CA2080596A1 - Process for preparing 3,4-difluoroaniline - Google Patents
Process for preparing 3,4-difluoroanilineInfo
- Publication number
- CA2080596A1 CA2080596A1 CA 2080596 CA2080596A CA2080596A1 CA 2080596 A1 CA2080596 A1 CA 2080596A1 CA 2080596 CA2080596 CA 2080596 CA 2080596 A CA2080596 A CA 2080596A CA 2080596 A1 CA2080596 A1 CA 2080596A1
- Authority
- CA
- Canada
- Prior art keywords
- process according
- hydroxylamine
- fluoro
- fluorobenzene
- difluoroaniline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/10—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of unsubstituted hydrocarbon radicals or of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
Abstract
A process for preparing 3,4-difluoroaniline comprising reacting 1-hydroxylamine-3-fluorobenzene with anhydrous hydrogen fluoride in the absence of oxygen. This compound is useful as a starting material for preparation of quinolone antibacterials.
3-Fluoro-1-hydroxylamine may be prepared by hydrogenating 3-fluoro-1-nitrobenzene.
3-Fluoro-1-hydroxylamine may be prepared by hydrogenating 3-fluoro-1-nitrobenzene.
Description
W~91/17138 2 0 8 U ~ 9 ~ PCT/US91/02~0 PROCESS FOR PREPARING 3.4-D~LUOROAN~ E
sackqround of the invention The present invention relates to a novel method for praparing 3,4-difluoroaniline. This compound is useful in the preparation of quinolone antibacterials as described in United States Patent 4,833,270.
United States Patent 4,145~364 refers to the prepara-tion of monofluoroanilines via a Bamberger rearrangement or an arylhydroxylamine route. The patent indicates that the arylhydroxylamine route "suffers from the disadvantage of concomitant formation of corresponding unfluorinated aniline, as well as the sym~etrioal azo and azoxy com-pounds" and that "considerable tar is formed making product isolation difficult." The patent also refers to tha preparation of monofluoroanilines and difluoroanilines by treating aromatic azid~s with anhydrous hydroge~ fluoride.
T.J. Broxton et al., J. Org. Chem., 42, 643-649 (1977) refer to the effect of oxygen and nitrogen atmospher~s on thermolysis of arenediazonium salts.
The process of the present invention is advantageous in that it uses hydroxyla~ines which ar~ relatively stable compared to aromatic azid~s. The latter are used as starting materials in the process of U.S. Patent 4,145,364~
Azides, on the other hand, are not 5table and tend to decompose whsn warmed or when left for a long period cf time at room temperature. Furthermore, hydroxylamines are, in most cases, ~rystalline and can be conveniently purified should the need aris~
~h~ process of the present invention does not result in the formation of a significant amount of unfluorina~ed ~aterial or tar. I have found that the use of anhydrous condikions and the exclusion of oxygen avoid such undesir-able results~
.
. -, . ~ . .
sackqround of the invention The present invention relates to a novel method for praparing 3,4-difluoroaniline. This compound is useful in the preparation of quinolone antibacterials as described in United States Patent 4,833,270.
United States Patent 4,145~364 refers to the prepara-tion of monofluoroanilines via a Bamberger rearrangement or an arylhydroxylamine route. The patent indicates that the arylhydroxylamine route "suffers from the disadvantage of concomitant formation of corresponding unfluorinated aniline, as well as the sym~etrioal azo and azoxy com-pounds" and that "considerable tar is formed making product isolation difficult." The patent also refers to tha preparation of monofluoroanilines and difluoroanilines by treating aromatic azid~s with anhydrous hydroge~ fluoride.
T.J. Broxton et al., J. Org. Chem., 42, 643-649 (1977) refer to the effect of oxygen and nitrogen atmospher~s on thermolysis of arenediazonium salts.
