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Патент USA US2603668

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Patented July 15, 1952
Pa., and Vincent
William F. Bruce, Havertown,
J. Webe'rs, Racine, Wis, assignors‘ to Wyeth
? . -
Incorporated, Philadelphia, Pa., a corporation ,
of Delaware
, _Application'August 19, 1948, ‘Serial No. 45,207'
1 Claims. (01. 260—-562)
The reaction may be postulated by the follow
The invention relates to the preparation of
formylamin'o‘and amino ‘derivatives andv more
particularly involves ‘a _ catalytic process for ob
taining formylamino compounds by the reaction
of a'ketone and a formamide.
The preparation of certain commercially im
portant amines has heretofore depended to a
great extent on the utilization of the well-known
Leuckart reaction. This’ reaction, *as ?rst’re
ported in the literature-involved the use of am 10
monium formate, which with benzophenone
formed. N-benzhydryl formamide. _The latter
compound when hydrolyzed formedv the .corre
sponding amine. ‘Subsequent to the disclosurev of 15
this reaction a great many ketones have been
tried and found to proceed as with benzophe-.
none. The Leuckart reaction has therefore been
adapted to the preparation of important physiol
ogically active amines, such as the sympatho 20
mimetic amines, by selecting the proper’ ketone
for'the reaction.v As an example, if one starts
with phenylacetone, the ?nal hydrolysis of the
formamideproduct will yield the central ner
vous stimulating compound, amphetamine,v An
important advantage of the Leuckart reaction is
essentially in the relative simplicity of thereac
tion. vl-Iowever, certain inherent difficulties in
' In the above formulae, R. is intended to repre
sent either hydrogen or lower alkyl radicals, pref carrying out this reaction have been a spur to
erably a- methyl or ethyl group, while B.’ and B",
seeking other methods for preparing important
may represent either alkyl, aryl,~aralkyl or sub
stitutedsaryl ‘or aralkyl radicals. Substituents'
The primary disadvantage of the Leuckart
for hydrogen atoms in the latter case may be
processiand the chief reason for seeking other
alkyl,.alkoxy, nitro or halogen radicals as de
methods of amine preparation is the requirement 35 sired, or in fact any substituent which does not
interfere in the reaction.
for ammonium vformate. Because of its insta
The ‘.reaction for the formation of formyl
bility, thisreagent is not known to be commer
cially available and therefore is prepared only for
amino products, as indicated above, is catalyzed '
in the presence of ‘a selected salt of a relatively
immediate use.‘ Moreover, the preparation of
ammonium formate is involved and di?icult to 40 strong acid and moderately strong to a relatively
weak base. Thus,bases of the group I metals
carry out on a relatively large scale.
are'excluded because they are strong bases in
This invention involves the discovery of a
contradistinction to the bases of the groupIL
methodjfor reacting vketones with commercially,
metals which form moderately strong bases“:
available and easily obtainable formamide or
The cation component. of the catalyst may be
simple formamide ‘derivatives and completely 45 either metallic or non-metallic but preferably it
avoiding the necessity for using ammonium for
is a di- and tri-valent metal and more preferably,
a di-' and vtri-valent metal selected from the
second or third groups of the periodic table. .The
covered process are in many cases as high or 50 e?ec'tiveness of the catalyst is believed to be
mate,by carrying out the reaction catalytically.
The yields obtained by following this newly dis
higher than that achieved by the standard
Leuckart reaction.
In some cases where the
based on its ability to furnish either a'proton.
or the equivalent of it, such ‘as single or multiple
positively charged metallic or non-metallic ions.‘
However it should be 'clearly understood that
than adequately compensate for the lower yields. 65 the invention is not to be limited to this theo
yields are somewhat lower, the bene?ts derived
by avoiding the use of ‘ammonium formate more
rical reason for the mode of action advanced
as a possible explanation.’
carbonate sublimed into the re?ux condenser,
and ammonia and carbon dioxide were evolved.
It‘ has been found that best results are ob
At exactly four hours after boiling started, the
tained if the‘ catalyst selected is appreciably
soluble in the reactants and does not completely
precipitate out of solution during the‘ reaction.
?ask was removed from the oil bath, allowed to
The preferred‘scatalytic» saltsnmay- be ‘obtained
much below :130§f,-_ the fermyl: derivative ~crystal
lized, and. removal froinithe?ask .Wamdi?icult.)
cool to about 140°, and cautiously poured into
about 200 cc. of cold water.
by reactingta- di- or triev'alent metal or metal salt
or hydroxide with strong mineral or organic
(If it was cooled
The ?ask was washed out with a little water,
‘ acids such as the halogen acids, as for example; 16 11 and the mixture of benzophenone, N-benzhydryl
hydrochloric, hydrobromic, hydroiodic acids; the _ ‘ jormamidejand water soluble substances was
*cooled; ‘seeded with a crystal of benzophenone,
acids such
and the mixture .of solids collected on a Buchner
ganic acids as formic, the-amend;.‘di-r.zandotriev ' _='fiinnel_~,~. ‘washed with a little water, and dried.
halogenated acetic acids, citric, etc.
' i
The; ‘amount; _ v.icenzophenone and. of N-benz
The ketonic reactant selected for the reaction
hydryl formamidein the mixture of solids was
depends in large measure on the-particularamino. . determined by distillation in vacuo without a col
compound desired as the ?nal product, the ke ' ' umn; Benzophenone boils at 114° at 1.2 mm., but
tone being represented by the general‘: formula -. _. wasc‘ollected at 120-130° in order to speed up the
distillation. When the benzophenone was all
gong, the boiling point rose :rapidly, at 160° the
receiYerphanged-I-Xand then .the remajnin'giormyl
derivative» was distilled with strongchcllghhcéét-i
ingjto preventcrystallization,,initheside arminf
where R’ and R" represent the radioalsaaindi-Y
cated previously. .Among the particular ketones
which may bereacted and from which one may
obtain substantial yields of‘ the oformyl deriva
tives‘ may be mentioned benzophenone; benzyl
the ?ask. The amidehoilsat'173.‘?,1.2 “111111.,
but: as ‘before, ,itsaveditimetci.collectl itmat "18.5;
acetophenone; 4.-methylpentanone-2 ;_ 4-methy1
1.9 of. ‘ A. small amount; {tan ,(aboutlagram) gree
mainedfinathe v€1aisen..?ask. . A yield .0fj,9.516%f
hexanone-Z;v 4-ethylhexanone-2'; heptanone-z;
'4- and 6-methylheptanone-2; phenylacetone;
benzhydrylformamidawas .thusobtainedi f
fluorenone; camphor; 1-methy1-1_-pheny1ace_ 3‘? -' “
irmAMPLEuL r. ~
~ -.
tone; and intact any ketone can be ‘used which
, .A'reaction as gde'scribed‘inExample Lwas'wr':
has been successfully reacted by the standard
Leuckart reaction depending-on ammonium for
riedcut, with pureiormamide (99 Y%") but without
a catalyst,v ,45 jgramsjofj benzophenone and 155cc:
mate as the reactant.
The temperature .conditions for the reaction 35 of ‘formamide' being used: "The temperaturewas
held" at“ about-200° G; (bath temperature) iwlith
may, range from about 120° to about 200° C. with
an-insi-de temperaturelof'-1-‘87°~ C. The-.yieldiof
a temperature of about 170-190° 0. preferred.
benzhydrylformamidexwasvfoundito'>[email protected] %". .
» Concerning the amounts ‘of reactants, an excess
of theformamide is preferred, with a ratio of
- about 6 moles of the formamide to about one mol
. of the ketone particularlypreferred.
The reac
having anair-condenser. Torthe?askjzvas also
addedkQQet g. .ofmagnesiu'mcarbcnatemixed. with
0.8. g. or. chlorcacetic .acidieq'uivalent T110 l gram.
of magnesium ~i=hloroacétateh QThegiflask was
higher vthanatmo'spheric are required if the ke
tone used boils below the reaction temperature.
