Note: Descriptions are shown in the official language in which they were submitted.
6~5~7
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he Invention
~: : .~
: 20 It has~be~n known to prepare p~rryl-2-acetonitriles~ ~or .
example, pyrryl-2-acetonitrile and N-methylpyrryl-2-acetonitrile,
: ~by~reacting tri.metXyl-(pyrryl-2-methylj-ammonium-iodide or tri-
~methyl-(N-me-thylpyrryl-2-methyl)-ammonium-iodide~ respectively~
With sodium:cyanide. Tr~methyl-(pyrryl-2-methyl)-ammonium-iod.ide
::25~ ~and. tri~ethyl-~N-methylpyrryl-2-methyl)-ammoni~-iodide are formed
j~ o- nner by add ng methyl l~dide to an alcob ~ Lc so
: ~ . . .; ; ~ . ;; : !. . ; ~ : ; ` .
11~?;4507
¦ of dimeth;~l-(pyrryl-2-methyl)-amine or dimethyl-(N-meth~lp~rryl-
¦ 2-methyl)-arnine, r~spectively, see J Amer~ Chem. Soc. 7~ 21
¦ (1951) and J. ~ner. Chem. Soc. 75, 48~ (1953).
¦ The above mentioned processes have particularly the
¦ d.lsad.vantage that the amrnonium salts prepared from -the Mannich
¦ bases by reaction with alkyl iod.ides in absolute alcohol r.~ust
¦ be isolated. prior to their further reaction to the corres~onding
¦ nitriles. Furthermore, the isolated ammoniurn compounds decompose
¦ easily, whereby the yield of pyrrylacetonitriles is adversely
¦ affected.
¦ To overcome the above d.ifficulties, Orth et al in U. S.
¦ 3,523,952 conducted. the d.isplacement in a water-immiscible
¦ solvent On the scale d.isclosed in the examples, the procedure
¦ of Orth e-t al apparently is satisfactory since the addition of
¦ the alkali cyani~.e to the qua~ernary salt at room tempera~ure
¦ does not produce reaction. However~ upon heating the reaction
¦ mixture to 80C, the reaction starts and. is cornpleted. by
::~ ¦ maintaining the temperature for two hours Since the reaction
:~ . ¦ is exothermic, such procedures are not practical ~or large scale
: 20 ¦ operat~ons because the exotherm causes severe evolution of gas,
¦ ~oaming and is d.if~icultly controlled upon heatlng the entire
¦ reactlon mass. The process of the present invention has been
. ¦ ~ound to overcome these disadvantages. There ls provided an
: : ¦ extremely efficacious and pr~ctical process ~or the production
¦ ~ pyrryl-2-acetonitriles.
¦ m e Invention
¦ The present in~ention provid.es improvement in a process
¦ ~or the preparation of pyrryl-2-acetonitriles_corresponding to .
the formula
3 ¦ ¦ ~ CH2-CN
¦ Rl
~O~q~S~7
wherein Rl is hydrogen or an alkyl group having 1-4 carbon
atoms, by reacting a dialkyl-(pyrryl-2-methyl~-amine corresponding
to the ~ormula
1~3L CH2- N ~
N ~ R3
Rl
wherein ~1 is hydrogen or an alkyl group having 1~ carbon
atoms and R2 and ~3 are independently selected ~`rom alkyl
groups having 1-l~ carbon atoms, the reaction being in an
aqueous system with an alkyl chloride or bromide ha~ing u~ to
two carbon atoms and a boiling point o~ not over about 20C.
at atmospheric pressureg the reaction being at an elevated
pressure not greater than 150 psig~ and thereby forming a
quaternary salt component and then feeding said quaternary
salt to an aqueous alkali metal cyanide in proportions o~
110 to 150 percent o~ the stoichiometric requirement based on
the original dialkyl-(pyrryl-2 methyl)-amine at a temperature ~.
o~ ærom about 75 to about 100C~ and in the presence o~ a water
immiscible solvent in proportions o~ ~rom about 1.5 to 10 parts
by weight per part o~ said origlnal dialkyl-(pyrryl-2-methyl~-
amine. .
In general, the process o~ the present i~vention
contemplates two reaction stages~ quaternization and dis-
placement. ~ particular ~eature o~ the present improved
process is controlling the rate o~ ~eed o~ the quaternary
salt to the hot aqueous alkali cyanide in the presence o~ the
water-immiscible solvent so that the evolution o~ gas during
the displacement is controlled and gradual and accomplished
w_thout e~cessive ~oaming~ r pid increase in pressure or
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temperature ~rom the reaction which is exothermic in natureO
Also, the controlled ~eed in the displacement reaction allows
substantial decrease in the amount o~ alkali cyanide employed
without decreasing the yield of the desired pyrryl-2-aceto-
nitrile. Ihe technique of the present process provides
production of pyrrole-2-acetonitriles with a high ratio of
this desired material as compared to other isomers, such as
nuclear-substituted c~anides, e,g., 1J2-dimethyl-5-cyanopyrrole.
The amount of alkylating agent employed in the present
process can range -from the stoichiometric amount to a large
excess. It is pre~erred to employ excess alkyl halide alkylatirlg
agent to insure that all of the Mannich base is reacted~ ~lso,
more alkylating agent a~ailable forreaction decreases sub-
stantially the time required for reactionO In general, the
amount o~ alkylating agent employed can be expressed as a
percentage o~ the stoichiometric amount required for reaction
with the Mannich base. Typically~ the amount Or alkyl halide
used in the present process can range from 100 to about 200
percent o-f the stoichiometric amount o~ alkyl halide based on
the Mannich base, i~e., the dialkyl-(pyrryl-2-methyl)-amine.
Preferably ~rom about 110 to about 150 percent o~ the stoichio-
metric amount o~ alkyl halide, on the same basis~ can be used.
Most preferably ~rom 120 to about 1~0 percent o~ the stoichio-
metric amount o~ alkyl halide can be employed in the present
process. me dialk~l groups o~ the amino radical can be an
alkyl group ha~ing 1-~ carbon atoms such as methyl~ ethyl,
propyl or butyl or their isomers~ as defined -for R2 and R3
hereinabo~e.
Because of the exothermic nature of the alkylation
reaction, the reaction mixture is cooled during the quaterniza-
tlon step. ~ny suitable means con~entional in the art can be
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~69L~
emplo~ed and is well understood by skilled practitioners inthe art. In general, the alkylating agents are normally
gaseous under ambient conditions and most o~ the alkyl halide
alkylating agents use~ul in this invention ha~e limited
solubllity in aqueous systemsO It is there~ore ad~antageous to
conduct the quaternization step under pressures greater than
atmospheric pressure in order to solubilize the reactants in
the aqueous reaction mixture. Without limiting the process
o~ this in~ention, it is believed that the quaternization
reaction occurs in the aqueous phase. Thus, the use o~ pressures
greater than atmospheric ~acilities solubilization o~ the alkyl
halide alkylating agent, thus increasing contact o~ reactants
and yield. Pressures ~rom about 20 to about 150 psig can be
employed. Howeverg pressures greater than a~out 150 psig
require more expensi~e pressure reactors and are less desirable
~rom a capital in~estment viewpoint.
The reaction mixture requires somewhat higher than
am~ient temperatures to obtain a good rate o~ reaction. In
general, temperatures in the range ~rom about 20 to about 50C.
can be emplo~ed in the process~ Pre~erabl~, te~peratures for
the quaternlæation reaction o~ about 30 to about ~0Cu have
been ~ound use~ul. Although somewhat hlgher temperatures can
be used without seriousl~ a~ecting the reaction, the attendant
increase in press~res at such higher te~peratures would require
more expensi~e pressure reactors which, as indicated abo~e,
would lncrease capital in~estment in a commercial operation.
Preferably, the reaction is conducted in aqueous
suspension w:ith skirring to insure intimate contact o~ reactants.
e reaction proceeds ~or a time su~icient to allow the
reactants to substantially complete the reaction. The
alk~lating agent can be added to the reactor o~er a period o~
~rom about 0.5 to about 3 hours or more based on the amount of
~C~6~ 7
alkylating agent used and the scale o~ the operation. A~ter
the addition o~ the alkylating agent, the reaction mixture can
be held with stirring to assure completion o~ the reaction.
It is convenient to maintain the reaction mixture ~or a period
of ~rom 1 to about 2 or more hours, again depending on the
scale of operation. ~ompletion of the reaction can be checked
by analysis of the reaction mixture ~or unreacted Mannich
base, e.g.~ dialkyl-(pyrryl-2-methyl)-amine. For convenience,
i~ the reaction contains one phase than it can be assumed that
the reaction was complete.
~ he displacement step is carried out by the controlled
reaction of the quaternary salt with aqueous alkali cyanide
solution of water-immiscible solvent, ~ny suitable alkali
cyanide can be employed, such as sodium or potassium cyanide,
pre~erably sodium cyanide. The amount of alkali cyanide should
be su~icient ko react with the quaternary salt produced. It
has been found that an excess o~ alkali cyanide is required
to obtain adequate yields. Previously~ over 100 percenk
excess has been employed. However, it has been ~ound that
~rom about 10 to about 80 percent excess is su~icient to
obtain good yields by the process o~ the present invention.
More pre~erably a 25 to l~o percent excess o~ alkali
cyanide can be used. Stated in other words~ thq amount of
alkali cyanlde employed can be within the range of 110 to
about 180 weight percent o~ the stoichiomekric amount based
on the Mannich base~ i.e., the dialkyl-(pyrryl 2-methyl)-
amine. Pre~erably~ an amount o~ alkali metal cyanide o~ from
about 125 to about 140 weight percent o~ the stoichiometric
amount based on the Man~ich base~ i~e., the dialkyl-(pyrryl-2-
methyl)-amine can be used.
.
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6~5~7
The water-immiscible solvent can be any liquid l~Jhich
is substantially inert to the reac-tants and has sufficient
solvent power for dissol~ing the product pyrryl-2-acetonitrilesO
Examples of such sol~ents are benzene and its homologs and
halogenated alkanes, such as for example, benzeneg toluene,
xylene, chlorinated hydrocarbons having a boiling point above
the reaction temperature, e.gO~ ethylene chloride, trichloro-
ethylene, perchloroethylene, methyl chloroform, and the likeO
Such sol~ents are conventional and described in U. S. 2~52~,952,
supra~ The amount of sol~ent employed should be only that
amount sufficient to maintain an easily stirred reaction
mixture. For convenienceJ the amount of solvent employed
is stated in terms o~ the amount o~ starting Mannich base
employed. The effect of the amount of sol~ent being too
low is to depress the yield of pyrryl-2-acetonitriles
produced. mus, it is pre~erred to employ at least about
1,50 parts of sol~ent per part of Mannich base, i.eO, per
part of dialkyl-(pyrryl-2~methyl)-amine. Preferably~ ~rom
about 1.5 to about 10 parts of sol~ent per part of Mannich
~ 07
¦ base carl ~J~a used. TIowever, to reduce the s~æe of reaction
¦ e~uipment and increase rea.ctor productivity an i.nte~nedia~e
¦ range is preferred. For examplel ~rom about 2.75 to about 3.50
¦ parts of solvent per part of Manni_h base has been found +o ~ive
¦ accepiable yields without und.uly increasing capi-tal in~estrnen~
¦ or d.ecreasing prod.uctivit~ of a given reaction vessel
¦ m e reaction temperature of the displacement re~ction
depend.s somnwhat upon the solvent selected. and the stage of
¦ reaction. The reaction begins about 80C and the temperature
¦ is controlled.~ preferably between about 76 to about 95C by
refluxing. The temperature being initial.ly at the upper port:;on
and grad.ually decreasing slightly as the low boiling by-product
amine forms Further, it is preferred. that the controlled addi.tie
¦ of -the quaternary salt or the aqueous alkali cyanid.e, depending
¦ on the reactants selected.J take place over a time sufficient to
: ¦ allow adequate venting, heat +ransfer and Yield. In general, .
¦ cycle times of from about 2 to about 8 hours or more, depending
~: ¦ upon the scale of operation and. the temperatures employed., can
¦ be used.
¦~ In general, the overall proced.ure with the preparation
of the pyrryl-2 acetonitrile compovnd.s of this invention can be
;: ¦ described. as follo~s~ To a suitable reaction vessel is charged.
¦ the Mannich base and. water. The reactor agitator and heating
,
¦ medium:on the reactor are started. Then, the reactor contents
~ 25 ¦ are warmed to about 50C and the alkyl halid.e alkylating agent
~: ¦ is add.ed until the-d.es.ired ~movnt is present over a period o~
¦ about 60-180 m:inutes su~ficient to maintain the reaetion temper-
¦:ature:at about 40C and the pressure at about 50 psig. The
: ¦~alkylating agent feea is stopped and reaction conditions are
~ ~ l
~ 30 ¦;maintained. for a period. sufficient to allow ~ompletion of the
~ '
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reactior., .~or example, about 60 to about 120 minutes, afte-r ~hich
the reaction mi~ture is checked to see whether a clear water~
soluble, one-phase solution, ~s obtained.. If this is the case,
the procedure is continued. I~ :not, agitation is continued until
a clear water-soluble, one-phase solution is obtained In a
separate reactor, are add.ed to]uene and water. r~he agitator is
activated. and. solid sod.i~n cyanide is ad.ded. to the reaçtor
Caution should be observed. in ad.ding the sod.ium cyanide because
o~ its toxicity. I'he reactor is heated. to reflux at about 90C.
lO The reaction mixt-lre ~rom the first reactor is then ad.d.ed. to l,he . .
second. reactor at a rate su~ficient to obtain good. reaction
without foaming or pressure build.-up frorn d.isplacement o~ alkyl-
amine, for example, about one gallon per minute and reflux is
maintained. ~or about 120 minutes after completi.ng the ad.dition.
A~ter this period., the phases are allowed. to separate ànd. the
: ~ bottom aqueous phase is removed... The organic phase is transferred.¦
: to product recovery operations.
In accord with this ~rocedure, the present invention
provid~es an easily controllable reaction procedure with high
20 ~ ratios of the desired pyrryl-2-acetonitrile. The ~ollowing
; examples illustrate the invention but should. not be considered as
:limiting thereo:~.
; EX~MPLE 1
: To a suitable reactor was ad.ded 276 parts of the Mannich
base d.imethyl-(N-me:thylpyrryl-2-methyl)-amine and 300 parts of
water. T.he stirrer was activated and. heating started on the
;~ reactlon vessel to bring the reaction mixture to 40C. Methyl .
chlor~de:liquid was then added at a controlled rate. The temper-
ature was ma~ntained at 40~C with a sll~ht cooling during the
; :: : ~
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~ . 1064507
addltion whi.ch took 73 m:inut~s. Pressure increased slo~rly durin~
addition and reached 50 psig ~t the end. of addition. Afte~
addition, the stirring was continued. for another 87 minutes. A
one-phase aqueous solution was obtained
In another reac-tor there was mixed 86~ parts of toluene
and 257 parts of wa-ter w:ith stirring. To this was added 12~ parts
of sodi~m cyanid.e, representing about 130~ of` theory based on
the Mannich base. Wh:ile continuing the stirring, the cyanide
solution was heated to re~lux, about 88C and. held at reflux.
Then the aqueous solution from the first reactor was add.ed. to
the refluxing cyanid.e over a period of about 60 m~mltes. After
completing addition, the reacti.on mixture continued. to reflux
~or another 120 minutes. During additîon and ~or some time
during the continued. reflux a gas was evolved. and. vented. which
on an analysis was d.etermined. to be trimethyl amine. After
refluxing was completed., the reaction mixture was cooled to
about 40C and allowed to stand while the phases separated. The
aqueous phase was removed snd the organic phase was analyzed by
: ~ vapor phase chromatograph with the following results:
Q0 ~ : Mole
1. Trimethylamine 0~22
2. Skarting Mannlch base 0.20
.~ ~. Tolue~e . 73.1
4. 1,2-Dimeth~1-5 cyanopyrrole1~4
: 25 5~ N-methylpyrrole-2-acetonitrile 1409
Total 89.77
: m e lack of closure on analysis was d.ue to the heavy
materials which would not show up in VPC analysis.
: ~ Following the sequence of steps outlined. above, a series
: o~ runs was made changing dif~erent vari&bles including reflux .
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~:'
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temperat;L~e, ti~r~Q 0~ addi-tion, amount Or alkylating agent and
the pressure of alkylating agent in the reactor to determine
their e~fect on the production o~ pyrryl-2-acetoni-trile6 by the
process of the present invention. Table I shows the results of
these r~s
As described. above, the procedure is carried. out in tSro
stages~ quaterlli7ation of the Mannlch base, which for lllus-tration
employs dimethyl-(N-rnethy:Lpyrryl-2~methyl)-amine, and d.isplace-
ment. In the quaternization step equimolar amounts of Ma~-nlch
base and alkylating agent were usually employed -for other types
of alkylating agent. However~ ~or methyl chlorid.e, excess can
be used.~rithout ad.verse ef~ect. In fact, it helps to push the
reaction to completion. Table I uses methyl chlorid.e as the
all~ylating agent for illustration only The d~splacement was
run und.er the same cond.itions to enable comparison of the
quaternization reaction variables,
In Table I, the quaternization step was conducted using
: temperatures from 23-43C, addition times o~ 30 to 180 minutes,
: holding times of 60 to 120 minutes, pressures from 31 to ~0 psig~
: 20 and from 100 to 200 percent of the stoichiometric amolmt of
a ~yL-ti ~e
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