U.S. patent application number 12/173596 was filed with the patent office on 2008-11-06 for process for halomethyl ethers of hydroxyiminomethyl quaternary pyridinium salts.
This patent application is currently assigned to Aerojet Fine Chemicals LLC.. Invention is credited to Olivier Dapremont, George R. Gettys, Der-Shing Huang, Aslam A. Malik.
Application Number | 20080275246 12/173596 |
Document ID | / |
Family ID | 46322010 |
Filed Date | 2008-11-06 |
United States Patent
Application |
20080275246 |
Kind Code |
A1 |
Huang; Der-Shing ; et
al. |
November 6, 2008 |
PROCESS FOR HALOMETHYL ETHERS OF HYDROXYIMINOMETHYL QUATERNARY
PYRIDINIUM SALTS
Abstract
A halide salt of a
1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane is
prepared by adding a pyridinealdoxime to a bis-halomethylether in
such a manner that the bis-halomethylether is maintained in excess
throughout the addition. This procedure produces the halide salt of
a 1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane in
high yield and purity, which facilitates its use as an intermediate
in the manufacture of an asymmetrically substituted
1,3-di(1-pyridino)-2-oxapropane, a class of compounds that are
generally useful antidotes to various toxic agents. A prominent
member of the class is the dimethylsulfonate salt of
1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropa-
ne. The use of mercaptoalkyl-functionalized polymers is disclosed
as a preferred metal ion scavenger for a final purification step in
the manufacture of these compounds.
Inventors: |
Huang; Der-Shing; (Folsom,
CA) ; Gettys; George R.; (Citrus Heights, CA)
; Dapremont; Olivier; (Citrus Heights, CA) ;
Malik; Aslam A.; (Cameron Park, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER, EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Aerojet Fine Chemicals LLC.
Rancho Cordova
CA
|
Family ID: |
46322010 |
Appl. No.: |
12/173596 |
Filed: |
July 15, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11133740 |
May 19, 2005 |
7414135 |
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12173596 |
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11061064 |
Feb 17, 2005 |
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11133740 |
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Current U.S.
Class: |
546/334 |
Current CPC
Class: |
C07D 213/53 20130101;
C07D 213/81 20130101 |
Class at
Publication: |
546/334 |
International
Class: |
C07D 213/02 20060101
C07D213/02 |
Claims
1. A process for the purification of a dimethanesulfonate salt of a
1,3-di-(1-pyridino)-2-oxapropane from a product mixture that is the
result of an ion exchange reaction of a halide salt of said
1,3-di-(1-pyridino)-2-oxapropane with a metallic methanesulfonate,
said process comprising contacting a liquid solution of said
product mixture with a water-insoluble mercaptoalkyl-functionalized
polymer.
2. The process of claim 1 wherein said metallic methanesulfonate is
silver methanesulfonate.
3. The process of claim 1 wherein said mercaptoalkyl-functionalized
polymer is a mercapto-(C.sub.1-C.sub.5 alkyl)-functionalized silica
gel or a mercapto-(C.sub.1-C.sub.5 alkyl)-functionalized polyalkyl
fiber.
4. The process of claim 1 wherein said mercaptoalkyl-functionalized
polymer is a mercapto-(C.sub.2-C.sub.4 alkyl)-functionalized silica
gel or a mercapto-(C.sub.1-C.sub.5 alkyl)-functionalized polyalkyl
fiber.
5. The process of claim 1 wherein said mercaptoalkyl-functionalized
polymer is a mercaptopropyl-functionalized silica gel.
6. The process of claim 1 wherein said
1,3-di-(1-pyridino)-2-oxapropane is a substituted
1,3-di-(1-pyridino)-2-oxapropane.
7. The process of claim 1 wherein said
1,3-di-(1-pyridino)-2-oxapropane is an asymmetrically substituted
1,3-di-(1-pyridino)-2-oxapropane.
8. The process of claim 1 wherein said
1,3-di-(1-pyridino)-2-oxapropane is substituted with at least one
substituent on a pyridino group, and at least one of said
substituents is 1-hydroxyiminomethyl.
9. The process of claim 1 wherein said
1,3-di-(1-pyridino)-2-oxapropane is of the formula ##STR00014##
wherein R.sup.1 is --CH.dbd.NOH, R.sup.2 is a member selected from
the group consisting of H, lower alkyl, --C(O)--O-(lower alkyl),
--C(O)--NH.sub.2, and --CH.dbd.NOH, and R.sup.3 and R.sup.4 are
members independently selected from the group consisting of H,
lower alkyl, --C(O)--O-(lower alkyl), --C(O)--NH.sub.2, and
--CH.dbd.NOH.
10. The process of claim 9 wherein said metallic methanesulfonate
is silver methanesulfonate and R.sup.1 is --CH.dbd.NOH, R.sup.2 is
H, R.sup.3 is --C(O)--NH.sub.2, and R.sup.4 is H.
11. The process of claim 9 wherein said metallic methanesulfonate
is silver methanesulfonate and R.sup.1 is 2-CH.dbd.NOH, R.sup.2 is
H, R.sup.3 is 4-C(O)--NH.sub.2, and R.sup.4 is H.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a division of, and claims benefit from,
U.S. patent application Ser. No. 11/133,740, filed May 19, 2005,
which is a continuation-in-part of, and claims benefit from, U.S.
patent application Ser. No. 11/061,064, filed Feb. 17, 2005, now
abandoned. The contents of the aforesaid patent applications are
hereby incorporated herein by reference for all purposes capable of
being served thereby.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention resides in the field of process chemistry for
the N-alkylation of pyridinealdoximes. In particular, this
invention addresses processes for the preparation of intermediates
for the synthesis of asymmetrical dipyridinomethyl ethers.
[0004] 2. Description of the Prior Art
[0005] The bis-quaternary salts of certain dipyridinomethyl ethers
are known to be effective antidotes for toxic agents that are known
in the military as nerve gases as well as for certain insecticides.
These antidotes are thus useful to the military, the agricultural
industry, and the home gardener, and in general any location or
application where there is a risk of exposure to the toxic
agents.
[0006] The most potent of the antidotes in this class are those
with asymmetrical structures, i.e., those in which one or more
substituents are present on one of the two pyridine rings and not
the other, or the substituent(s) on one of the two pyridine rings
differ in either structure or position from those on the other.
Unfortunately, antidotes with asymmetrical structures are difficult
to manufacture, with known synthesis routes tending to produce low
yields and high levels of undesired co-products. An illustration of
the difficulty is found in U.S. Pat. No. 5,130,438 (Hsiao, L. Y.
Y., et al., Jul. 14, 1992, entitled "Bis-Methylene Ether Pyridinium
Compound Preparation"). The product mixtures in this patent include
the desired asymmetrical ether together with symmetrical ethers and
quaternary salts of the pyridinium compounds that are used as
starting materials. One of the most potent compounds disclosed in
the patent is
1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropa-
ne (commonly known as "HI-6"), shown as both the dichloride and
dimethanesulfonate salts. This compound is only one of four
reaction products in the product mixture, however, and recovery of
the desired compound requires a lengthy isolation procedure
involving multiple recrystallizations and resulting in a low yield.
Other disclosures of potential relevance to this invention are U.S.
Pat. No. 3,773,775 (Hagedom, I., Nov. 20, 1973, entitled
"Bis-Quaternary Pyridinium Salts") and U.S. Pat. No. 3,852,294
(Hagedom, I., Dec. 3, 1974, entitled "Bis-Quaternary Pyridinium
Salts"). All patents and other literature cited in this
specification is hereby incorporated herein by reference.
SUMMARY OF THE INVENTION
[0007] It has now been discovered that the yield of salts of
asymmetrical
1-(hydroxy-iminomethyl-1-pyridino)-3-(substituted-1-pyridino)-2-oxapropan-
es, which as a class are antidotes of the toxic agents discussed
above, as well as the purity of these compounds, can be increased
by modifying the manufacturing process to form a salt of a
1-(hydroxy-iminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane as
an intermediate by adding a pyridinealdoxime to a
bis-halomethylether in such a manner that the bis-halomethylether
is maintained in excess throughout at least most of, and preferably
all, of the addition. This procedure is distinct from that of the
prior art, particularly the disclosures of Hagedom cited above, in
which a reverse addition procedure is used, i.e., the
bis-halomethylether is added to the pyridinealdoxime, and this
invention achieves a significant and surprising improvement in both
product yield and product purity. This invention thus resides in a
process for the preparation of salts of asymmetrical
1,3-di-(1-pyridino)-2-oxapropanes, as well as a process for the
preparation of the intermediates. Further objects, advantages, and
aspects of this invention will be apparent from the descriptions
that follow.
[0008] It has also been discovered that dimethanesulfonate salts of
1,3-di-(1-pyridino)-2-oxapropanes can be purified to a particularly
high degree from a product mixture containing metallic
methanesulfonate salts by contacting a liquid solution of said
product mixture with an insoluble mercaptoalkyl-functionalized
polymer. The resulting purity is unexpectedly greater than the
purity achieved by the use of other purifying media.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
[0009] The antidotes that are the end product of the processes of
this invention are represented by the formula
##STR00001##
[0010] In this formula, the symbol R.sup.1 represents --CH.dbd.NOH,
and the symbols R.sup.2, R.sup.3, and R.sup.4 independently
represent either H, lower alkyl, --C(O)--O-(lower alkyl),
--C(O)--NH.sub.2, or --CH.dbd.NOH, provided that the selection of
the substituents, their arrangement on the pyridine rings, or both,
result in an asymmetric structure. The term "asymmetric" in this
specification and the appended claims denotes that the substituents
are such that the two pyridino rings differ from each other, either
because one is substituted and the other is not, or because a
substituent appears on one that does not appear on the other, or
the ring vertices to which the various substituents are bonded
differ between the two rings, or a combination of these
differences. The term "independently selected" is used herein to
denote that R.sup.2, R.sup.3, and R.sup.4 can be all the same, all
different, or two the same and the third different. The alkyl
groups are either linear or branched, and preferred lower alkyls
are C.sub.1-C.sub.3 alkyl, preferably linear, and most preferably
CH.sub.3. Preferred among the R.sup.1 groups are --C(O)--O-(lower
alkyl), --C(O)--NH.sub.2, and --CH.dbd.NOH other than 2-CH.dbd.NOH.
Also preferred are lower alkyl, --C(O)--O-(lower alkyl),
--C(O)--NH.sub.2 in the 4-position (i.e., the para-position) on the
pyridine ring. More preferred are --C(O)--O-(lower alkyl) and
--C(O)--NH.sub.2, and the most preferred is --C(O)--NH.sub.2,
particularly 4-C(O)--NH.sub.2.
[0011] The symbol X represents any atom or group capable of forming
a pharmaceutically acceptable anion. Preferred examples are
halides, hydrocarbyl sulfonates, and halohydrocarbyl sulfonates, of
the generic formula R.sup.5SO.sub.3--. Of the halides, Br and Cl
are preferred, and Cl is the most preferred. Of the sulfonates,
aliphatic and aromatic sulfonates are included, with preferred
sulfonates being those in which R.sup.5 is C.sub.1-C.sub.4 alkyl,
halo(C.sub.1-C.sub.4 alkyl), cyclohexyl, or phenyl, and the most
preferred is that in which R.sup.5 is methyl or halomethyl. The
sulfonate in which R.sup.5 is methyl is referred to herein as
methanesulfonate.
[0012] The intermediate of interest in this invention is a
1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane,
halide salt, whose formula is
##STR00002##
wherein X is a halogen atom. Conversion of this intermediate to the
antidote of Formula (I) will result in a product in which the anion
X is the same halogen atom. This anion can be exchanged for other
anions, including dimethanesulfonate and the other pharmaceutically
acceptable anions, by ion exchange, as will be demonstrated
below.
[0013] Addition of the pyridinealdoxime to bis-halomethylether is
achieved such that the unreacted bis-halomethylether remains in
stoichiometric excess for most, if not all, of the addition. This
is preferably achieved by adding the pyridinealdoxime to a body of
the bis-halomethylether at a slow rate with continuous agitation.
Dropwise addition is one means of accomplishing this result. The
excess of unreacted bis-halomethylether is preferably maintained
for at least until 75% of the pyridinealdoxime has been added, more
preferably until at least 90% has been added, and most preferably
throughout the entire addition.
[0014] The bis-halomethylethers are known compounds, commercially
available and disclosed for example in the Hsiao et al. and Hagedom
patents cited above, as well as U.S. Pat. No. 3,137,702
(Luttringhaus, A., et al., Jun. 6, 1964, entitled "Preparation of
Bis-Quaternary Pyridinium Salts"). Bis-chloromethylether for
example can be prepared by reaction of paraformaldehyde with
hydrochloric acid and chlorosulfonic acid.
[0015] The bis-halomethylether is in the liquid phase during the
addition of the pyridinealdoxime, and this can be achieved by using
the ether in neat form since it is a liquid at ambient temperature
and any elevated temperatures at which the reaction might be
performed, or the ether can be dissolved in a solvent. If a solvent
is used, any conventional solvent that is inert to the reaction
will suffice. Examples are tetrahalomethanes, dimethylformamide,
trihalomethanes, dihalomethanes, N,N-dimethylacetamide,
1-methyl-2-pyrrolidone, acetonitrile, dioxane, tetrahydrofuran, and
2-methyltetrahydrofuran. Conversion of the intermediate (II) to the
product asymmetrical 1,3-di-(1-pyridino)-2-oxapropane (I) is
achieved by reacting the intermediate with a substituted pyridine
of the formula
##STR00003##
in which R.sup.3 and R.sup.4 are as defined above. This reaction is
likewise performed in a liquid reaction medium, and a solvent can
be used if desired. The solvents listed above are examples of
solvents that can be used in this reaction as well.
[0016] Of the compounds employed in the processes of these
invention and expressed generically above, certain subgenera are
preferred. One preferred subgenus of pyridinealdoximes, for example
is that represented by the formula
##STR00004##
[0017] Another preferred subgenus is that represented by the
formula
##STR00005##
[0018] A particularly preferred pyridinealdoxime is
2-pyridinealdoxime, whose formula is
##STR00006##
[0019] Regarding the substituted pyridines of Formula (III), one
preferred subgenus is that represented by the formula
##STR00007##
[0020] Another is that represented by the formula
##STR00008##
[0021] A third is that represented by the formula
##STR00009##
[0022] A particularly preferred substituted pyridine is
4-carbamoylpyridine of the formula
##STR00010##
[0023] Both reactions can be conducted in batch-wise or continuous
manner, provided that the reaction to form the intermediate (II) is
performed with a continuous excess of the bis-halomethyl ether for
most, if not all, of the duration of the reaction. The reaction to
form the intermediate (II) is preferably accompanied by agitation,
and can be performed at ambient temperature but is preferably
performed at an elevated temperature of from about 30.degree. C. to
about 100.degree. C., or most preferably from about 35.degree. C.
to about 60.degree. C. The reaction between the intermediate (II)
and the substituted pyridine (III) can likewise be performed at
ambient temperature but is preferably performed at an elevated
temperature within the same ranges. Both reactions can be performed
at atmospheric pressure or slightly above or below. Both reactions
can be performed in air or in an inert atmosphere such as nitrogen
or argon.
[0024] Reaction products at either stage can be isolated by
conventional means. Liquid products can thus be recovered by
conventional phase separation, including decantation and
centrifugation, and solid products can be recovered by filtration
or centrifugation. Conversion of the chloride salts to salts of
other anions, including methanesulfonate (which is also referred to
as "mesylate"), can be achieved by ion exchange. The ion exchange
may be performed with metallic salts such as silver
methanesulfonate, sodium methanesulfonate, and calcium
methanesulfonate, or common ion exchange resins, all of which are
commercially available.
[0025] As noted above, one of the products that can be synthesized
by the methods of this invention is
1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropa-
ne (commonly known as "HI-6") methanesulfonate salt, a highly
effective anti-nerve agent. The synthesis of this product is most
successful when the metallic salt used is silver methansulfonate.
It is also preferable, for reasons of both solubility and toxicity,
that any heavy metallic ions, such as Ag.sup.+ ions, be in a low
concentration when such ions are present in the reaction
system.
[0026] As also noted above, functionalized polymers, and notably
mercaptoalkyl-functionalized polymers, have been found to be a
particularly effective class of metal scavenging media for the
isolation of dimethanesulfonate salts of
1,3-di-(1-pyridino)-2-oxapropanes from metallic methanesulfonate
salts. This quality makes these polymers particularly useful in
product purification procedures following the conversion of
dihalide salts of the 1,3-di-(1-pyridino)-2-oxapropanes to
dimethylsulfonate form. Examples of these polymers are silica gels,
polyolefins, polystyrene, polyvinyl alcohol, polyepichlorohydrin,
polyoxetane, and crosslinked polyalkyl fiber, all functionalized
with mercaptoalkyl groups. Preferred among the mercaptoalkyl
functional groups are mercapto-(C.sub.1-C.sub.5 alkyl) groups, more
preferred are mercapto-(C.sub.2-C.sub.4 alkyl) groups, and the most
preferred is mercaptopropyl. The metal ions that these polymers are
effective in removing include Ag.sup.+, Hg.sup.++, Pd.sup.+, and
Pt.sup.4+ ions. For the purposes of the present invention, the
polymers are of particular interest in removing Ag.sup.+ ions.
Mercaptopropyl-functionalized silica gel is one example. Other
silica gels that are efficient Ag.sup.+ ion scavengers and can be
used herein are silica gels bonded with triaminetetraacetic acid
groups (SiliaBond TAAcOH) and propylthiourea groups (SiliaBond
Thiourea), both of which are commercially available from Silicycle,
Inc., Quebec, Canada. Examples of functionalized polyalkyl fibers
that are known to be effective in removing Ag.sup.+ ion are
polyalkyl fibers functionalized with benzylthio groups
(SMOPEX.RTM.-111x), isothionium groups (SMOPEX.RTM.-112x) and
mercaptoethyl acrylate groups (SMOPEX.RTM.-234x), all of which are
commercially available from Johnson Matthey plc., United Kingdom.
The metal scavenging can be performed either by stirring the
scavenger medium in the reaction mixture or by pumping the reaction
mixture through one or several columns packed with the scavenger
medium, with the columns connected either in series or in parallel.
The metal scavenging can be performed in a continuous manner using
a scavenging unit similar to a continuous catalytic reactor. Metal
scavenging can be performed at any temperature within the range of
0.degree. C. to 150.degree. C., using conventional heating or
microwave heating. Metal scavenging can also be enhanced in certain
cases by the use of ultrasound.
[0027] The dimethanesulfonate salts of
1,3-di-(1-pyridino)-2-oxapropanes that are purified in this manner
include salts of both substituted and unsubstituted
1,3-di-(1-pyridino)-2-oxapropanes, symmetrical and asymmetrical,
and the preferred 1,3-di-(1-pyridino)-2-oxapropanes are those
listed above as preferred embodiments for the synthesis reactions
described herein.
[0028] The following examples are offered for purposes of
illustration only.
EXAMPLE 1
Comparative Study
Preparation of
1-(2-Hydroxyiminomethyl-1-Pyridino)-3-(Chloromethyl)-2-Oxapropane,
Chloride Salt, by Process of This Invention vs. Process of the
Prior Art
[0029] This example compares the yield and purity of
1-(2-hydroxyiminomethyl-1-pyridino)-3-(chloromethyl)-2-oxapropane,
chloride salt as obtained by the process of the present invention
with the yield and purity as obtained by the reverse order of
reactant addition as disclosed in Hagedom, I., et al., U.S. Pat.
No. 3,773,775, Example 10. The structure of
1-(2-hydroxyiminomethyl-1-pyridino)-3-(chloromethyl)-2-oxapropane,
chloride salt is as follows:
##STR00011##
[0030] For both procedures, bis-chloromethylether was prepared by
first cooling a mixture of paraformaldehyde (21.1 g, 0.7 mole) and
37% hydrochloric acid (16.7 g) to 10.degree. C., then slowly adding
chlorosulfonic acid (55.1 g, 0.6 mole) and stirring overnight. The
phases were then separated to obtain bis-chloromethylether as the
neat liquid. The procedure used for this paragraph is described in
Buc, S. R., Organic Syntheses, Collective Volume IV: pp. 101-103,
1963.
[0031] Following the process of the invention, pyridine-2-aldoxime
(27.7 g, 0.23 mole) dissolved in chloroform (119.4 g) was then
added to the bis-chloromethylether in dropwise manner over a period
of 60 minutes (by adding one drop of pyridine-2-aldoxime
approximately every second) at 45.degree. C. with continuous
stirring. Once the addition was completed, stirring was continued
for three hours at the same temperature. The reaction mixture was
then cooled to 18.degree. C., and the product was filtered, washed
with chloroform (66 g), and vacuum dried at 40.degree. C. The
product was identified by proton NMR as
1-(2-hydroxyiminomethyl-1-pyridino)-3-(chloromethyl)-2-oxapropane,
chloride salt, plus the bis-impurity
1,3-di-(2-hydroxyiminomethyl-1-pyridino)-2-oxapropane. .sup.1H-NMR
(300 MHz, D.sub.2O): mono-product: .delta. (6.18 (s, 2H,
--CH.sub.2O), and 6.28 (2H)), bis-impurity: 6.48 (s, 4H,
--CH.sub.2OCH.sub.2--). The yield was 78.7%, and from the NMR
analysis, the product purity was 97.3%, with the bis-impurity as
the remainder.
[0032] Following the process of Hagedom et al., the
bis-chloromethylether (28.7 g, 0.250 mole) prepared as described
above was added to pyridine-2-aldoxime (28.3 g, 0.227 mole) in
dropwise manner over a period of 30 minutes (by adding one drop of
bis-chloromethylether approximately every 0.5 second) at 45.degree.
C. with continuous stirring. Once the addition was complete,
stirring was continued for three hours at the same temperature. The
reaction mixture was then cooled to 18.degree. C., and the product
was filtered, washed with chloroform (66 g), and vacuum dried at
40.degree. C. The product was again identified by proton NMR as
1-(2-hydroxyiminomethyl-1-pyridino)-3-(chloromethyl)-2-oxapropane,
chloride salt, with
1,3-di-(2-hydroxyiminomethyl-1-pyridino)-2-oxapropane as an
impurity (referred to herein as the "bis-impurity"). The yield was
56.4%, and from the NMR analysis, the product purity was 52.6%,
with the bis-impurity as the remainder.
[0033] The addition of the pyridine-2-aldoxime to the
bis-chloromethylether in accordance with the process of the
invention thus resulted in a product of both significantly higher
yield and purity as compared to the prior art process in which the
bis-chloromethylether was added to the pyridine-2-aldoxime.
EXAMPLE 2
Illustrating This Invention
Conversion of
1-(2-Hydroxyiminomethyl-1-Pyridino)-3-(Chloromethyl)-2-Oxapropane,
Chloride Salt, to
1-(2-Hydroxyiminomethyl-1-Pyridino)-3-(4-Carbamoyl-1-Pyridino)-2-Oxapropa-
ne, Dichloride Salt
[0034] This example illustrates the conversion of
1-(2-hydroxyiminomethyl-1-pyridino)-3-(chloromethyl)-2-oxapropane,
chloride salt, to
1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropa-
ne, dichloride salt. The structure of the latter is as follows:
##STR00012##
[0035] A 1-liter jacketed flask fitted with a mechanical stirrer, a
temperature probe, a reflux condenser, and a positive nitrogen
atmosphere was charged with
1-(2-hydroxyiminomethyl-1-pyridino)-3-(chloromethyl)-2-oxapropane,
chloride salt (29.3 g, 0.124 mole) (as prepared by the procedure
set forth in Example 1 in accordance with the invention),
isonicotinamide (57.6 g, 0.472 mole) and N,N-dimethylformamide (600
mL). The slurry was heated to 35-40.degree. C. and maintained at
that temperature for 20 hours, then chilled to 0-5.degree. C. The
solids were then isolated by filtration, to yield a cake that was
off-white in color. The cake was then washed with three 50-mL
portions of isopropyl alcohol and dried in a vacuum oven at
40-50.degree. C. to yield 45 g, representing a 95.7% yield, of a
beige solid identified by proton NMR as
1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropa-
ne, dichloride salt. .sup.1H-NMR (300 MHz, D.sub.2O), 6, 6.14 (s,
2H, --CH.sub.2OCH.sub.2), 6.27 (s, 2H, --CH.sub.2OCH.sub.2), 7.97
(m, 1H), 8.33 (m, 3H), 8.36-8.53 (m, 2H), 8.9 (d, 1H), 9.05 (d, 2H)
(aromatic protons and --CH.dbd.NOH).
EXAMPLE 3
Illustrating This Invention
Conversion of
1-(2-Hydroxyiminomethyl-1-Pyridino)-3-(4-Carbamoyl-1-Pyridino)-2-Oxapropa-
ne, Dichloride Salt, to Dimethanesulfonate Salt
[0036] This example illustrates the conversion of the dichloride
salt produced by the procedure of Example 2 to the corresponding
dimethanesulfonate salt, by ion exchange with alternative metallic
salts of methanesulfonate. The structure of the dimethanesulfonate
salt is as follows:
##STR00013##
[0037] From silver methanesulfonate: A 250-mL jacketed flask fitted
with a mechanical stirrer, a temperature probe, a reflux condenser,
and a positive nitrogen atmosphere was charged with
1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropa-
ne, dichloride salt, as prepared in Example 2, (7.18 g, 0.020
mole), silver methanesulfonate (8.2 g, 0.040 mole), and a mixture
of 90% methanol and 10% water (by weight) (160 g). The resulting
slurry was heated to 50-60.degree. C. and maintained at that
temperature for 22 hours. A sample was then taken for reaction
completion analysis by proton NMR), and the reaction mixture was
chilled to 15-20.degree. C. for work-up. The insolubles were
filtered off and washed with two 20-mL portions of methanol. The
combined filtrates were distilled under reduced pressure to a thick
slurry (16.0 g) which was quenched with 180 mL denatured ethanol.
The slurry was then further distilled under vacuum and then chilled
to 0-5.degree. C. The product was then isolated by filtration to
yield a light purple solid, which was then washed with two 10-mL
portions of denatured ethanol and dried to give 9.4 g of the crude
dimethanesulfonate salt. The salt was then dissolved in 50 mL
water, and the insolubles were filtered off and washed with 20 mL
water. The combined filtrates were distilled under reduced pressure
and solvent exchanged to ethanol. After water was removed, a slurry
of tan color was formed and then chilled to 0-5.degree. C. The
solid was isolated by filtration, then washed with two 10-mL
portions of denatured ethanol and dried to give 8.24 g (86.1%
yield) of the dimethanesulfonate as a tan-colored solid.
[0038] From sodium methanesulfonate: The procedure of the preceding
paragraph was repeated except that 2.7 g (7.52 mmoles) of the
dichloride salt were used, sodium methanesulfonate (1.80 g, 15.24
mmoles) was used in place of the silver methanesulfonate, and 75 mL
of methanol was used in place of the methanol-water mixture. The
mixture was heated to reflux (65.degree. C.) for 17 hours, and the
product isolated and purified to yield 1.95 g (54.2% yield) as an
off-white solid.
[0039] Via ion exchange resin: The ion exchange resin,
AMBERLYST.RTM. (Dow Chemical Co., Midland, Mich., USA) A-26 (OH
form) (6.0 g) was placed in a 125-mL Erlenmeyer flask and treated
with 35 mL 1M methanesulfonic acid aqueous solution. The mixture
was poured into a glass column 3/4-inch in diameter. The solution
was drained and the resin was rinsed with deionized water until the
pH was 4.15. The dichloride salt of
1-(2-hydroxy-iminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxaprop-
ane (1.0 g, 2.78 mmoles) was dissolved in water 6.5 g and the
solution was passed through the resin bed at least five times. The
resin bed was then eluted with 30 mL 0.5 mM methanesulfonic acid
aqueous solution. After elution, the combined eluate was
decolorized with 0.35 g activated charcoal, filtered through a bed
of CELITE.RTM. (diatomaceous earth, product of Celite Corporation,
Lompoc, Calif., USA), and distilled with ethanol under reduced
pressure to remove water. The resulting residues were triturated
with ethanol to give a light yellow slurry. After isolation, the
cake was washed with 2.times.10 mL ethanol, and dried in vacuum
oven to give HI-6 dimesylate 0.79 g (59.3% yield) as a light yellow
solid.
EXAMPLE 4
Purification of
1-(2-Hydroxyiminomethyl-1-Pyridino)-3-(4-Carbamoyl-1-Pyridino)-2-Oxapropa-
ne, Dimethanesulfonate Salt with Charcoal
[0040] The product of Example 3 (prepared by silver
methanesulfonate) (8.23 g) was suspended in 60 mL of water in a
125-mL Erlenmeyer flask, where it was agitated with a mechanical
stirrer. Insolubles were present, and charcoal (0.28 g) was added
while stirring continued for 5 minutes. The resulting slurry was
then filtered through a CELITE bed which was subsequently washed
with two 10-mL portions of water. The filtrate was clear yellow in
color and was distilled under reduced pressure. The solvent was
then replaced with ethanol, and the resulting white slurry was
chilled to 0-5.degree. C. The solid product was isolated by
filtration to yield an off-white solid, which was then washed with
two 10-mL portions of denatured ethanol and dried in a vacuum oven
at 40-50.degree. C. to yield 7.74 g of pure
1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropa-
ne, dimethanesulfonate salt, representing a 94.0% recovery.
.sup.1H-NMR (300 MHz, D.sub.2O): .delta. 2.82 (s, 6H,
CH.sub.3SO.sub.3), 6.31 (s, 2H, --CH.sub.2O), 6.43 (s, 2H,
--CH.sub.7O), 8.11 (m, 1H), 8.50 (m, 3H), 8.68 (m, 2H), 9.03, 9.05
(d, 1H), 9.22, 9.24 (d, 2H) (aromatic protons and --CH.dbd.N--OH);
.sup.13C NMR (D.sub.2O): .delta. 38.6, 85.8, 87.1, 126.9, 127.8,
128.1, 142.1, 144.7, 145.4, 147.2, 148.4, 151.0, 166.5; DSC
(10.degree. C./min): 163.degree. C. (dec.).
EXAMPLE 5
Purification of
1-(2-Hydroxyiminomethyl-1-Pyridino)-3-(4-Carbamoyl-1-Pyridino)-2-Oxapropa-
ne, Dimethanesulfonate Salt with Mercaptopropyl-Functionalized
Silica Gel
[0041] In a parallel procedure to that of Example 4, 1.0 g of the
product of Example 3, which was prepared by silver methanesulfonate
and found to contain 1.0% residues (as silver ion) was dissolved in
9.6 mL of water in a 50-mL flask, where it was agitated with a
mechanical stirrer. To the solution was added 1.0 g of
3-mercaptopropyl-functionalized silica gel (SiliCycle Inc., Quebec
City, Quebec, Canada, and Sigma-Aldrich Corporation, St. Louis,
Mo., USA). The resulting mixture was heated to 50-55.degree. C. for
three hours and filtered. After filtration, the silica gel was
washed with 10 mL water. The aqueous filtrate was concentrated
under reduced pressure to give a colorless oil which was then
triturated with 20 mL ethanol to give a white slurry. The slurry
was filtered to leave a white cake, which was washed with 10 mL of
ethanol and dried to give 0.89 g (89% yield) of pure
1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropa-
ne, dimethanesulfonate salt, as a white solid. Thermogravimetric
analysis (TGA) at 900.degree. C. revealed that the solid contained
less than 0.06% silver residues.
[0042] The foregoing is presented for purposes of illustration.
Further variations and modifications that similarly employ or
embody the features and concepts that define this invention will be
readily apparent to those skilled in the art.
* * * * *