Note: Descriptions are shown in the official language in which they were submitted.
l~Z986~
This invention relates to an improved method for preparing
3~ pyridinyl)aniline, an intermediate for preparing rosoxacin, an
antibacterial agent.
Gelotte et al United States Patents 4,Q26,900 and
4,075,217 disclose, and 4,075,217 claims, the process of heating
the oxime of 3-(4-pyridinyl)-2-cyclohexen-l~one with an acetylatiny
agent to produce the corresponding 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 80 to 140C~, preferably 100 to 120C. The N-acetyl-
3-(4-pyridinyl)aniline was then hydrolyzed to produce 3-(4-pyridinyl)
aniline, an intermediate for preparing rosoxacin.
Newman and Hung [J. Org. Chem. 38, 4073-407~ ~1973)] showed
the conversion of certain oximes of ~-tetralones (7-m~thyl- and
7-chloro-~-tetralones) to the corresponding N-(l-naphthyl)
acetamides by heating the oxime in acetic anhydride and anhydrous
phosphoric acid at 80C. for thirty minutes. Due to side-reactions,
unsuccessful results were obtained using these reaction conditions
with the oxime of 6-methoxy-~-tetralone. Phosphorus pentoxide was
used to prepare the anhydrous phosphoric acid.
The present invention provides an improvement in the
process for preparing 3-~4-pyridinyl)anilinè by acetylating
3-(4-pyridinyl)-2-cyclohexen-1-oxime to produce the corresponding
O-acetyl oxime and heating the latter under acidic conditions
to produce N-acetyl-3-(4-pyridinyl)aniline and hydrolyzing the
:
864
N-acetyl compound, the improvement consisting in 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, sub~tantially
neutralizing the remaining mixture by the addition of concentrated
aqueous alkali, extracting N-acetyl-3-(~-pyridinyl)aniline rom the
concentrated aqueous phosphate solution with a water-miscible lower
alkanol, and hydrolyzing the remaining N-acetyl-3-(4-pyridinyl)
aniline, preferably under alkaline conditions. In a preferred
embodiment, the first step of the process may be run using about
7 to lO mole-equivalen-ts of acetic anhydride and about 3 to 10
mole-equivalents of anhydrous phosphoric acid per mole equivalent
of oxime. A further preferred feature is to heat the reactants
at about 90 to 120C., preferably 95 to 120C. in the first step.
The anhydrous phosphoric acid used in the process may be
prepared by dehydrating 85% phosphoric acid by reacting it with
acetic anhydride.
The first step of the process can be run using more
acetic-anhydride and anhydrous phosphoric acid than indicated
above as preferred ranges, vis., up to about 15-20 mole-equivalents
of each per mole-equivalent of oxime, but to no particular
advantage.
The extraction step is preferably carried out at 50 to
80C. Ethanol is a preferred extracting solvent.
The hydrolysis step is conveniently run using an aqueous
alkali metal hydroxide, preferably sodium hydroxide. 35~ by weight
aqueous sodium hydroxide solution is preferred, and the temperature
is preferably between 50C and the reflux temperature of the
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solution at this stage of the process
The following examples will further illustrate the
invention without, however, limiting it thereto.
Example 1
3-(4-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 ace-tic
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 50C. with occasional cooling. To the clear
warm solution was added 188 g. (1 mole) of 3-(4-pyridinyl)-2-
cyclohexen-l-one oxime in one portion. The initially clear,
yellow solution was heated on a steam bath to about 95C. 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
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the reaction mixture very gradually increased to about 110-120C. As soon as
the temperature started to decrease, steam was again applied for 90 minutes.
The ge~eratcd acetic acid ~colorless ~Ipper layer, 650-700 ml.) was then re-
moved by vacuum distillation followed by removal of the excess acetic
anhydride in vacuo. l`he continuously stlrred and heated viscous residue was
readily d:issolved 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 60-80C. to a weakly basic pH (8-9). Some pre-
cipitated solid was solubilized by the addition of 500 ml. of ethanol and
heating to 80C. The colorless viscous lower layer containing mostly phos-
phate salts was drawn off while hot ~1 1., 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 5C. The crystallized solid was filtered, pressed well and then washed
with the minimum amount (just the amount to cover the 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 60C. to afford 134.5 g. ~79%) of
the desired beige product, 3-(4-pyridinyl)aniline, m.p. 168-171; single spot
on tlc ~silica; CHC13: CH30H: i-C3H7NH2 90:5:5; UV)-
Example 2
3-~4-Pyridinyl)aniline 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
100C. The solution was heated to 120C. and the steam shut off. A solution
~298~i~
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 ancl one-half hours resulting in a full kettle. PressurP steam
~35-~0lbs.) was applied to ~egin dlstillation of acetic acid. ~fter one-hal
hour, there was room in the kettle and the remaining oxime solution was added
51OW1YJ maintaining distillation. The clear acetic acid layer was distilled
off at atmosp}-eric pressure over two hours leaving a dark and viscous, but
stirrable residue at 120C. Vacuum was applied gradually to remove the re-
maining acetic acid and acetic anhydride, keeping the pot temperature over
100C. With the residue stirring at 100C., (heat off), 20 1. of water was
added over 5 minutes. The temperature dropped to 85C. but stirring was main-
tained. The kettle was cooled with water to 60C., and 54 kg. of 35% aqueous
sodium hydroxide was added over one-half hour, temperature 50-65C. Ethanol,
20 1., was added and the mixture cooled to 30C. 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 ~83C.) for 12 hours. In the morning, the mixture was cooled from 60
to 5C. 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 l. of
water at 30 C. for one-half hour and refiltered. The solids were washed
generously with water and dried 60C./air/overnight. There resulted 10.08
kg., or 10080/77.8x170 = 76.3% of theory, of the tan product, 3-(4-pyridinyl)
aniline, m.p. = 165-7C.
