Note: Descriptions are shown in the official language in which they were submitted.
This invention relates to the manufacture of
chloromethyl chloroformate, which is a rraterial useful
in numerous oxganic syntheses but not easily available
on an inclustrial scale.
The synthesis of ~-chlorinated chloroformates,
of general formula: P~-CHCl-O-C-Cl, in which R is an
aliphatic or aroma-tic substltuent, is very difficult if
L0 it is desired to avoid -the introduction of additional
chlorine atoms in the radical ~ during the synthesis.
~luller, in Liebiy's Annalen der Chemie, 1890, volume
257l pages 50 and following, has suggested a process
which is still the only one known and in use to date.
This process consists of photoly-tically chlorinating
the corresponding chloroforma-te, which is not substituted
in the f.~ posi-tion. Unfor-tunately, in addition to the
desired product, one obtains numerous by-produc-ts
which are more chlorinated -than it was intended.
20 ~uller has counted not less than five of these by-
produc-ts in the case of the ethyl chloroformate which he
studied. The presence of these by-produc-ts is very
disturbing due to the main subsequent application oE
the chloroformates, -that is their transformation into
carbonates, notably used in the synthesis of fine pharma-
ceutica:Ls such as penicillin acids acylals. A distil-
lation of the reac-tion product is -thus indispensable,
although delicate to carry out due to the presence of
numerous by-products.
Another old publication, German Paten-t 121/223,
hich issued in 1901, describes the synthesis of 1,2/2,2-
tetrachloroethyl chloroformate and f~-chiorobenzyl
chloroformate, by phosgenation of chloral and benzalde-
hyde respectively, in the presence of a stoichiometric
amount of a tertiary amine, which does not belong to
-the pyridine series.
However, if i-t is attemp-ted to phosgenate,
~0 under the same conditions, other aldehydes, in addition
to xpecific chloral and benzaldehyde, such as acetalde-
hyde, there is noted the forrnation of nurnerous cornplexes
and by-prodllcts in addition
, ~
-- 2
rnab/ '
~909313
to the ~ -~hloroethyl chloroformate, the latter being obtained
with poor yield, which renders -this process not suit~ble on an
industrial scale. Moreover, if one -tries to carry ou-t this
phosgenation with an alipha-tic -tertiary amine such as trietnyl-
amine, one mainly notes the destruc-tion of this amine, with
formation of a very small amoun-t o:E the derived chl.oroformate.
`Thus, there is a need of a manufacturing process of
pure .~-chlorinated chloroformates in yields.which will permit
a complete application of these .f)~chlorinated chloroformates,
compounds of simple chemical structure and substantial value as
intermediates.
A process for manufac-turing -',-chlorinated chloro
formates :Eree of the by-prod~cts resulting from substi-tution
of chlorine for hydro~Jen has recen-tly been proposed from inex-
pensive raw materials and in e.xcellen-t yield. This process,
described in Irish Paten-t Application ~ , consists of
phosgenating an aldehyde of formula RCHO in the presence of
catalysts, so as to obtain /~-chlorinated RCHClOCOCl chloro-
formate. However, this process cannot be applied to formalde-
hyde itself, HCHQ and does not permit to prepare ~ -chloromethyl
chloroformate C~2Clococl.
In the case of chloromethyl chloroformate, it is
known that it may be obtained by chlorination of methyl chloro-
~ormate or methyl formate. M~TZNER et al, in Chemical Re~iew 64,
page 6~6 (196~), yive several references of known methods bu-t
these methods are always delicate syntheses leading to numerous
by-products, difficult to separate from the desired product.
An object of the present invention is to provide a
process for the manufacture of .~ chloromethyl chloroformate
in a high yield.
The crux of the present invention resides in intro-
ducing previously-dried gaseous monomeric formaldehyde into a
reactor containing phosgene and a catalyst, selected from the
group consisting of substituted amines, tetrasubstituted ureas
and thioureas, nitrogen completely substituted phosphoramides,
quaternary ammonium halides, having a total of at least 16
carbon atoms and preferably those in which every substituent
includes at least ~ carbon atoms, alkali or alkaline-earth
halides associated to a seques-tering agent of their cation
3~ (
as well as the reac-tion products of -these catalys-ts with phos-
gene. The reaction takes place in the total absence of water
and hydrochloric acid, at a temperature between -10C and +60C.
According to a specific embodimen-t of the invention, the react--
ion oF formalclehyde and phosgene, in the presence of a catalys-t,
is carried out in a solvent, which is toluene, methylene chlor-
ide, chloroform or carbon tetrachloride.
~ ccording to a preferred embodiment of the invention,
the catalyst is benzyl-tributyl ammonium chloride, potassium
chloride associated to a crown ether or to a cryptate capable
of complexing its cation or phosgenated tetrabutyl urea.
The process according to the invention consists of
carrying out the reac~ion of dry gaseous formaldehyde in lts
monomeric form with phosgene in a reactor at a temperature
hetween -10C and 60C in the presence of a catalyst and in
total absence of water and hydrochloric acid.
According to the invention, the formaldehyde must be
perfectly dry and completely monomeric. It is thus necessary,
before starting the reaction, to dry the formaldehyde and, in
general, to depolymerize it since formaldehyde cannot be stored
in the monomeric form, but forms either the trimer trioxane or
a linear polymer of general formula ~CH2otn; which is known as
paraformaldehyde, in which "n" is an integer,usually between 6
and 100.
The forma]dehyde is dried in a dryer, in the presence
of a good drylng agent such as phosphorus pentoxide. The oper-
ation of drying the formaldehyde may be performed before or
during the depolymerization but, in any e~-ent, before its
introduction into the phosgenation reactor. The drying oper-
ation is essential for the process according to the invention,
and it must be complete. Indeed, any trace of moisture causes
repolymerization of the monomeric formaldehyde and lowers the
yield of -the phosgenation since only monomeric formaldehyde
reacts with phosgene. Monomeric formaldehyde is obtained in a
known manner, such as by thermal depolymerization in the case of
paraformaldehyde, or by depolymerization in the presence of
catalysts in the case of trioxane. Depolymerization can tak~
place either during the drying of formaldehyde or after drying
of the polymeric formaldehyde. Dry formaldehyde/ in monomeric
form, is then introduce~ into a perfect]y dry reactor, containing
the catalyst and the phosgene. Wlthin the scope of the present
invention, the term "catalyst" must be unders-tood restric-tively.
The compound added as catalyst is esSential to tlle react-
ion but does not directly participate to the reaction and is used
in relatively small amounts with respect to the formaldehyde. It
is indeed a catalyst, but contrary to what is the general view of
catalysts, it cannot always be reused for another reaction once
the introduction oE phosgene has been stopped. No theoretical
explanation may be suggested for this phenomenon.
It hss been possible to find a definition cornmon to a
certain number o catalysts suitable for the invention. These
catalysts are organic or inorganic substances which can generate,
in a medium containing formalclehyde, phosgene and a solvent if
applicable, a pair of ions, one of which is a halide anion and t~e
other one a cation sufficiently separated from the halide anion
so that it possesses a nucleophilic acti~ity allowing it to re-
act with the aldehyde function of the formaldehyde. Catalysts
according to the invention and Ealling within this definition
include among others, the following as such or as their reaction
products with phosgene: substituted amides, tetrasubstituted
ureas and thioureas, nitrogen completely substituted phosphor-
amides, quaternary ammonium halides, the substituents of
which include a total of at least 16 carbon atoms and preferably
those whose every constituent includes at least 4 car~on atoms
and alkali and alk~line-earth halides associated to a sequester-
ing agen-t of their cation. ~he preferred halide is chloride.
As mentioned hereinabove, certain catalysts generate
a halide ion either directly, or after reaction with phosgene.
In this case, the general mechanism of the catalyst is probably
as follows:
M Cl - ~ ~C ~ O -> ~9 ~ C1 - C - 01
t
~1 Cl Cl- ~/
Cl - C -- O - C ~ Cl ~) M
H O ~HCOH o
3~ (
in which M is an organic or inorganic cation, complexed or not,
present as such in the catalyst from the start or formed at the
beginning of the reaction by the action oE phosgene on the cat-
alyst. Thus, M may be a complexed metalli.c cation or a fully-
organic cation o:E onium type, $uc~ as, for instance:
~ O K O N Cl
0~ 0 ~ /
or M+ may be formed from the more or less advanced reaction oE
phosgene and the substance responsible for the catalytic action,
such as in the following sequence, for ins-tance:
- Bu~ ~ ~Bu Cl~
IN ~ C ~ N ~ _~ C = O
Bu/ `,? ~ Cl~
Bu~ ~j N~ -~ Cl ~ CO2
~u~ ~ Cl
. HCOH
in which M is a large chlorimonium ca-tion.
It has been noted that the most interesting results
have been obtained with the following catalysts: substi-tu-ted
amides, particularly dimethylformamide; tetrasubstituted ureas
and thioureas, particularly tetraalkyl ~ ~ s' such as tetra-
butylurea and tetramethylurea; completely nitrogen substi-tuted
phosphoramides, particularly hexamethylphosphotriamide, quater-
nary ammonium halides which include a total of at least 16 carbon
atoms and preferably each substituent has at least 4 carbon
atoms, such as tri.butylbenzyl ammonium chloride; alkali or
alkaline-earth halides associated to a sequestering agent of
their cation, particularly potassium chloride associated to a
crown ether such as 18-crown-6 or a cryptate such as (222) or
diaza-1,10 hexaoxa - 4,7,13,16,21,24 - bicyclo(8~8,8)hexacosane.
Naturally, in this latter case, it is preferable to
associate a sequestering agent which forms with the metal chlor-
ide cation a complex with a high stability constant, which is
-- 7
very easy to achieve due to the numerous studies per~ormed in
this field, such as the study of Kappenstein published in the
~ulletin de la ~ocie-te Chimique de France, 197~, N l-2, pages
~9-109 and the work of J.M. LEHN published in Structure and Bon-
ding, volume 16, pages 2-6~, Sp.r:inger Verlag (197~). The term
"halide" essentially indicates a chloride, bromide, or iodide,
it being understood that a chloride is preferred, so that even
the first molecule of formaldehyde transformed t.hrough the ac-
tion of the halide coming from the catalyst is transformed into
chloromet.hyl chloroformate.
The ratio of catalyst used is important but is not
essential to the process according to the inven-tion. Indeed,
when -the catalys-t is very efective, a xatio of catalys-t of 0.5
to 10 percent in moles (preferably 2 to 7 percent) with respect
to the molar ~uantity of phosgene used is satisfactory. On the
other hand, some catalys-ts according to the invention are less
effective and a highex ratio, about l -to 50 percent (preferably
5 to 40 percent) must be used.
I'he order o~ introduction of the reagents into the
reactor is impor-tant. It is indeed essential to introduce the
monomeric gaseous Eormaldehyde into the reactor already containing
the catalys-t and phosgene, so tha-t the formaldehyde reacts imme~
diately with the phosgene wi-thou-t having the time to repolymerize,
because the ra-te of reaction of formaldehyde with phosgene i.s
hiyher -than its rate of polymerization under the operatiny con-
ditions used. The reactor must thus contain at ].east the cata-
lyst with all the phosgene being introduced into the reactor
before the start of the reaction or being introduced at the same
time the formaldehyde is introduced at the bottom of the vessel
containing phosgene and catalyst. On the other hand, within the
present invention, it is not possible to place in a vessel the
formaldehyde and the catalyst to introduce the phosyene into this
vessel since, in this case, the formaldehyde would polymerize
and the phosgenation reaction would become virtually impossible~
The phosgenation reaction advantageously takes place
under stirriny. The temperature of the reaction medium is pre-
ferahly kept be-tween -10C and -~30C duriny the introduction of
forrnaldehyde. It is still better to keep the temperature of the
reaction medium at abou-t 0C at the beyinning of the introduction
-- 8 --
of the formaldehyde and by the end of -the introduction of the
formaldehyde, -the temperature is allowed to reach about 20C.
It may be advantageous to end the reaction by heating the re-
action mixture up to a temperature between ~0 and 60C.
The reac-tion mix-ture must be totally free of any trace
of water or hydrochloric acid so as to avoid all risks of formal-
dehyde repolymerization. For this purpose, the reactor must be
flushed with dry air or with a dry inert gas before the reaction.
Althou~h this is not a preferred embodiment of the
invention, it is possible to carry out the reaction in the pre-
sence of a sol~ent. One.must, however, avoid using solvents
which react with phosgene to form hydrochlori.c acid, s~lch as
alcohols and amlnes or solvents which break down to form hydro-
chloric acid, such as ketones and t.etrahydrofuran and finally,.
solvents which are difficult to dry, such as ethers. If desired,
it is possible to use solvents such as toluene or chlorinated
aliphatic solvents such as methylene chloride, chloroform and
carbon tetrachloride. However, the use of a solvent may some-
times prove useful since, when the reaction takes place in the
presence of a solvent, the temperature may be kept between 30
and 60C even during the introduction of formaldehyde.
The following examples illustrate the utilization of
the process according to the in~ention.
Exam~le 1
The apparatus used is a 100-ml capacity glass reactor,
fitted with a dry ice cooler, a thermometer, a stirrer and an
inlet for the introduction of a gas. The reactor is flushed with
dry nitrogen. Phosgene 0.3X mole (38 grams), which ~.n.tains 3-3
grams (0.0106 mole of perfectly dry benzyl tributylammonium
chloride, is introduced into the reactor.
While the temperature of the mi~ture is kept at
around 0C, there is introduced through the yas inlet tube, dip-
ping in the phosgene, the formaldehyde which is taken from a
bottle containing 18 grams (0.6 mole) paraformaldehyde and 10
grams phosphorus pentoxide P2O5, this bottle being flushed with
dry nitrogen and being heated at 150~. The addition of formal-
dehyde is carried on for 30 minutes, until full disappearance
of the paraformaldehyde and the reaction mixture is allowed to
- 9 -- ~
reach 20C and is kept stirred for one hour at this temperature.
The residual phosgene is removed by deaeration and the chloro-
methyl chloroformate obtained is purified first by evaporation
under vacuum and then by distillation at atmospheric pressure.
The boiling point is 106C. There is obtained 20.7 grams of
perfectly dry product, which is e~uivalent to a yield of 42
percent with respect to the phosgene used. In ~MN spectrography,
chloromethyl chloroformate is characteri~ed by a singlet at 5.5
ppm.
Example 2
One operates as described in example 1 above, with 10
grams phosgene, 10 grams paraformalAehyde and 5 grams P2O5, using
phosgenated tetra n-butyl urea as catalyst. This catalyst is
prepared by phosgenating 1.5 grams tetra n-butyl urea at 50C
according to the following reaction scheme:
n butyl n butyl
n butyl C1Cl - C f n butyl --~
~N n butyl COC12~ ~ n butyl
~ butyl `n butyl
The reaction temperature is brought up to 50C for one hour after
the end of the introduction of the formaldehyde.
There is ob-tained chloromethyl chloroformate with a
yield of 91.5 percent with respect to the phosgene used. This
yield is determined by RMN dosing, using toluene as internal
standard.
Example 3
The process is carried out as described in example 2
above, with 20 grams phosgene, 15 grams paraformaldehyde and 10
grams P2O5, using as catalyst 1.3 grams potassium chloride as-
sociated -to 0.4 grams cryptate (2,2,2). Chloromethyl chloro-
formate with a yield of 63 percent with respect to the phosgene
used, is obtained.
-- 10 -
Example 4
The apparatus used is identical to the apparatus de-
scribed in example 1 above. The reac-tor is fl~lshed wi-th ary
nitrosen. Phos~ene, 20 grams is introduced in-to this reactor,
which already contains 1.3 ~rams potass:ium chloride associated
to 0.4 gram cryptate (2,2,2).
While -the temperature of the mixture is kept at about
0C, there is introduced through the bubblin~ tube which dips
in~o the phosgene, the formaldehyde coming from a bottle contain-
ing 15 grams paraformaldehyde, heated at 150C. This bottle has
previously been flushed dry with nitrogen and the paraformalde-
hyde dried over P2O5 under a vacuum of 0.1 mm Hg in a drier be-
fore being inserted into the depolymerizing bottle. The intro-
duction of formaldehyde is carried out ~or 30 minutes, then the
reaction mixture is heated at 50C for one hour to allow the
reaction to proceed to completion. There is obtained chloro-
methyl chloroformate with a yield of 73 percent with respect to
the phosgene used.
Example 5
The same apparatus as described under Example 1 is
used. The reactor is flushed with dry nitrogen. There is intro-
duced, 40 ml anhydrous carbon tetrachloride as a solvent, 12
grams of phosgene and, as catalyst, phosgenated tetra n-butyl
urea, prepared as described in example 2 from 1.5 grams tetra
n~butyl urea.
After the temperature of the reaction mixture has
been raised to ~0C, t.here is introduced formaldehyde, prepared
as described in example 4 from 3O8 grams paraformaldehyde. The
reaction mixture is kept at 40C for 2 hours after introduction
o~ the formaldehyde.
There is obtained chloromethyl chloroformate with a
yield of 65 percent with respect to the formaldehyde used.