The process of the present invention is advantageous in that it uses hydroxyla~ines which ar~ relatively stable compared to aromatic azid~s. The latter are used as starting materials in the process of U.S. Patent 4,145,364~
Azides, on the other hand, are not 5table and tend to decompose whsn warmed or when left for a long period cf time at room temperature. Furthermore, hydroxylamines are, in most cases, ~rystalline and can be conveniently purified should the need aris~
~h~ process of the present invention does not result in the formation of a significant amount of unfluorina~ed ~aterial or tar. I have found that the use of anhydrous condikions and the exclusion of oxygen avoid such undesir-able results~
.
. -, . ~ . .
2 0 8 0 ~ .9 6 PCT/US91/02540 Summary of the Invention The present invention relates to a process for pre paring 3,4-fluoroaniline comprising reactin~ l-hydroxyl-amine-3-fluorobenzene with anhydrous hydrogen fluoride in S the absence of oxygen. Preferably, oxygen is excluded by conducting the reaction under an inert atmosphere such as nitrogen or argon. The solvent for the foregoing reaction is preferably pyridine.
In one embodiment of the invention, l-hydroxylamine-3-fluorobenzene is prepared by hydrogenating 3-fluoro-l-nitro-benzene. The hydrogenation is preferably accomplished by reacting the latter compound with hydrazine hydrate in the presence of platinum on carbon in an alcoholic solvent such as ethanol.
Deta~ Descri~tion of the Invention The presant invention also relates to the novel compound 3-fluoro-l-hydroxylamine.
The reaction of l-hydroxylamine-3-fluorobenzene with hydrogen fluoride should be conducted in an inert solvent.
Suitable solvents include acetonitrile and pyridine.
Pyridine is a preferred solvent. The reaction will generally be conducted at a temperature from about 0C to about 50C, preferably from about 20C to 25OC. The temperature is most preferably 25C.
The hydrogenation of 3-fluoro-l-nitrobenzene is preferably accomplished by reacting the compound with hydrazine in the presence of platinum on carbon. Othex sources of hydrogen such a-~ ammonium formate and other hydrogenation catalysts such as Raney Nickel may also be used. Suitable solvents for the hydrogenation reaction include most alcohols. The preferred solvent is ethanol.
The reaction temperature will generally be from about -20C
to about 50C, preferably from about 0C to about ~C. The temperature is most preferably 0C.
The prqssures of the foregoing react.ions are not critical. The reactions will generally be conducted at a ' . ~ , .
, , WO 91/17138 PCr/US91/02540 pressure of about 0.5 to about 2 atmospheres, preferably at ambient pressure (generally about one atmosphere).
In one embodiment of the invention, l-hydroxylamine-3-fluorobenzene is prepared by hydrogenating 3-fluoro-l-nitro-benzene. The hydrogenation is preferably accomplished by reacting the latter compound with hydrazine hydrate in the presence of platinum on carbon in an alcoholic solvent such as ethanol.
Deta~ Descri~tion of the Invention The presant invention also relates to the novel compound 3-fluoro-l-hydroxylamine.
The reaction of l-hydroxylamine-3-fluorobenzene with hydrogen fluoride should be conducted in an inert solvent.
Suitable solvents include acetonitrile and pyridine.
Pyridine is a preferred solvent. The reaction will generally be conducted at a temperature from about 0C to about 50C, preferably from about 20C to 25OC. The temperature is most preferably 25C.
The hydrogenation of 3-fluoro-l-nitrobenzene is preferably accomplished by reacting the compound with hydrazine in the presence of platinum on carbon. Othex sources of hydrogen such a-~ ammonium formate and other hydrogenation catalysts such as Raney Nickel may also be used. Suitable solvents for the hydrogenation reaction include most alcohols. The preferred solvent is ethanol.
The reaction temperature will generally be from about -20C
to about 50C, preferably from about 0C to about ~C. The temperature is most preferably 0C.
The prqssures of the foregoing react.ions are not critical. The reactions will generally be conducted at a ' . ~ , .
, , WO 91/17138 PCr/US91/02540 pressure of about 0.5 to about 2 atmospheres, preferably at ambient pressure (generally about one atmosphere).
3,4-Difluoroaniline may be reacted as described in United States Patent 4,833,270 to provide 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, which may be used to prepare various quinolone antibiotics, including danofloxacin. As discussed in that patent, an aqueous solution of 3,4-difluoroaniline and hydroxylamine hydrochloride containing hydrochloric acid is reacted with an aqueous solution of chloral hydrate and sodium sulfate at the reflux temperature, then filtered while hot, giving N-(3,4-difluorophenyl)-2-(hydroxyimino)-acetamide. The latter compound is reacted with concentrated sulfuric acid with heat, then added to cracked ice, giving 5,6-difluoro-lH-indole-2,3-dione. A basic aqueous solution o~ the dione is treated with hydrogen peroxide and heat, and then cooled and acidified, giving 2-amino-4,5-difluorobenzoic acid. The 2-amino-4,5-difluorobenzoic acid is added to a mixture o anhydrous copper at 0-5C, and then added to a dilute mineral acid, giving 2-chloro-4,5-difluorobenzoic acid.
A solution o~ 2-chloro-4,5-difluorobenzoic acid in acetonitrile containing a catalytic amount of dimethyl-formamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro-4,5-difluorobenzoic acid chloride, which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, which is then added to ice water and acidified to pH 2.5, giving (2-chloro-4,5-difluoro-benzoyl)propanedioic acid diethyl ester. A solution o~ the diethyl ester in p-dioxane and water is heated at refiux, and then evaporated and distilled, gi~ing 2 chloro-4~5-di~luoro-B-oxobenzenepropanoic acid ethyl ester. A
solution of the ethyl ester and triethyl ortho~ormate in acetic anhydride is heated at 150C for 2 hours, giving 2-chloro-a-(ethoxymethylene)-4,5-difluoro-B-oxobenzenepro-panoic acid ethyl ester. Cyclopropylamine is added to a . . : , , . : ~ , . .
. . , , , . : . . : , --... . . , , :.. , :. .. . .
';. '' , ~ , , :, , ~ , , ~' . ' :
-:' '- ' ' ': - . :. ',: .', :
., , .. ' ., , : ,: .: : . ., , .. :
- . ., :. :. . . .
WO91/17138 2 0 8 0 ~ ~ 6 PCT/US91/02~0 ~
solution of the latter ethyl ester in ethanol, giviny 2-chloro-~-[(cyclopropylamino)methylene]-4,5-difluoro-B-oxobenzenepropanoic acid ethyl ester, which is reacted with sodium hydride in dxy dimethylformamide under an inert atmosphere with heat, gi~ing l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinol`lnecarboxylic acid ethyl ester, which is t~en refluxed with acid, giving l-cyclopropyl-6,7-difluoro-l,4-dihydro 4-oxo-3-quinolinecarboxylic acidO
Danofloxacin may be prepared by reacting the acid thus prepared with (S,S)-2-methyl-2,5-diazabicyclo[2.2.l]heptane and an amine base.
Quinolone antibacterials such as danofloxacin (dis-closed in U.S. Patent 4,861,779) and the pharmaceutically acceptable acid addition salts thereof are useful in the treatment of bacterial infections of broad spectrum, particularly the treatment of gram-positive bacterial strains.
Th~ quinolone antibacterials of U.S. Patent 4,861,779 may be administered alone, but will generally be adminis-tered in admixture with a phar~aceutical carrier selectedwith regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. In the case of animals, they are advantageously contained in an animal feed or drinking water in a concen-tration of 5-5000 ppm, preferably 25-500 ppm. They can be injected parenterally, for exampl~, intramuscularly, intravenously or subcutaneouslyO For parenteral adminis-tration, they ar best used in the ~orm of a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to made the solution isotonic. In the case of animals, compounds can be administered intra-muscularly or subcutaneously at dosage levels of about ,- , :
-, - .. : . , . , .: . .. . .
