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Description  |
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FIELD OF THE INVENTION
This invention is directed to a process for producing chlorosulfate and
sulfamate esters of
2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose and
(1-methylcyclohexyl)methanol. The process in particular is a two step
procedure involving in the first step reacting an alcohol with sulfuryl
chloride in the presence of a tertiary or heterocyclic amine base in a
solvent selected from the group consisting of toluene, t-butyl methyl
ether or tetrahydrofuran to produce a chlorosulfate intermediate, and in
the second step reacting the resulting intermediate with an amine in a
solvent selected from the group consisting of t-butyl methyl ether,
tetrahydrofuran and lower alkanol.
BACKGROUND OF THE INVENTION
Sulfamates of the formula I:
##STR1##
wherein X is O or CH.sub.2 and R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
R.sub.5 are as herein defined, are known compounds that have been found to
exhibit anticonvulsant activity and thus are useful in the treatment of
conditions such as epilepsy. These compounds are disclosed in U.S. Pat.
Nos. 4,582,916 and 4,513,006, which also disclose processes for
production of such compounds. The entire disclosure of these two patents
are hereby incorporated herein by reference.
One reaction scheme disclosed in these prior art patents covers the
reaction of an alcohol of the formula RCH.sub.2 OH with a chlorosulfamate
of the formula ClSO.sub.2 NH.sub.2 or ClSO.sub.2 NHR.sub.1 in the presence
of a base such as potassium t-butoxide or sodium hydride (NaH) at a
temperature of about -20.degree. C. to 25.degree. C. and in a solvent such
as toluene, tetrahydrofuran (THF) or dimethylformamide (DMF), wherein R is
a moiety of the formula II:
##STR2##
This process has two major disadvantages. One disadvantage is that it calls
for a combination of NaH and DMF which has an uncontrollable exotherm and
is therefore potentially explosive. See J. Buckley et al., Chemical &
Engineering News, Jul. 12, 1982, page 5; and G. DeWail, Chemical &
Engineering News, Sep. 13, 1982. Another disadvantage is that the process
also uses highly toxic and corrosive chlorosulfonyl isocyanate (CSI) to
prepare the commercially unavailable sulfamyl chloride (ClSO.sub.2
NH.sub.2). The CSI is not only difficult to work with, because of its
toxicity and corrosiveness, but also is available front only one
commercial supplier.
Another known process disclosed in the above mentioned U.S. Pat. No.
4,513,006 for producing the compounds of formula I comprises the reaction
of an alcohol of the formula RCH.sub.2 OH with sulfuryl chloride of the
formula SO.sub.2 Cl.sub.2 in the presence of a base such as triethylamine
or pyridine at a temperature of about -40.degree. C. to 25.degree. C. in a
diethyl ether or methylene chloride solvent to produce a chlorosulfate of
the formula RCH.sub.2 OSO.sub.2 Cl. The chlorosulfate of the formula
RCH.sub.2 OSO.sub.2 Cl may then be reacted with an amine of the formula
R.sub.1 NH.sub.2 at a temperature of about -40.degree. C. to 25.degree. C.
in a methylene chloride or acetonitrile solvent to produce the compound of
the formula I. This process (utilizing diethyl ether, methylene chloride
and acetonitrile solvents) produces relatively low yields of the desired
end product of formula I in comparison with the process of the present
invention.
The final process disclosed in the two patents comprises the reaction of
the chlorosulfate of formula RCH.sub.2 OSO.sub.2 Cl formed as described
previously with a metal azide such as sodium azide in a solvent such as
methylene chloride or acetonitrile to yield an azidosulfate of the formula
RCH.sub.2 OSO.sub.2 N.sub.3. The azidosulfate is then reduced to a
compound of the formula I wherein R.sub.1 is hydrogen, by catalytic
hydrogenation. The disadvantage with this process is that explosions may
occur when handling the azide compounds. Also the process contains an
additional chemical transformation involving the reduction of the azide to
the NH.sub.2 moiety.
It is an object of the present invention to provide a new and improved
process for producing compounds of the formula I, which uses readily
available materials, can be carried out under safe conditions and at
relatively high yields. The advantages of the present invention are
described in part below and in part will be obvious from this description
and by comparison to the prior art processes described in the Examples
section below.
SUMMARY OF THE INVENTION
According to the present invention, compounds of the formula 1:
##STR3##
wherein X is O or CH.sub.2 and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 are as hereinafter defined are synthesized in two steps by
reacting an alcohol of the formula RCH.sub.2 OH, wherein R is a moiety of
the formula II:
##STR4##
with sulfuryl chloride, in the presence of a base, preferably a tertiary
or heterocyclic amine, in a solvent selected from the group consisting of
toluene, t-butyl methyl ether (TBME) or tetrahydrofuran (THF), preferably
toluene to form a chlorosulfate intermediate compound of the formula
RCH.sub.2 OSO.sub.2 Cl (formula III), and thereafter in a second step
reacting the compound of formula III with an amine of the formula R.sub.1
NH.sub.2, preferably ammonia, in a solvent selected from the group
consisting of THF, TBME, and lower alkanol (e.g. methanol or ethanol),
preferably tetrahydrofuran to produce the compound of formula I:
##STR5##
In a preferred embodiment of the process of the invention the chlorosulfate
intermediate is stabilized by removing residual acidity by aqueous wash of
the product or by treatment with a base such as sodium bicarbonate or more
preferably by both treatment with a base and aqueous wash.
It is to be understood that both the foregoing general and the following
detailed description are exemplary and explanatory only and are not
intended to be restrictive of the invention as claimed.
DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made in detail to particularly preferred embodiments
of the invention. Examples of the preferred embodiments are illustrated in
the following Examples section.
The novel process of the invention is inherently much safer than the prior
art process which employs the potentially explosive combination of
NaH/DMF. It also uses sulfuryl chloride and ammonia instead of the highly
toxic and corrosive chlorosulfonyl isocyanate (CSI). Further the sulfuryl
chloride is more commercially accessible and much less costly than CSI.
Moreover, the process results in relatively high yields of about 85% to
97%, as compared with the prior art processes which have yields in the
range of from about 1% to 60%. The apparent reason for the high yields are
the particularly selected solvents chosen for each step of the reaction
sequence and the stabilization of the intermediate chlorosulfate by
aqueous wash and/or treatment with a base prior to its reaction with an
amine. The combination of the use of inexpensive and readily accessible
sulfuryl chloride and the higher yields of purer product results in a much
more economical and/or safer process when compared to the prior art
processes.
More particularly, the present invention is directed to a process for
synthesizing compounds of the formula I:
##STR6##
wherein X is CH.sub.2 or O; R.sub.1 is hydrogen or C.sub.1 -C.sub.4 alkyl;
and
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are independently hydrogen or alkyl,
and, when X is O, R.sub.2 and R.sub.3 and/or R.sub.4 and R.sub.5,
together, may be a methylenedioxy group the following formula IV:
##STR7##
wherein R.sub.6 and R.sub.7 are the same or different and are hydrogen,
alkyl or are both alkyl and joined to form a cyclopentyl or cyclohexyl
ring, with the proviso that R.sub.6 and R.sub.7 may not both be hydrogen
at the same time.
R.sub.1 in particular is hydrogen or alkyl of about 1 to 4 carbons, such as
methyl, ethyl and isopropyl. Alkyl groups for R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6 and R.sub.7 are of 1 to 3 carbons and include methyl,
ethyl, isopropyl and n-propyl. Alkyl throughout this specification
includes straight and branched chain alkyl groups.
This process is particularly useful for producing compounds of the formula
I wherein X is oxygen and both R.sub.2 and R.sub.3, and R.sub.4 and
R.sub.5 together are methylenedioxy groups of the formula IV, wherein
R.sub.6 an R.sub.7 are both alkyl.
The process comprises reacting an alcohol of the formula RCH.sub.2 OH with
sulfuryl chloride of the formula SO.sub.2 Cl.sub.2 in the presence of a
tertiary or heterocyclic amine base such as pyridine, pyridine derivatives
or triethylamine, preferably pyridine at a temperature of about
-78.degree. C. to 40.degree. C., more preferably at a temperature of about
0.degree. C. to 40.degree. C. in a solvent such as toluene, t-butyl methyl
ether (TBME), or tetrahydrofuran (THF), preferably toluene, to produce a
chlorosulfate of the formula III, i.e. RCH.sub.2 OSO.sub.2 Cl, wherein R
is a moiety of the formula II:
##STR8##
The chlorosulfate of the formula III RCH.sub.2 OSO.sub.2 Cl is stabilized
by aqueous wash from the product mixture or by treatment with a base such
as sodium bicarbonate, or preferably by aqueous wash and treatment with a
base. The stabilized chlorosulfate intermediate is then reacted with an
amine of the formula R.sub.1 NH.sub.2 at a temperature of about
-50.degree. C. to 50.degree. C., more preferably of about 15.degree. C. to
20.degree. C. in a solvent such as THF, TBME, methanol or ethanol,
preferably THF to produce a compound of formula I.
The reaction with the amine of the formula R.sub.1 NH.sub.2 can be carried
out using any appropriate amine source, preferably ammonia gas (R.sub.1
=H) from an ammonia gas generating source such as aqueous or anhydrous
ammonia under pressure of from about atmospheric to 50 psi, more
preferably at about 20-30 psi, or the amine can be bubbled into the
reaction solution. The reaction can also be carried out using a
pre-saturated solution of ammonia in THF.
To obtain a purer product the compound of formula I may be recrystallized
by conventional techniques such as from ethanol/water or ethyl
acetate/hexane.
The starting materials of the formula RCH.sub.2 OH may be obtained
commercially from Aldrich Chemical Corporation or synthesized by
techniques well known in the art. For example, starting materials of the
formula RCH.sub.2 OH, wherein R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
methylenedioxy groups of the formula IV may be obtained by the method of
R. F. Brady in "Carbohydrate Research", 1970,15, p. 35-40 or by reaction
of the trimethylsilyl enol ether of a R.sub.6 COR.sub.7 ketone or aldehyde
with fructose at a temperature of about 25.degree. C. in a solvent such as
an alkyl halide, e.g. methylene chloride in the presence of a protic acid
such as hydrochloric acid or a Lewis Acid such as zinc chloride. The
trimethylsilyl enol ether reaction is described by G. L. Larson et al in
J. Org. Chem., 1973,38, No. 22, p. 3935.
A particularly preferred process according to the present invention
comprises reacting a compound of the formula V:
##STR9##
with sulfuryl chloride of the formula SO.sub.2 Cl.sub.2 in the presence of
an amine base, preferably pyridine and in toluene at a temperature of
about 0.degree. C. to 4.degree. C. and a pressure of about atmospheric to
produce a compound of the formula VI:
##STR10##
The compound of formula VI is thereafter reacted with ammonia at a pressure
of ca. 30 psi in THF at a temperature of about 15.degree. to 20.degree. C.
to produce the compound of the formula VII:
##STR11##
The two-step process of the invention involves (1) the generation of a
chlorosulfate VI, followed by (2) treatment with ammonia to generate the
sulfamate ester VII. The generation of chlorosulfates using sulfuryl
chloride and pyridine is known, however, some sugar derived
chlorosulphates have been shown to further react to form chlorinated
by-products. See Jennings, H. J. et. al. Can. J. Chem. 1965, 43, 2372, and
3018. Jennings et. al. demonstrated that treatment of
methyl-D-glucopyranoside 1 with sulfuryl chloride and pyridine at
0.degree. C. gave the 6-chloro-glucopyranoside 2 as the sole isolated
product.
##STR12##
Using the experimental conditions of the present inventive process for
preparing chlorosulfate VI, there is no indication of similar chemistry
taking place. In light of Jenning's work, the preparation and isolation of
high yields of chlorosulfate VI in accordance with the present invention
is unexpected.
It is further a surprising discovery that ammonia gas may be used as the
amine source in the second reaction step of the process. Prior studies of
reaction of chlorosulfates with ammonia indicate production of mixtures of
N-alkylated products. See e.g. Buncel E., Chemical Reviews, 1970, 70, No.
3, Pp. 323-337 and Kinkead S. A. et. al. J. Am. Chem. Soc., 1984, 106,
7496. The production of higher yields of pure products from the present
process utilizing ammonia gas as the amine source is favorably surprising.
The reaction of chlorosulfates with ammonia to generate sulfamates is not
well understood and often leads to mixtures of N-alkylated products. Alkyl
chlorosulfates can follow three reaction pathways when treated with a
nucleophile such as an amine (shown below). Pathway "a" results in C--O
bond cleavage to afford an alkylated product, while pathways "b" and "c"
result in reaction at sulfur followed by S--O and S--Cl bond cleavages
respectively. The pathway chosen is dependent on both the structural
properties of the chlorosulfate and nucleophilic amine used.
##STR13##
Chlorosulfates prepared from primary alcohols tend to follow the
alkylation pathway "a" when ammonia is employed as the nucleophilic amine,
however, when the amine is alkylated, such as ethyl amine the pathway
chosen tends to be "c". This is best illustrated with the reaction of
ethyl chlorosulfate and ammonia. Reaction of ethyl chlorosulfate and
ammonia yields mono-, di-, and triethylamine, the products of C--O
cleavage (pathway "a"). Also found in the reaction mixture are the
alkylated sulfamates 3a and 3b; the products from pathway "c" involving
"in situ" generated ethyl- and diethylamine. This demonstrates that
ammonia reacts at carbon (pathway "a") and not sulfur, while ethyl- and
diethylamine do react at sulfur and cleave the S--Cl bond (pathway "c").
None of sulfamate 4, the product of ammonia displacement (pathway "c") was
observed. Considering the tendency of ammonia to react at carbon via
pathway "a", it is unexpected that sulfamate VII would be the major
product formed from the reaction involving chlorosulfate VI and ammonia.
##STR14##
Kochetkov et al, J. Gen. Chem. USSR 1971, 41, 1874 compares the reaction
products of ammonia or diethyl amine with the galactopyranose
chlorosulfate 5 (an analog of the chlorosulfate VI) and found they react
quite differently. With ammonia as the amine source the only identified
product was the sulfamate dimer 6, while no sulfamate 8 was produced. In
contrast, when 5 is reacted with diethyl amine the only product isolated
was the N,N-diethyl sulfamate 7.
##STR15##
In summary, the overall high yield of sulfamates for the two step process
of the invention is unexpected, in light of teaching by prior art.
Contrary to the prior art teachings, in the present invention (1) sulfuryl
chloride and pyridine react with primary alcohols V to afford the desired
chlorosulfates VI, in high purity and yield and (2) ammonia reacts at
sulfur and not carbon at chlorosulfates VI to generate the desired
sulfamates VII.
Maryanoff and Gardocki in U.S. Pat. No. 4,582,916 report that
chlorosulfates (VI) may be reacted with monosubstituted amines (i.e.;
R.sub.1 NH.sub.2) at temperatures of -40 to 25 degrees C in solvents like
methylene chloride or acetonitrile to produce N-alkylated sulfamates. This
patent discloses the preparation of sulfamates using chlorosulfates and
amines; the specific use of ammonia as the amine to prepare sulfamate VII
is not, however, actually utilized in the experimental section thereof.
Advantageously, the reaction conditions for the two step process of the
present invention leads to unexpectedly cleaner product in higher yields
than that obtained by Maryanoff and Gardocki. The present two step
inventive process involves the distinctive improvements of an extractive
work-up and isolation to stabilize the chlorosulfate intermediate and the
use of particular solvents to achieve its superior results.
The same process can be used to make the L-fructopyranose derived
enantiomer instead of the D-fructopyranose enantiomer of formula VII by
using the L-enantiomer starting material instead of the D-enantiomer
starting material of formula V.
The invention will now be illustrated by examples. The examples are not
intended to be limiting of the scope of the present invention but read in
conjunction with the detailed and general description above, provide
further understanding of the present invention and outline a method of
practicing the process of the invention.
EXAMPLES
Examples 1 and 2 show the production of intermediates according to the
present invention. Example 3-5 are examples of the production of the final
desired sulfamate (VII) product by the two step process of the invention.
Examples 6-10 are prior art comparative examples for preparing VII
following the conditions described by Maryanoff B. E. et. al. in U.S. Pat.
No. 4,582,916. Table 1 compares the yields of the prior art processes of
examples 6-10 with the yields of the two step processes of the present
invention (Examples 3-5) for producing the compound of formula VII.
Table 2 compares the yields of the process of the present invention
(Example 14) with the yields of prior art processes (Examples 11-13) for
producing (1-methylcyclohexyl)methane sulfamate. As is apparent from the
Tables 1 and 2 the process of the present invention results in yields of
final product greatly in excess of the yields of the prior art processes
and superior purity of the final product.
TABLE 1
__________________________________________________________________________
Comparison of Present Invention (Ex. 3-5) vs. Prior Art
Process (Ex. 6-10) for Preparing Sulfamate VII
##STR16##
##STR17##
Phys. Descript
Purity (%)
Yield #
Process solvent 1
solvent 2
NH.sub.3
(VII) (VII) (VII)
__________________________________________________________________________
Ex. 3 toluene
THF 30 psi
wh. solid 99.70 93.50
Ex. 4 toluene
THF bubbling
wh. solid 96.20 87.20
Ex. 5 toluene
THF saturation
wh. solid -- 83.30*
Ex. 6 CH.sub.2 Cl.sub.2
CH.sub.2 Cl.sub.2
bubbling
bl.tar 15.10 36.83
Ex. 7 CH.sub.2 Cl.sub.2
CH.sub.3 CN
bubbling
bl.tar 25.80 60.40
Ex. 8 ether CH.sub.2 Cl.sub.2
bubbling
bl.tar 14.80 32.43
Ex. 9 ether CH.sub.3 CN
bubbling
bl.tar 18.70 41.91
Ex. 10 ether CH.sub.2 Cl.sub.2
pressure
bl.tar 0.55 1.08
__________________________________________________________________________
#Yield based on purity by GLC analysis.
*Isolated crude yield.
TABLE 2
__________________________________________________________________________
Comparison of Present Invention (Ex. 14) vs. Prior Art Process
(Ex. 11-13) for Preparing (1-Methylcyclohexyl)methane Sulfamate
##STR18##
Process
solvent 1
solvent 2
NH.sub.3
Phys. Descript
Purity (%)
Yield #
__________________________________________________________________________
Ex. 11
CH.sub.2 Cl.sub.2
CH.sub.3 CN
bubbling
bl.tar 2.24 1.34
Ex. 12
ether CH.sub.3 CN
bubbling
bl.tar 0.00 0.00
Ex. 13
CH.sub.2 Cl.sub.2
CH.sub.2 Cl.sub.2
bubbling
bl.tar 29.10 23.97
Ex. 14
toluene
THF 28 psi
yel.oil 95.00 81.33
__________________________________________________________________________
#Yield based on purity by GLC analysis.
Example 1
Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
Under nitrogen, acetone (144.0 L, 113.0 kg, 1946 mol) was cooled to
0.degree.-10.degree. C. With stirring, concentrated sulfuric acid (7.2 L,
13.2 kg, 135.6 mol) was added gradually (approx. 0.5 h) so that the
temperature did not exceed 20.degree. C. (jacket temperature at
-15.degree. C.). External cooling was discontinued and D-fructose (12.0
kg, 66.6 mol) was added gradually (in 2.0 kg portions) over 2 h while
maintaining the temperature between 8.degree.-15.degree. C. The suspension
was stirred at room temperature for an additional 2-3 h after all the
fructose had dissolved. The solution was then cooled to 5.degree. C. and
50% sodium hydroxide (24.0 kg, 297.6 mol) was added at a rate so as to
maintain the solution temperature below 20.degree. C. (addition was
complete in 1 h with a jacket temperature at -15.degree. C.). The
resulting slurry was centrifuged to remove the precipitated salt (sodium
sulfate). Solvent was removed from the filtrate by vacuum distillation and
the residual oil was stored at room temperature. The semi-solid reaction
product was dissolved in t-butyl methyl ether (48.8 kg, 66.4 L). The
solution was washed with distilled water (2.times.9.0 L) and concentrated
to give an oil. The oil was dissolved in hexane (24.0 L)/isopropanol (3.5
L) with gradual warming to 60.degree. C. The product crystallized with
cooling. The solid was collected by centrifugation and dried in a vacuum
oven at 38.degree. C. for 8.0 h to give 10.8 kg (62.4% yield, 100.8%
purity by GLC) of a white solid, mp 95.degree.-96.degree. C.
Example 2
Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfonyl chloride (chlorosulfate)
A solution of sulfuryl chloride (486.9 g, 3.60 mol) and toluene (4.0 L) was
cooled to -10.degree. C. A solution of the alcohol of Example 1 (782.4 g,
3.00 mol) and pyridine (285.3 g, 3.60 mol) in toluene (4.0 L) was added to
the cooled sulfuryl chloride solution. The rate of addition was regulated
so that the reaction temperature was maintained between -10.degree. to
5.degree. C. (required 1.5 h). A white solid precipitated from the
reaction immediately. After the addition was complete, the cooling bath
was removed and the mixture stirred for 2.0 h. The reaction mixture was
diluted with distilled water (4.0 L) and the resultant layers separated.
The organic layer was then washed sequentially with a 10% citric acid
solution (2.6 L), distilled water (2.6 L), a saturated sodium bicarbonate
solution (2.6 L), and a saturated sodium chloride solution (2.6 L).
Removal of the solvent by vacuum distillation (in a 45.degree. C. bath at
<5 mm) afforded chlorosulfate (1101 g, 102.2%) as an almost colorless oil.
The product was found to be 98.3% pure (wt % by GLC) giving a corrected
yield of 100.5%.
Example 3
Preparation of 2,3:4,5-bis-O-(1-methylethylidene) .beta.-D-fructopyranose
sulfamate (ammonolysis at 30 psi)
Chlorosulfate (1076.4 g, 3.0 mol) of Example 2 in tetrahydrofuran (8.0 L)
was added to a 12.0 L stainless steel autoclave. The autoclave was then
pressurized with anhydrous ammonia to 30 psi and stirred (400 rpm) at
ambient temperature for 24.0 h. A mild exotherm was noticed after 2.0 h
(25.degree. to 38.degree. C.). The autoclave was depressurized by venting
to the air. The light yellow solution, containing a white granular solid,
was filtered and the filter cake washed with tetrahydrofuran (400 mL). The
tetrahydrofuran was removed in vacuo (50.degree. C., house vac) to afford
the product as a light yellow oil (1110.0 g, 109.0%). The oil was slurried
in n-hexane (2.1 L) and warmed on a steam bath for 0.5 h. The oil changed
to a white paste and then crystallized. After cooling to room temperature,
the title compound was collected by filtration and air dried for 24.0 h
(955.1 g, 93.8% yield and 99.7% pure by GLC giving a corrected yield of
93.5%).
A sample (900 g) was recrystallized from 95% ethanol (900 mL) with the
addition of distilled water (1800 mL) and the pH adjusted to 8-8.5 by
adding 50% NaOH (3.5 mL). The solid was collected by vacuum filtration and
air dried (72.0 h) to yield the title compound (828.0 g, 92.0% isolated
yield, 100.1% pure by GLC) as a white solid, mp 123.degree.-124.degree. C.
Example 4
Preparation of 2,3:4,5-bis-O-(1-methylethylidene) .beta.-D-fructopyranose
sulfamate (ammonolysis by bubbling ammonia gas)
Into a 500 mL, four-neck round bottom flask equipped with an overhead
stirrer, bubbler, thermometer, and inlet tube was placed 19.90 g (0.0556
mol) of the chlorosulfate of Example 2 which was dissolved in 200 mL of
tetrahydrofuran. Anhydrous ammonia was bubbled into the solution at room
temperature for about 5 h. The reaction mixture was filtered to remove the
precipitate and the solvent removed in vacuo. The oil was slurried in
hexane (50 mL) with warming on a steam bath until it became pasty white.
The oil crystallized with stirring on cooling to room temperature. The
mixture was left to stand at room temperature overnight. The mixture was
then filtered, washed with hexane, and air dried to give the title
compound as a white solid (17.11 g, 96.2% pure by GLC, 87.2% yield).
Example 5
Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate (saturation ammonolysis)
Anhydrous ammonia was added to 490 kg of THF until a pressure of 22 psi was
reached. While maintaining a pressure of 22 psi, a solution of the
chlorosulfate (303 kg, 845 mol) prepared as in example 2, and dissolved in
415 kg of THF was pumped into the presaturated NH.sub.3 /THF solution over
a 2 h period while maintaining an internal temperature of
15.degree.-20.degree. C. After 3 h the excess ammonia was vented and the
reaction mixture filtered. The THF solution was concentrated in vacuo to a
syrup, diluted with isopropanol (185 kg), and concentrated again. The
resultant residue was dissolved in a solution of isopropanol (150 kg) and
petroleum spirits (370 kg) containing 8.0 kg of activated charcoal and
warmed to 80.degree. C. for 30 min. The warm solution was filtered to
remove charcoal and cooled. After cooling to 0.degree.-5.degree. C., the
title compound was collected by filtration and dried under vacuum at
45.degree. C. (239 kg, 83.3% yield).
Example 6--(Comparative Example)
Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate
Under nitrogen, a solution of the alcohol of Example 1 (15.0 g, 0.0576 mol)
and pyridine (15 mL, 0.18 mol) in methylene chloride (60 mL) was cooled to
-40.degree. C. in a dry ice/isopropanol bath. With stirring, a solution of
sulfuryl chloride (16.0 g, 0.118 mol) in methylene chloride (10 mL) was
added gradually (approx. 50 minutes) so that the temperature did not
exceed -25.degree. C. The ice bath was removed as soon as the addition was
complete and the reaction mixture stirred for an additional 2 h. During
this time the light yellow precipitate became a clumpy brown solid.
Solvent was removed in vacuo to yield a sticky, brown residue. The residue
was dissolved in 100 mL methylene chloride and anhydrous ammonia was
bubbled through the mixture overnight at ambient temperature. The dark
reaction mixture was concentrated in vacuo to give 47.7 g of the title
compound as a black residue. The crude product was found to be 15.10% pure
by GLC giving a corrected yield of 36.83 %.
Example 7--(Comparative Example)
Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate
The reaction was carried out the same as in Example 6 except acetonitrile
was used as the second solvent instead of methylene chloride. The title
compound was isolated as a black residue (45.77 g). The crude product was
found to be 25.8% pure by GLC giving a corrected yield of 60.40%.
Example 8--(Comparative Example) Preparation of
2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose sulfamate
The reaction was carried out the same as in Example 6 except ether was used
instead of methylene chloride in the first step. The title compound was
isolated as a black residue (42.84 g). The crude product was found to be
14.8% pure by GLC giving a corrected yield of 32.43%.
Example 9--(Comparative Example)
Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate
The reaction was carried out the same as in Example 6 except ether was used
instead of solvent 1 (methylene chloride) and acetonitrile was used
instead of methylene chloride for solvent 2 (see Table 1). A black residue
(43.82 g) was obtained on work-up. The crude product was found to be
18.70% pure by GLC giving a corrected yield of 41.91%.
Example 10--(Comparative Example)
Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate
The reaction was carried out the same as in Example 8 except that the
chlorosulfate/methylene chloride solution was placed in a pear shaped
pressure bottle and cooled in a dry ice/isopropanol bath. Anhydrous
ammonia was bubbled through the mixture for approximately 30 minutes; then
the bottle was tightly stoppered and allowed to slowly warm to room
temperature overnight. The bottle was cooled back down before opening and
the mixture concentrated in vacuo to give 38.51 g of the title compound as
a brown tar. The crude product was found to be only 0.55% pure by GLC
giving a corrected yield of 1.08%.
Example 11--(Comparative Example)
Preparation of (1-methylcyclohexyl)methane sulfamate
Under nitrogen, a solution of (1-methylcyclohexane)methanol (7.4 g, 0.057
mol) and pyridine (15 mL, 0.179 mol) in methylene chloride (100 mL) was
cooled to -10.degree. C. in a ice/methanol bath. With stirring, a solution
of sulfuryl chloride (16.0 g, 0.118 mol) in methylene chloride (20 mL) was
added gradually (approx. 1.0 h) so that the temperature did not exceed
-5.degree. C. The ice bath was removed and the light yellow solution
allowed to slowly warm to room temperature over a 2.0 h period. Solvent
was removed in vacuo and the resulting yellow slush was slurried in
acetonitrile (140 mL). Anhydrous ammonia was bubbled through the mixture
for 4.0 h. The mixture was filtered, washed with fresh acetonitrile, and
concentrated in vacuo to give the title compound (7.12 g) as a dark oil.
The crude product was found to be only 2.24% pure by GLC giving a
corrected yield of 1.34%.
Example 12--(Comparative Example)
Preparation of (1-methylcyclohexyl)methane sulfamate
The reaction was carried out the same as that in Example 11 except
diethylether was used for methylene chloride as solvent 1. (see Table 2).
No product was isolated based on GLC analysis.
Example 13--(Comparative Example)
Preparation of (1-methylcyclohexyl)methane sulfamate
The reaction was carried out the same as that in Example 11 except
methylene chloride was used instead of acetonitrile as solvent 2 (see
Table 2). A product (9.85 g) was isolated as a dark oil. The crude product
was found to be 29.1% pure by GLC giving a corrected yield of 23.97%.
Example 14
Preparation of (1-methylcyclohexyl)methane sulfamate
Under argon, sulfuryl chloride (18.67 g, 0.138 mol) in toluene (150 mL) was
cooled to -50.degree. C. in a dry ice/acetone bath. With stirring, a
solution of 1-methyl-1-cyclohexane methanol (14.74 g, 0.115 mol) and
pyridine (10.94 g, 0.138 mol) in toluene (150 mL) was added gradually
(approx. 40-50 minutes) so that the temperature did not exceed -45.degree.
C. The ice bath was removed as soon as the addition was complete. After
stirring for an additional 30 minutes water (300 mL) was added and the
layers separated. The organic layer was washed with 10% citric acid
(2.times.60 mL), water (2.times.100 mL), saturated sodium bicarbonate
(1.times.100 mL), and saturated sodium chloride (1.times.200 mL), then
dried over solid sodium sulfate, filtered, and concentrated in vacuo to
give the chlorosulfate (23.53 g, 90.6% yield) as a brownish yellow oil.
The oil was dissolved in tetrahydrofuran (300 mL) and the solution added
to a 1.0 L autoclave (with glass liner). The autoclave was pressurized
with anhydrous ammonia to 28 psi and stirred (290 rpm) at ambient
temperature for 16 h. A mild exotherm was noticed after 1.0 h
(22.degree.-35.degree. C.). The autoclave was depressurized by venting to
the air. The mixture was filtered and the solvent removed in vacuo to give
20.41 g of the title compound as a yellow oil. The product was found to be
95.0% pure by GLC giving a corrected yield of 81.33%.
Examples 15-18--Comparative Examples
In these examples sulfamates were prepared using the process of the present
invention (i.e., Ex. 3) but limiting the choice of solvents to those
disclosed by Maryanoff, B. E. et. al. in U.S. Pat. No. 4,582,916. The
results obtained in these comparative examples are disclosed in Table 3
below.
TABLE 3
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Comparison of Present Invention (Ex. 3) vs. Prior Art
Solvents (Ex. 15-18) for Preparing Sulfamate VII
##STR19##
##STR20##
##STR21##
Purity (%)
Yield #
Process
solvent 1 solvent 2
NH.sub.3
(VII) (VII)
______________________________________
Ex. 3 toluene THF 30 psi
99.70 93.50
Ex. 15 CH.sub.2 Cl.sub.2
CH.sub.2 Cl.sub.2
30 psi
96.76 87.08
Ex. 16 CH.sub.2 Cl.sub.2
CH.sub.3 CN
30 psi
93.19 77.95
Ex. 17 ether CH.sub.2 Cl.sub.2
30 psi
96.20 83.85
Ex. 18 ether CH.sub.2 CN
30 psi
94.09 77.60
______________________________________
A comparison of the examples of the present invention (Exs. 3-5 and 14)
versus those comparative examples of the prior art (Exs. 6-13) in Tables 1
and 2 evidences the advantages of the use of the particularly selected
solvents of the process of the present invention to produce surprisingly
superior results over the prior art processes. A direct comparison of Ex.
4 of the invention utilizing the preferred solvents of the invention, e.g.
toluene and THF versus comparitive prior art Exs. 6-9 in Table 1 shows a
yield improvement of at least 40% and a significant purity improvement for
the final product
2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose sulfamate.
Analagous process result improvements are illustrated in Table 2 for the
preparation of (1-methylcyclohexyl)methane sulfamate.
Table 3 illustrates not only the importance of solvent selection but also
the importance of stabilization of the chlorosulfate intermediate to
contribute to improved yields obtainable by the process of the invention
as compared to the prior art. For example, comparing Ex. 10 (Table 1) of
the prior art with Ex. 17 (Table 3) of the invention, whereby, both use
the same prior art solvents, but Ex. 17 provides the additional step of
stabilizing the chlorosulfate intermediate, reveals significant
improvement in yield and purity for Ex. 17.
The scope of the present invention is not limited by the description,
examples and suggested uses described herein and modifications can be made
without departing from the spirit of the invention. For example, other
sulfamates may be produced utilizing the process of the invention beyond
those exemplified herein.
Applications of the process and methods of the present invention can be
accomplished by any synthetic method and technique as is presently or
prospectively known to those skilled in the chemical and pharmaceutical
process arts. Thus it is intended that the present invention cover any
modifications and variations of this invention provided that they come
within the scope of the appended claims and their equivalents.
* * * * *
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