GB2065635A - Process for preparing 3-(4- pyridinyl)aniline from 3-(4-pyridinyl)-2- cyclohexen-1-one oxime - Google Patents
Process for preparing 3-(4- pyridinyl)aniline from 3-(4-pyridinyl)-2- cyclohexen-1-one oxime Download PDFInfo
- Publication number
- GB2065635A GB2065635A GB8031533A GB8031533A GB2065635A GB 2065635 A GB2065635 A GB 2065635A GB 8031533 A GB8031533 A GB 8031533A GB 8031533 A GB8031533 A GB 8031533A GB 2065635 A GB2065635 A GB 2065635A
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- GB
- United Kingdom
- Prior art keywords
- pyridinyl
- oxime
- aniline
- acetic anhydride
- preparing
- 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.)
- Withdrawn
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An improved method of preparing 3-(4-pyridinyl)aniline comprises heating 3-(4-pyridinyl)-2-cyclohexen-1-one oxime with an excess each of acetic anhydride and anhydrous phosphoric acid, distilling off the acetic acid by- product and excess acetic anhydride, and hydrolyzing the remaining N- acetyl-3-(4-pyridinyl)aniline.
Description
SPECIFICATION
Process for preparing 3-(4-pyridinyl) aniline from a 3-(4-pyridinyl)-2-cyclohexen-1 -one oxime
This invention relates to an improved method for preparing 3-(4-pyridinyl)aniline, an intermediate for preparing rosoxacin, an antibacterial agent.
U.S. Patents 4,026,900 and 4,075,217 disclose heating the oxime of 3-(4-pyridinyl)-2-cyclohexen-1-one with an acetylating agent to produce the resulting O-acetyl oxime and then heating the O-acetyl oxime under acidic conditions, preferably in the presence of a strong mineral acid. The acetylation and subsequent heating steps were preferably run in combination by heating the oxime with acetic acid, acetic anhydride and hydrogen halide, preferably hydrogen chloride gas. The reaction was run in the range of about BOO to 140"C., preferably 100 to 1200C. The N-acetyl-3-(4-pyridinyl)aniline was then hydrolyzed to produce 3-(4pyridinyl)aniline, an intermediate for preparing rosoxacin.
Newman and Hung [J. Org. Chem. 38,4073-4074 (1973)1 showed the conversion of certain oximes of a-tetralones (7-methyl- and 7-chloro-a-tetralones) to the corresponding N-(1-naphthyl)acetamides by heating the oxime in acetic anhydride and an hydros phosphoric acid at 80"C. for thirty minutes. Unsuccessful results due to side-reactions resulted using these reaction conditions with the oxime of 6-methoxy-a- tetralone. Phosphorus pentoxide was used to prepare the anhydrous phosphoric acid.
The invention relates to an improvement in the process for converting 3-(4-pyridinyl)-2-cyclohexen-1 -one oxime to 3-(4-pyridinyl)aniline, the improvement which comprises heating said oxime with an excess each of acetic anhydride and anhydrous phosphoric acid, distilling off the acetic acid formed by the reaction and then hydrolyzing N-acetyl-3-(4-pyridinyl)aniline.
This invention resides in an improvement in the process for preparing 3-(4-pyridinyl)aniline, by acetylating 3-(4-pyridinyl)-2-cyclohexen-1-oxime to produce the corresponding O-acetyl oxime and heating the latter under acidic conditions, said improvement consisting of heating 3-(4-pyridinyl)-2-cyciohexen-1 -one oxime with an excess each of acetic anhydride and an hydros phosphoric acid, distilling off the acetic acid by-product and excess acetic anhydride, and hydrolyzing the remaining N-acetyl-3-(4-pyridinyl)aniline under alkaline conditions.In a preferred embodiment the first step of the process was run using about 7 to 10 mole-equivalents of acetic anhydride and about 3 to 10 mole-equivalents of anhydrous phosphoric acid per mole-equivalent of oxime and heating the reactants at about 90 to 1 200C., preferably 95 to 120"C.
The anhydrous phosphoric acid used in the process was prepared by dehydrating 85% phosphoric acid by reating it with acetic anhydride.
The first step of the process can be run using more acetic-anhydride and anhydrous phosphoric acid, viz., up to about 15-20 mole-equivalents of each per mole-equivalent of oxime, but to no particular advantage.
The second step is conveniently run using an aqueous alkali metal hydroxide, preferably sodium hydroxide.
The following examples will further illustrate the invention without, however, limiting it thereto.