In order to avoid degradation of the reactants
heated‘in a wax‘bath,and‘airv ‘ asgdisplaced-with
inert gas; Be?uxingbecamewigorous at-'_l-60"~ -_‘.'?
~4shours". Therea'ction
and; the -> product, >-oxygen. must be substantially
inert gas'suchas
reaction:-v :fil’his
ketone vwere. placed ,in .a.2_00 cc. 'acetylation :?ask
tion is generally carried out under atmospheric
pressure conditions, although higher pressures
may} of course be .used if desired.
110 be‘. rermamide-andvsejg. of-methyl isobutyl.
gen,‘ hydrogen, carbon monoxide: or carbonxiipxs:
washedwithether; and-'thele'theri was evaporated
idescontinuouslylthrough'ithelreaction :zoneidurL-a
ing “the- heating operation.Z i'lt-“hasileeriiound.
on a steam bath.
The ether extract. was».-1iow.
vacuum-distilled; Spme'ketone stillxremaining
that substantial yields. may be obtained .wvith:-a
distilled. over .at 1305352‘5G. ‘.atzli mm
reactionttime o'f~‘about;-2 to abouts4 hours.- .Z'dh'e 55
fraction'idistilled Dyenat175t‘-81?°fe;l3it'f1
amount of catalyst necessar'ynfor athereactionrlis.
was_;2 ,[email protected] gIts-refrac»
notcritical. fThus,-as.>little as .0.051mol'; of :cata
lyst’lias been. used iperr mol of: ketone reactantzbnt
with-hydrochloric acid which; resultedintheferr.
largeramounts have I also Lheen iusedreifectively. . - %
Thefo'llowin'g: speci?c‘ examples .will illustrate: 60
the‘ invention in detail; butzit? is to be understood
that thesegexamples are notitosbe’ cbnsidered E35.‘
‘limitative ofithe conditions or ofttheipairticular.
reactants used.
tiveiindex at 20° G.-was 1141528. _alt_.,was,-then_mixed
mationiof 2,-aminoré-methyl .pentane. hydrochloe
ride, sublimingatlSOfQ.
' Q
‘The reaction as‘ describedéin'l' Elxample -I was
carried~out"using PMOGOCHBM. ‘The-inside
temperature-was- maintainedé at. about 1.86.8110:
A: yield lof f57;2‘% otilthe'zformamide - wassobtaineda.
85-. sramssof : benzophenone (0.46’? ;'[email protected];-.:. 1%;
cc. ;of;99_% formamide-(G.xosi?l'mole) , 3. .grams, of
. l The .- reaction as; described
Example ,-I. was
Mgr'Clra-nd a?Chip??pQrQuS plate were placed in
2.1200‘; cc: balloon ?askaequipped with -an;,ai-r-.re_.. 70. carriedputusing .ZnClz. "The, yield of the forms:
midewas 69%.
?ux: condenser. ; The; air was-‘displaced .w-ithn .1
tween. and .I-the Filask ~ immersed rinaem oils-bath
maintained-atrabout i997?!) °
180-190? ;i€-.:.~.aadr;a:small
in .-.E-Xamn1e¢
salt characterized'by its stability and its appre
ciable solubility in the reaction mixture, said salt
The reaction as described in Example I was
being a salt of a strong acid and a base no
carried out using A1C13. The yield of the form
stronger than bases of the group II metals.
5. The process comprising catalytically' react
ing, in the substantial absence of oxygen, a‘ketone
and an amide selected from the group consisting
The reaction as described in Example I was
of unsubstituted formamide and a lower alkyl
carried out using 3 g. of (NH4)2SO4 in place of
formamide, to form an N-formyl compound, and
MgClz. The yield of the formamide was 80%. 10 carrying out said reaction in the presence of a
salt of a strong acid and a base no stronger than
bases of the group II metals, said salt being
Hydrolysis of formyl benzhydrylamine
further characterized by its stability and its ap
preciable solubility in the reaction mixture.
