U.S. patent number RE48,510 [Application Number 15/938,151] was granted by the patent office on 2021-04-13 for phosphorus functional antimicrobial coatings for metal surfaces.
This patent grant is currently assigned to Nano Safe Coatings Incorporated. The grantee listed for this patent is NANO SAFE COATINGS INCORPORATED. Invention is credited to Daniel Foucher, Lukasz Porosa, Gideon Wolfaardt.
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United States Patent |
RE48,510 |
Porosa , et al. |
April 13, 2021 |
Phosphorus functional antimicrobial coatings for metal surfaces
Abstract
The invention relates to quaternary ammonium multi-dentate
mono-, bis-, tris- and tetrakis-phosphonate compounds, processes
for preparing quaternary ammonium multi-dentate mono-, bis-, tris-
and tetrakis-phosphonate compounds, antimicrobial coating
compositions comprising quaternary ammonium multi-dentate mono-,
bis-, tris- and tetrakis-phosphonate compounds and method of
treating a surface with said compositions to provide a durable,
antimicrobial-treated surface.
Inventors: |
Porosa; Lukasz (Scarborough,
CA), Wolfaardt; Gideon (Mississauga, CA),
Foucher; Daniel (Toronto, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
NANO SAFE COATINGS INCORPORATED |
Jupiter |
FL |
US |
|
|
Assignee: |
Nano Safe Coatings Incorporated
(Jupiter, FL)
|
Family
ID: |
51390427 |
Appl.
No.: |
15/938,151 |
Filed: |
March 28, 2018 |
PCT
Filed: |
February 12, 2014 |
PCT No.: |
PCT/CA2014/000104 |
371(c)(1),(2),(4) Date: |
August 11, 2015 |
PCT
Pub. No.: |
WO2014/127451 |
PCT
Pub. Date: |
August 28, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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61766533 |
Feb 19, 2013 |
|
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Reissue of: |
14767052 |
Feb 12, 2014 |
9642369 |
May 9, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A01N
57/12 (20130101); C07F 9/3817 (20130101); C07F
9/3873 (20130101); A01N 57/20 (20130101); C07F
9/4006 (20130101); C07F 9/5728 (20130101); C07F
9/4009 (20130101); C09D 5/14 (20130101); C09D
5/1625 (20130101); B05D 3/0272 (20130101); C07F
9/6552 (20130101); C07F 9/3808 (20130101); A01N
57/20 (20130101); A01N 33/12 (20130101) |
Current International
Class: |
A01N
57/20 (20060101); B05D 3/02 (20060101); C07F
9/38 (20060101); A01N 57/12 (20060101); C07F
9/40 (20060101); C07F 9/572 (20060101); C07F
9/655 (20060101); C09D 5/14 (20060101); C09D
5/16 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2318733 |
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Jul 1999 |
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CA |
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2318733 |
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Jul 1999 |
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CA |
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2636052 |
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Jul 2008 |
|
CA |
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2858596 |
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Jun 2013 |
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CA |
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0279475 |
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Aug 1988 |
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EP |
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2282209 |
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Sep 2011 |
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EP |
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0125171 |
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Apr 2001 |
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WO |
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2012/160187 |
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Nov 2012 |
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WO |
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2014127451 |
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Aug 2014 |
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WO |
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Other References
Porosa, Lukasz M., et al., "Synthesis, structures and properties of
self-assembling quatemary ammonium dansyl fluorescent tags for
porous and non-porous surfaces", J. Mater. Chem. B, 2014, 2,
1509-1520. cited by applicant .
Portet, David, et al., "Comparative Biodistribution of Thin-Coated
Iron Oxide Nanoparticles TCION: Effect of Different Bisphosphonate
Coatings", Drug Development Research 54: 173-181 (2001). cited by
applicant .
Brodersen, Nicolai, et al., "Synthesis of novel amphipilic
conjugates with a biological recognition function for developing
targeted triggered liposomal delivery systems", Tetrahedron 67
(2011) 7763-7774. cited by applicant .
Takashi, Jin, "A New Fluorometric Method for the Deection of the
Neurotransmitter Acetylcholine in Water Using Dansylcholine Complex
with p-Sulfonated Calix[8]arene", Journal of inclusion Phenomena
and Macrocyclic Chemistry 45: 196-201, 2003. cited by applicant
.
Karimi, Ali, et al., "Effect of chain length and electrical charge
on properties of ammonium-bearing bisphosphonate-coated
superparamagnetic iron oxide nanoparticles formulation and
physicochemical studies", J. Nanopart Res (2010) 12:1239-1248.
cited by applicant .
Huang, Xiao-Jun, et al., "Surface Modification of
Polyacrylonitrile-Based Membranes by Chemical Reactions to Generate
Phospholipid Moieties", Langmuir 2005, 21, 2941-2947. cited by
applicant .
Queffelec, Clemence, et al., "Surface Modification Using Phosphonic
Acids and Esters", Chem. Rev. 2012, 112, 3777-3807. cited by
applicant .
Page, Kristopher, et al., "Antimicrobial surfaces and their
potential in reducing the role of the inanimate environment in the
incidence of hospital-acquired infections", J. Mater. Chem., 2009,
19, 3819-3831. cited by applicant .
Kugel, Alex, et al., "Antimicrobial coatings produced by
"tethering" biocides to the coating matrix, A comprehensive
review", Progress in Organic Coatings 72 (2011) 222-252. cited by
applicant .
Boczula, Dorota, et al., "Structural and vibrational
characteristics of amphiphillic phosphonate salts", Journal of
Molecular Structure 1007 (2012) 220-226. cited by applicant .
Banerjee, Indrani, et al., "Antifiouling Coatings: Recent
Developments in the Design of Surfaces that Prevent Fouling by
Proteins, Bacteria, and Marine Organisms", Adv. Mater 2011, 23,
690-718. cited by applicant .
International Search Report for PCT/CA2014/000104 dated Jun. 12,
2014. cited by applicant .
International Search Report for PCT/CA2014/050796 dated Dec. 23,
2014. cited by applicant .
BR112016018532 English language published May 8, 2018, Abstract of
corresponding document WO2014127451(a1). cited by applicant .
Porosa, LM. et al. "Rapid Microwave-Assisted Synthesis of
.gamma.-Phosphonic Acid Quaternary Ammonium Antimicrobials for
Biomedical Applications", Current Microwave Chemistry, vol. 2, No.
1, 2015, pp. 69-82(14). cited by applicant.
|
Primary Examiner: Johnson; Jerry D
Attorney, Agent or Firm: Caesar Rivise, PC
Claims
We claim:
1. A process for preparing a quaternary ammonium mono-phosphonate
.Iadd.acid free .Iaddend.compound of formula (I) ##STR00135##
wherein R.sub.1 and R.sub.2 are independently methyl, ethyl,
isopropyl or n-propyl; m is 15, 16, 17, 18 or 19; n is 0, 1, 2, 3,
4, 5 or 6; and X is chloro, bromo or iodo, comprising the steps of
(a) reacting a compound of formula (II) ##STR00136## wherein R is
independently methyl, ethyl, isopropyl, n-butyl or phenyl, with a
compound of formula (III) ##STR00137## wherein X and n are as above
and Y is a halogen selected from chloro or bromo to give a compound
of formula (IV) ##STR00138## (b) reacting the compound of formula
(IV) with a compound of formula (V) ##STR00139## wherein R.sub.1
and R.sub.2 are independently methyl, ethyl, isopropyl or n-propyl,
and m is 15, 16, 17, 18 or 19, to give a compound of formula (VI)
##STR00140## and (c) reacting a compound of formula (VI) with
SiR.sub.3R.sub.4R.sub.5Z wherein R.sub.3, R.sub.4 and R.sub.5 are
independently methyl or ethyl and Z is chloro, bromo, iodo or
triflate .Iadd.in the presence of dichloromethane (DCM) between 8
to 12 hours at room temperature.Iaddend., or a mineral acid
selected from HCl, HBr or HI to give a compound of formula
(I).Iadd., wherein the compound of formula (I) is isolated in pure
form without chromatographic purification.Iaddend..
2. The process of claim 1 wherein R.sub.1 and R.sub.2 are
methyl.
3. The process of claim 1 wherein R is ethyl.
4. The process of claim 1 wherein n is 1 or 2.
5. The process of claim 1 wherein m is 17.
6. The process of claim 1 wherein R.sub.3, R.sub.4 and R.sub.5 are
the same and methyl.
7. The process of claim 1 wherein Z is chloro or triflate.
8. The process of claim 1 wherein X is bromo.
.[.9. A compound of formula ##STR00141## .].
.Iadd.10. The process of claim 1 further wherein the compound of
formula (I) is purified by recrystallization..Iaddend.
.Iadd.11. The process of claim 1 wherein the compound of formula
(I) is N,N-dimethyl-N-(3-phosphonopropyl) octadecan-1-ammonium
bromide..Iaddend.
.Iadd.12. The process of claim 11 wherein the compound of formula
(I) has the following characterization: Mp=118-120.degree. C.;
.sup.1H NMR (400 MHz, MeOD, .delta.): 3.38-3.33 (m, 2H, H8),
3.28-3.23 (m, 2H, H7), 3.02 (s, 6H, H6), 2.02-1.90 (m, 2H, H5),
1.75-1.65 (m, 4H, H4, H3), 1.20 (brs, 30H, H3), 0.82 (t, J=6.9 Hz,
3H, H1), ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz, .delta.): 64.26
(C7) 63.57 (C8), 49.94 (C6), 31.68 (C2 overlap), 29.41-28.86 (C2
overlap), 26.03 (C2 overlap), 22.45-22.17 (C3, C4), 16.47 (d,
.sup.1J.sub.C-P=4.07 Hz, C5), 13.08 (C1) ppm; .sup.31P NMR (121.45
MHz, CDCl.sub.3, .delta.): 26.92 ppm; HRMS-DART (m/z): [M.sup.+]
+calculated for C.sub.23H.sub.51NO.sub.3P, 420.3601; found,
420.3608..Iaddend.
Description
BACKGROUND OF THE INVENTION
Bacterial infections in hospital environments are spread by two
different ways: external contamination or in vivo contamination
from implants. Patients can develop external infections through
contact with surfaces such as door handles, pens, telephones,
health care workers uniforms ("HCWU"), stethoscopes, or sterile
packaging that have been colonized by microorganisms.
Hospital-acquired infections ("HAI") from contact with pathogenic
microorganisms affect approximately 2 million people and result in
more than 100,000 deaths in the U.S.A. each year. Such infections
require 10-20 days of additional patient hospitalization, costing
the already strained U.S. health-care systems approximately
$25,000-30,000 per infection totaling billions of dollars per
year.
The second route for bacteria to infect patients is through
hospital invasive support equipment such as intravascular lines and
implanted medical devices such as artificial prosthetics,
cardiovascular implants and urinary catheters. Implant associated
infections ("IAI") occur in more than one million patients and cost
an estimated $3 billion in the U.S. per year. For example,
approximately 10-50% of patients with implanted catheters run the
risk of developing urinary tract infections ("UTI") resulting in
additional healthcare costs. The rise in the frequency and severity
of HAI's and IAI's can be attributed to decreased antibiotic
efficacy against drug-resistant strains of pathogens found in
surface biofilms.
Biofilm formation involves three phases beginning with the initial
reversible adhesion of bacteria on a surface through
polysaccharides and adhesion proteins on the bacterial membrane
(phase I). Under appropriate conditions, bacteria subsequently
firmly attach to a surface (phase II), followed by the secretion of
a protective polymeric matrix (biofilm, phase III) in which the
bacteria typically show a marked increase in resistance to
antibiotics, compared to none-adherent bacteria. As a result, once
the infection occurs, it becomes difficult to treat. Thus,
strategies that prevent bacterial contamination or destroy adsorbed
microorganisms that lead to biofilm formation are actively
sought.
In order to prevent the formation of biofilm, strategies have been
employed in the past to make surfaces inhospitable to bacteria. For
example, small molecule monolayers or polymer thin films either
"grafted to" or "grown from" a surface have been widely used to
prepare antimicrobial surfaces and clothing. These prior art
monolayers or polymer coatings include, for example, non-biofouling
coatings which are passive strategies that rely on preventing
bacterial adhesion with hydrophobic or zwitterionic thin films, but
do not kill the approaching bacteria. A second class of
antibacterial thin films kills microbes on contact either by
releasing a biocidal agent or immobilizing a biocidal agent. A
third class of antibacterial thin films utilize a combination
strategy of including a non-biofouling and biocidal component into
the coating.
Organophosphorus Antimicrobial Surfaces Based on Monolayers
The first quaternary ammonium phosphonate compounds (phosphonate
quats) were disclosed in the early 1950's in U.S. Pat. No.
2,774,786 and Dutch patent NL 79189 for use as synthetic
detergents. In the patents syntheses, the final product could only
be isolated as a sodium salt of the phosphobetaine after hydrolysis
of the phosphonate ester with HCl followed by treatment with
NaHCO.sub.3. In a similar synthesis Germanaud et al., (Bulletin de
la Societe Chimique de France, 1988, 4, 699-704) published the
isolation of the phosphonate quats as betaines by purification on
an anion exchange resin. The products disclosed in the patents were
not spectrally characterized and were used as is, while Germanaud's
purification was costly and the product wasn't isolated as a
phosphonic acid.
Phosphonate monolayers for the antimicrobial treatment of surfaces
have been shown to be advantageous over self-assembled monolayers
(SAMs) of thiols and silanes in terms of durability, long-term
stability and surface coverage, especially on titanium and
stainless steel. Thiol-based SAM's lack substrate specificity
(mainly reserved for gold surfaces) and long-term stability needed
for biomedical applications, (i.e. implants). Over time, the
thiol-based SAM's become oxidized to sulfonates, which lack
affinity for gold and become displaced from the surface.
In comparison to silane based SAM's on metal oxide surfaces,
phosphonate based SAM's are advantageous because they resist
hydrolysis under physiological conditions and higher surface
coverage can be obtained without harsh acid surface pretreatment
(to increase the OH content). Siloxanes are also known to be
unstable and are easily hydrolyzed under physiological
conditions.
Both active and passive strategies to prevent biofilm formation
have been described with both mono- and bis-phosphonate monolayers.
Examples for active surfaces include contact killing monolayers
employing immobilized quaternary ammonium salts and the antibiotic
daptomycin. Passive strategies have been described employing
hydrophobic perfluorinated bisphosphonates on stainless steel,
silicon, and titanium oxidize surfaces for anticorrosion
applications.
U.S. Pat. No. 4,101,654 teaches phosphonate-pendant nitrogen
heterocyclic compounds that are quaternized by alkyl halides and
their use as corrosion inhibitor compounds.
U.S. Pat. No. 4,420,399 teaches phosphonate-quaternary ammonium
compounds having a methylene group linking the phosphorus and
nitrogen atoms and their use as corrosion inhibitor compounds.
U.S. Pat. No. 4,962,073 teaches porous surfaces treated with
phosphoric acid esters.
U.S. Pat. No. 5,770,586 teaches phosphonate/phosphoric
acid-quaternary ammonium compounds for use as dental care
ingredients and for bone density treatment.
U.S. Pat. No. 5,888,405 teaches methods of inhibiting bacteria from
adhering to submerged surfaces using amino-phosphonic acid
compounds.
U.S. Patent Application Publication No. 2002/0023573 teaches
phosphonate, phosphate and phosphinate compounds linked to mineral
oxide surfaces through the oxygen atoms of the phosphorus
moieties.
U.S. Patent Application Publication No. 2002/0128150 teaches
phosphonate, phosphate and phosphinate sulfur compounds linked to
mineral oxide surfaces through the oxygen atoms of the phosphorus
moieties.
PCT Application Publication WO 2007/080291 teaches
bisphosphonate-amines and quaternary ammonium compounds, their
preparation and attachment to metal and metal-oxide surfaces and
testing for antibacterial activity.
PCT Application Publication WO 2008/017721 teaches
bisphosphonate-amines and quaternary ammonium compounds, their
preparation and attachment to silicon and metal surfaces and cell
proliferation testing.
U.S. Patent Application Publication No. 2008/0220037 teaches
bisphosphonic acid compounds having pendant oxygen, sulfur or at
least two quaternary ammonium functional groups, their preparation
and treatment of mineral and metal surfaces and antibacterial or
biofilm formation testing.
Guerro G et al., Pathologic Biologie, 2009, 57, 36-43 teaches
surfaces modified with materials such as phosphonate quaternary
ammonium compounds and phosphonate silver coatings, and their
bacterial adhesion and inhibition properties.
Queffelec C et al., Chemical Reviews, 2012, 112(7), 3777-3807
teaches phosphonic acids and esters, their synthesis and
modification of surfaces using functionalized phosphonic acids and
esters. The functional groups include heterocycles, amino groups
and larger organic molecules.
Thus, there has been a long-felt need for a durable and
environmentally safe antimicrobial metal or mineral surface
treatment and a process to manufacture the same.
SUMMARY OF THE INVENTION
According to one aspect of the invention there is provided a
quaternary ammonium mono-phosphonate compound of formula (I) and a
process for preparing a compound of formula (I)
##STR00001## wherein R.sub.1 and R.sub.2 are independently lower
alkyl groups preferably saturated hydrocarbon chains being one, two
or three carbon atoms in length, more preferably selected from
methyl, ethyl, isopropyl or n-propyl groups, even more preferably
methyl groups, m is 15, 16, 17, 18 or 19, n is 0, 1, 2, 3, 4, 5 or
6, and X is chloro, bromo or iodo, comprising the steps of (a)
reacting a compound of formula (II)
##STR00002## where R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, with
an alkyl halide of formula (III)
##STR00003## where X and n are as above and Y is a halogen selected
from chloro or bromo, more preferably bromo to give a compound of
formula (IV)
##STR00004## (b) reacting the compound of formula (IV) with a
compound of formula (V)
##STR00005## wherein R.sub.1 and R.sub.2 are each independently a
lower alkyl group, preferably saturated hydrocarbon chains being
one, two or three carbon atoms in length, more preferably selected
from methyl, ethyl, isopropyl or n-propyl groups, even more
preferably methyl groups, and m is 15, 16, 17, 18 or 19, to give a
compound of formula (VI)
##STR00006## and (c) reacting a compound of formula (VI) with
SiR.sub.3R.sub.4R.sub.5Z wherein R.sub.3, R.sub.4 and R.sub.5 are
independently methyl or ethyl and Z is chloro, bromo, iodo or
triflate, or a mineral acid selected from HCl, HBr or HI, to give a
compound of formula (I). In a preferred embodiment the process may
take place neat or in a polar, protic reaction solvent, preferably
a lower alkanol selected from methanol, ethanol and isopropanol.
The process may be carried out at the refluxing temperature of the
reaction solvent. The process is considered complete when the
compound of formula (VI) is no longer observable via thin-layer
chromatography. Optionally the compound of formula (I) may be
purified, preferably by chromatography or recrystallization.
According to another aspect of the invention there is provided a
quaternary ammonium bis-phosphonate compound of formula (VII) and a
process for preparing a compound of formula (VII)
##STR00007## wherein R' is independently hydrogen, methyl, ethyl,
isopropyl, n-butyl or phenyl, preferably the same, more preferably
ethyl, and Z is chloro, bromo or hydroxy, preferably bromo, R.sub.1
and R.sub.2 are each independently a lower alkyl group, preferably
saturated hydrocarbon chains being one, two or three carbon atoms
in length, more preferably methyl, m is 15, 16, 17, 18 or 19, n is
0, 1, 2, 3, 4, 5, or 6, and o is 1, 2 or 3, comprising the steps of
(a) reacting, preferably at least two equivalents of compound of
formula (IX)
##STR00008## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, per
equivalent of a compound of formula (X)
##STR00009## to give a compound of formula (XI)
##STR00010## which is then reacted with a compound of formula
(V)
##STR00011## where R, R.sub.1, R.sub.2, m, n and Z are as defined
above, to give a compound of formula (VII).
According to another aspect of the invention there is provided a
quaternary ammonium bis-phosphonate compound of formula (VII) and a
process for preparing a compound of formula (VII) wherein R' is
independently hydrogen, methyl, ethyl, isopropyl, n-butyl or
phenyl, preferably the same, more preferably ethyl or hydrogen and
even more preferably hydrogen, R.sub.1 and R.sub.2 are each
independently a lower alkyl group, preferably saturated hydrocarbon
chains being one, two or three carbon atoms in length, more
preferably methyl groups, m is 15, 16, 17, 18 or 19 and Z is
chloro, bromo or hydroxyl, preferably bromo, comprising the steps
of:
(a) reacting a compound of formula (XI)
##STR00012## where R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, n is
0, 1, 2, 3, 4, 5, or 6, o is 1, 2 or 3 and Z is selected from
chloro, bromo or hydroxyl, preferably bromo, with p-toluenesulfonyl
chloride, trimethyl ammonium chloride, trimethylamine in a polar,
aprotic solvent preferably acetonitrile, dimethylformamide or
dichloromethane, more preferably dichloromethane, (b) adding a
compound R.sub.1R.sub.2NH where R.sub.1 and R.sub.2 are each
independently a lower alkyl group, preferably saturated hydrocarbon
chains being one, two or three carbon atoms in length, more
preferably methyl, in a polar, protic solvent selected from
methanol, ethanol or isopropanol optionally in the presence of
water, to give a compound of formula (XII)
##STR00013## and (c) reacting the compound of formula (XII) with a
compound of formula (XIII)
##STR00014## where m is 15, 16, 17, 18 or 19, and Z is chloro,
bromo or hydroxyl, preferably bromo, to give a compound of formula
(VII).
According to another aspect of the invention there is provided a
quaternary ammonium bis-phosphonate of formula (XIV) and a process
for preparing a compound of formula (XIV)
##STR00015## where R' is independently hydrogen, methyl, ethyl,
isopropyl, n-butyl or phenyl, preferably the same, more preferably
ethyl or hydrogen and even more preferably hydrogen, R.sub.1 and
R.sub.2 are each independently a lower alkyl group, preferably
saturated hydrocarbon chains being one, two or three carbon atoms
in length, more preferably methyl groups, m is 15, 16, 17, 18 or
19, n is 0, 1, 2, 3, 4, 5, or 6, and Z is selected from chloro or
bromo, preferably bromo, comprising the steps of (a) reacting a
compound of formula (XV) wherein R is defined as above
##STR00016## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, with
a compound of formula (XVI)
##STR00017## to give a compound of formula (XVII)
##STR00018## which is treated with p-toluenesulfonic acid,
methanesulfonyl chloride, triethylamine, and R.sub.1R.sub.2NH where
R.sub.1 and R.sub.2 are defined as above, and a compound of formula
(XIII)
##STR00019## where Z is chloro or bromo, preferably bromo to give a
compound of formula (XIV), or (c) reacting a compound of formula
(XVIII)
##STR00020## where n is as defined above with at least one
equivalent of O.dbd.PH(OR).sub.2 where R is independently methyl,
ethyl, isopropyl, n-butyl or phenyl, preferably the same, more
preferably ethyl, in the presence of an alkali metal carbonate,
preferably potassium carbonate, methanesulfonyl chloride and an
organic amine base, and further reacted with sodium hydride and at
least a second equivalent of O.dbd.PH(OR).sub.2 to give a compound
of formula (XIX)
##STR00021## where R is as defined above and (d) reacting the
compound of formula (XIX) with hydrazine, and an aldehyde selected
from formaldehyde or acetaldehyde in the presence of zinc metal,
and a compound of formula (XIII)
##STR00022## where Z is chloro or bromo, preferably bromo, and m is
15, 16, 17, 18 or 19, to give a compound of formula (XIV).
According to another aspect of the invention there is provided a
bis-phosphonate compound of formula (XVII) and a process for
preparing a compound of formula (XVII)
##STR00023## where R is independently hydrogen, methyl, ethyl,
isopropyl, n-butyl or phenyl, preferably the same, more preferably
ethyl, and n is 0, 1, 2, 3, 4, 5 or 6, comprising the steps of
reacting a compound of formula (XX)
##STR00024## where R is as defined above, with a compound of
formula (XXI)
##STR00025## to give a compound of formula (XVII).
According to another aspect of the invention there is provided a
bis-phosphonate compound of formula (XXII) and a process for
preparing a compound of formula (XXII)
##STR00026## where R is methyl, ethyl, isopropyl, n-butyl or
phenyl, preferably the same, more preferably ethyl, R.sub.1 and
R.sub.2 are each independently a lower alkyl group preferably
saturated hydrocarbon chains being one, two or three carbon atoms
in length, more preferably methyl groups, and n is 0, 1, 2, 3, 4, 5
or 6, comprising reacting a compound of formula (XXIII)
##STR00027## with O.dbd.P(OR).sub.2Cl where n and R are as defined
above, in the presence of lithium diisopropylamide in a polar,
aprotic solvent to give a compound of formula (XXII) which
optionally can be reacted with an alkyl halide of formula (XIII) to
give a quaternary ammonium bis-phosphonate of formula (XIV) where
R, R.sub.1, R.sub.2 and m are as defined above.
According to another aspect of the invention there is provided a
bis-phosphonate compound of formula (XXIV) and a process for
preparing a compound of formula (XXIV) where R is hydrogen, methyl,
ethyl, isopropyl, n-butyl or phenyl, preferably the same, more
preferably ethyl, and n is 0, 1, 2, 3, 4, 5 or 6,
##STR00028## comprising reacting a compound of formula (XXV)
##STR00029## with O.dbd.P(OR).sub.2Cl where R and n are as defined
above, in the presence of lithium diisopropylamide in a polar,
aprotic solvent to give a compound of formula (XXIV).
According to another aspect of the invention there is provided a
quaternary ammonium bis-phosphonate compound of formula (XXVI) and
a process for preparing a compound of formula (XXVI)
##STR00030## where R' is independently hydrogen, methyl, ethyl,
isopropyl, n-butyl or phenyl, preferably the same, more preferably
ethyl or hydrogen and even more preferably hydrogen, R.sub.1 and
R.sub.2 are each independently a lower alkyl group, preferably
saturated hydrocarbon chains being one, two or three carbon atoms
in length, more preferably methyl groups, m is 15, 16, 17, 18 or 19
and Z is selected from chloro or bromo, preferably bromo,
comprising the steps of (a) reacting oxalyl chloride with
##STR00031## in chilled dichloromethane in the presence of a
compound of formula (II) to give a compound of formula (XXVII)
##STR00032## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, and
R.sub.1 and R.sub.2 are as defined above, and (b) reacting the
compound of formula (XXVII) with a compound of formula (XIII)
##STR00033## to give a compound of formula (XXVI) where R',
R.sub.1, R.sub.2, m and Z are as defined above.
According to yet another aspect of the invention there is provided
a quaternary ammonium mono-phosphonate compound of formula (XXVIII)
and a process for preparing a compound of formula (XXVIII)
##STR00034## where R' is independently hydrogen, methyl, ethyl,
isopropyl, n-butyl or phenyl, preferably the same, more preferably
ethyl or hydrogen and even more preferably hydrogen, R.sub.1 and
R.sub.2 are each independently a lower alkyl group, preferably
saturated hydrocarbon chains being one, two or three carbon atoms
in length, more preferably methyl groups, n is 0, 1, 2, 3, 4, 5 or
6, p is 0, 1, 2, 3, 4, 5 or 6, and Z is selected from chloro or
bromo, preferably bromo, comprising the steps of (a) reacting a
compound of (XXIX)
##STR00035## with a compound of formula (XXX)
##STR00036## where R.sub.1, R.sub.2 and p are as defined above, in
a polar, aprotic solvent in the presence of an organic amine base
to give a compound of formula (XXXI)
##STR00037## and (b) reacting a compound of formula (XXXI) with a
compound of formula (XXXII)
##STR00038## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, and
n and Z are as defined above, in a polar, aprotic solvent to give a
compound of formula (XXVIII).
In preferred embodiments, for chemical reactions involving reagents
that are sensitive to protons, the processes may take place neat or
in polar, aprotic reaction solvents, for example but not limited to
dichloromethane, acetonitrile and dimethylformamide. For chemical
reactions involving reagents that are not sensitive to protons, the
processes may take place in a lower alkanol preferably methanol,
ethanol and isopropanol. The processes may be carried out at
temperatures from about -80.degree. C. to about 150.degree. C. The
process is considered complete when the starting material is no
longer observable via thin-layer chromatography. The final products
optionally may be purified, preferably by chromatography or
recrystallization.
According to yet another aspect of the invention, there is provided
quaternary ammonium multidentate tri- and tetra-substituted
phosphonate compounds of formula (XXXIII), (XXXIV), (XXXV), (XXXVI)
and (XXXVII) and processes for preparing the compounds of formula
(XXXIII), (XXXIV), (XXXV), (XXXVI) and (XXXVII)
##STR00039## ##STR00040## where R' is independently hydrogen,
methyl, ethyl, isopropyl, n-butyl or phenyl, preferably the same,
more preferably ethyl or hydrogen and even more preferably
hydrogen, m is 15, 16, 17, 18 or 19 and Z is selected from chloro
or bromo, preferably bromo, comprising the steps of: a) alkylating
a tetralkyl methylenebisphosphonate (TAMBP) compound,
mono-deprotecting TAMBP followed by mono alkylation to lead to
alpha (C--H) bisphosphonates, and performing a second
deprotonation/alkylation with dialkyl chlorophosphate to provide
trisphosphonates; b) Michael addition of dialkyl vinylphosphite to
provide beta aminobisphosphonates and further deprotonation and
phosphorylation with dialkyl chlorophosphate to provide
tetraphosphonates; or c) Lewis acid-mediated Abrzov addition of
trialkylphosphite three times to three reactive bromoacteylTRISBOC
and the radical addition of dialkyl phosphite to terminal vinyl
groups on the TRIS BOC scaffold to give trisphosphonates.
According to yet another aspect of the invention there is provided
an antimicrobial composition comprising any one of a compound of
formulae (I), (VII), (XIV), (XXVI), (XXVIII), (XXXIII), (XXXIV),
(XXXV), (XXXVI) and (XXXVII) and a process for treating a surface
with an antimicrobial coating comprising the steps of contacting
the surface with a composition comprising any one of a compound of
formulae (I), (VII), (XIV), (XXVI), (XXVIII), (XXXIII), (XXXIV),
(XXXV), (XXXVI) and (XXXVII).
According to yet another aspect of the invention, there is provided
a phosphonate antimicrobial coating composition for treating
surfaces to give a stable and durable phosphonate antimicrobial
coating surface treatment, said composition comprising any one of a
compound of formulae (I), (VII), (XIV), (XXVI), (XXVIII), (XXXIII),
(XXXIV), (XXXV), (XXXVI) or (XXXVII) in a suitable carrier. In one
embodiment said suitable carrier is an environmentally friendly
carrier comprising a lower alkanol selected from the group
consisting of methanol, ethanol, n-propanol and i-propanol, water
or a mixture thereof depending on the solubility of the phosphonate
compound in the carrier. The phosphonate antimicrobial coating can
be applied onto a given surface preferably by dip coating, painting
or with aerosol spraying with an about 1 to an about 20 mM solution
of the phosphonate compound for a length of time so as to
completely coat the surface. In one embodiment, the coating process
may be repeated to apply additional layers of the phosphonate
antimicrobial coating. Preferably the stable and durable
phosphonate antimicrobial coatings may be coated onto various
material surfaces such as, but not limited to, metal oxides or
metal alloys of aluminum, copper, iron, steel, titanium, zirconium
and silicon (silica). Even more preferably, phosphonate
antimicrobial coating strength and stability may be further
enhanced by subjecting the uncoated surface to a pretreatment
oxidation step known as passivation (Min, S. L., Smiley, K. J.
& Gawalt, E. S. J. Am. Chem. Soc. 193-204 (2011)). Without
being bound by any theory, passivation creates a metal hydroxide
layer that provides additional binding sites for the phosphonate
compounds of the phosphonate antimicrobial coating to bind to.
Passivation can be accomplished known processes in the art such as
thermal annealing (subjecting the uncoated surface to temperatures
of about 100-140.degree. C. for about 18 hours) or reduced pressure
annealing (subjecting the uncoated surface to pressures of about
0.05 to about 0.3 Torr, more preferably 0.1 Torr) (Raman, A.,
Dubey, M., Gouzman, I. & Gawalt, E. S. Formation of
Self-Assembled Monolayers of Alkylphosphonic Acid on the Native
Oxide Surface of SS316L. Langmuir 22, 6469-6472 (2006); Lecollinet,
G. et al. Self-Assembled Monolayers of Bisphosphonates: Influence
of Side Chain Steric Hindrance. Langmuir 25, 7828-7835 (2009)).
Further and other aspects will be appreciated by the skilled
reader.