- - . . - -- . .: : . . ,. , .. , . ~ .
, . . . . . .
.
A solution o~ 2-chloro-4,5-difluorobenzoic acid in acetonitrile containing a catalytic amount of dimethyl-formamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro-4,5-difluorobenzoic acid chloride, which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, which is then added to ice water and acidified to pH 2.5, giving (2-chloro-4,5-difluoro-benzoyl)propanedioic acid diethyl ester. A solution o~ the diethyl ester in p-dioxane and water is heated at refiux, and then evaporated and distilled, gi~ing 2 chloro-4~5-di~luoro-B-oxobenzenepropanoic acid ethyl ester. A
solution of the ethyl ester and triethyl ortho~ormate in acetic anhydride is heated at 150C for 2 hours, giving 2-chloro-a-(ethoxymethylene)-4,5-difluoro-B-oxobenzenepro-panoic acid ethyl ester. Cyclopropylamine is added to a . . : , , . : ~ , . .
. . , , , . : . . : , --... . . , , :.. , :. .. . .
';. '' , ~ , , :, , ~ , , ~' . ' :
-:' '- ' ' ': - . :. ',: .', :
., , .. ' ., , : ,: .: : . ., , .. :
- . ., :. :. . . .
WO91/17138 2 0 8 0 ~ ~ 6 PCT/US91/02~0 ~
solution of the latter ethyl ester in ethanol, giviny 2-chloro-~-[(cyclopropylamino)methylene]-4,5-difluoro-B-oxobenzenepropanoic acid ethyl ester, which is reacted with sodium hydride in dxy dimethylformamide under an inert atmosphere with heat, gi~ing l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinol`lnecarboxylic acid ethyl ester, which is t~en refluxed with acid, giving l-cyclopropyl-6,7-difluoro-l,4-dihydro 4-oxo-3-quinolinecarboxylic acidO
Danofloxacin may be prepared by reacting the acid thus prepared with (S,S)-2-methyl-2,5-diazabicyclo[2.2.l]heptane and an amine base.
Quinolone antibacterials such as danofloxacin (dis-closed in U.S. Patent 4,861,779) and the pharmaceutically acceptable acid addition salts thereof are useful in the treatment of bacterial infections of broad spectrum, particularly the treatment of gram-positive bacterial strains.
Th~ quinolone antibacterials of U.S. Patent 4,861,779 may be administered alone, but will generally be adminis-tered in admixture with a phar~aceutical carrier selectedwith regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. In the case of animals, they are advantageously contained in an animal feed or drinking water in a concen-tration of 5-5000 ppm, preferably 25-500 ppm. They can be injected parenterally, for exampl~, intramuscularly, intravenously or subcutaneouslyO For parenteral adminis-tration, they ar best used in the ~orm of a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to made the solution isotonic. In the case of animals, compounds can be administered intra-muscularly or subcutaneously at dosage levels of about ,- , :
-, - .. : . , . , .: . .. . .
- - . . - -- . .: : . . ,. , .. , . ~ .
, . . . . . .
.
0.1-50 mg/kg/day, advantageously 0.2-10 mg/kg/day given in a single daily dose or up to 3 divided doses.
The quinolone antibacterials can be administered to humans for the treatment of bacterial diseases by either the oral or parenteral routes, and may be administered advantageously 0.1-50 mg/kg/day given in a single dose or up to 3 divided doses. For intramuscular or intravenous administration, dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50 mg/kg/day. While intramuscular administration may be single dose or up to 3 divided doses, intravenous administration can include a continuous drip. Variations will necessarily occur depending on the particular route of administration chosen as will be known to those skilled in the art.