Example 1 3-64-Pyridinyl)aniline, alternatively named 3-(4)pyridinyl)benzeneamine - Anhydrous phosphoric acid was
prepared by the addition of 1,020 g. (10 moles, d 1.082,940 ml.) of acetic anhydride to 540 g. (4.68 moles,
d 1.7,320 ml.) of vigorously stirred 85% phosphoric acid over 20 minutes maintaining the temperature near 50"C. with occasional cooling. To the clear warm solution was added 188 g. (1 mole) of 3-(4-pyridinyl)-2cyclohexen-1-one oxime in one portion. The initially clear, yellow solution was heated on a steam bath to about 95"C. where the steam was shut off. At this point the reaction mixture started to separate into two layers, eventually forming a mobile water-white upper layer and a yellow-brown viscous gum.The internal temperature of the reaction mixture very gradually increased to about 110-120 C. As soon as the temperature started to decrease, steam was again applied for 90 minutes. The generated acetic acid (colorless upper layer, 650-700 ml.) was then removed by vacuum distillation followed by removal of the excess acetic anhydride in vacuo. The continuously stirred and heated viscous residue was readily dissolved in 500 ml. of warm water. The clear dark solution was treated gradually and with occasional cooling with about 800 ml. of 35% aqueous sodium hydroxide at 60-80 C. to a weekly basic pH (8-9).Some precipitated solid was solubilized by the addition of 500 ml. of ethanol and heating to 80"C. The colorless viscous lower
layer containing mostly phosphate salts was drawn off while hot (11., 1,430 g.); it solidified at ambient temperature. To the remaining dark solution was added 320 ml. of 35% aqueous sodium hydroxide and the resulting two-phased reaction mixture was heated at reflux overnight (about 16 hours). The dark, homogeneous solution was cooled to 5"C. The crystallized solid was filtered, pressed well and then washed with the minimum amount (just amount to cover solid) of ice-methanol cooled 50% aqueous ethanol.To
remove any remaining inorganic salts in the filter cake, the solid was washed exhaustively with warm water (about 35 to 50 C.). The residue was dried in vacuo at 60"C. to afford 134.5 g. (79%) of the desired beige product, 3-(4-pyridinyl)aniline, m.p. 168171O; single spot on tIc (silica; CHOl3: CH3OH: i-C3H7NH2 90:5:5; UV).
Example 2 3-(4-Pyridinyl)anlline was prepared in comparable yield on a pilot laboratory scale using the same procedure, as follows: Acetic anhydride, 55 kg., was charged to the 30 gallon glass-lined reactor of a distillation unit. The phosphoric acid was added over one-half hour, with temperature rising to 1 00 C. The solution was heated to 120"C. and the steam shut off. A solution of 14.6 kg. of oxime in 36 1. of acetic acid was added at a rate to maintain reflux but not cause distillation. Approximately 3/4th of the solution was added over one and one-half hours resulting in a full kettle. Pressure steam (35-40 Ibs.) was applied to begin distillation of acetic acid.After one-half hour, there was room in the kettle and the remaining oxime solution was added slowly, maintaining distillation. The clear acetic acid layer was distilled off at atmospheric pressure over two hours leaving a dark and viscous, but stirrable residue at 1 200C. Vacuum was applied gradually to remove the remaining acetic acid and acetic anhydride, keepting the pot temperature over 1 OO"C. With the residue stirring at 100 C., (heat off), 20 1. of water was added over 5 minutes. The temperature dropped to 850C. but stirring was maintained. The kettle was cooled with water to 60"C., and 54 kg. of 35% aqueous sodium hydroxide was added over one-half hour, temperature 50-650C.Ethanol, 20 1., was added and the mixture cooled to 30"C. before being allowed to separate. A clear aqueous layer, 66 1., was drawn off and the very dark organic layer, 56 1., was transferred to a stainless steel kettle. 35% Aqueous sodium hydroxide, 34 kg., was added to the kettle and the mixture was refluxed (83"C.) for 12 hours. In the morning, the mixture was cooled from 60 to 5"C. before filtration. The dark solids were washed with 3 x 6 1.
of cold 25% ethanol to give a tan product. The wet cake was slurried in 40 1. of water at 30 C. for one-half hour and refiltered. The soiids were washed generously with water and dried 600C.lairlovernight The resulted 10.08 kg., or 10080177.8x170 = 76.3% of theory, of the tan product, 3-(4-pyridinyl)aniline, m.p. = 1 65-70C.
Claims (5)
1. A process for preparing 3-(4-pyridinyl)aniline by acetylating 3-(4-pyridinyl)-2-cyclohexen-1 -one oxime to produce the corresponding O-acetyl oxime and heating the latter under acidic conditions, which comprises heating 3-(4-pyridinyl)-2-cyclohexen-1-one oxime with an excess each of acetic anhydride and anhydrous phosphoric acid, distilling off the acetic acid by-product and excess acetic anhydride, and hydrolyzing the remaining N-acetyl-3-(4-pyridinyl)aniline.
2. A process according to claim 1, wherein about 7 to 10 mole-equivalents of acetic anhydride and about 3 to 10 mole-equivalents of anhydrous phosphoric acid are used per mole-equivalent of oxime.
3. A process according to claim 2, wherein the reactants in the first step are heated at about 90 to 1 200C.
4. A process for preparing 3-(4-pyridinyl)aniline substantially as herein described with reference to the
Examples.
