CA1064507A - Process for preparation of pyrryl-2-acetonitriles - Google Patents

Abstract

Abstract of the Disclosure Pyrryl-2-acetonitrile compounds are made by an improved process wherein a dialkyl-(pyrryl-2-methyl)-amine is reacted with an alkyl chloride or alkyl bromide, having up to two carbon atoms in the alkyl, forming a corresponding trialkyl-(pyrryl-2-methyl)-ammonium chloride quaternary salt which solution is then fed to an aqueous solution of alkali cyanide in the presence of a water-immiscible solvent, the alkali cyanide being in defined excess and the reaction being at a controlled temperature level.

Description

6~5~7 ` ~ -...

, ~
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 i ~

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~64507 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 _ .;' 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 ~ ' :~ ~ 1 ~ - 8.-~: ~. " I:
~ :~ I: ' - _.~

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 ; :: : ~

~:
: -~9 _ , '~ .
.

~ . 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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~:' 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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Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. In a process for the production of pyrryl-2-acetonitriles of the formula wherein R1 is an alkyl group having 1-4 carbon atoms by reacting a dialkyl-(pyrryl-2-methyl)-amine corresponding to the formula wherein R1 is defined as above and R2 and R3 are independently selected from the same or different alkyl groups having 1 to about 4 carbon atoms with an alkyl halide alkylating agent to form the corresponding quaternary salt and displacing an amine on said salt with aqueous alkali metal cyanide in the presence of a water-immiscible solvent in which the product pyrryl-2-acetonitrile is soluble, the improvement comprising reacting in an aqueous system an alkyl chloride or bromide having up to two carbon atoms and a boiling point not greater than about 20°C. at atmospheric pressure said reaction being at an elevated pressure not greater than 150 psig. and then feeding the quaternary salt so formed to an aqueous alkali metal cyanide in proportions of 110 to 150 percent of the stoichiometric requirement based on the original dialkyl-(pyrryl-2-methyl)-amine at a temperature of from about 75 to about 100°C. and in the presence of a water immiscible solvent in proportions of from about 1.5 to about 10 parts by weight per part of said original dialkyl-(pyrryl-2-methyl)-amine.

2. The process of claim 1 wherein said alkyl halide alkylating agent is an alkyl chloride selected from the group consisting of methyl chloride and ethyl chloride.

3. The process of claim 1 wherein said solvent is present in proportions of about 3 to about 5 parts by weight per part of said original dialkyl-(pyrryl-2-methyl)-amine.

4. The process of claim 1 wherein said alkyl halide alkylating agent is an alkyl chloride selected from the group consisting of methyl chloride and ethyl chloride and wherein said solvent is present in proportions of about 3 to about 5 parts by weight per part of said original dialkyl-(pyrryl-2-methyl)-amine.

5. The process of claim 1, 2 or 3 wherein said quaternization reaction is carried out at a pressure of from about 30 to about 90 psig. and at a temperature of from about 20 to about 50°C.

6. A process according to claim 1, 2 or 3 wherein said dialkyl-(pyrryl-2-methyl)-amine is dimethyl-(N-methyl-pyrryl-2-methyl)-amine.