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Патент USA US3084175

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United States Patent
‘Patented Apr. 2,’ 1963.
'corneapp'arent to those skilled in ‘the art a, which this
invention pertains from the ensuing description thereof.
This invention ‘partially resides in the discovery of new
W. Hearne, Lafayette, and George A. Kurhaiec,
2,4,6-tris (isubstituted)-trioxanes. These novel trioxanes
‘may be considered as derivatives of .trioxane which has the
Grinda, Calih, assignors to Shell Oil 'Cornpany, New
York, N.Y., a corporation of Delaware
following structure:
No Drawing. Filed Dec. 29, 1960, Ser. No. 792,120
4 Claims. (Cl. 260-340)
. /l\
This invention relates to novel trioxanes and to a proc
H-(i-H 11-45-11
ess for their preparation. More particularly, it relates to 10
novel 2,4,6-tris(substituted)-trioxanes and to a novel
process for their preparation.
The novel trioxanes of the present invention ?nd im
portant utility in the ?eld of chemical intermediates.
‘in which only one hydrogen atom on each .ring carbon
atom has. been replaced by a carbon atom of an alkyl
‘group bearing .la'haloge'n atom or a cyano radical on the
‘More speci?cally, they ‘are useful as chemical inter
‘beta carbon atom thereof, that is, the carbon atom ad
mediates ‘in the preparation of the alpha-amino acids, that
jacent to ‘the carbonatom linking the alkyl group to the
is, those amino acids containing an {amino (NHZ) or sub
carbon atom of the trioxane ring. Or they may be
stituted amino group on a-carbon atom alpha to the car
boxyl ‘(-—COOH) group. They are especially useful in
the preparation of the biologically important alpha-amino
thought of as 'trimers, that is, tr-irrieric condensation prod
20 pcts of three molecules at a beta-cyanoalkyl aldehyde or
derivatives of the di'carboxylic acids. Certain of these
amino acids are alpha-amino acids of‘ he general formula
jbeta-haloalkyl aldehyde, thereby resulting in the trimer
nitrlile or trimer halide, respectively.
In addition to the novel trioxanes per so, this invention
HOOCRCHQQHQCOOH, wherein R represents an alkyl
further resides in the preparation of these novel 2;4,6
group. The biologically important all ‘ha-amino-acids de 25 trisésubstituted)-trioxanes by reacting an alphabeta-nn
termine, in large ‘measure, ‘the physiological activity of
saturated aliphatic aldehyde, e.g., an alpha,beta-ole?nically
.plants and animals. Gerta-inialpha-arnino acids are con
unsaturated aliphatic aldehyde, with a hydrogen halide,
sidered essential to growth and life itself. Moreover, cer
thereby obtaining ‘the ‘corresponding beta-haloalkyl alde
tain alpha-amino acids and mixtures of amino acids pre
hyde which in turn is trimerized to the betarhaloalkyl
rparedibyi?ie‘hydrolysis 0t proteins-have been ‘found ‘effec 30 trioxaue. This trioxane is then treated with ‘cyanide ion
tive when taken by mouth orgiven intravenously for the al
to yield the, corresponding beta-cyanoalkyl tr’ioxane.
leviation of hypoprotonemia, liver damage, gastrointestinal
The toreg'oiug ‘objects of this ‘invention are accom
ulcers, muscular‘weaknes's and-other'biological conditions.
.plis'hed byproviding, as new compositionsof matter, novel
2,4;6-1l'lSQSllbS'litlltBd)rl'l'lOXanCS having the general tor
Recognitionof :the clinical as well as the nutritional value
of vamino acids has ‘led to increased interest in the manu 35
tacture of alpha-amino acids and mixtures of amino acids
for therapeutic'purposes.
'Of primary importance ‘has been the alpha-amino di
carboxylic acid, glutamic acid. 'Glutamic acid has long
been used in the hold of medicine to combat various meta 40
bolic and mental disorders. Moreover, it?rids widespread
use in the food industry in the form of the mono
sodium salt, monoso'dium -glutamate,‘to enhance the ?avor
of various 'food'produ'cts. Glutamic acid, tor these and
other uses, ‘has heretofore primarily ‘been obtained ‘from 45
natural'sources suchasjfor'example, ‘by the acid'lhydrolysis
of ‘wheat gluten and sugarfb'eet waste. The process em
ployed for obtaining ‘the acid tr‘om such ‘sources is com
in which R represents a ‘hydrogen atom or an alkyl'radi
cal containing from 1 to 12 carbon atoms which may be
plex and costly and results-in comparatively expensive
either straight vor branched chain, .and X represents a
have been proposed, but such methods are disadvanta
geous because of relatively high'cost of the starting mate
rials {and concomitant high \cost of the ‘intermediates ob
2,4,6-tris(substituted)-trioxanes having the general for
atom or a cyano radical._
glutarnic ‘acid. IRouftes for synthesizing this acid from 50 halogen
A preferred embodimentgot this invention relates to
starting materials and intermediates obtained therefrom
mula, as above de?ned, in which R represents a hydrogen
atom or a straight-chain alkyl radical containing from 1
tained therefrom. The starting materials of, the present 55 to 6 carbon atoms, and X represents a chlorine atom or a
cyano radical.
invention and the novel intermediates obtained present
An especially preferred embodiment relates to 2,4,6
arelatively inexpensive‘synthetic route to the synthesis of
tris(substituted)-trioxanes having the general formula, as
glutamic acid, as well as to the synthesis of other im
above de?ned/in-which Rrepresents a hydrogen atom and
portant. alpha-‘amino acids.
represents {a chlorine atom or a cyano radical.
An object ot the present invention is to provide novel 60 X Most
conveniently, the trioxanes of the invention may
triox-anes and a .proces for their preparation. Another
be prepared by reacting (.1) an alpha,beta-ole?nically un
object lisithe i-provision of novel 2,'4,6-'trfis(substituted)-tri
saturated aliphatic aldehyde with a hydrogen halide,
oxanes and ;a process for their preparation. A further
object is ‘the provision of ‘novel 2,4,6-tris(2-cyan0alkyl)
trioxanes and 2,4,6-tris(2-haloalkyl)itrioxanes, useful as
intermediates in the Ys'ynthesisof alpha-amino acids, espe
cially glutamic acid. A still lturther object is "the pro
vision of .novel 2,4,6--tris(>2-cyanoethyl) -trioxane and 2,4,
6-tris(2-chloroethyl)-trioxane ‘useful as intermediates in
the \synthesisof .glutamic acid. A further speci?c object
isito provide novel trimers of beta-cyanopropionaldehyde
and beta-chloropropionaldehyde. Other objects ‘will be
thereby obtaining the corresponding beta-haloalkyl alde
hyde; (2) allowing the beta-haloalkyl aldehyde to
trimerize to the corresponding beta-haloalkyl trioxane;
1(3) and treating the resulting trioxane with cyanide ion,
thereby obtaining the corresponding beta-cyanoalkyl
,The alpha,beta-ole?nically unsaturated aliphatic alde
hyde ‘vaporand ‘anhydrous thydrogen ihalide are mixed in
a jet atfthe top of 'a vertical tube ‘cooled with tap water.
aoea, 1 68
The reaction may take place either in the vapor phase or in
a liquid ?lm on the wall of the reactor. A slight excess,
halide over the
aldehyde is preferred 1n order to facilitate condensation
aldehyde rtrimer
then reacted with a 2:1 excess of so
dium cyanide over the tn'rner chloride in methyl Cello
solve for about 16 hours to give
the corresponding trimer
of the beta-haloalkyl aldehyde into the corresponding
aldehyde trimer. The temperature range of the reaction
In conducting the process of the invention, the relative
between the aldehyde and the hydrogen halide primarily
depends upon the boiling point. of the particular starting
proportions of the reactants can ‘be varied. It is preferred
to employ a slight excess of the hydrogen halide over
aldehyde. A temperature range of from about 50° to
about 150° C. maybe employed. A temperature range
the alphabeta-ole?nically unsaturated aliphatic aldehyde
in order to aid in promoting trimerizat-ion of the aldehyde.
Also, it may lb? advantageous to employ an excess of
of from about 50° toabout 110° C. is preferred, with a
most preferred temperature range of from about 50° to
about 60° C. The trimerization of the beta-haloalkyl alde
hyde may partially occur spontaneously at the above re
to each carbon atom attached to a trioxane ring carbon
15 atom.
Representative alpha,beta-ole?nically unsaturated ali
about —-50°
phatic aldehydes which :may be employed in the practice
ofv {this invention include, for example, acrolein, meth
The haloalkyl trioxane
acrolein, crotonaldehyde, ‘beta-methyl crotonaldehyde; 2
methyl-Z-butenal; Z-hexenal; alpha-isopropyl acrolein; 2
heptenal; 2-ethyl-2-hexenal; 2-nonenal; 2-undecenal; and
the like. Representative hydrogen halides which may be
employed are hydrogen chloride, hydrogen bromide, hy
drogen iodide and hydrogen ?uoride. Representative sol
may be employed include the alcohols such
preferred temperature range of
about 128° C.
The cyanide ion reacts with the alpha,beta-ole?nically
unsaturated aliphatic aldehyde e.g., acrolein, at the car
bonyl group.
In many compounds '
bonyl group. in the trimeric dorm
aldehyde, e.g., beta-chloropropionaldehyde, the carbonyl
cyanide and barium cyanide;
as, for example, silver cyanide, copper cyanide, and
We have discovered that
group is converted to the étrioxane ring (cyclic acetal)
tris(2- yanoethyD-trioxane
tively hydrolyzed to monomeric beta-cyanopropionalde
lein, hydrogen chloride and cyanide ion were employed,
about 80% of the beta-chloropropionaldehyde trimer was
converted into the beta-cyanopropionaldehyde trimer.
For illustrative purposes, the preparation of 2,4,6—tris—
(Z-chloroethyD-trioxane (II) and 2,4,6 - tris(2 - cyano~
ethyD-trioxane (III) may be shown by the following re
action scheme:
solution was
cyanide. The
C. at which point
the excess ammonium carbonate decomposes. This aque
ous solution of the hydantoin of heta-cyanopropionalde
hyde was then heated to 180° C. in an autoclave with
:barium hydroxide. After hydrolysis of the hydantoin,
55 ammonium canbonate Was added to precipitate barium
oanbonate. The ?ltrate was then concentrated to about
one-tenth its volume. In this step the excess ammonium
carbonate was again destroyed. Acidi?cation to a pH
of about 3.2 and evaporation produced glutamic acid in
a yield of about 65% :based on the trimer nitrile and 55%
(II) 60 based
on acrolein.
similar experiment the trimer
nitrile was hydrolyzed
in the presence
The above reaction may be looked upon as a vapor phase
reaction ‘between acrolein and excess hydrogen chloride to
give the monomeric beta-chloropropion-aldehyde Which in
turn trimerizes at about 10° C. The beta-chloropropion~
75 pertains.
tions and equivalents will be apparent to one skilled in
Example I.—-2,4,6-Tris(Z-Chloroethyl)~Tri0xane
the art and the invention is, therefore, limited only by the
scope of the appended claims.
To 285 ml. (4.1 moles) of acrolein was added 150 g
(4.1 moles) of anhydrous hydrogen chloride over a period
of about 21/6 hours. The acrolein vapor and anhydrous
We claim as our invention:
1. The compound 2,4;6-tris(2-cyanoethyl)-trioxane.
hydrogen chloride were mixed in a jet at the top of a
2. The process for the preparation of 2,4,6-tris(2
vertical tube cooled with tap water. A ?ow rate of about
cyanoethyl)-trioxane, which comprises reacting acrolein
two moles per hour was maintained by a rotometer. Ap
with hydrogen chloride, thereby obtaining beta-chloro
proximately ll.2 g. of hydrogen chloride was added per
minute. At the end of about 21/6 hours, 150 g. of hydro
propionaldehyde monomer; trirnerizing said monomer at a
temperature of from —50° C. to +150“ C., thereby ob
gen chloride had reacted with 285 ml. of acrolein to form
taining 2,4,6-tris(2-chloroethyl)-trioxane; and reacting
said trioxane with cyanide ion, thereby obtaining 2,4,6
about 380 g. (41 moles) of a clear, water-white liquid
product containing beta-chloropropionaldehyde.
The monomeric beta-chloropropionaldehyde obtained
3. The 2,4,6-tris(2-cyanoalkyl) -trioxane of the formula
was allowed to trimerize at a temperature of about 0° C. 15
The resultant trimer, 2,4,6_tris(2-chloroethyl)-trioxane,
was obtained as a white solid at room temperature, M.P.
25-30° C.
Example II.—2,4,6-Tris(Z-Cjtanoethyl) -Tri0xane
To 443 g. (9.04 moles) of ‘sodium cyanide in one liter 20
of methyl Cellosolve was added 367 g. (1.32 moles) of
2,4,6-tris-(2-chloroethyl)-trioxane. The reaction mixture
was heated to gentle re?ux (about 110° C.) for ap
wherein R is selected from the group consisting of hy
proximately 21 hours. The reaction mixture was then
cooled to about 75° C. and ?ltered. The crude product 25 drogen and straight-chain alkyl of 1 to 6 carbon atoms, at
least one R on the number =1-carbon atom of each Z-cyano
(about 1890 g.) was washed with 200 ml. methyl Cello
alkyl moiety being hydrogen.
solve. About one-half of the washed crude product was
4. The process for the preparation of the 2,4,'6-tris(2
added to 2.5 liters of water and ‘stirred for about one
cyanoalkyl)-trioxane of the formula
hour and then ?ltered to give 154 g. of crude trioxane.
The second half of the washed crude product was treated 30
chat-(545E HBO-Mam
1‘. R l, H t t l.
in a similar manner to yield 200 g. of crude trioxane.
The crude trioxanes were combined and washed with
water. The trioxane obtained from this treatment was
?ltered out and dried to yield 256 g. (1.02 moles) or 77% 35
of 2,4,6-tris(2-cyanoethyl)-trioxane, as white or very light
yellow crystals, M.P. 126-127" C. ‘(corrected value 127
128° C.).
Stripping of the above ?ltrate yielded an additional
46 g. of the trioxane and a combined yield of 91° (theory). 40 wherein R is selected from the group consisting of hydro
A procedure has been developed for obtaining excellent
gen and straight-chain alkyl of '1 to 6 carbon atoms, at least
yields of 2,4,6-tris(2-cyanoethyl)-trioxane. The cyano
one R on the number l-carbon atom of each 2-cyanoalkyl
trimer is prepared by heating to a re?ux a 2:1 mixture of
moiety being hydrogen, which comprises reacting the
sodium cyanide and beta-chloropropionaldehyde trimer
[2,4,6-tris(2-chloroethyl)-trioxane] with methyl Cello
alpha-beta ole?nically unsaturated aliphatic aldehyde of
the formula C(R2) =O(R) CHO with hydrogen halide,
solve as solvent. The cyano trimer [2,4,6-tn's~(2-cyano 45 thereby obtaining the corresponding beta-haloalkyl alde
ethyl)~trioxane] has a melting point of l27-128° C. (re
hyde monomer; trirnerizing said monomer at a temperature
cryst. CHgOH).
of from —S0° C. to +150° 0., thereby obtaining the cor
responding 2,4,6-tris(2-haloalkyl)-trioxane; and reacting
0 i H
Calculated for CHHHOQNK (M.W. 249.30)--."
Found _____________________________________ __
As indicated in this disclosure, the novel trioxanes of 55
the invention have important utility in the ?eld of chemi
cal intermediates, especially as intermediates in the prepa
ration of glutamic acid.
It is to be understood, however, that the invention is
not to be limited to the exact details of operation or exact 60
compounds shown and described, as obvious modi?ca
said trioxane with cyanide ion, thereby obtaining the cor
responding 2,4,6-tris4(2-cyanoalkyl)atrioxane.
References Cited in the ?le of this patent
2,83 1,896
Holly ________________ __ Apr. 22, 195 8
Baer et al. __________ __ Dec. 116, 1958
Schnizer ______________ .__ June '20, 1961
Farberov et al.: “Zhur. Obschei Khim,” volume 28,
pages 2151-62 (1958).
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