5. 3-(4-PyridinylXaniline when prepared by the process according to any one of the preceding claims.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10319179A | 1979-12-13 | 1979-12-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2065635A true GB2065635A (en) | 1981-07-01 |
Family
ID=22293865
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8031533A Withdrawn GB2065635A (en) | 1979-12-13 | 1980-09-30 | Process for preparing 3-(4- pyridinyl)aniline from 3-(4-pyridinyl)-2- cyclohexen-1-one oxime |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS5687563A (en) |
| KR (1) | KR830004246A (en) |
| AR (1) | AR225058A1 (en) |
| AT (1) | ATA509880A (en) |
| AU (1) | AU532087B2 (en) |
| BE (1) | BE885570A (en) |
| CA (1) | CA1129864A (en) |
| DE (1) | DE3038778A1 (en) |
| DK (1) | DK432880A (en) |
| ES (1) | ES495606A0 (en) |
| FI (1) | FI803131L (en) |
| FR (1) | FR2471375A1 (en) |
| GB (1) | GB2065635A (en) |
| IL (1) | IL61089A (en) |
| IT (1) | IT1193982B (en) |
| LU (1) | LU82843A1 (en) |
| NL (1) | NL8005661A (en) |
| NO (1) | NO803010L (en) |
| NZ (1) | NZ194952A (en) |
| PT (1) | PT71818B (en) |
| SE (1) | SE8007188L (en) |
| ZA (1) | ZA806200B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4026900A (en) * | 1976-03-19 | 1977-05-31 | Sterling Drug Inc. | 3-(Pyridinyl)-2-cyclohexen-1-ones |
-
1980
- 1980-09-15 NZ NZ194952A patent/NZ194952A/en unknown
- 1980-09-19 IL IL61089A patent/IL61089A/en unknown
- 1980-09-19 PT PT71818A patent/PT71818B/en unknown
- 1980-09-22 AU AU62594/80A patent/AU532087B2/en not_active Ceased
- 1980-09-22 IT IT24826/80A patent/IT1193982B/en active
- 1980-09-30 GB GB8031533A patent/GB2065635A/en not_active Withdrawn
- 1980-10-02 FI FI803131A patent/FI803131L/en not_active Application Discontinuation
- 1980-10-03 ES ES495606A patent/ES495606A0/en active Granted
- 1980-10-08 BE BE1/9976A patent/BE885570A/en not_active IP Right Cessation
- 1980-10-08 ZA ZA00806200A patent/ZA806200B/en unknown
- 1980-10-08 FR FR8021517A patent/FR2471375A1/en active Pending
- 1980-10-09 NO NO803010A patent/NO803010L/en unknown
- 1980-10-09 JP JP14191380A patent/JPS5687563A/en active Pending
- 1980-10-13 DK DK432880A patent/DK432880A/en not_active Application Discontinuation
- 1980-10-13 KR KR1019800003934A patent/KR830004246A/en unknown
- 1980-10-13 LU LU82843A patent/LU82843A1/en unknown
- 1980-10-14 AT AT0509880A patent/ATA509880A/en not_active Application Discontinuation
- 1980-10-14 AR AR282874A patent/AR225058A1/en active
- 1980-10-14 NL NL8005661A patent/NL8005661A/en not_active Application Discontinuation
- 1980-10-14 DE DE19803038778 patent/DE3038778A1/en not_active Withdrawn
- 1980-10-14 SE SE8007188A patent/SE8007188L/en not_active Application Discontinuation
- 1980-12-10 CA CA366,467A patent/CA1129864A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| PT71818B (en) | 1981-07-07 |
| BE885570A (en) | 1981-04-08 |
| IL61089A (en) | 1983-11-30 |
| LU82843A1 (en) | 1981-06-04 |
| IT1193982B (en) | 1988-08-31 |
| AU532087B2 (en) | 1983-09-15 |
| DK432880A (en) | 1981-06-14 |
| ES8107188A1 (en) | 1981-09-01 |
| IL61089A0 (en) | 1980-11-30 |
| SE8007188L (en) | 1981-06-14 |
| ES495606A0 (en) | 1981-09-01 |
| DE3038778A1 (en) | 1981-06-19 |
| NL8005661A (en) | 1981-07-16 |
| JPS5687563A (en) | 1981-07-16 |
| KR830004246A (en) | 1983-07-09 |
| PT71818A (en) | 1980-10-01 |
| FR2471375A1 (en) | 1981-06-19 |
| AR225058A1 (en) | 1982-02-15 |
| ATA509880A (en) | 1983-09-15 |
| NO803010L (en) | 1981-06-15 |
| ZA806200B (en) | 1981-09-30 |
| CA1129864A (en) | 1982-08-17 |
| FI803131L (en) | 1981-06-14 |
| IT8024826A0 (en) | 1980-09-22 |
| AU6259480A (en) | 1981-06-25 |
| NZ194952A (en) | 1982-09-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |