WO2006114676A2 - A process for the preparation of rupatadine - Google Patents
A process for the preparation of rupatadine Download PDFInfo
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- WO2006114676A2 WO2006114676A2 PCT/IB2006/000964 IB2006000964W WO2006114676A2 WO 2006114676 A2 WO2006114676 A2 WO 2006114676A2 IB 2006000964 W IB2006000964 W IB 2006000964W WO 2006114676 A2 WO2006114676 A2 WO 2006114676A2
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- rupatadine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the present invention relates to a commercially feasible process for the preparation of Rupatadine and salts thereof.
- Rupatadine (formula-I) - chemically named as 8-chlorol l-[l-[(5-methyl3- pyridinyl)methyl]-4-piperidinylidene]-6, 11 -dihydro-5H-benzo-[5,6]cyclohepta[l ,2-b] pyridine is a potent orally active dual antagonist of platelet-activating factor (PAF) and histamine (Hl) and effects through its interaction with specific receptors.
- PAF platelet-activating factor
- Hl histamine
- ES2042421 [which is equivalent to US 5476856, US5407941,ES2076817T3 ] discloses preparation of Rupatadine which involves bromination of 3,5 lutidine in CC14 using NBS followed by reaction of the product formed with Desloratadine using 4-(dimethylamino)pyridine at room temperature for 18 hours followed by extractive workup using dichloromethane solvent and chromatographic purification to give Rupatadine in 40 % yield.
- Rupatadine is further converted to different salts like trihydrochloride, hemipentafumarate, dioxalate and hemicitrate in which Rupatadine is taken in Ethyl acetate and salts made therefrom using corresponding acid in solvent ; for hemipentafumarate and citrate salts, the corresponding acids are taken in methanol and for dioxalate salt, oxalic acid is taken in ethyl acetate, while for making trihydrochloride salt ,diethyl ether saturated with HCl gas is used.
- the main drawbacks of this process in the step of preparing Rupatadine are (i) Long reaction times of the order of 18 hours , (ii) Chromatographic purification used for isolating Rupatadine (iii) The yield of 40 % makes the process commercially unviable.
- a process for the preparation of Rupatadine is described in ES2120899 which comprises reacting [ 8-chloro-6,l l dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridine- 11-one with 3-[(4-M-substitutedpiperidin-l-yl)methyl]-5-methylpyridine (where M is MgX or Li; being X, a halogen atom ) to give 4-[8-chloro 6,11-dihydro-l 1-hydroxy - 5H-benzo[5,6]ciclohepta[l,2-b]piperidin-l l-yl]-l-[(5-methyl-3- pyridinyl)methyl]piperidine which on dehydration gives Rupatadine. Rupatadine is then transformed into a pharmaceutically acceptable salt.
- the main drawbacks of the process are
- reaction product need to be chromatographed on silica gel to get pure compound
- the present invention provides a process for preparation of Rupatadine and further to its salts without intermediate purification / isolation steps.
- the main object of the invention is to provide a commercially feasible process for the preparation of Rupatadine.
- Rupatadine by taking a solution of 3- bromomethyl 5-methyl pyridine ( prepared from 3,5 dimethyl pyridine without ⁇ isolation of 3-bromomethyl 5-methyl pyridine) and reacting with Desloratadine using a phase transfer catalyst and an aqueous alkali in a biphasic system .
- the process for preparing Rupatadine involves N-alkylation of Desloratadine with 3- bromomethyl-5 -methyl pyridine using a base and a phase transfer catalyst in biphasic solvent system.
- the process of this invention discloses a method of preparing Rupatadine fumarate from Rupatadine by reacting Rupatadine in ketonic solvents with a methanolic solution of fumaric acid. This process has short reaction times, gives high yields and avoids extensive workup of the reaction products.
- Rupatadine is prepared from Desloratadine by N-alkylation of Desloratadine with 5- A
- the alkali used in the reaction is selected from alkali and alkaline metal hydroxides ,carbonates , bicarbonates such as NaOH, KOH,
- the reaction medium for reaction of step (a) comprises a biphasic solvent system which comprises water and a second water immiscible . organic solvent.
- the organic solvent is selected from :
- Aromatic Hydrocarbon solvents such as benzene, toluene, xylene, ethylbenzene or mixtures thereof;
- Ethers such as diethyl ether, diisopropyl ether, dibutyl ether etc or mixtures thereof; Ketonic solvents such as MIBK.
- Halogenated solvents such as CC14, CHC13, CH2C12, chlorobenzene, trichloroethylene, tetrachloroethylene or mixtures thereof,
- the preferred solvent for N-alkylation is CC14, trichloroethylene, tetrachloro ethylene, dichloromethane.
- Phase transfer catalyst used for reaction step (a) is selected from a group of quaternary ammonium salts of general formula :
- N(R1R2R3R4)X where R1,R2,R3, and R4 is Cl to C13 alkyl ot aralkyl group, cycloalkyl, aryl, or heterocyclyl.
- X is a monovalent anion .
- the preferred catalyst is Triethyl benzyl ammonium chloride, or Tetrabutyl ammoniun bromide, or tetrabutyl ammonium hydrogen sulfate. Quat. Phosphonium salts
- PEG ethers such as PEG-400, PEG-600 and their like.
- the preferred PTC is Tetrabutyl ammonium bromide.
- the temperature for the reaction of step (a) varies between O to 5O 0 C preferably room temperature.
- step ( c ) for preparing Rupatadine Fumarate can be further extended for preparing other pharmaceutically acceptable salts such as hydrochloride , hydrobromide , maleate, mesylate ,besylate , citrate, tartrate , sulfate , phosphate.
- the present invention is illustrated with following examples, without limiting the scope of the invention.
- the organic phase is filtered and solvent is distilled under vacuum at 35-40 0 C. Weight of residue is 110 gms. To it 560 ml acetone is added at room temperature and stirred to dissolve it. 160 gms silica gel is added to it and stirred for one hour at room temperature. The silica gel is removed by filtration and washed with acetone and solvent is removed to give Rupatadine.
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
Abstract
Rupatadine is synthesized by phase transfer catalysed N-alkylation of Desloratadine in biphasic solvent system using aqueous alkali by reaction of a compound of formula (I), with Desloratadine at temperature up to 500C , wherein solvent selected is water immiscible organic solvent. Rupatadine is further converted to Rupatadine fumarate by reaction of Rupatadine in ketonic solvent with an alcoholic solution of fumaric acid.
Description
A PROCESS FOR THE PREPARATION OF RUPATADINE AND SALTS FIELD OF INVENTION:
The present invention relates to a commercially feasible process for the preparation of Rupatadine and salts thereof.
BACKGROUND AND PRIOR ART :
Rupatadine (formula-I) - chemically named as 8-chlorol l-[l-[(5-methyl3- pyridinyl)methyl]-4-piperidinylidene]-6, 11 -dihydro-5H-benzo-[5,6]cyclohepta[l ,2-b] pyridine is a potent orally active dual antagonist of platelet-activating factor (PAF) and histamine (Hl) and effects through its interaction with specific receptors.
ES2042421 [ which is equivalent to US 5476856, US5407941,ES2076817T3 ] discloses preparation of Rupatadine which involves bromination of 3,5 lutidine in CC14 using NBS followed by reaction of the product formed with Desloratadine using 4-(dimethylamino)pyridine at room temperature for 18 hours followed by extractive workup using dichloromethane solvent and chromatographic purification to give Rupatadine in 40 % yield.
Rupatadine is further converted to different salts like trihydrochloride, hemipentafumarate, dioxalate and hemicitrate in which Rupatadine is taken in Ethyl acetate and salts made therefrom using corresponding acid in solvent ; for hemipentafumarate and citrate salts, the corresponding acids are taken in methanol and for dioxalate salt, oxalic acid is taken in ethyl acetate, while for making trihydrochloride salt ,diethyl ether saturated with HCl gas is used. The main drawbacks of this process in the step of preparing Rupatadine are (i) Long reaction times of the order of 18 hours , (ii) Chromatographic purification used for isolating Rupatadine (iii) The yield of 40 % makes the process commercially unviable.
A process for the preparation of Rupatadine is described in ES2120899 which comprises reacting [ 8-chloro-6,l l dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridine- 11-one with 3-[(4-M-substitutedpiperidin-l-yl)methyl]-5-methylpyridine (where M is MgX or Li; being X, a halogen atom ) to give 4-[8-chloro 6,11-dihydro-l 1-hydroxy - 5H-benzo[5,6]ciclohepta[l,2-b]piperidin-l l-yl]-l-[(5-methyl-3- pyridinyl)methyl]piperidine which on dehydration gives Rupatadine. Rupatadine is then transformed into a pharmaceutically acceptable salt. The main drawbacks of the process are
(j) Long reaction times of the order of 18 hours ,
(ii) The reaction product need to be chromatographed on silica gel to get pure compound,
(iii) The overall yield of 42 % [ 50% for Grignard addition and 84% for dehydration] makes the process commercially unviable.
U.S. Patent No. 6803468 describes a process for the preparation of N-(5- methylnicotinoyl)-4 hydroxypiperidine - a key intermediate ofRupatadine wherein reaction of 5-methylnicotinic acid with alkyl chloroformate or pivaloyl chloride in a suitable solvent in the presence of an organic base gives corresponding mixed anhydride which reacts with 4-hydroxypiperidine to give N-(5-methylnicotinoyl)-4 hydroxypiperidine.
The shortcoming of this process is that it involves multi step extractive work-up making it commercially unattractive.
ES 2087818 Al discloses preparation of Rupatadine which involves bromination of
3,5 lutidine in CC14 using NBS followed by reaction of the product formed with
Desloratadine using 4-(dimethylamino)pyridine at room temperature for 18 hours followed by extractive workup using dichloromethane solvent and chromatographic purification to give Rupatadine in 40 % yield . Further Rupatadine is converted to
Rupatadine fumarate using ethanol solvent in 70 % yield .
The main drawbacks of this process are
(i) Long reaction times of the order of 18 hours ,
(ii) Chromatographic purification used for isolating Rupatadine
(iii) The yield of 40 % makes the process commercially unviable.
It is desirable to minimize the number of reaction steps including chromatographic separations to make the process commercially operable. The present invention provides a process for preparation of Rupatadine and further to its salts without intermediate purification / isolation steps.
SUMMARY OF THE INVENTION:
The main object of the invention is to provide a commercially feasible process for the preparation of Rupatadine.
It is another object of the invention to provide a process for the preparation of
Rupatadine with lower reaction times.
It is yet another object of the invention to provide a process for the preparation of
Rupatadine without extensive workup.
It is yet another objective to prepare Rupatadine by taking a solution of 3- bromomethyl 5-methyl pyridine ( prepared from 3,5 dimethyl pyridine without ■ isolation of 3-bromomethyl 5-methyl pyridine) and reacting with Desloratadine using a phase transfer catalyst and an aqueous alkali in a biphasic system .
The process for preparing Rupatadine involves N-alkylation of Desloratadine with 3- bromomethyl-5 -methyl pyridine using a base and a phase transfer catalyst in biphasic solvent system. The process of this invention discloses a method of preparing Rupatadine fumarate from Rupatadine by reacting Rupatadine in ketonic solvents with a methanolic solution of fumaric acid. This process has short reaction times, gives high yields and avoids extensive workup of the reaction products.
DETAILED DESCRIPTION OF THE INVENTION:
The process of the invention is illustrated in Scheme- 1 : Scheme-1
-OH1-OTS1-OMS1-OAC, RUPATADINE
-OAr1-Br1-CI1-I
RUPATADINE IN + ALCOHOLIC SOLUTION RUPATADINE
KETONIC SOLVENT OF FUMARIC ACID FUMARATE
Rupatadine is prepared from Desloratadine by N-alkylation of Desloratadine with 5- A
DESLORATADINE
X = leaving group such as
Thus in accordance with this invention
( a ) a solution of a compound of formula-A in organic solvent is treated with
Desloratadine using aqueous alkali and a phase transfer catalyst at temperature up to
( b ) The organic and aqueous layers are separated , the aqueous layer is discarded and the organic layer is distilled at reduced pressure to yield Rupatadine ,
( c ) The Rupatadine is dissolved in ketonic solvent and reacted with alcoholic solution of fumaric acid to give Rupatadine fumarate.
For step (a)
The alkali used in the reaction is selected from alkali and alkaline metal hydroxides ,carbonates , bicarbonates such as NaOH, KOH,
LiOH, Ca(OH)2 ,Ba(OH)2 ; Na2CO3, K2CO3 Li2CO3, CaCO3, KHC03 ,
NaHC03 and their like, more preferably NaOH,
The reaction medium for reaction of step (a) comprises a biphasic solvent system which comprises water and a second water immiscible . organic solvent. The organic solvent is selected from :
Aromatic Hydrocarbon solvents such as benzene, toluene, xylene, ethylbenzene or mixtures thereof;
Ethers such as diethyl ether, diisopropyl ether, dibutyl ether etc or mixtures thereof; Ketonic solvents such as MIBK.
Halogenated solvents such as CC14, CHC13, CH2C12, chlorobenzene, trichloroethylene, tetrachloroethylene or mixtures thereof,
The preferred solvent for N-alkylation is CC14, trichloroethylene, tetrachloro ethylene, dichloromethane.
Phase transfer catalyst used for reaction step (a) is selected from a group of quaternary ammonium salts of general formula :
N(R1R2R3R4)X where R1,R2,R3, and R4 is Cl to C13 alkyl ot aralkyl group, cycloalkyl, aryl, or heterocyclyl. X is a monovalent anion .The preferred catalyst is Triethyl benzyl ammonium chloride, or Tetrabutyl ammoniun bromide, or tetrabutyl ammonium hydrogen sulfate. Quat. Phosphonium salts
PEG ethers such as PEG-400, PEG-600 and their like. The preferred PTC is Tetrabutyl ammonium bromide.
The temperature for the reaction of step (a) varies between O to 5O0C preferably room temperature.
The process described in step ( c ) for preparing Rupatadine Fumarate can be further extended for preparing other pharmaceutically acceptable salts such as hydrochloride , hydrobromide , maleate, mesylate ,besylate , citrate, tartrate , sulfate , phosphate. The present invention is illustrated with following examples, without limiting the scope of the invention. Example 1
Preparation of3-bromomethyl-5-methylpyridine hydrochloride: A mixture of carbon tetrachloride (4000ml), azobisisobutyronitrile (45.96gm, 0.279mol), 3,5-lutidine (150gm, 1.399mol) and N-bromosuccinamide (299.4gm, 1.682mol) is refluxed for 2 hours. The reaction mixture is cooled to room temperature and solid is filtered. HCl gas is passed to the filtrate and solid obtained is separated and filtered. Yield is 196gm Yield is 67.66%. Example 2
Preparation of Rupatadine :
A mixture of desloratadine (5.0gm, 0.016mol), methylene chloride (15ml), tetrabutylammonium bromide (0.575gm, 0.0018mol) and sodium hydroxide solution (2.5gm, 0.064mol in 8ml water) is cooled to 0 to 50C. 3-bromomethyl-5- methylpyridine hydrochloride (7.18gm, 0.032mol) in methylene chloride (35ml) is
added to above mixture. The reaction mixture is stirred at 0 to 50C for 1 hour and at room temperature for 12 hours. Layers are separated and organic layer is washed with dilute HCl solution and water. Methylene chloride is distilled. Yield = 9.5g %Yield =
67.66%.
Example 3
Preparation of "Rupatadine fumarate:
A solution of fumaric acid (3.3gm) in methanol (46ml) is added to solution of
Rupatadine (4.5gm) in ethyl acetate (30ml) at room temperature. The reaction mass is cooled to -5 to O0C for 4 hours. Rupatadine fumarate is separated filtered and Washed with ethylacetate. Yield = 5.5 gm.
Example 4
Preparation of 3-bromomethyl-5-methylpyridine
(a) Take 3,5-Lutidine (100 gms ) in 5.0 L capacity four necked round bottom flask equipped with overhead stirrer, reflux condenser ,thermometer, with nitrogen gas passing facility. Then charge 3500 ml carbon tetrachloride followed by (133 gms ) N- Bromosuccinimide and ( 15.38 gms ) AIBN i.e. 2,2'-Azobisisobutyronitrile. Slowly heat the reaction mass to 70°C.Maintain the temperature for 4 hours. Cool the reaction mass to room temperature (20-30°C).Filter the reaction mass and filterate is used as such for the next stage.
Preparation of Rupatadine:
(b) 3.7 L of the solution from product of Example 4 (a) is stirred with 60 Gms Desloratadine , 7.6 gms Tetrabutyl ammonium bromide. To it aqueous solution of sodium hydroxide(18.66 gms sodium hydroxide in 100 ml water) is added at room temperature. And the reaction mass is stirred for 6-8 hours at room temperature. Stirring is stopped and the reaction mass is allowed to settle and layers are separated . The organic layer is charged in round bottom flask and 500 ml water is added to it. The reaction mass is stirred for 15 to 20 minutes and allowed to settle. The layers are separated. The aqueous layer is discarded. The organic phase is dried over anhydrous sodium sulfate. The organic phase is filtered and solvent is distilled under vacuum at 35-400C. Weight of residue is 110 gms. To it 560 ml acetone is added at room temperature and stirred to dissolve it. 160 gms silica gel is added to it and stirred for one hour at room temperature. The silica gel is removed by filtration and washed with acetone and solvent is removed to give Rupatadine.
Weight of Rupatadine obtained = 60 gms. Preparation of Rupatadine fumarate:
( c ) A solution of 60.0 gms. of Rupatadine in 300 ml acetone is charged in 1.0 L capacity round bottom flask under nitrogen atmosphere at room temperature ( 20- 30 C). A solution of fumaric acid (17.0gms) in methanol (255 ml) is then charged with stirring. The reaction mass is stirred at room temperature for 8-10 hours. Solid Rupatadine fumarate salt is precipitated. The solid is filtered and washed with acetone ( 2x60ml). The product is dried under vacuum oven at 50-550C for 8 to 10 hours.
Wt. of Rupatadine Fumarate = 36 grήs. Purity > 99 area % by HPLC M.P.=196-990C
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention
Claims
(1) A process for preparation of Rupatadine fumarate which comprises (a) reacting a solution of a compound of formula- A
X = leaving group such as
with desloratadine in water immiscible organic solvent using aqueous alkali and a phase transfer catalyst at temperature up to 5O0C , (b) separating the organic and aqueous layers,
( c ) removing the organic solvent from the organic layer, dissolving the residue in an organic solvent and treating with silica gel or alumina followed by removal of solvent to yield Rupatadine and converting Rupatadine to Rupatadine fumarate by reacting a solution of Rupatadine in ketonic solvent with a solution of fumaric acid in an alcoholic solvent.
(2) A process for the preparation of Rupatadine as claimed in claim (1) , where compound A is 3-bromomethyl 5 -methyl pyridine.
(3) A process for the preparation of Rupatadine as claimed in claim (1) wherein the solvent used for phase transfer catalysed N-alkylation is a biphasic solvent system which comprise water and a second water immiscible organic solvent , which is selected from :
Aromatic Hydrocarbon solvents such as benzene, toluene, xylene, ethylbenzene or optionally mixtures thereof
Ethers such as diethyl ether, diisopropyl ether, dibutyl ether etc or optionally mixtures thereof
Ketonic solvents such as MIBK.
Halogenated solvents such as CC14, CHC13, CH2C12, chlorobenzene, trichloroethylene, tetrachloroethylene or optionally mixtures thereof, The preferred solvent for N-alkylation is CC14, CH2C12 , trichloroethylene, tetrachloro ethylene.
(4) A process for the preparation of Rupatadine as claimed in claim (1) wherein the base used for phase transfer catalysed N-alkylation of Desloratadine is selected from alkali and alkaline metal hydroxides, carbonates , bicarbonates such as NaOH, KOH, LiOH, Ca(OH)2 ,Ba(OH)2 ; Na2CO3, K2CO3 Li2CO3, CaCO3, KHCO3 , NaHCO3 , and their like, most preferable being NaOH.
(5) A process for the preparation of Rupatadine as claimed in claim (1) wherein the phase transfer catalyst used for N-alkylation is selected from :
[a] quaternary ammonium salts of general formula :
N(R1R2R3R4)X where R1,R2,R3, and R4 is Cl to C13 alkyl ot aralkyl group, cycloalkyl, aryl, or heterocyclyl. X is a monovalent anion .The preferred catalyst is Triethyl benzyl ammonium chloride, or Tetrabutyl ammoniun bromide, or tetrabutyl ammonium hydrogen sulfate.
[b]
Quat. Phosphonium salts
[C]
PEG ethers such as PEG-400, PEG-600 etc.
The more preferred PTC is Tetrabutyl ammonium bromide.
(6) A process for the preparation of Rupatadine as claimed in claim (1) wherein the temperature for the reaction phase transfer catalysed N-alkylation varies between 0 to 500C , preferably room temperature.
(7) For preparing Rupatadine fumarate salt, as per claim-(l) , the preferred solvents for dissolving Rupatadine base are ketonic solvents and the preferred solvents for dissolving Fumaric acid are alcoholic solvents.
(8) For preparing Rupatadine fumarate salt, as per claim-(l) , the preferred solvent for dissolving Rupatadine base is acetone and the preferred solvent for dissolving Fumaric acid is Methanol.
(9) A process for preparing • Rupatadine salts which include preparation of pharmaceutically acceptable salts such as hydrochloride , hydrobromide , maleate, mesylate ,besylate , citrate, tartrate , sulfate , phosphate ; by mixing a ketonic solution of Rupatadine with an alcoholic solution of corresponding acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN516MU2005 | 2005-04-27 | ||
| IN516/MUM/2005 | 2005-04-27 |
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| Publication Number | Publication Date |
|---|---|
| WO2006114676A2 true WO2006114676A2 (en) | 2006-11-02 |
| WO2006114676A3 WO2006114676A3 (en) | 2007-01-25 |
| WO2006114676A8 WO2006114676A8 (en) | 2007-11-22 |
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| ES (1) | ES2311426B1 (en) |
| WO (1) | WO2006114676A2 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102680622A (en) * | 2011-12-17 | 2012-09-19 | 东莞达信生物技术有限公司 | A kind of liquid chromatography detection method of rupatadine fumarate content |
| CN101531654B (en) * | 2009-04-13 | 2013-07-17 | 浙江赐富医药有限公司 | Preparation method for Rupatadine |
| CN103304542A (en) * | 2013-06-21 | 2013-09-18 | 四川海思科制药有限公司 | Rupatadine fumarate compound |
| CN102043025B (en) * | 2009-10-22 | 2014-04-16 | 北京万全阳光医学技术有限公司 | Method for measuring materials associated with rupatadine intermediate by high performance liquid chromatography |
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| EP2824103A1 (en) | 2013-07-09 | 2015-01-14 | Cadila Pharmaceuticals Limited | An improved process for the preparation of Rupatadine Fumarate |
| US10463656B2 (en) | 2017-01-05 | 2019-11-05 | Iowa State University Research Foundation, Inc. | Methods and compositions for prevention of feedlot bovine respiratory disease |
| CN114133353A (en) * | 2021-12-10 | 2022-03-04 | 重庆华邦制药有限公司 | Rupatadine fumarate intermediate and preparation method of rupatadine fumarate |
| CN114920727A (en) * | 2022-05-26 | 2022-08-19 | 重庆华邦制药有限公司 | Preparation method of rupatadine |
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| CN109456143A (en) * | 2018-11-27 | 2019-03-12 | 郑州师范学院 | The purification process of tetrachloro-ethylene |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2042421B1 (en) * | 1992-05-22 | 1994-08-01 | Uriach & Cia Sa J | PROCEDURE FOR OBTAINING 8-CHLORINE-11- * 1 - * (5-METHYL-3-PIRIDIL) METHYL * -4-PIPERIDILIDEN * -6,11-DIHYDRO-5H-BENZO * 5,6 * CYCLOHEPTA * 1 , 2-B * PIRIDINE. |
| ES2087818B1 (en) * | 1993-11-24 | 1997-03-16 | Uriach & Cia Sa J | 8-CHLORINE-11- (1 - ((5-METHYL-3-PIRIDYL) METHYL) -4-PIPERIDYLIDEN) -6,11-DIHYDRO-5H-BENZO- (5,6) CYCLOHEPTAL (1,2-B) PIRIDINE, SMOKING. |
| WO2004080945A1 (en) * | 2003-03-12 | 2004-09-23 | Natco Pharma Limited | Process for the preparation of n-methyl-1-naphthalenemethanamine |
-
2006
- 2006-04-22 WO PCT/IB2006/000964 patent/WO2006114676A2/en not_active Ceased
- 2006-04-22 ES ES200750036A patent/ES2311426B1/en active Active
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531654B (en) * | 2009-04-13 | 2013-07-17 | 浙江赐富医药有限公司 | Preparation method for Rupatadine |
| CN102043025B (en) * | 2009-10-22 | 2014-04-16 | 北京万全阳光医学技术有限公司 | Method for measuring materials associated with rupatadine intermediate by high performance liquid chromatography |
| JP2014526438A (en) * | 2011-06-28 | 2014-10-06 | フジアン・ミンドン・レジュヴネイション・ファーマスーティカル・カンパニー・リミテッド | Anti-allergic benzocycloheptathiophene derivatives |
| CN102680622A (en) * | 2011-12-17 | 2012-09-19 | 东莞达信生物技术有限公司 | A kind of liquid chromatography detection method of rupatadine fumarate content |
| CN103304542A (en) * | 2013-06-21 | 2013-09-18 | 四川海思科制药有限公司 | Rupatadine fumarate compound |
| EP2824103A1 (en) | 2013-07-09 | 2015-01-14 | Cadila Pharmaceuticals Limited | An improved process for the preparation of Rupatadine Fumarate |
| CN104163786A (en) * | 2014-06-10 | 2014-11-26 | 上海应用技术学院 | Method for preparing 5-methyl-3-bromomethylpyridine hydrobromide |
| US10463656B2 (en) | 2017-01-05 | 2019-11-05 | Iowa State University Research Foundation, Inc. | Methods and compositions for prevention of feedlot bovine respiratory disease |
| CN114133353A (en) * | 2021-12-10 | 2022-03-04 | 重庆华邦制药有限公司 | Rupatadine fumarate intermediate and preparation method of rupatadine fumarate |
| CN114133353B (en) * | 2021-12-10 | 2023-12-01 | 重庆华邦制药有限公司 | Rupatadine fumarate intermediate and preparation method of rupatadine fumarate |
| CN114920727A (en) * | 2022-05-26 | 2022-08-19 | 重庆华邦制药有限公司 | Preparation method of rupatadine |
| CN114920727B (en) * | 2022-05-26 | 2023-07-25 | 重庆华邦制药有限公司 | Preparation method of rupatadine |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006114676A8 (en) | 2007-11-22 |
| ES2311426A1 (en) | 2009-02-01 |
| WO2006114676A3 (en) | 2007-01-25 |
| ES2311426B1 (en) | 2009-12-22 |
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