DETAILED DESCRIPTION OF THE INVENTION
Brief Summary of Figures
FIG. 1 shows the .sup.1H NMR of compound (1) of Referential Example
1
FIG. 2 shows the .sup.13C NMR of compound (1) of Referential
Example 1
FIG. 3 shows the .sup.31P NMR of compound (1) of Referential
Example 1
FIG. 4 shows the .sup.1H NMR of compound (2) of Example 1
FIG. 5 shows the .sup.13C NMR of compound (2) of Example 1
FIG. 6 shows the .sup.31P NMR of compound (2) of Example 1
FIG. 7 shows the .sup.1H NMR of compound (3) of Example 2
FIG. 8 shows the .sup.13C NMR of compound (3) of Example 2
FIG. 9 shows the .sup.31P NMR of compound (3) of Example 2
FIG. 10 shows the .sup.1H NMR of compound (4) of Example 3
FIG. 11 shows the .sup.13C NMR of compound (4) of Example 3
FIG. 12 shows the .sup.31P NMR of compound (4) of Example 3
FIG. 13 shows the .sup.1H NMR of compound (5) of Example 4
FIG. 14 shows the .sup.13C NMR of compound (5) of Example 4
FIG. 15 shows the .sup.31P NMR of compound (5) of Example 4
FIG. 16 shows the .sup.1H NMR of compound (6) of Example 5
FIG. 17 shows the .sup.31P NMR of compound (6) of Example 5
FIG. 18 shows the .sup.1H NMR of compound (7) of Example 6
FIG. 19 shows the .sup.13C NMR of compound (7) of Example 6
FIG. 20 shows the .sup.31P NMR of compound (7) of Example 6
FIG. 21 shows the .sup.1H NMR of compound (8) of Example 7
FIG. 22 shows the .sup.13C NMR of compound (8) of Example 7
FIG. 23 shows the .sup.31P NMR of compound (8) of Example 7
FIG. 24 shows the .sup.1H NMR of compound (9) of Example 8
FIG. 25 shows the .sup.13C NMR of compound (9) of Example 8
FIG. 26 shows the .sup.31P NMR of compound (9) of Example 8
FIG. 27 shows the .sup.1H NMR of compound (10) of Example 9
FIG. 28 shows the .sup.13C NMR of compound (10) of Example 9
FIG. 29 shows the .sup.1H NMR of compound (11) of Example 10
FIG. 30 shows the .sup.13C NMR of compound (11) of Example 10
FIG. 31 shows the .sup.1H NMR of compound (12) of Example 11
FIG. 32 shows the .sup.31P NMR of compound (12) of Example 11
FIG. 33 shows the .sup.1H NMR of compound (13) of Example 12
FIG. 34 shows the .sup.31P NMR of compound (13) of Example 12
FIG. 35 shows the .sup.1H NMR of compound (14) of Example 13
FIG. 36 shows the .sup.13C NMR of compound (14) of Example 13
FIG. 37 shows the .sup.31P NMR of compound (14) of Example 13
FIG. 38 shows the .sup.1H NMR of compound (15) of Example 14
FIG. 39 shows the .sup.13C NMR of compound (15) of Example 14
FIG. 40 shows the .sup.31P NMR of compound (15) of Example 14
FIG. 41 shows the .sup.1H NMR of compound (16) of Example 15
FIG. 42 shows the .sup.13C NMR of compound (16) of Example 15
FIG. 43 shows the .sup.31P NMR of compound (16) of Example 15
FIG. 44 shows the .sup.1H NMR of compound (17) of Example 16
FIG. 45 shows the .sup.13C NMR of compound (17) of Example 16
FIG. 46 shows the .sup.31P NMR of compound (17) of Example 16
FIG. 47 shows the .sup.1H NMR of compound (18) of Example 17
FIG. 48 shows the .sup.13C NMR of compound (18) of Example 17
FIG. 49 shows the .sup.1H NMR of compound (19) of Example 18
FIG. 50 shows the .sup.13C NMR of compound (19) of Example 18
FIG. 51 shows the .sup.1H NMR of compound (20) of Example 19
FIG. 52 shows the .sup.13C NMR of compound (20) of Example 19
FIG. 53 shows the .sup.31P NMR of compound (20) of Example 19
FIG. 54 shows the .sup.1H NMR of compound (21) of Example 20
FIG. 55 shows the .sup.13C NMR of compound (21) of Example 20
FIG. 56 shows the .sup.31P NMR of compound (21) of Example 20
FIG. 57 shows the .sup.1H NMR of compound (30) of Example 21
FIG. 58 shows the .sup.13C NMR of compound (30) of Example 21
FIG. 59 shows the .sup.1H NMR of compound (31) of Example 22
FIG. 60 shows the .sup.13C NMR of compound (31) of Example 22
FIG. 61 shows the .sup.31P NMR of compound (31) of Example 22
FIG. 62 shows the .sup.1H NMR of compound (32) of Example 23
FIG. 63 shows the .sup.13C NMR of compound (32) of Example 23
FIG. 64 shows the .sup.31P NMR of compound (32) of Example 23
The present invention is directed to quaternary ammonium mono- and
multidentate-phosphonate compounds, methods for manufacturing the
compounds, compositions comprising said compounds and methods for
treating surfaces and/or articles with the compounds to provide a
durable, antimicrobial-treated article.
The term quaternary ammonium mono-phosphonate refers to quaternary
ammonium compounds that have been substituted with a single
phosphonate group O.dbd.P(OR).sub.2 where R is selected from
methyl, ethyl, isopropyl, n-butyl or phenyl or hydrogen, preferably
ethyl or hydrogen and even more preferably hydrogen, and the
phosphonate group can be linked to the quaternary ammonium nitrogen
centre by a one, two, three or four carbon atom chain, preferably a
saturated chain. The term quaternary ammonium
multidentate-phosphonate refers to quaternary ammonium compound
that have been substituted with two or more phosphonate groups
O.dbd.P(OR).sub.2 where R is as above.
The term polar, aprotic solvent means a solvent that has a dipole
moment but does not have an acidic hydrogen. Non-limiting examples
include acetonitrile, dimethylformamide, dimethylsulfoxide and
dichloromethane.
The term polar, protic solvent means a solvent that has a dipole
moment and has an acidic hydrogen. Non-limiting examples including
lower alkanols, carboxylic acids and water.
The term surface means any metallic or non-metallic article surface
that is capable of forming phosphorus-oxygen bonds. Non-limiting
examples include steel, stainless steel, titanium, silica glass and
clays.
The term neat means without the use of solvents, specifically
directed to chemical reactions that do not involve the use of
solvents.
All microwave reactions were performed in sealed glass reaction
tube utilizing the Biotage.RTM. Initiator Microwave Synthesizer at
the indicated temperature and time
The quaternary ammonium mono- and bis-phosphonate compounds of the
present invention can be prepared via one of several processes. In
one embodiment, a quaternary ammonium mono-phosphonate compound of
formula (I)
##STR00041## wherein R.sub.1 and R.sub.2 are each independently a
lower alkyl group preferably saturated hydrocarbon chains being
one, two or three carbon atoms in length, more preferably methyl
groups, m is 15, 16, 17, 18 or 19, n is 0, 1, 2, 3, 4, 5 or 6, and
X is chloro, bromo or iodo, can be prepared by a process comprising
the steps of (a) reacting a compound of formula (II)
##STR00042## where R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same and more preferably ethyl,
with an alkyl halide of formula (III)
##STR00043## where n and X are as above and Y is a halogen selected
from chloro or bromo, more preferably bromo to give a compound of
formula (IV)
##STR00044## (b) reacting the compound of formula (IV) with a
compound of formula (V)
##STR00045## wherein R.sub.1 and R.sub.2 are each independently a
lower alkyl group, preferably saturated hydrocarbon chains being
one, two or three carbon atoms in length, more preferably methyl
groups, and m is 15, 16, 17, 18 or 19, to give a compound of
formula (VI)
##STR00046## and (c) reacting a compound of formula (VI) with
SiR.sub.3R.sub.4R.sub.5Z wherein R.sub.3, R.sub.4 and R.sub.5 are
independently methyl or ethyl and Z is chloro, bromo, iodo or
triflate, or a mineral acid selected from HCl, HBr or HI, to give a
compound of formula (I). The process may take place neat or in a
polar, protic reaction solvent, preferably a lower alkanol selected
from methanol, ethanol and isopropanol. The process may be carried
out at the refluxing temperature of the reaction solvent. The
process is considered complete when the compound of formula (VI) is
no longer observable via thin-layer chromatography. The final
product optionally may be purified, preferably by chromatography or
recrystallization.
In another embodiment, a quaternary ammonium bis-phosphonate
compound of formula (VII)
##STR00047## wherein R' is independently hydrogen, methyl, ethyl,
isopropyl, n-butyl or phenyl, preferably the same, more preferably
ethyl or hydrogen and even more preferably hydrogen, R.sub.1 and
R.sub.2 are each independently a lower alkyl group, preferably
saturated hydrocarbon chains being one, two or three carbon atoms
in length, more preferably methyl groups, m is 15, 16, 17, 18 or
19, n is 0, 1, 2, 3, 4, 5 or 6, o is 1, 2 or 3, and Z is chloro,
bromo or hydroxy, preferably bromo, is prepared by a process
comprising the steps of (a) reacting at least two equivalents of
compound of formula (IX)
##STR00048## where R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, with
per equivalent of a compound of formula (X)
##STR00049## where n is 0, 1, 2, 3, 4, 5 or 6, and Z is selected
from chloro, bromo or hydroxyl, preferably bromo, to give a
compound of formula (XI)
##STR00050## where n, o, R and Z are as defined above. which is
reacted with a compound of formula (V)
##STR00051## where R.sub.1 and R.sub.2 are independently lower
alkyl groups preferably saturated hydrocarbon chains being one, two
or three carbon atoms in length, preferably methyl groups, and m is
15, 16, 17, 18 or 19, to give a compound of formula (VII) where R',
R.sub.1, R.sub.2, m, n, o and Z are as defined above. The process
for preparing the compound of formula (XI) can take place in a
polar, aprotic solvent selected from but not limited to
acetonitrile or dichloromethane, or neat, preferably neat, at a
temperature from about -5.degree. C. to about 10.degree. C. then
warmed to about 90.degree. C. to about 140.degree. C. for about one
hour. The product of formula (XI) can be isolated by extraction and
optionally purified, preferably by chromatography. The process
alternatively can take place in the presence of microwave radiation
at a temperature of about 120.degree. C. to about 140.degree. C.,
preferably 130.degree. C., for about five minutes. The microwave
radiation has a frequency of about 2500 MHz.
The process for preparing the compound of formula (VII) from the
compound of formula (XI) can take place in a neat mixture of a
compound of formula (XI) and a compound of formula (V) where R,
R.sub.1, R.sub.2 and Z are as defined above. The process can take
place in the absence of reaction solvent at a temperature of about
90.degree. C. to about 110.degree. C., preferably 100.degree. C.,
for about one hour, or alternatively, in the presence of microwave
radiation at a temperature of about 140.degree. C. to about
160.degree. C., preferably 150.degree. C., for about one to three
minutes, preferably about two minutes. The microwave radiation has
a frequency of about 2500 MHz.
In an alternative embodiment, the quaternary ammonium
bis-phosphonate compound of formula (VII) is prepared by a process
comprising the steps of
(a) reacting a compound of formula (XI)
##STR00052## where R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl,
R.sub.1 and R.sub.2 are each independently a lower alkyl group,
preferably saturated hydrocarbon chains being one, two or three
carbon atoms in length, more preferably methyl groups, n is 0, 1,
2, 3, 4, 5 or 6, o is 1, 2 or 3, and Z is selected from chloro,
bromo or hydroxyl, preferably bromo, with p-toluenesulfonyl
chloride, trimethyl ammonium chloride, an organic amine, preferably
triethylamine, in a polar, aprotic solvent selected from but not
limited to acetonitrile, dimethylformamide or dichloromethane,
preferably dichloromethane, (b) adding a compound R.sub.1R.sub.2NH
where R.sub.1 and R.sub.2 are defined as above, in a polar, protic
solvent selected from but not limited to methanol, ethanol or
isopropanol, optionally in the presence of water, to give a
compound of formula (XII)
##STR00053## and (c) reacting the compound of formula (XII) with a
compound of formula (XIII)
##STR00054## where m is 15, 16, 17, 18 or 19, and Z is chloro,
bromo or hydroxyl, preferably bromo, to give a compound of formula
(VII). The process of step (a) can take place at a temperature of
about 20.degree. C. to about 30.degree. C. The process of step (b)
can take place at a temperature of about 90.degree. C. to about
115.degree. C., preferably 100.degree. C., and for a reaction time
of about one hour. Alternatively, the process of step (b) can take
place in the presence of microwave radiation at a temperature of
about 100.degree. C. to about 120.degree. C., preferably
110.degree. C., for about five minutes. The microwave radiation has
a frequency of about 2500 MHz. The process of step (c) can take
place neat at a temperature of about 90.degree. C. to about
115.degree. C. for about one hour or, alternatively, in the
presence of microwave radiation at a temperature of about
140.degree. C. to about 160.degree. C., preferably 150.degree. C.,
for about two minutes. The microwave radiation has a frequency of
about 2500 MHz.
In another embodiment, the quaternary ammonium bis-phosphonate
compound of formula (XIV)
##STR00055## where R' is independently hydrogen, methyl, ethyl,
isopropyl, n-butyl or phenyl, preferably the same, more preferably
ethyl or hydrogen and even more preferably hydrogen, R.sub.1 and
R.sub.2 are each independently a lower alkyl group, preferably
saturated hydrocarbon chains being one, two or three carbon atoms
in length, more preferably methyl groups, m is 15, 16, 17, 18 or
19, n is 0, 1, 2, 3, 4, 5 or 6, and Z is selected from chloro or
bromo, preferably bromo, is prepared by a process comprising the
steps of (a) reacting a compound of formula (XV)
##STR00056## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, with
a compound of formula (XVI)
##STR00057## to give a compound of formula (XVII)
##STR00058## where n and R are as defined above, which is
preferably not isolated and used in the next step, and (b) treating
a compound of formula (XVII) with p-toluenesulfonic acid,
methanesulfonyl chloride, triethylamine and R.sub.1R.sub.2NH where
R.sub.1 and R.sub.2 are defined as above, and a compound of formula
(XIII)
##STR00059## where m is as defined above and Z is chloro or bromo,
preferably bromo to give a compound of formula (XIV), or
alternatively (c) reacting a compound of formula (XVIII)
##STR00060## wherein n is 0, 1, 2, 3, 4, 5, or 6, with one
equivalent of O.dbd.PH(OR).sub.2 where R is independently methyl,
ethyl, isopropyl, n-butyl or phenyl, preferably the same, more
preferably ethyl, in the presence of an alkali metal carbonate,
preferably potassium carbonate, methanesulfonyl chloride and an
organic amine base, preferably triethylamine, and further reacted
with sodium hydride and a second equivalent of O.dbd.PH(OR).sub.2
to give a compound of formula (XIX)
##STR00061## where n and R are as defined above and (d) reacting
the compound of formula (XIX) with hydrazine, an aldehyde selected
from formaldehyde or acetaldehyde in the presence of zinc metal,
and a compound of formula (XIII)
##STR00062## where Z is chloro or bromo, preferably bromo, and m is
15, 16, 17, 18 or 19, to give a compound of formula (XIV). The
process of step (c) can take place in a polar, aprotic solvent
selected from but not limited to acetonitrile, tetrahydrofuran or
dioxane, preferably acetonitrile or dioxane, at a temperature of
about 25.degree. C. to about 75.degree. C., preferably 60.degree.
C.
In another embodiment, the bis-phosphonate compound of formula
(XVII)
##STR00063## where n is 0, 1, 2, 3, 4, 5, or 6, and R is
independently methyl, ethyl, isopropyl, n-butyl or phenyl,
preferably the same, more preferably ethyl, is prepared by a
process comprising the step of reacting a compound of formula
(XX)
##STR00064## where R is as defined above, with a compound of
formula (XXI)
##STR00065## to give a compound of formula (XVII).
In another embodiment of preparing a compound of formula (XIV), the
bis-phosphonate compound of formula (XXII)
##STR00066## where n is 0, 1, 2, 3, 4, 5 or 6, R is independently
methyl, ethyl, isopropyl, n-butyl or phenyl, preferably the same,
more preferably ethyl, R.sub.1 and R.sub.2 are each independently a
lower alkyl group, preferably saturated hydrocarbon chains being
one, two or three carbon atoms in length, more preferably methyl,
is prepared by a process comprising reacting a compound of formula
(XXIII)
##STR00067## with O.dbd.P(OR).sub.2Cl where n, R, R.sub.1 and
R.sub.2 are as defined above, in the presence of lithium
diisopropylamide in a polar, aprotic solvent to give a compound of
formula (XXII) which optionally is reacted with an alkyl halide of
formula (XIII) to give a quaternary ammonium bis-phosphonate of
formula (XIV) where R, R.sub.1, R.sub.2, Z, m and n are as defined
above.
In another embodiment, the compound of formula (XXIV)
##STR00068## where n is 0, 1, 2, 3, 4, 5 or 6, and R is
independently methyl, ethyl, isopropyl, n-butyl or phenyl,
preferably the same, more preferably ethyl, is prepared by a
process comprising reacting a compound of formula (XXV)
##STR00069## with O.dbd.P(OR).sub.2Cl in the presence of lithium
diisopropylamide in a polar, aprotic solvent to give a compound of
formula (XXIV) where R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl.
In another embodiment, the quaternary ammonium bis-phosphonate
compound of formula (XXVI)
##STR00070## where R' is independently hydrogen, methyl, ethyl,
isopropyl, n-butyl or phenyl, preferably the same, more preferably
ethyl or hydrogen and even more preferably hydrogen, R.sub.1 and
R.sub.2 are each independently a lower alkyl group, preferably
saturated hydrocarbon chains being one, two or three carbon atoms
in length, preferably methyl groups, m is 15, 16, 17, 18 or 19 and
Z is selected from chloro or bromo, preferably bromo, is prepared
by the process comprising the steps of (a) reacting oxalyl chloride
with
##STR00071## in chilled dichloromethane in the presence of a
compound of formula (II) to give a compound of formula (XXVII)
##STR00072## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, and
(b) reacting the compound of formula (XXVII) with a compound of
formula (XIII) to give a compound of formula (XXVI).
The process of step (a) can take place in a polar, aprotic solvent
selected from but not limited to acetonitrile or dichloromethane,
preferably dichloromethane, and the term chilled means a
temperature from about -5.degree. C. to about 10.degree. C., rising
to about 20.degree. C. to about 30.degree. C. for about one
hour.
In another embodiment of the present invention, a quaternary
ammonium mono-phosphonate compound of formula (XXVIII)
##STR00073## where n is 0, 1, 2, 3, 4, 5 or 6, p is 0, 1, 2, 3, 4,
5 or 6, R' is independently hydrogen, methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl or
hydrogen and even more preferably hydrogen, R.sub.1 and R.sub.2 are
each independently a lower alkyl group, preferably saturated
hydrocarbon chains being one, two or three carbon atoms in length,
preferably methyl groups, m is 15, 16, 17, 18 or 19 and Z is
selected from chloro, bromo, iodo or mesyl, preferably bromo, is
prepared by a process comprising the steps of (a) reacting a
compound of (XXIX)
##STR00074## with a compound of formula (XXX)
##STR00075## where p, R.sub.1 and R.sub.2 are as defined above, in
a polar, aprotic solvent in the presence of an organic amine base
to give a compound of formula (XXXI)
##STR00076## and (b) reacting a compound of formula (XXXI) with a
compound of formula (XXXII)
##STR00077## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, and
n and Z are as defined above, in a polar, aprotic solvent to give a
compound of formula (XXVIII). The dansyl group
##STR00078## is used as a UV fluorescing marker to indicate the
presence of the quaternary ammonium mono-phosphate compound after a
compound of formula (XXVIII) has been applied to a surface.
In another embodiment of the present invention, quaternary ammonium
multidentate tri- and tetra-substituted phosphonate compounds of
formula (XXXIII), (XXXIV), (XXXV), (XXXVI) and (XXXVII)
##STR00079## ##STR00080## are prepared where R' is independently
hydrogen, methyl, ethyl, isopropyl, n-butyl or phenyl, preferably
the same, more preferably ethyl or hydrogen and even more
preferably hydrogen, R.sub.1 and R.sub.2 are each independently a
lower alkyl group, preferably saturated hydrocarbon chains being
one, two or three carbon atoms in length, preferably methyl groups,
m is 15, 16, 17, 18 or 19 and Z is selected from chloro or bromo,
preferably bromo. Multidentate phosphonic acid antimicrobials may
generally be prepared by introduction of the bis-, tris- or
tetraphosphonate anchor prior to quaternization and dealkylation
with trimethylbromosilane (TMBr). The most direct way to synthesize
bisphosphonates is through the alkylation of tetralkyl
methylenebisphosphonate (TAMBP). Monodeprotonation of TAMBP
followed by mono alkylation leads to alpha (C--H) bisphosphonates
whereas a second deprotonation/alkylation with dialkyl
chlorophosphate provides trisphosphonates. A second method for the
synthesis of bisphosphonates is through Michael addition of dialkyl
vinylphosphite to provide beta aminobisphosphonates. Further
deprotonation and phosphorylation with dialkyl chlorophosphate
provides tetraphosphonates. Alternatively the TRIS BOC scaffold
containing three reactive groups may be turned into
trisphosphonates via established synthetic routes used to prepare
monophosphonates. Two examples include the lewis acid-mediated
Abrzov addition of trialkylphosphite three times to three reactive
bromoacteylTRISBOC and the radical addition of dialkyl phosphite to
terminal vinyl groups on TRISBOC. General schemes for producing
quaternary ammonium bis-, tris- and tetraphosphonate compounds are
as follows:
##STR00081## wherein R.sub.1 and R.sub.2 are independently lower
alkyl groups, preferably methyl.
##STR00082## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl,
R.sub.1 and R.sub.2 are independently lower alkyl groups,
preferably methyl and m is 15, 16, 17, 18 or 19.
##STR00083## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl,
R.sub.1 and R.sub.2 are independently lower alkyl groups,
preferably methyl and m is 15, 16, 17, 18 or 19.