259 g. of formyl benzhydrylamine was added to
6. The process comprising catalytically react
200 cc. of concentrated hydrochloric acid and the 15
ing in the substantia1 absence of oxygen a ketone
whole was re?uxed for one hour, giving at ?rst a
boiling within a temperature range of about 120°
gummy material which soon became a hard
to about 200° C., and an amide selected from the
crystalline mass. This was removed from the
group consisting of unsubstituted formamide and
?ask, ground in a mortar, washed with water and
dried to give 95% of the expected benzhydryl 20 a lower alkyl formamide, to form an N-formyl
compound, and carrying out said reaction in the
amine hydrochloride. This was converted to free
presence of a salt of a strong acid and a base no
amine by addition of excess sodium hydroxide,
stronger than bases of the group II metals, said
extraction with benzene, and distillation, B. P.
salt being further characterized by its stability
120° C.
It should be noted that benzophenone was se 25 and its appreciable solubility in the reaction mix
lected as the ketone in substantially all of the _ ture, said reaction being carried out at a tempera
ture of about 120°-200° C.
examples described above in view of the fact that
7. The process of preparing N-formyl com
side reactions are at a minimum with this com
pounds, comprising reacting a ketone, free of re
pound and the product obtained is readily
amide was 89.1%.
30 action-interfering groups with an amide of the .
We claim as our invention:
group consisting of formamide and a lower alkyl
substituted formamide to form an N-formylcom
pound, and carrying out said reaction in the pres
ence of a salt catalyst which is stable and ap
l. The process comprising reacting a ketone
free of interfering radicals with a iormamide
selected from the group consisting of unsubsti- '
tuted formamide and a lower-alkyl formamide 0
preciably soluble in the reaction, mixture, and
which constitutes a metal selected from the group
consisting of divalent and trivalent metals, com
bined with an anion of a strong acid.
the process.
2. In the process of reacting a ketone with an 40
in the presence of magnesium chloride as a cata
lyst for the reaction and separating the formyl
amido compound thus produced as a product of
amide selected from the group consisting of un
substituted formamide and a lower alkyl forma
mide to form an N-formyl compound, the im
The following references are of record in the
provement consisting in conducting said reaction
catalytically by the addition to said reagents of
an inorganic salt characterized by its stability
and its appreciable solubility in the reaction mix
?le of this patent:
ture, said salt being a salt of a strong acid and
a base no stronger than bases of the group II
Kastner __________ __ Aug.‘ 6. 1940
Nabenhauer ____ __ June 24, 1941
Burwell et a1. ____.._ June 19. 1,945
Shonle et a1. ______ .._ Oct. 9. 1945
amide selected from the group consisting of un
substituted iormamide and a lower alkyl form
amide to form an N-formyl compound, the im
Nabenhauer ______ .... Feb. 5, 1946
3. In the process of reacting a ketone with an
provement consisting in conducting said reaction
catalytically by the addition to the reaction zone
of a metal salt characterized by its stability and
Ingersoll et al., “J. Am. Chem. 800.," vol. 58
55 (1936) , pp. 1808 to 1811.
its appreciable solubility in the reaction mixture,
said salt being a salt of a strong acid and a base
no stronger than bases of the group II metals.
4. In the process of reacting a ketone with an
amide selected from the group consisting of un
substituted formamide and a-lower alkyl form
amide to form an N-formyl compound, the im
provement consisting in conducting said reaction 65
catalytically .by the addition to the reagent of a
Novelli, “J. Am. Chem. Soc,” vol. 61 (1939),
pp. 520-521.
Schiedt, “J. Prakt. Chem,” vol. 157 (1941), pp.
203 and 204.
Adams et al., “Organic Reactions,” vol. V
(1949) , pp..305, 306, 310, 311 and 317.
Houben, “Die Methoden der Organischen
Chemie,” 3rd ed., vol. 3 (1943), p. 576.
Weygand, “Organic Preparations,"
pp. 253-255.
(1945) ,
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