromide Chemical compound [Br-].C=1C=CC=CC=1C([C@@]12CC[N@@+](CCOCC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 PEJHHXHHNGORMP-AVADPIKZSA-M 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000000543 intermediate Substances 0.000 title abstract description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 13
- ZUEBXWFONILVTP-UHFFFAOYSA-N 4-bromo-1-azabicyclo[2.2.2]octane Chemical compound C1CN2CCC1(Br)CC2 ZUEBXWFONILVTP-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 11
- 239000012965 benzophenone Substances 0.000 claims description 10
- 150000003839 salts Chemical group 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
- FWOHDAGPWDEWIB-UHFFFAOYSA-N 2-bromoethoxymethylbenzene Chemical compound BrCCOCC1=CC=CC=C1 FWOHDAGPWDEWIB-UHFFFAOYSA-N 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 239000012264 purified product Substances 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- FVTWTVQXNAJTQP-UHFFFAOYSA-N diphenyl-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol Chemical compound C=1C=CC=CC=1C(C12CC[N+](CCOCC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 FVTWTVQXNAJTQP-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229960004258 umeclidinium Drugs 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 229940110339 Long-acting muscarinic antagonist Drugs 0.000 description 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 2
- -1 benzene halides Chemical class 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000011418 maintenance treatment Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 125000006016 2-bromoethoxy group Chemical group 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 208000011623 Obstructive Lung disease Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 229960005012 aclidinium bromide Drugs 0.000 description 1
- XLAKJQPTOJHYDR-QTQXQZBYSA-M aclidinium bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1 XLAKJQPTOJHYDR-QTQXQZBYSA-M 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940124748 beta 2 agonist Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940127212 long-acting beta 2 agonist Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229960004026 vilanterol Drugs 0.000 description 1
- DAFYYTQWSAWIGS-DEOSSOPVSA-N vilanterol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 DAFYYTQWSAWIGS-DEOSSOPVSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Definitions
- the objective of COPD therapy is mainly towards instant relief, symptoms reduction, as well as decreased risk of future adverse health events.
- Bronchodilators are essential for management in COPD.
- the choice between beta2-agonists, anticholinergic agents, theophylline, or combination therapy depends on availability of these drugs and patient response.
- Two long-acting anticholinergic agents are approved for the long-term maintenance treatment of bronchospasm associated with COPD: tiotropium bromide and aclidinium bromide are the well known agents for effective treatment of respiratory disorders.
- the present invention provides a process for preparation of umeclidinium bromide and intermediates thereof.
- the process of the present invention is a synthetic, eco-friendly, non- hazardous and cost effective process.
- a process for preparation of umeclidmium bromide and intermediates thereof comprises: i. mixing 4-bromoquinuclidine with a predefined quantity of a metal and a catalyst in a solvent to obtain a mixture of 4-bromoquinuclidine of Formula 2; ii. reacting the mixture of 4-bromoquinuclidine, of Formula 2 with benzophenone in a solvent, to form an intermediate of Formula 3;
- the metal is selected from magnesium, zinc, indium, and lithium.
- the catalyst is selected from iodine, ultrasound, and heat.
- the solvents are selected from chloroform, dichloromethane, dichloroethane, acetonitrile, toluene, tetrahydrofuran (THF), dimethyl ether, and a combination thereof.
- the process for the preparation of umeclidinium. bromide advantageously avoids .multiple numbers of steps of synthesis.
- the process shows increase in % yield of umeclidinium bromide by about 20 % to 25%.
- the process for the preparation of umeclidinium bromide advantageously involves simplified steps and advantageously avoids use of expensive reagents, solvents, chemicals, and the like. Further, the process for the preparation of umeclidinium bromide saves the processing time avoids use of hazardous chemicals.
- the process of the present invention is suitable for the preparation of umeclidinium bromide on commercial scale, thereby reducing the manufacturing cost by around 20% to 30%.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Provided herein is a process for the preparation of umeclidinium bromide and intermediates thereof, wherein pure form of umeclidinium bromide is achieved by a two step process under mild conditions.
Description
A PROCESS FOR THE PREPARATION OF UMECLIDINIUM BROMIDE
AND INTERMEDIATES THEREOF
FIELD OF THE INVENTION
This disclosure relates to an improved process for the preparation of umeclidinium bromide.
BACKGROUND OF THE INVENTION
Umeclidinium is a long-acting muscarinic antagonist (LAMA) used as maintenance treatment for symptoms of chronic obstructive pulmonary disease (COPD). It is used as an inhalation monotherapy or as a fixed-dose combination product with the long-acting beta2-agonist vilanterol. COPD is a progressive obstructive lung disease characterized by shortness of breath, cough, sputum production, and chronically poor airflow with a forced expiratory volume in 1 second (FEV1) of less than 80%. By blocking the M3 muscarinic receptor which is highly expressed in airway smooth muscle of the lungs, umeclidinium inhibits the binding of acetylcholine and thereby opens up the airways by preventing bronchoconstriction. Its use has been shown to provide clinically significant, sustained improvements in lung function.
The objective of COPD therapy is mainly towards instant relief, symptoms reduction, as well as decreased risk of future adverse health events. Bronchodilators are essential for management in COPD. The choice between beta2-agonists, anticholinergic agents, theophylline, or combination therapy depends on availability of these drugs and patient response. Two long-acting anticholinergic agents are approved for the long-term maintenance treatment of bronchospasm associated with COPD: tiotropium bromide and aclidinium
bromide are the well known agents for effective treatment of respiratory disorders.
The known processes of synthesis of umeclidinium bromide include lithium reagent, bromobenzene, chlorobenzene and other benzene halides as the starting material and requires long reaction times or solvents. The preparation of umeclidinium bromide becomes difficult on commercial scale via route of synthesis disclosed in art.
Accordingly there is need of a synthetic, eco-friendly, non- hazardous and cost effective process for the preparation of umeclidinium bromide and intermediates with high yield and purity thereof that overcomes the above mentioned drawbacks of the prior art.
Summary of the invention:
In one aspect, described herein is a process for preparation of umeclidinium bromide and intermediates thereof. The process for preparation of umeclidinium bromide comprises the steps of: i. mixing 4-bromoquinuclidine with a predefined quantity of a metal and a catalyst in a solvent to obtain a mixture of 4- bromoquinuclidine of Formula 2;
ii. reacting the mixture of 4-bromoquinuclidine of Formula 2 with benzophenone in the solvent, to form an intermediate of Formula
3;
forming quaternary salt of Formula 1 by;
a. mixing the intermediate of Formula 3 in a solvent mixture; and
b. reacting with ((2-bromoethoxy)methyl)benzene to form a white solid quaternary salt of Formula 1.
The proeess further comprises the step of pouring the reaction mixture of step (i) upon adding benzophenone into ice water; extracting with ethyl acetate; and separating the organic layer. The organic layer in concentrated in vacuum and is crystallized to obtain the purified product of Formula 3. Step (i) is conducted at an ambient temperature. The solvent in step (ii) (a) is a mixture of acetonitrile and chloroform . The metal in step (i) is a magnesium metal. The catalyst in step (i) is iodine. Further, the solvent in step (i) is tetrahydrofuran (THF). However, it is to
be noted that in alternative embodiments, the type of metal and type of catalyst may vary. The quaternary salt of Formula 1 has a purity of between 98 % to 100% and the yield of umeclidinium bromide is about 20 % to 25%.
Detailed description of the invention:
The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.
Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.
References in the specification to "preferred embodiment" means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions 20 and functions for clear description of the present invention.
In general aspect, the present invention provides a process for preparation of umeclidinium bromide and intermediates thereof. The process of the present invention is a synthetic, eco-friendly, non- hazardous and cost effective process.
In an embodiment, provided herein is a process for preparation of umeclidmium bromide and intermediates thereof. The process comprises: i. mixing 4-bromoquinuclidine with a predefined quantity of a metal and a catalyst in a solvent to obtain a mixture of 4-bromoquinuclidine of Formula 2; ii. reacting the mixture of 4-bromoquinuclidine, of Formula 2 with benzophenone in a solvent, to form an intermediate of Formula 3;
iii. forming quaternary salt of Formula 1 by; a. mixing the intermediate of formula 3 in a solvent mixture; and b. reacting with ((2-bromoethoxy)methyl)benzene to form a white solid quaternary s alt of Formula 1.
At an initial step of the Grignard's reaction, 4-brornoquinuclidine is stirred with a metal and a catalyst in a solvent to obtain a mixture of 4- bromoquinuclidine. Step (i) is initiated at a temperature range of 70 °C to 80 °C. The reaction of mixture of 4 -br om oqu inu c 1 i din e of Formula 2 with benzophenone is initiated at ambient temperature of 25 °C for a predefined period of time. The solution of benzophenone in the solvent is added in portions over a predefined period of time. The reaction is conducted in aproti c solvents such as chloroform, dichloromethane (DCM), dichloroethaire, acetonitrile, toluene, tetrahydrofuran (THE) and dimethyl ether and the like, preferably in THF .
Upon completion of addition of benzophenone, the reaction mixture was poured into ice water and extracted with ethyl acetate. The intermediate of Formula 3 is mixed with solvent mixture of acetonitrile and diloroform before reacting with ((2 -bromo ethoxy)m ethyDbenzen e . The pure form of white solid quaternary salt of Formula 1 was obtained by washing the resulting residue with diethyl ether.
Advantageously, the process is conducted under mild conditions to obtain a pure form of quaternary salt of Formula 1. The quaternary salt of Formula 1 has a purity of about 98 % to 100%. The yield of umeclidinium bromide of Formula 1 is about 20 % to 25%.
In some embodiments of the reaction, the metal is selected from magnesium, zinc, indium, and lithium.
In some embodiments of the reaction, the catalyst is selected from iodine, ultrasound, and heat.
In some embodiments of the reaction, the solvents are selected from chloroform, dichloromethane, dichloroethane, acetonitrile, toluene, tetrahydrofuran (THF), dimethyl ether, and a combination thereof.
The reaction scheme of preparing compound of Formula 1 is represented below:
EXAMPLES
The following examples illustrate the invention, but are not limiting thereof.
Example 1: Grignard reaction of 4-bromoqumuclMine (1)
To a mixture of 4-bromoquinuclidine (1) (2.0 equiv), Mg metal (2.0 equiv) and a catalytic amount of iodine (0.05 equiv) in THF (15 inL) was stirred over a period of 30 min at 0 °C. To this mixture, a solution of benzophenone (2) (1 equiv) in THF was added in portions over a period of 30 min. Upon completion of addition of benzophenone, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated and concentrated in
vacuum. The resulting residue was purified by crystallization to obtain the pure product (3).
To an intermediate (3) (1 equiv), mixture of acetonitrile and chloroform (10 'mL, 2:3) and. ((2-bromoethoxy)methyl)benzene (4) was added. The mixture was stirred at room temperature for 35 to 48h. The solvents, acetonitrile and chloroform were evaporated,, and the resulting residue was washed with diethyl ether to obtain a pure form of quaternary salt of (5) as a white solid.
The process for the preparation of umeclidinium. bromide advantageously avoids .multiple numbers of steps of synthesis. The process shows increase in %
yield of umeclidinium bromide by about 20 % to 25%. The process for the preparation of umeclidinium bromide advantageously involves simplified steps and advantageously avoids use of expensive reagents, solvents, chemicals, and the like. Further, the process for the preparation of umeclidinium bromide saves the processing time avoids use of hazardous chemicals. The process of the present invention is suitable for the preparation of umeclidinium bromide on commercial scale, thereby reducing the manufacturing cost by around 20% to 30%.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
Claims
Claims : 1. A process for prep aration of umeclidinium bromide comprising: i. mixing 4-bromoquinuelidine with a predefined quantity of a metal and a catalyst in a solvent to obtain a mixture of 4- bromoquinucl i dine of F ormul a 2;
ii. reacting 4-bromoquinuclidine, of Formula 2 with benzophenone in a solvent, to form an intermediate of Eormula 3;
a. mixing the intermediate of Formula 3 in a solvent mixture; and
b. reacting with ((2-bromoethoxy)methyl)benzene to form a .white s olid quaternary salt of Formu la 1.
2. The process as claimed in claim 1, further comprises the step of :
i. pouring the reaction mixture of step (i) upon adding benzophenone into ice water;
ii. extracting with ethyl acetate; and
iii. separating the organic layer.
3. The process as claimed in claim 2 further comprises concentrating the organic layer in vacuum and crystallizing the purified product of Formula III.
4. The process as claimed in claim 1, wherein the metal in step (i) is a magnesium metal, catalyst in step (i) is iodine and the solvent in step (i) is tetrahydrofuran (THF).
5. The process as claimed in claim 1, wherein step (i) is conducted at a temperature range of 70 °C to 80 °C.
6. The process as claimed in claim 1, wherein the solvent in step (ii) (a) is a mixture of acetonitrile and chloroform .
7. The process of claim 1, wherein the quaternary salt of Formula 1 has a purity of 98% to 100%.
8. The process of claims 1 to 7, wherein the yield of umeclidinium bromide is about 20% to 25%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201741008151 | 2017-03-08 | ||
| IN201741008151 | 2017-03-08 |
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| Publication Number | Publication Date |
|---|---|
| WO2018163212A1 true WO2018163212A1 (en) | 2018-09-13 |
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ID=63447482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2018/050130 WO2018163212A1 (en) | 2017-03-08 | 2018-03-08 | A process for the preparation of umeclidinium bromide and intermediates thereof |
Country Status (1)
| Country | Link |
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| WO (1) | WO2018163212A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005104745A2 (en) * | 2004-04-27 | 2005-11-10 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
| CN105461710A (en) * | 2015-10-23 | 2016-04-06 | 安徽德信佳生物医药有限公司 | Preparation method of umeclidinium bromide |
-
2018
- 2018-03-08 WO PCT/IN2018/050130 patent/WO2018163212A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005104745A2 (en) * | 2004-04-27 | 2005-11-10 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
| CN105461710A (en) * | 2015-10-23 | 2016-04-06 | 安徽德信佳生物医药有限公司 | Preparation method of umeclidinium bromide |
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