Example 1 1-Hydeoxlamine-3-fluorobenzene 3-Fluoro-1-nitrobenzene (20 g, 0.14 mol) was dissolved weight %) was added. The mixture was then cooled with an ice bath to 0°C and hydrazine hydrate (1308 ml, 0.25 mmol) was added dropwise over a period of 45 minutes. After an additional stirring period of 30 minutes, the reaction mixture was filtered through diatomaceous earth (Celite (trademark)) and the solvent was evaporated under vacuo.
The residual oil was suspended in 400 ml of water and extracted with 3x500 ml of methylene chloride. The com-bined organic solvents were dried (MgSO4) and evaporated to produce 12.84 g of an off white solid in 71% yeild, m.p.
58-59°C Anal. calc'd for C6H6NF: C, 56.69; H, 4.76; n, 11.02; Found: C. 56.73; H, 4.80; N, 11.14.
Example 2 3,4-Difluoroaniline A plastic bottle was charged with 75 ml of HF -pyridine under an inert atmosphere at 0°C and to that WO91/17138 2 0 ~ 0 ~ 9 G PCT/US91/025~0 1-hydroxylamine-3-fluoro~enzene (5.0 g, 39.4 mmol) was added carefully. The reaction mixture was allowed to warm to room temperature and was stirred for 48 hours. The reaction mixture was carefully quenched with 2 1 of sat-urated aqueous NaHCO3 solution and extracted with 5 x 500 mlportions of methylene chloride. The combined organic solvents were washed with saturated CuS04 solution (3x), dried (MgSO4) and evaporated to produce 4.6 g of an oil in 90% yield. NMR(CDCl3): ~ 6.95 (q, lH~, 6.55 (m, lH), 6.34 (m, lH), 3.6 (broad, 2H).
. ' ' ' ' ,' . . ' . ' ' . , ,, " ,. ''., ~ . ', . " ' , ," . ' . , , ':
,' ' . ................ . . ~ .
. ' ' ' . , ' ' . .
The quinolone antibacterials can be administered to humans for the treatment of bacterial diseases by either the oral or parenteral routes, and may be administered advantageously 0.1-50 mg/kg/day given in a single dose or up to 3 divided doses. For intramuscular or intravenous administration, dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50 mg/kg/day. While intramuscular administration may be single dose or up to 3 divided doses, intravenous administration can include a continuous drip. Variations will necessarily occur depending on the particular route of administration chosen as will be known to those skilled in the art.
Example 1 1-Hydeoxlamine-3-fluorobenzene 3-Fluoro-1-nitrobenzene (20 g, 0.14 mol) was dissolved weight %) was added. The mixture was then cooled with an ice bath to 0°C and hydrazine hydrate (1308 ml, 0.25 mmol) was added dropwise over a period of 45 minutes. After an additional stirring period of 30 minutes, the reaction mixture was filtered through diatomaceous earth (Celite (trademark)) and the solvent was evaporated under vacuo.
The residual oil was suspended in 400 ml of water and extracted with 3x500 ml of methylene chloride. The com-bined organic solvents were dried (MgSO4) and evaporated to produce 12.84 g of an off white solid in 71% yeild, m.p.
58-59°C Anal. calc'd for C6H6NF: C, 56.69; H, 4.76; n, 11.02; Found: C. 56.73; H, 4.80; N, 11.14.
Example 2 3,4-Difluoroaniline A plastic bottle was charged with 75 ml of HF -pyridine under an inert atmosphere at 0°C and to that WO91/17138 2 0 ~ 0 ~ 9 G PCT/US91/025~0 1-hydroxylamine-3-fluoro~enzene (5.0 g, 39.4 mmol) was added carefully. The reaction mixture was allowed to warm to room temperature and was stirred for 48 hours. The reaction mixture was carefully quenched with 2 1 of sat-urated aqueous NaHCO3 solution and extracted with 5 x 500 mlportions of methylene chloride. The combined organic solvents were washed with saturated CuS04 solution (3x), dried (MgSO4) and evaporated to produce 4.6 g of an oil in 90% yield. NMR(CDCl3): ~ 6.95 (q, lH~, 6.55 (m, lH), 6.34 (m, lH), 3.6 (broad, 2H).
. ' ' ' ' ,' . . ' . ' ' . , ,, " ,. ''., ~ . ', . " ' , ," . ' . , , ':
,' ' . ................ . . ~ .
. ' ' ' . , ' ' . .
Claims (9)
1. A process for preparing 3,4-difluoroaniline comprising reacting 1-hydroxylamine-3-fluorobenzene with anhydrous hydrogen fluoride in the absence of oxygen.
2. A process according to claim 1, wherein the oxygen is excluded by conducting the reaction under an inert atmosphere.
3. A process according to claim 2, wherein the atmosphere is nitrogen or argon.
4. A process according to claim 1, wherein the solvent is pyridine.
5. A process according to claim 2, wherein the solvent is pyridine.
6. A process according to claim 3, wherein the solvent is pyridine.
7. A process according to claim 1, wherein said 1-hydroxylamine-3-fluorobenzene is prepared by hydrogenating 3-fluoro-1-nitrobenzene.
8. A process according to claim 7, wherein the hydrogenation is accomplished by reacting said 3-fluoro-1-nitrobenzene with hydrazine hydrate in the presence of platinum on carbon.
9. 1-Hydroxylamine-3-fluorobenzene.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51726490A | 1990-05-01 | 1990-05-01 | |
| US517,264 | 1990-05-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2080596A1 true CA2080596A1 (en) | 1991-11-02 |
Family
ID=24059091
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2080596 Abandoned CA2080596A1 (en) | 1990-05-01 | 1991-04-12 | Process for preparing 3,4-difluoroaniline |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0527154A1 (en) |
| JP (1) | JPH05502036A (en) |
| CA (1) | CA2080596A1 (en) |
| IE (1) | IE911444A1 (en) |
| PT (1) | PT97530A (en) |
| WO (1) | WO1991017138A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19610571A1 (en) * | 1996-03-18 | 1997-09-25 | Basf Ag | Process and intermediates for the preparation of pyridyl-4-fluoroanilines |
| DE59807486D1 (en) * | 1997-09-05 | 2003-04-17 | Basf Ag | METHOD FOR PRODUCING (HETERO) AROMATIC HYDROXYLAMINE |
| DE102010036533B4 (en) | 2010-07-21 | 2023-05-11 | Dr. Ing. H.C. F. Porsche Aktiengesellschaft | Electric vehicle with electric machines on a front axle and a rear axle |
| CN116606214A (en) * | 2023-07-19 | 2023-08-18 | 山东国邦药业有限公司 | Synthesis method of 3, 4-difluoroaniline |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4145364A (en) * | 1977-11-30 | 1979-03-20 | Merck & Co., Inc. | Preparation of fluorinated anilines |
| IL97026A (en) * | 1990-02-07 | 1995-01-24 | Ciba Geigy | Pyrimidinylphenyl hydroxylamine derivatives, their preparation and their use as microbicides |
-
1991
- 1991-04-12 CA CA 2080596 patent/CA2080596A1/en not_active Abandoned
- 1991-04-12 JP JP50789191A patent/JPH05502036A/en active Pending
- 1991-04-12 EP EP19910907990 patent/EP0527154A1/en not_active Withdrawn
- 1991-04-12 WO PCT/US1991/002540 patent/WO1991017138A1/en not_active Application Discontinuation
- 1991-04-30 PT PT9753091A patent/PT97530A/en not_active Application Discontinuation
- 1991-04-30 IE IE144491A patent/IE911444A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05502036A (en) | 1993-04-15 |
| EP0527154A1 (en) | 1993-02-17 |
| PT97530A (en) | 1992-02-28 |
| IE911444A1 (en) | 1991-11-06 |
| WO1991017138A1 (en) | 1991-11-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |