GB2097000A - Process for the preparation of 1,4-bis(2,2,2- trifluoroethoxy)benzene - Google Patents
Process for the preparation of 1,4-bis(2,2,2- trifluoroethoxy)benzene Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
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Abstract
A process for preparing 1,4- bis(2,2,2-trifluoroethoxy)benzene comprises reacting paradibromobenzene or para- dihydroxybenzene with a compound of formula CF3CH2O-A wherein A is -SO2CF3 or an alkali metal. The antiarrhythmic agent 2,5-bis(2,2,2-tri- fluoroethoxy)-N-(2-piperidyl- methyl)benzamide (flecainide) may be produced by acetylating the product of a process according to the invention in the presence of a Lewis acid catalyst, then either chlorinating the acetylated product, adding a buffering base and further chlorinating to form the corresponding alpha , alpha , alpha - trifluoroacetophenone or reacting the acetylated acetophenone with hypochlorite to form the corresponding benzoic acid and reacting the acid with inorganic acid chloride to provide the corresponding acid chloride, and then reacting the product of either of the latter pair of steps with 2-aminomethyl-piperidine to form the flecainide product in one step or with two 2-aminomethyl-pyridine followed by reduction to form the flecainide product in two steps.
Description
SPECIFICATION
Process for the preparation of 1 ,4-bis(2,2,2-trifluoroethoxy) benzene
This invention relates to a process for the preparation of 1 ,4-bis(2,2,2-trifluoroethoxy)benzene from bromo- or hydroxy-substituted benzenes.
This process is particularly useful as the first step of an improved process for the preparation of the antiarrhythmic agent 2, 5-bis(2,2,2-trifluoroethoxy)N-(2-piperidylmethyl)benzamide (flecainide) and its salts. The preparation of flecainide by a series of steps including this process is the subject of United
Kingdom Patent Application No. 8009041, published under the Serial No. 2,045,760.
The present invention provides a process for preparing the compound 1 ,4-bis(2,2,2-trifluoroethoxy)benzene which comprises reacting a compound of the formula
wherein all of the X's are the same and are selected from OH and Br with a suitable alkylating agent of the formula CF3CH2O-A wherein A is -SO2-CF3 or an alkali metal.
The preparation of flecainide may be achieved by subsequently performing the following additional steps:
(2) acetylating 1 ,4-bis(2,2,2-trifluoroethoxy) benzene in the presence of a Lewis acid catalyst to provide a substituted acetophenone of the formula
(3) then either (a) chlorinating the substituted acetophenone (e.g. in acetic acid) to form the corresponding a,a
dichloroacetophene
(b) adding a buffering base and further chlorinating to provide the et,cg,-trifluoroacetophenone
(c) reacting the substituted acetophenone with hypochlorite to form the corresponding benzoic
acid for
and
(d) reacting the acid with an inorganic acid chloride to provide the acid chloride
(4) and then reacting the product of step 3(b) or step 3(d) with
2-(aminomethyl)piperidine to form the desired product in one step, or with
2-(aminomethyl)pyridine and then reducing to form the desired product, option as the free base.
The process of the invention followed by the foregoing additional steps provides the following reaction sequence:
In a process according to the invention, when X is OH, A is suitably -S02CF3 and the reactions are heated together in a solvent such as acetone or N,N-dimethylformamide and in the presence of a base, preferably a weak base such as an alkali metal carbonate, e.g. potassium or sodium carbonate.
When X is Br, 1 ,4-dibromobenzene / is reacted with the 2,2,2-trifluoroethoxide ion in a strongly polar solvent mixture at a temperature up to the reflux temperature of the solution in the presence of cuprous or cupric ion to provide the desired product in good yield. The 2,2,2-trifluoroethoxide ion is obtained from the corresponding alcohol by reaction with a strong base such as sodium hydroxide or preferably sodium hydride. Suitable solvent mixtures include dimethyi sulfoxide, N,N-dimethylacetamide and preferably N,N-dimethylformamide, each with about 10 to 50 percent, and preferably about 20 percent, of 2,2,2-trifluoroethanol. Cuprous ion is provided, e.g. by a cuprous halide such as cuprous iodide or cuprous bromide. Cupric ion is provided e.g. by cupric bromide, cupric sulfate or cupric acetate.
The product of a process according to the invention may be utilized to produce flecainide by performing additionally steps (2), (3a), (3b) and (4) aforementioned or steps (2), (3c), (3d) and (4) aforementioned.
In step (2) 1 ,4-bis(2,2,2-trifluoroethoxy) benzene 11 is acetylated by reacting under mild conditions with any acetylating agent such as acetyl chloride or acetic anhydnde in the presence of a
Lewis acid catalyst such as tin chloride, ferric chloride or, preferably, aluminum chloride. The acetylation is carried out in a suitable non-reactive solvent such as a chlorinated hydrocarbon, such as dichloromethane, trichloroethylene or 1 2-dichloroethane, diethyl ether, tetrahydrofuran and the like.
Unexpectedly, this reaction provides high yields of the desired acetophone IIl.
The reaction of step (3)(a) is a simple chlorination of the intermediate 111 in a suitable solvent such as ethyl acetate, a chlorinated hydrocarbon or, preferably, an acetic acid solution. This reaction is carried out at a moderate temperature, preferably 50 to 600C.
The product IV can be isolated if desired, or the chlorination carried on as in step (3)(b) to obtain the intermediate Vby adding a buffering agent e.g. an acetate salt such as sodium acetate and raising the temperature slightly for example, to 80 to 1 000C. while continuing the chlorination.
The reaction of step (3)(c) is most conveniently carried out by adding the acetophenone Ill to a cold solution of an alkali metal or alkaline earth hydroxide (such as sodium hydroxide, potassium hydroxide or calcium hydroxide) which has been saturated with chlorine to pH 7 (forming the corresponding hypochlorite). The reaction is then facilitated by warming the reaction mixture. A very high yield of the desired 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid V/ is obtained.
In step (3)(d) the acid is converted to the corresponding acyl chloride by reaction with an inorganic acid chloride such as thionyl chloride, phosphorous trichloride or phosphorous pentachloride (preferably phosphorous trichloride) at reflux with or without a suitable non-reactive solvent such as benzene or toluene or a halogenated hydrocarbon.
Step (4) of the overall process may be carried out directly from the saturated diamine 2 (aminoethyl)piperidine or indirectly from the unreduced diamine 2-(aminomethyl)pyridine. Thus, 2
aminomethylpiperidine can be reacted with the trichloroacetophenone product of step (3)(b) or the compound 2-aminomethylpyridine can be reacted with the trichloroacetophenone product Vof step (3)(b). In either case, the reaction proceeds readily without external heating in an inert solvent such as toluene, benzene, isopropyl alcohol, cyclohexane and the like. The reaction proceeds particularly readily and in high yield when the unreduced diamine is reacted in a mixture of toluene and cyclohexane.
When the final step of the overall process is carried out, starting with the acid chloride product VII of step (3)(d), it is also carried out directly from 2-(aminomethyl)piperidine or indirectly from 2-(aminomethyl)pyridine. The acid chloride product of step (3)(d) is reacted by heating in a non-reactive solvent such as glyme, benzene, toluene or diethyl ether (preferably glyme). Alternatively, 2-aminomethylpyridine can be reacted with the acid chloride product of step (3)(d) in the presence of a non-reactive solvent such as toluene or benzene. This mixture is heated at reflux in the presence of an acid acceptor (e.g. a tertiary amine such as triethylamine).The adduct obtained from the reactive of an 2-(aminomethyl)pyridine with either compound Vor VII is reduced to the desired product VIII by catalytic hydrogenation in the presence of platinum oxide or (preferably) platinum on carbon. The solvent used
for this reaction is methanol or a lower alkanoic acid such as (and preferably) glacial acetic acid and the preferred temperature range is 15 to 300 C. When acetic acid is used the product obtained is flecainide acetate.
In the following examples, Examples 1 and 2 are according to the invention. Examples 2 to 1 2 are examples of additional steps in the preparation of flecainide from the product of a process according to the invention.
Example 1 A=SO2CF3 and X=OH To a mixture of 2.42 moles (334.4 g.) of potassium carbonate, 2.2 moles (510.6 g.) of 2,2,2trifluoroethyl trifluoromethanesulfonate in 1.02 liters of acetone is added a solution of 1.0 mole (110 g.) of hydroquinone in 1.1 liters of acetone, slowly over a 2 hour period. The reaction is then heated at reflux for 24 hours, the reaction mixture is evaporated, and 2 liters of chloroform and 2 liters of water are added to the residue. The chloroform layer is separated, the aqueous layer is washed twice with 1 liter of chloroform, and the combined chloroform solution is washed with 1 liter of water. The chloroform solution is dried over magnesium sulfate, then concentrated under vacuum.Hexane is added to the residue and the solid product is collected by filtration and washed with hexane. Additional material is collected from the concentrated residues. A yield of 88 percent, 241 g. of 1,4-bis(2,2,2- trifluoroethoxy)benzene, m.p. 75-770C. is obtained.
Example 2
A=Na and X=Br
To 0.20 mole (9.6 g.) of 50 percent sodium hydride in 40 ml. of N,N-dimethylformamide is added 40 ml. of 2,2,2-trifluoroethanol followed by 0.034 mole (8.0 g.) of 1,4-dibromobenzene and 0.006 mole (1.0 g.) of cuprous iodide. The mixture is heated at its reflux temperature for 4 hours, then cooled to about 250C. and filtered. The residue is washed with N,N-dimethylformamide. The solution is then poured into water, and the precipitate is separated by filtration. The product is dissolved in diethyl ether and filtered, and the filtrate solution is evaporated to provide a solid residue which is washed with hexane and dried. The product is 7.3 g. (80 percent) of 1 ,4-bis(2,2,2-trifluoroethoxy)benzene, m.p. 77 to 790C.
The reaction is rerun as follows, varying the conditions and proportions of the constituents and utilizing cupric bromide as the catalyst: To a mixture of 4.8 g. of sodium hydride in 40 ml. of N,Ndimethylformamide is added 20 ml. (27.4 g.) of 2,2,2-trifluoroethanol. To this mixture is added 0.034 mole (8.0 g.) of 1,4-dibromobenzene and 1.0 g. of cupric bromide. The reaction mixture is heated to about 1 O00C. for two hours, then quenched with ice water. Acidification with hydrochloric acid and filtration produces 9.2 g. (99 percent) of white solid 1 ,4-bis(2,2,2-trifluoroethoxy)benzene. The structure is confirmed by infrared spectral analysis.
Example 3
Step (2) utilizing acetic anhydride as the acetylating agent
To a mixture of 2.43 moles (324 g.) of aluminum chloride in 648 ml. of dichloromethane is added a solution of 0.88 mole (274 g.) of 1 ,4-bis(2,2,2-trifluoroethoxy)benzene and 0.97 mole (92 ml.) of acetic anhydride in 880 ml. of dichloromethane over a 3 hour period while maintaining the temperature at above OOC. The reaction mixture is then heated to its reflux temperature and stirred at reflux for 5 hours. The progress of the reaction is followed using thin-layer chromatography. The reaction mixture is placed in an ice bath and ice and 10 percent hydrochloric acid are added slowly to decompose the aluminum chloride complex. The temperature of the reaction mixture is not allowed to exceed 250C.The organic phase is separated and washed once with 2 liters of 10 percent hydrochloric acid and then with 2 liters of water. The combined aqueous phase is extracted with several liters of dichloromethane. The organic phase is dried over magnesium sulfate, then evaporated to provide a moist residue. Hexane is added to the residue and the resulting solid is collected by filtration and washed with hexane. Upon drying, 250 g. of light yellow crystalline 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is obtained. The yield is 90 percent, the m.p. is 84 to 860 C.
Example 4
A scale up of the run of Example 3
To a mixture of 4,367 grams (32.75 moles) of aluminum chloride and 8.8 liters of dichloromethane at OOC. is added gradually a solution of 3,267 grams of 1 ,4-bis(2,2,2-trifluoroethoxy)benzene and 1.399 kilograms (13.7 moles) of acetic anhydride in 1.3 liters of dichloromethane. The reaction temperature is maintained at 5 to 1 OOC. while stirring the mixture for about 1 6 hours. The reaction mixture is then heated to its reflux temperature and maintained under reflux for 4 hours. The reaction mixture is then acidified with 8.76 kilograms of 10 percent hydrochloric acid. Ice is added to the mixture to maintain the temperature below 200 C. The organic layer is separated and the aqueous layers are extracted several times with dichloromethane.The organic layers are dried, then evaporated to provide a residue which is triturated with hexane to provide a yellow solid product. Two crops of product are obtained providing a total yield of 3.088 kilograms of 2,5-bis(2,2,2-trifiuoroethoxy)acetophenone, m.p. 84 to 880C., yield 82 percent.
Example 5
Step (2) utilizing acetyl chloride as the acetylating agent
To a mixture of 0.022 mole (2.8 g.) of aluminum chloride and 100 ml. of 1,2-dichloroethane is added dropwise at 250C. a solution of 0.020 mole (5.6 g.) of 1 ,4-bis(2,2,2-trifluoroethoxy)benzene and 0.022 mole (1.7 6.) of acetyi chloride in 20 ml. of 1,2-dichloroethane. After stirring for 4 hours the reaction mixture is washed with ice water and hydrochloric acid and the organic layer is dried.
Evaporation produces a residue which is recrystallized from hexane to provide 4.1 g. (71 percent) of pale yellow needles of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (as verified by infrared spectral analysis).
Example 6
Step (3)(a)
A mixture of 0.25 mole (79.1 g.) of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone in 1 50 ml. of acetic acid is heated to 500 C. Chlorine gas is bubbled into the solution and the temperature increases gradually to 550C. The chlorine addition rate is adjusted to maintain the temperature between 55 and 600 C. After about 75 minutes the temperature begins to decrease (indicating that no more chlorination is taking place). The total amount of chlorine added is 35.5 g. The resulting product is 2,5-bis(2,2,2trifl uornethoxy)-a,-dichlornacetophenone.
Example 7
Step (3)(b)
To the product of the preceding example (without isolation or purification) is added 0.35 mole (28.7 g.) of sodium acetate. The temperature increases to about 800 C., and the solution is heated to 850C. Chlorine addition is resumed and the temperature increases to 1 0O0C. After about 20 minutes the theoretical amount of chlorine has been taken up, and the mixture is poured into a mixture of ice and water. The precipitate which forms is collected by filtration, rinsed with water, dissolved in dichloromethane and dried. Evaporation provides a residue which is triturated with hexane to provide a white solid. A yield of 94 g. (90 percent) of 2,5-bis(2,2,2-trifluoroethoxy)a,a,-trichloro- acetophenone, m.p. 45 to 480C. is obtained.
Example 8
Step (3)(c)
To a solution of 7.3 moles (292 g.) of sodium hydroxide in 600 ml. of water is added ice to make the total volume of 1.75 liters. Chlorine gas is passed into the solution while maintaining the temperature below 1 OOC. until it is neutral to litmus, and 2.19 moles (87.6 g.) of sodium hydroxide dissolved in 200 ml. of water is added. The combined solution is warmed to 500 C., and 0.73 mole (230 g.) of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is added slowly. The reaction mixture is stirred while heating until an exotherm begins about 75 C. and is thereafter maintained at about 800 C. by cooling.The mixture is stirred for about 16 hours at about 80 to 900 C. while monitoring the extent of the reaction by thin-layer chromatography. The excess hypochlorite is then destroyed by adding 75 g.
of sodium bisulfite in 250 ml. of water, and the mixture is cooled to about 250C. and carefully acidified with 10 percent hydrochloric acid. The light yellow solid product is collected by filtration, washed with water, and dried. A 94.5 percent yield of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid, m.p. 120-1 220C.
is obtained.
Example 9
Step (3)(d)
To a solution of 0.688 mole (219 g.) of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid in 657 ml. of benzene is added 1,376 M. (100 ml.) of thionyl chloride slowly over 1 hour while heating to about 600 C. The mixture is then heated at reflux for about 8 hours, then evaporated to provide the desired product, 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride as a residue. The structure is verified by means of infrared spectral analysis.
Example 10
Step (4) carried out in two reactions starting with intermediate V
To a solution of 0.05 mole (21.0 g.) of 2,5-bis(2,2,2-trifluoroethoxy)-a,a,a-trichloro- acetophenone in 60 ml. of toluene is added dropwise a solution of 0.055 mole (6.0 g.) of 2-aminomethylpyridine in 50 ml. of cyclohexane and 10 ml. of toluene. The reaction is exothermic, and a precipitate forms immediately. Additional toluene and cyclohexane are added to obtain a mixture consistency that permits stirring, and the stirring is continued for two hours at about 25"C. The solid is then separated by filtration, washed with a mixture of toluene and cyclohexane and dried to provide a white solid.The product is 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide, m.p.10'i 1 060C., 17.8 g., 89 percent yield.
A mixture of 0.33 mole (134.7 g.) of 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)- benzamide, 1.347 liters of glacial acetic acid and 13.5 g. of 5 percent platinum on carbon is reduced in a Parr apparatus at about 30 pounds of hydrogen at room temperature. The reaction is complete in 67 hours. The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and washings are evaporated to provide a residue. Hexane is added to the residue and the resulting white solid is collected and recrystallized from a mixture of acetone and hexane. A 71 percent yield of 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate, m.p. 1 50 to 1 520C., is obtained.By concentrating the residual liquid, an additional 1 8 percent of product is obtained as a second crop with a melting point of 148-1 500 C.
Example I 11 Step (4) carried out in a single reaction starting with intermediate V
To a solution of 0.01 mole (4.19 g.) of 2,5-bis(2,2,2-trifluoroethoxy)- -trichloro- acetophenone in 50 ml. of isopropyl alcohol is added 0.01 mole (1.2 g.) of 2-aminomethylpiperidine.
The mixture gradually turns solid over a period of 30 minutes. The mixture is allowed to sit for about 1 6 hours, then 0.01 M of acetic acid and 5 ml. of isopropyl alcohol are added, and the solution is warmed to dissolve all of the solid. On cooling, 3.0 g. of a white solid are obtained. The filtrate is evaporated, and the residue recrystallized from isopropyl alcohol to give additional product as a white solid. The product is 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate according to its infrared and nuclear magnetic resonance spectra.
Example 12
Step (4) carried out in two reactions starting with intermediate VII
To a mixture of 0.77 mole (83.3 g.) of 2-aminomethylpyridine, 0.77 mole (106.7 ml.) of triethylamine and 300 ml. of benzene is added 0.70 mole (236 g.) of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride in 472 ml. of benzene over 1 hour.
The reaction mixture is stirred for about 1 6 hours at 250C., refluxed for one hour, then washed twice-with 2 liters of water. The aqueous phase is washed with 2 liters of benzene, and the combined organic phases are dried over magnesium sulfate, then evaporated under vacuum. Recrystallization from a mixture of benzene and hexane gives 240 9., 86 percent, of off-white 2,5-bis(2,2,2-trifluoro ethoxy)-N-(2-pyridylmethyl)benzamide, m.p. 100 to 1 020C.
A mixture of 0.33 mole (134.7 g.) 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide, 1.347 liter of glacial acetic acid and 1 3.5 g. of 5 percent platinum on carbon is reduced in a Parr apparatus at a pressure of about 10 pounds of hydrogen at room temperature. The reaction is complete in 6-7 hours. The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and washings are evaporated to provide a residue. Hexane is added to the residue and the resulting white solid is collected and recrystallized from a mixture of acetone and hexane. A 71 percent yield of 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate, m.p. 1 50 to 1520 C., is obtained. By concentrating the residual liquid an additional 1 8 percent of product is obtained as a second crop with a melting point of 148-1 500 C.
Claims (4)
1. A process for preparing the compound 1,4-bis(2,2,2-trifluoroethoxy)benzene which comprises reacting a compound of the formula
wherein all of the X's are the same and are selected from OH and Br with a suitable alkylating agent of the formula CF3CH20-A wherein A is -SO2CF3 or an alkali metal.
2. A process according to claim 1 substantially as hereinbefore described in Example 1 or 2.
3. A process according to claim 1 followed by chlorinating the product.
4. A process according to claim 3 followed by adding a buffering base and further chlorinating the product.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2133179A | 1979-03-19 | 1979-03-19 | |
| US2133279A | 1979-03-19 | 1979-03-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2097000A true GB2097000A (en) | 1982-10-27 |
| GB2097000B GB2097000B (en) | 1983-11-30 |
Family
ID=26694559
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8214964A Expired GB2097000B (en) | 1979-03-19 | Process for the preparation of 1,4-bis(2,2,2-trifluoroethoxy) benzene | |
| GB8009041A Expired GB2045760B (en) | 1979-03-19 | 1980-03-18 | Xy)-n-(2-piperidylmethyl) benzamide (flecanide) process for the preparation of 2,5-bis(2,2,2-trifluoroetho |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8009041A Expired GB2045760B (en) | 1979-03-19 | 1980-03-18 | Xy)-n-(2-piperidylmethyl) benzamide (flecanide) process for the preparation of 2,5-bis(2,2,2-trifluoroetho |
Country Status (14)
| Country | Link |
|---|---|
| JP (8) | JPH01125344A (en) |
| CA (1) | CA1137486A (en) |
| CH (1) | CH643829A5 (en) |
| DE (1) | DE3010195A1 (en) |
| DK (3) | DK167062B1 (en) |
| ES (1) | ES8104227A1 (en) |
| FR (7) | FR2454438A1 (en) |
| GB (2) | GB2045760B (en) |
| IE (1) | IE49558B1 (en) |
| IL (1) | IL59623A (en) |
| IT (1) | IT1195262B (en) |
| NL (1) | NL191486C (en) |
| PT (1) | PT70967A (en) |
| SE (5) | SE447992B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0175188A1 (en) * | 1984-09-11 | 1986-03-26 | Nihon Tokushu Noyaku Seizo K.K. | Carbamoylimidazole derivatives |
| US4675448A (en) * | 1985-02-13 | 1987-06-23 | Ethyl Corporation | Chlorination process |
| EP0273409A1 (en) * | 1986-12-31 | 1988-07-06 | Hoechst Aktiengesellschaft | Nitrohaloalkoxybenzenes, processes for their preparation and their use |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2519974A1 (en) * | 1982-01-21 | 1983-07-22 | Rhone Poulenc Spec Chim | PROCESS FOR THE ACYLATION OF HALOGENO OR TRIHALOGENOMETHYLBENZENES |
| FR2519975A1 (en) * | 1982-01-21 | 1983-07-22 | Rhone Poulenc Spec Chim | PROCESS FOR PREPARING TRIFLUOROMETHOXY OR TRIFLUOROMETHYLTHIOPHENYLCETONES |
| FR2519980A1 (en) * | 1982-01-21 | 1983-07-22 | Rhone Poulenc Spec Chim | PROCESS FOR THE SULFONYLATION OF HALOGENO OR TRIHALOGENOMETHYLBENZENES |
| FR2519979A1 (en) * | 1982-01-21 | 1983-07-22 | Rhone Poulenc Spec Chim | PROCESS FOR THE PREPARATION OF TRIFLUOROMETHOXY OR TRIFLUOROMETHYLTHIOPHENYLSULFONES |
| FR2525588A1 (en) * | 1982-04-22 | 1983-10-28 | Rhone Poulenc Spec Chim | PROCESS FOR PREPARING PHENYLCETONES FROM HALOGENO OR TRIHALOGENOMETHYLBENZENES AND ALIPHATIC OR AROMATIC TRIHALOGENOMETHYL COMPOUNDS |
| FR2579591B1 (en) * | 1985-03-29 | 1988-10-14 | Rhone Poulenc Spec Chim | PROCESS FOR THE PREPARATION OF PENTAFLUOROETHOXY AND PENTAFLUOROETHYLTHIOBENZENIQUE DERIVATIVES |
| FR2579594B1 (en) * | 1985-03-29 | 1987-06-05 | Rhone Poulenc Spec Chim | PROCESS FOR THE PREPARATION OF TRIFLUOROETHOXY OR TRIFLUOROETHYLTHIOBENZENES |
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| DE3786037T2 (en) * | 1986-04-25 | 1993-11-25 | Abbott Lab | Tracer for use in immunological fluorescence polarization methods for the detection of flecainide. |
| FR2640262B1 (en) * | 1988-12-14 | 1991-05-31 | Rhone Poulenc Chimie | PROCESS FOR THE PREPARATION OF TRIFLUOROETHOXYLATED ARYLIC KETONES |
| IL120715A (en) | 1997-04-21 | 2000-07-16 | Finetech Ltd | Process for the preparation of (2,2,2,-trifluoroethoxy)benzoic acids |
| US6316627B1 (en) | 1997-04-21 | 2001-11-13 | Fine Tech Ltd. | Process for the preparation of flecainide |
| IL121288A (en) | 1997-07-11 | 2000-10-31 | Finetech Ltd | Process and a novel intermediate for the preparation of flecainide |
| US7196197B2 (en) | 2003-09-17 | 2007-03-27 | Apotex Pharmachem Inc. | Process for the preparation of Flecainide, its pharmaceutically acceptable salts and important intermediates thereof |
| JP4894226B2 (en) * | 2005-10-31 | 2012-03-14 | Ｄｉｃ株式会社 | Method for producing fluorine-containing liquid crystal compound having hydroquinone skeleton |
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| US3772304A (en) * | 1969-10-30 | 1973-11-13 | Hoffmann La Roche | 4-hydroxy-isoquinolines and processes for their preparation |
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| US3719687A (en) * | 1970-07-22 | 1973-03-06 | Riker Laboratories Inc | N-(2-dialkylaminoalkylene)amides of 1,1-dihydroperfluoroalkoxy-substituted aryl acids and salts thereof |
| US3967949A (en) * | 1973-06-18 | 1976-07-06 | Eli Lilly And Company | Fluoroalkoxyphenyl-substituted nitrogen heterocycles as plant stunting agents |
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| IL49803A (en) * | 1975-06-28 | 1979-11-30 | Fisons Ltd | Preparation of pyrogallol |
| DE2616478C2 (en) * | 1976-04-14 | 1986-05-22 | Brickl, Rolf, Dr., 7951 Warthausen | Medicines, biocides and cosmetics containing fluoroacylresorcins |
| JPS6023656B2 (en) * | 1976-09-02 | 1985-06-08 | 川研フアインケミカル株式会社 | Method for producing alkoxy aromatic compounds |
| US4097481A (en) * | 1976-11-08 | 1978-06-27 | Riker Laboratories, Inc. | Tertiary amide derivatives of pyrrolidine and piperidine |
| US4071524A (en) * | 1976-11-08 | 1978-01-31 | Riker Laboratories, Inc. | Derivatives of urea |
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0
- GB GB8214964A patent/GB2097000B/en not_active Expired
-
1980
- 1980-03-04 CA CA000346919A patent/CA1137486A/en not_active Expired
- 1980-03-14 DK DK112180A patent/DK167062B1/en not_active IP Right Cessation
- 1980-03-14 IL IL59623A patent/IL59623A/en unknown
- 1980-03-14 SE SE8002003A patent/SE447992B/en not_active IP Right Cessation
- 1980-03-16 NL NL8001551A patent/NL191486C/en not_active IP Right Cessation
- 1980-03-17 ES ES489629A patent/ES8104227A1/en not_active Expired
- 1980-03-17 DE DE19803010195 patent/DE3010195A1/en active Granted
- 1980-03-18 IT IT20746/80A patent/IT1195262B/en active Protection Beyond IP Right Term
- 1980-03-18 CH CH212880A patent/CH643829A5/en not_active IP Right Cessation
- 1980-03-18 GB GB8009041A patent/GB2045760B/en not_active Expired
- 1980-03-18 FR FR8006019A patent/FR2454438A1/en active Granted
- 1980-03-18 PT PT70967A patent/PT70967A/en active IP Right Revival
- 1980-03-18 IE IE549/80A patent/IE49558B1/en not_active IP Right Cessation
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1981
- 1981-01-07 FR FR8100144A patent/FR2468590A1/en active Granted
- 1981-01-07 FR FR8100140A patent/FR2468569A1/en active Granted
- 1981-01-07 FR FR8100145A patent/FR2468591A1/en active Granted
- 1981-01-07 FR FR8100143A patent/FR2468576A1/en active Granted
- 1981-01-07 FR FR8100142A patent/FR2468571A1/en active Granted
- 1981-01-07 FR FR8100141A patent/FR2468570A1/en active Granted
-
1984
- 1984-03-21 SE SE8401555A patent/SE463260B/en not_active IP Right Cessation
- 1984-03-21 SE SE8401554A patent/SE447993B/en not_active IP Right Cessation
-
1988
- 1988-06-01 JP JP63135370A patent/JPH01125344A/en active Granted
- 1988-06-01 JP JP63135365A patent/JPH01104044A/en active Granted
- 1988-06-01 JP JP63135369A patent/JPH01125343A/en active Granted
- 1988-06-01 JP JP63135364A patent/JPH01104043A/en active Granted
- 1988-06-01 JP JP63135367A patent/JPH01125341A/en active Granted
- 1988-06-01 JP JP63135363A patent/JPH01104045A/en active Granted
- 1988-06-01 JP JP63135366A patent/JPH01125339A/en active Granted
- 1988-06-01 JP JP63135368A patent/JPH01125342A/en active Granted
-
1989
- 1989-04-27 SE SE8901532A patent/SE463418B/en not_active IP Right Cessation
- 1989-04-27 SE SE8901533A patent/SE463419B/en not_active IP Right Cessation
-
1990
- 1990-05-17 DK DK122290A patent/DK164857C/en not_active IP Right Cessation
-
1991
- 1991-04-30 DK DK91798A patent/DK79891D0/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0175188A1 (en) * | 1984-09-11 | 1986-03-26 | Nihon Tokushu Noyaku Seizo K.K. | Carbamoylimidazole derivatives |
| US4675448A (en) * | 1985-02-13 | 1987-06-23 | Ethyl Corporation | Chlorination process |
| EP0273409A1 (en) * | 1986-12-31 | 1988-07-06 | Hoechst Aktiengesellschaft | Nitrohaloalkoxybenzenes, processes for their preparation and their use |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PE20 | Patent expired after termination of 20 years |
Effective date: 20000317 |