##STR00084## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl,
R.sub.1 and R.sub.2 are independently lower alkyl groups,
preferably methyl and m is 15, 16, 17, 18 or 19.
##STR00085## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl, and
m is 15, 16, 17, 18 or 19.
##STR00086## wherein R is independently methyl, ethyl, isopropyl,
n-butyl or phenyl, preferably the same, more preferably ethyl,
R.sub.1 and R.sub.2 are independently lower alkyl groups,
preferably methyl and m is 15, 16, 17, 18 or 19.
In another embodiment, the quaternary ammonium mono- and
bis-phosphonate and multidentate tri- and tetra-substituted
phosphonate compounds of the present invention may be used to
antimicrobially treat hard surfaces. A surface may be an inner
surface and/or an outer surface. Specifically, there is provided a
phosphonate antimicrobial coating composition for treating surfaces
to give a stable and durable phosphonate antimicrobial coating
surface treatment, said composition comprising any one of a
compound of formulae (I), (VII), (XIV), (XXVI), (XXVIII), (XXXIII),
(XXXIV), (XXXV), (XXXVI) or (XXXVII) in a suitable carrier. In one
embodiment said suitable carrier is an environmentally friendly
carrier comprising a lower alkanol selected from the group
consisting of methanol, ethanol, n-propanol and i-propanol, water
or a mixture thereof depending on the solubility of the phosphonate
compound in the carrier. The phosphonate antimicrobial coating may
be applied onto a given surface preferably by dip coating, painting
or with aerosol spraying with an about 1 to an about 20 mM solution
of the phosphonate compound for a length of time so as to
completely coat the surface. In one embodiment, the coating process
may be repeated to apply additional layers of the phosphonate
antimicrobial coating. Preferably the stable and durable
phosphonate antimicrobial coatings may be coated onto various
material surfaces such as, but not limited to, metal oxides or
metal alloys of aluminum, copper, iron, steel, titanium, zirconium
and silicon (silica). Even more preferably, phosphonate
antimicrobial coating strength and stability may be further
enhanced by subjecting the uncoated surface to a pretreatment
oxidation step known as passivation. Without being bound by any
theory, passivation creates a metal hydroxide layer that provides
additional binding sites for the phosphonate compounds of the
phosphonate antimicrobial coating to bind to. Passivation is
accomplished by known processes in the art such as thermal
annealing (subjecting the uncoated surface to temperatures of about
100-140.degree. C. for about 18 hours) or reduced pressure
annealing (subjecting the uncoated surface to pressures of about
0.05 to about 0.3 Torr, more preferably 0.1 Torr).
The following non-limiting examples are provided.
ACRONYMS
AIBN--Azobisisobutyronitrile
ACN--acetonitrile
DCM--dichloromethane
DMF--dimethylformamide
Hrs--hours
LDA--lithiumdiisopropylamide
NaH--sodium hydride
MsCl--mesylchloride
ON--overnight
RT--room temperature
TMSBr--trimethylsilylbromide
TosCl--tosyl chloride
TOL--toluene
ST--sealed tube
uW--microwave
Monophosphonic Acid Quaternary Ammonium Antimicrobials (MPQ).
##STR00087## Synthesis of Monophosphonic Acid Quats.
##STR00088##
Referential Example 1
Diethyl (3-bromopropyl)phosphonate (1)
According to a general procedure reported in Li, F. et al.
Photopolymerization of Self-Assembled Monolayers of Diacetylenic
Alkylphosphonic Acids on Group-III Nitride Substrates. Langmuir 26,
10725-10730 (2010), to a flame dried 250 mL round bottom flask
equipped with a reflux condenser connected to an inert atmosphere
manifold, was added 1,3-dibromopropane (40 mL, 394 mmol, 4 eq.)
followed by triethylphosphite (13 mL, 75.8 mmol). The flask was
evacuated (2 min), backfilled with N.sub.2 and the reaction mixture
refluxed overnight (175.degree. C.) using a sand bath. The solution
was then cooled to room temperature and excess 1,3-dibromopropane
was vacuum distilled (1.times.10.sup.-2 mm Hg) using a shortpath
distillation head attached to a Schlenk line. Once all of the
excess 1,3-dibromopropane was removed as judged by TLC, the title
compound was vacuum distilled utilizing an oil bath (150.degree.
C.) to afford a clear, colourless liquid. Yield: 79% (15.54 g). TLC
(50% EtOAc:hexanes, KMnO.sub.4 stain), R.sub.f=0.60; .sup.1H NMR
(400 MHz, CDCl.sub.3, .delta.): 4.12-4.00 (m, 4H, H5), 3.43 (t, 2H,
J=4.3 Hz, H4), 2.16-2.05 (m, 2H, H3), 1.90-1.81 (m, 2H, H2), 1.28
(t, J=7.0 Hz, 6H, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3,
.delta.): 61.6 (d, .sup.2J.sub.C-P=6.5 Hz, C5), 33.71 (C4), 25.92
(d, .sup.2J.sub.C-P=4.4 Hz, C2), 23.64 (s, C3), 16.4 (d,
.sup.2J.sub.C-P=6.2 Hz, C1) ppm; .sup.31P NMR (121.45 MHz,
CDCl.sub.3, .delta.): 30.2 ppm.
##STR00089##
Example 1
N-(3-diethoxyphosphorylpropyl)-N,N-dimethyloctadecan-1-ammonium
bromide (2)
The compound has been previously reported in: Brunet, S.,
Germanaud, L., Le, P., Pierre & Sillion, B. Neutral
phosphobetaines, their preparation, and their use in petroleum
recovery. Fr. Demande, 33 (1986); Chevalier, Y. et al. Zwitterionic
amphiphiles: synthesis and physical properties. Commun. Journ. Com.
Esp. Deterg. 18, 231-45 (1987); Gallot, B., Germanaud, L.,
Chevalier, Y. & Le, P., P. Mesomorphic structure of neutral
amphiphilic phosphotobetaines having different interionic distances
I. Ethylphosphonatobetaines. J. Colloid Interface Sci. 121, 514-21
(1988); Germanaud, L., Brunel, S., Le, P., P. & Sillion, B.
Surfactant properties of neutral phosphobetaines with a modulated
intercharge distance. Rev Inst Fr Pet 41, 773-85 (1986); and
Germanaud, L., Brunel, S., Chevalier, Y. & Le, P., Pierre.
Synthesis of neutral amphiphilic phosphobetaines with variable
interionic distances. Bull. Soc. Chim. Fr., 699-704 (1988). To a
flame dried and evacuated 20 mL screw cap vial was added dimethyl
(3-bromopropyl)phosphonate (1.264 g, 4.88 mmol) followed by
N,N-dimethyloctadecylamine (DMOA) by pasteur pipette (1.7075 g, 5.1
mmol, 1.1 eq.) and the closed vial placed in a 100.degree. C. sand
bath for 35 min until it solidified. The mixture was then cooled to
room temperature, centrifuged from hexanes (15 mL), and
recrystallized from 20 mL ethyl acetate/hexanes (1:5) to afford
N-(3-(diethoxyphosphoryl)propyl)-N,N-dimethyloctadecan-1-ammonium
bromide as a white waxy solid. Yield: 67% (1.82 g).
Mp=54-55.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.):
4.09-4.01 (m, 2H, H10), 3.66-3.22 (m, 2H, H9) 3.43-3.38 (m, 2H,
H8), 3.31 (s, 6H, H7), 2.03 (brs, 2H, H6), 1.84-1.80 (m, 2H, H5),
1.67 (brs, 2H, H4), 1.33-1.25 (m, 6H, H3), 1.19 (brs, 30H, H2),
0.83-0.79 (m, 3H, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3,
.delta.): 64.45 (C8), 63.09 (d, .sup.3J.sub.C-P=6.54 Hz C9), 62.97
(d, .sup.2J=6.54 Hz, C10), 51.25 (C7), 31.86 (C2 overlap),
29.64-29.19 (C2 overlap), 22.69 (C4), 22.62 (C5), 16.45-16.39 (C6,
C3), 14.05 (C1) ppm; .sup.31P NMR (121.45 MHz, CDCl.sub.3,
.delta.): 29.54 ppm. HRMS-DART (m/z): [M.sup.+] calculated for
C.sub.33H.sub.73N.sub.2O.sub.6P.sub.2, 476.4227. found,
476.4240.
##STR00090##
Example 2
N,N-dimethyl-N-(3-phosphonopropyl)octadecan-1-ammonium bromide
(3)
The internal salt of this compound has been previously reported in:
Martinelli, M. J. & Pollack, S. R. Bromotrimethylsilane, John
Wiley & Sons Ltd, 2011); and Conibear, A. C., Lobb, K. A. &
Kaye, P. T. 31P NMR kinetic study of the tandem cleavage of
phosphonate esters by bromotrimethylsilane. Tetrahedron 66,
8446-8449 (2010). Inside a flame dried and evacuated 20 mL screw
cap vial
N-(3-(diethoxyphosphoryl)propyl)-N,N-dimethyloctadecan-1-ammonium
bromide (0.2768 g, 0.46 mmol) was dissolved in anhydrous DCM (5
mL). To the clear stirred solution was added TMSBr (0.25 mL, 1.9
mmol, 4.0 eq.) through a rubber septum via syringe and the reaction
was stirred at room temperature overnight. Completion of the
reaction was followed by .sup.31P after which the reaction was
quenched with EtOH (10 mL) and stirred for 1 h followed by addition
of H.sub.2O (1 mL). Volatiles were removed with a rotovap connected
to a high vacuum Schlenk line and the crude product was centrifuged
with Et.sub.2O (2.times.10 mL) to remove brown colored impurities
(0.9422 g, 94%). A small portion of the title compound was
recrystallized from EtOAc/IPA for MS & X-ray analysis. Clear,
long needles. Mp=118-120.degree. C.; .sup.1H NMR (400 MHz, MeOD,
.delta.): 3.38-3.33 (m, 2H, H8), 3.28-3.23 (m, 2H, H7), 3.02 (s,
6H, H6), 2.02-1.90 (m, 2H, H5), 1.75-1.65 (m, 4H, H4, H3), 1.20
(brs, 30H, H3), 0.82 (t, J=6.9 Hz, 3H, H1), ppm; .sup.13C NMR
(CDCl.sub.3, 100 MHz, .delta.): 64.26 (C7) 63.57 (C8), 49.94 (C6),
31.68 (C2 overlap), 29.41-28.86 (C2 overlap), 26.03 (C2 overlap),
22.45-22.17 (C3, C4), 16.47 (d, .sup.1J.sub.C-P=4.07 Hz, C5), 13.08
(C1) ppm; .sup.31P NMR (121.45 MHz, CDCl.sub.3, .delta.): 26.92
ppm; HRMS-DART (m/z): [M.sup.+]+ calculated for
C.sub.23H.sub.51NO.sub.3P, 420.3601. found, 420.3608.
.alpha.-Amino Bisphosphonic Acid Antimicrobials (.alpha.-ABPQ).
##STR00091## Synthesis of .alpha.-Amino Bisphosphonic Quats-Via
Double Kabachnik Fields Reaction.
##STR00092##
Example 3
Tetraethyl
(((3-bromopropyl)azanediyl)bis(methylene))bis(phosphonate) (4)
To a 20 mL glass screw cap vial, equipped with a magnetic stir bar
was added diethylphosphite (2.77 mL, 21.56 mmol, 2.2 eq.) and the
vial was placed on ice meanwhile 3-aminopropyl-1-bromide
hydrobromide (.about.2.5 g, .about.11 mmol) was treated with KOH
(6N, 6 g in 20 mL) and stirred at 0.degree. C. until a yellow oil
appeared (.about.5 min). The mixture was then extracted without
solvent, collecting the upper yellow layer of the free base
aminopropyl-1-bromide (incompletely dry by NMR, 50% water present).
The amine (1.350 g, 9.78 mmol) was added to the vial containing
diethyl phosphite and cooled at 0-5.degree. C. (ice bath). To the
chilled, stirred solution was added formalin, dropwise (37%, 2.12
mL, 25.43 mmol, 2.6 eq.) over 10 min while maintaining the reaction
temp under 10.degree. C., then warming the mixture to room
temperature for 30 min, and finally to 100.degree. C. for 1 h. The
reaction was diluted with 0.2N NaOH (.about.300 mg in 40 mL) and
extracted with CHCl.sub.3 (1.times.30 mL, 1.times.10 mL), the
organic layer was separated, washed with brine (1.times.20 mL) and
dried over anhydrous MgSO.sub.4 filtered and concentrated to afford
a yellow oil. The title compound was in poor yield, however
analysis by .sup.1H NMR revealed >98% purity and required no
further purification. Yield 20.9% (0.7658 g); TLC (5% MeOH in
EtOAc), R.sub.f=0.48; .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.):
4.17-4.07 (m, 8H, H6), 3.47 (t, 2H, J=6.7 Hz, H5), 3.14 (d, 4H,
J=8.5 Hz, H4), 2.93 (t, 2H, J=6.6 Hz, H3), 2.00 (q, 2H, J=6.58 Hz,
H2), 1.31 (t, 12H, J=7.1 Hz, H1); .sup.13C NMR (100 MHz,
CDCl.sub.3, .delta.): 61.9 (t, .sup.2J.sub.C-P=3.36 Hz, C6), 55.08
(C3), 49.43 (C4), 31.09 (C5), 30.96 (C2), 16.49 (t,
.sup.3J.sub.C-P=2.94 Hz, C1); .sup.31P NMR (121.45 MHz, CDCl.sub.3,
.delta.): 24.60 ppm.
##STR00093##
Example 4
Tetraethyl
(((3-chloropropyl)azanediyl)bis(methylene))bis(phosphonate) (5)
To a 20 mL glass screw cap vial, equipped with a magnetic stir bar
was added diethylphosphite (2.86 g, 20.74 mmol, 2.0 eq.). The vial
was placed on ice to cool. In a separate beaker,
3-aminopropyl-1-chloride hydrochloride (2.0 g, 11.4 mmol) was
treated with NaOH (.about.12 N, 2 g in 5 mL) and stirred at
0.degree. C. until a yellow oil appeared (.about.5 min). The
mixture was then extracted without solvent, adding the upper yellow
layer of the free base 3-aminopropyl-1-chloride to the vial
containing diethyl phosphite cooled to 0-5.degree. C. (ice bath).
To the chilled solution was added formalin, dropwise, via syringe
(37%, 2.15 mL, 25.79 mmol, 2.5 eq.) over 10 min maintaining the
reaction temp under 10.degree. C. The mixture was then warmed, with
stirring, to room temperature for 10 min, then heated to
100.degree. C. for 30 min. Excess formaldehyde and water via
rotovap and the crude material purified by Dry Column Vacuum
Chromatography (DCVC) on silica gel (20 g silica, 3.5 cm.times.4.5
cm) eluting with 80 mL EtOAc and collecting 50 mL (20% MeOH/EtOAc).
Yield 50% (2.03 g); TLC (10% MeOH in EtOAc), R.sub.f=0.70; .sup.1H
NMR (400 MHz, CDCl.sub.3, .delta.): 4.18-4.09 (m, 8H, H6), 3.62 (t,
2H, J=6.6 Hz, H5), 3.17 (d, 4H, J=8.6 Hz, H4), 2.97 (t, 2H, J=6.6
Hz, H3), 2.00 (p, 2H, J=6.64 Hz, H2), 1.33 (t, 12H, J=7.1 Hz, H1);
.sup.13C NMR (100 MHz, CDCl.sub.3, .delta.): 61.84 (p,
.sup.2J.sub.C-P=3.58 Hz, C6), 53.93 (t, .sup.3J.sub.C-P=7.44 Hz,
C5), 50.18 (dd, .sup.1J.sub.1C-P=6.08 Hz, .sup.1J.sub.1C-P=6.00 Hz,
C4), 42.47 (C3), 30.77 (C2), 16.45 (t, .sup.3J.sub.C-P=2.94 Hz,
C1); .sup.31P NMR (121.45 MHz, CDCl.sub.3, .delta.): 24.40 ppm.
##STR00094##
Example 5
Tetraethyl
(((3-hydroxypropyl)azanediyl)bis(methylene))bis(phosphonate)
(6)
This compound has been previously reported in: Cavero, E.,
Zablocka, M., Caminade, A. & Majoral, J. P. Design of
Bisphosphonate-Terminated Dendrimers. Eur. J. Org. Chem., 2759-2767
(2010); Chougrani, K., Boutevin, B., David, G., Seabrook, S. &
Loubat, C. Acrylate based anticorrosion films using novel
bis-phosphonic methacrylates. J. Polym. Sci., Part A: Polym. Chem.
46, 7972-7984 (2008); and Chougrani, K., Boutevin, B., David, G.
& Boutevin, G. New N,N-amino-diphosphonate-containing
methacrylic derivatives, their syntheses and radical
copolymerizations with MMA. Eur. Polym. J. 44, 1771-1781 (2008). To
a 20 mL glass screw cap vial, equipped with a magnetic stir bar was
added diethylphosphite (2.86 g, 20.74 mmol, 2.0 eq.) and
3-amino-1-propanol (0.768 g, 10.24 mmol,) and the mixture cooled to
0-5.degree. C. (ice bath). To the chilled solution was added
formalin, dropwise, via syringe (37%, 2.15 mL, 25.79 mmol, 2.5 eq.)
over 10 min maintaining the reaction temp under 10.degree. C. The
mixture was warmed, with stirring, to room temperature for 30 min,
then heated to 100.degree. C. for 60 min. Excess formaldehyde and
water were removed via rotovap and the crude material purified by
Dry Column Vacuum Chromatography (DCVC) on silica gel (20 g silica,
3.5 cm.times.4.5 cm) eluting with 100 mL EtOAc (20% MeOH/EtOAc).
Yield 50% (2.03 g); TLC (10% MeOH in EtOAc), R.sub.f=0.50; .sup.1H
NMR (400 MHz, CDCl.sub.3, .delta.): 4.18-4.09 (m, 8H, H6), 3.62 (t,
2H, J=6.6 Hz, H5), 3.17 (d, 4H, J=8.6 Hz, H4), 2.97 (t, 2H, J=6.6
Hz, H3), 1.61 (p, 2H, J=5.56 Hz, H2), 1.32 (t, 12H, J=7.1 Hz, H1)
ppm; .sup.31P NMR (121.45 MHz, CDCl.sub.3, .delta.): 25.0 ppm.
##STR00095##
Example 6
3-(bis((diethoxyphosphoryl)methyl)amino)propyl
4-methylbenzenesulfonate (7)
To a flame dried and evacuated 25 mL round bottom flask, equipped
with a magnetic stir bar was added sequentially trimethylamine
hydrochloride (0.045 g, 0.24 mmol, 0.24 eq.), DCM (1 mL),
triethylamine (0.58 mL, 2.5 mmol, 2.5 eq) the alcohol (0.375 g, 1
mmol) and the solution cooled to 0.degree. C. in an ice bath. To
the chilled, stirred solution was added, dropwise, tosyl chloride,
anhydrous DCM (2 mL) and the cloudy yellow mixture was stirred for
1 hr at room temperature at which point TLC showed disappearance of
the starting amine (5% MeOH in EtOAc, 10 mL). The reaction was
diluted with water (1.times.15 mL) and extracted with DCM (10 mL
total), the aqueous layer was re-extracted with EtOAC (15 mL) and
the combined organic layers were dried over MgSO.sub.4, filtered
and evaporated to give a yellow oil. The crude material was
purified by flash chromatography on silica gel (20 g silica, 1.5 cm
i.d) with gradient elution: 100% EtOAc (35 mL) then 5% MeOH:EtOAc
(90 mL) to obtain the title compound as a yellow oil. Yield 56.7%
(0.3003 g); TLC (5% MeOH in EtOAc), R.sub.f=0.42; .sup.1H NMR (400
MHz, CDCl.sub.3, .delta.): 7.76 (d, 2H, J=8.24 Hz, H9), 7.32 (d,
2H, J=8.04 Hz, H8), 4.13-4.05 (m, 10H, H7+H6), 3.08 (d, 4H, J=8.40
Hz, H5), 2.83 (t, 2H, J=6.70 Hz, H4), 2.42 (s, 3H, H3), 1.81 (t,
2H, J=6.65 Hz, H2), 1.30 (t, 12H, J=7.08 Hz, H1); .sup.13C NMR (100
MHz, CDCl.sub.3, .delta.): 44.67 (C11), 133.19 (C10), 129.81 (C8),
127.83 (C9), 68.50 (C7), 61.86 (t, .sup.2J.sub.C-P=3.19 Hz, C6),
52.67 (dd, .sup.1J.sub.C-P=6.02 Hz, C5), 52.67 (C4), 27.22 (C2),
21.57 (C3), 16.46 (t, .sup.3J.sub.C-P=2.78 Hz, C1) ppm; .sup.31P
NMR (121.45 MHz, CDCl.sub.3, .delta.): 24.56 ppm.
##STR00096##
Example 7
Tetraethyl
(((3-(dimethylamino)propyl)azanediyl)bis(methylene))bis(phospho-
nate) (8)
To a 20 mL glass screw cap vial equipped with a magnetic stir bar
containing the bromo amino bisphosphonate (0.954 g, 1.8 mmol) was
added NHMe.sub.2 (5.6 M in EtOH, 2.5 mL, excess) followed by
H.sub.2O (0.5 mL) and the clear mixture was stirred at reflux
sealed for 1.5 hr, at which point TLC showed disappearance of the
starting material (1% NH.sub.4.sup.+OH.sup.- in Acetone, 10 mL,
R.sub.f=0.95). The cooled yellow reaction diluted with water
(1.times.20 mL, pH was 11) and extracted with CHCl.sub.3
(2.times.30 mL), dried over MgSO.sub.4, filtered and evaporated to
give an orange oil. The title compound was isolated >98% purity
(.sup.1H and .sup.31P NMR) and required no further purification.
Yield 62% (0.4461 g); TLC (1% NH.sub.4.sup.+OH.sup.- in Acetone, 10
mL) or (20% MeOH (6% NaBr): MeCN, R.sub.f=0.47; .sup.1H NMR (400
MHz, CDCl.sub.3, .delta.): 4.15-4.06 (m, 8H, H7), 3.11 (d, 4H,
J=8.9 Hz, H6), 2.80 (t, 2H, J=6.8 Hz, H5), 2.27 (t, 211, J=7.5 Hz,
H4), 2.18 (s, 6H, H3), 1.61 (p, 2H, J=7.15 Hz, H2), 1.28 (t, 12H,
J=7.0 Hz, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, .delta.):
61.8 (t, .sup.2J.sub.CP=3.3 Hz, C7), 57.24 (C4), 55.03 (C5), 50.92
(dd, .sup.1J.sub.CP=7.1 Hz, C6), 49.36 (dd, .sup.1J.sub.CP=6.7 Hz,
C6), 45.48 (C3), 25.65 (C2), 16.48 (t, .sup.3J.sub.CP=2.8 Hz, C1)
ppm; .sup.31P NMR (121.45 MHz, CDCl.sub.3, .delta.): 24.89 ppm.
##STR00097##
Example 8
N-(3-(bis((diethoxyphosphoryl)methyl)amino)propyl)-N,N-dimethyloctadecan-1-
-aminium (9)
To a flame dried and evacuated 20 mL screw cap vial, equipped with
a magnetic stir bar was added a mixture of bromoaminobisphosphonate
(0.2 g, 0.51 mmol) and DMOA (0.143 g, 0.6 mmol, 1.19 eq.) was which
was sealed and heated to 100.degree. C. on a sand batch. After 1
hr, TLC showed the disappearance of the starting amine (5% MeOH in
EtOAc, 10 mL). The mixture was partitioned between hexanes
(.about.7 mL) and MeOH/H.sub.2O (4:1, 5 mL), the bottom yellow
methanolic layer was separated and concentrated (2.times.5 mL ACN
to azeotrope excess water) to afford a yellow oily solid (0.3082
g). The crude material was purified by Dry Column Vacuum
Chromatography (DCVC) on silica gel (20 g silica, 3.5 cm.times.4.5
cm) pre-washed with 60 mL 20% MeOH (NaBr 6%): ACN then eluting with
the same eluent (1st 40 mL removed upper R.sub.f impurity, product
was obtained in the next 7 fractions total 95 mL) as a yellow oil
after filtering off NaBr through a pad of Celite washing with
CHCl.sub.3. Yield 46.1% (0.162 g). TLC (20% MeOH (NaBr 6%): ACN),
R.sub.f=0.5; .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.) 4.15-4.08
(m, 8H, H11), 3.72-3.69 (m, 2H, H10), 3.55-3.51 (m, 2H, H9), 3.33
(s, 6H, H8), 3.12-3.08 (m, 4H, H7), 2.99-2.97 (m, 2H, H6), 2.0-1.98
(m, 2H, H5), 1.74-1.71 (m, 2H, H4), 1.24-1.20 (br m, 42H, H2, H3,
overlap) 0.88-0.83 (m, 3H, H1) ppm; .sup.13C NMR (100 MHz,
CDCl.sub.3, .delta.): 62.15-62.0 (overlap, C7, C9, C10, C11), 51.1
(C6, C8 overlap), 31.91 (C2 overlap), 29.67-29.27 (C2 overlap),
22.84 (C4), 22.67 (C5), 16.58-16.50 (m, J.sub.CP=unresolved, C3),
14.10 (C1) ppm; .sup.31P NMR (121.45 MHz, CDCl.sub.3, .delta.)
24.40 ppm. HRMS-DART (m/z): [M.sup.+] calculated for
C.sub.33H.sub.73N.sub.2O.sub.6P.sub.2, 655.4937. found,
655.4938.
##STR00098## Synthesis of .alpha.-Amino Bisphosphonic Quats-Via
Triazinane Intermediate.
##STR00099##
Example 9
3,3',3''-(1,3,5-triazinane-1,3,5-triyl)tris(propan-1-ol) (10)
To a 125 mL round bottom flasks, formalin (0.813 mL, 10 mmol) was
added to a solution of 3-amino-1-propanol (0.751 g, 10 mmol) in
MeCN (10 mL). The reaction was stirred at room temperature
overnight. Evaporation of volatiles followed by (DCVC) on silica
gel (20 g silica, 3.5 cm.times.4.5 cm) eluting with 5%
NH.sub.4.sup.+OH.sup.- in acetone (50 mL) then collecting (150 mL)
provided pure product. Yield 92% (0.8 g). TLC (5%
NH.sub.4.sup.+OH.sup.- in acetone, 10 mL), R.sub.f=0.3; .sup.1H NMR
(400 MHz, CDCl.sub.3, .delta.): 4.37 (s, 6H, H5), 3.84 (t, 6H,
J=7.0 Hz, H4), 3.71 (s, 3H, H3), 2.97 (t, 6H, J=5.6 Hz, H2), 1.60
(q, 6H, J=5.40 Hz, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3,
.delta.): 83.06 (C4), 68.12 (C3), 47.78 (C2), 22.45 (C1) ppm.
##STR00100##
Example 10
3,3',3''-(1,3,5-triazinane-1,3,5-triyl)tris(N,N-dimethylpropan-1-amine)
(11)
To a 125 mL round bottom flask, paraformaldehyde (1.652 g, 55 mmol,
1.1 eq.) was added to a solution of N,N-dimethylpropane-1,3-diamine
(6.29 mL, 50 mmol) in toluene (15 mL). The reaction was refluxed
using a dean-stark trap for 1.5 hr. Toluene was evaporated and a
portion of the residue (1.9757 g) was partitioned between
CHCl.sub.3 (15 mL) and water (5 mL). The organic layer was
separated, dried with MgSO.sub.4 and concentrated to give a clear
oil. Yield 66% (1.3067 g). TLC (20% MeOH in EtOAc, 10 mL),
R.sub.f=0.05; .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.): 3.29
(brs, 6H, H5), 2.40 (t, 6H, J=7.5 Hz, H4), 2.25 (t, 6H, J=7.5 Hz,
H3), 2.18 (s, 18H, H2), 1.59 (p, 6H, J=7.5 Hz, H1) ppm; .sup.13C
NMR (100 MHz, CDCl.sub.3, .delta.): 74.65 (C5), 57.83 (C3), 50.78
(C4), 45.54 (C2), 25.88 (C1) ppm.
.beta.-Amino Bisphosphonic Acid Antimicrobials (.beta.-ABPQ)
Scheme 3.0 Synthesis of .beta.-Amino Bisphosphonic Quats.
##STR00101##
Example 11
Tetraethyl
(((3-hydroxypropyl)azanediyl)bis(ethane-2,1-diyl))bis(phosphona-
te) (12)
This compound has been previously reported in: Pothayee, N. et al.
Synthesis of `ready-to-adsorb` polymeric nanoshells for magnetic
iron oxide nanoparticles via atom transfer radical polymerization.
Polymer 52, 1356-1366 (2011). To a 25 mL round bottom flask
equipped with a magnetic stir bar, was added a stirred solution of
the primary amine (0.448 g, 5.9 mmol) in distilled water (5 ml) at
room temperature. Two equivalents of diethyl vinylphosphonate
(1.637 g, 12.03 mmol, 2.01 eq.) was then added and the reaction
stirred at room temperature overnight. The reaction was transferred
to a 125 mL round bottom flask along with 30 mL MeCN and evaporated
to a clear oil (2.1446 g, containing .apprxeq.7% starting material
by .sup.31P NMR). The crude material was purified by Dry Column
Vacuum Chromatography (DCVC) on silica gel (20 g silica, 3.5
cm.times.4.5 cm) eluting with 30% MeOH:EtOAc (240 mL). The
fractions containing the title compound were filtered through a pad
of Celite evaporated to obtain the title compound as a clear oil.
Yield 95% (1.9687 g); TLC (30% MeOH:EtOAc), R.sub.f=0.33; .sup.1H
NMR (400 MHz, CDCl.sub.3, .delta.): 4.16-4.03 (m, 8H, H7),
3.75-3.67 (m, 3H, H6), 2.83-2.75 (m, 4H, H5), 2.64-2.59 (m, 2H,
H4), 1.97-1.86 (m, 4H, 1H), 1.68 (q, 2H, J=5.58 Hz, H2), 1.31 (t,
12H, J=7.06 Hz, H1) ppm; .sup.31P NMR (121.45 MHz, CDCl.sub.3,
.delta.): 30.00 ppm.
##STR00102##
Example 12
Tetraethyl
(((3-(dimethylamino)propyl)azanediyl)bis(ethane-2,1-diyl))bis(p-
hosphonate) (13)
Synthesized from alcohol via mesylate and dimethylamine, see
Tetraethyl
(((3-(dimethylamino)propyl)azanediyl)bis(methylene))bis(phosphonate)
procedure; .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.): 4.11-3.99
(m, 8H, H8), 2.76-2.69 (m, 4H, H7), 2.40 (t, 2H, J=7.12 Hz, H6),
2.22 (t, H5, J=7.14 Hz, H5), 2.16 (s, 6H, H4), 1.91-1.81 (m, 4H,
H3), 1.60-1.53 (m, H2, 2H), 1.28 (t, H1, J=7.04 Hz) ppm; .sup.31P
NMR (121.45 MHz, CDCl.sub.3, .delta.): 30.57 ppm.
Bisphosphonic Acid Antimicrobials (BPQ).
Syntheses of Bisphosphonic Quats--Direct Alkylation of
Tetraethylmethylene Bisphosphonate.
##STR00103## ##STR00104## Syntheses of Bisphosphonic Quats--Via
.alpha.-Mesylate.
##STR00105##
Example 13
Diethyl (4-(1,3-dioxoisoindolin-2-yl)-1-hydroxybutyl)phosphonate
(14)
A 25 mL round bottom flask, equipped with a magnetic stir bar and a
condenser was charged with the aldehyde (2.281 g, 10.5 mmol),
diethylphosphonate (1.523 g, 11.03 mmol, 1.05 eq.), K.sub.2CO.sub.3
(0.073 g, 0.53 mmol, 0.05 eq.) and MeCN (5 mL). The heterogeneous
solution was stirred at 60.degree. C. for 15 min at which point TLC
showed disappearance of the starting aldehyde (60% EtOAc in
hexanes, 10 mL). The reaction was cooled to 0.degree. C., filtered
and evaporated. The resulting yellow oil solidified under high
vacuum (10 min) and was recrystallized from hot EtOAc (5 mL) after
cooling for 20 min at 0.degree. C. Yield 69.1% (2.5787 g); TLC (60%
EtOAc in hexanes), R.sub.f=0.2; .sup.1H NMR (400 MHz, CDCl.sub.3,
.delta.): 7.83-7.79 (m, 4H, H8), 7.71-7.64 (m, 4H, H7), 4.18-4.07
(m, 4H, H6), 3.89 (quintet, J=4.59 Hz, 1H, H5), 3.77-3.66 (m, 2H,
H4), 2.05-1.95 (m, 2H, H3), 1.87-1.68 (m, 2H, H2), 1.29 (t, J=7.08
Hz, 6H, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, .delta.):
168.37 (C10), 133.90 (C9), 132.10 (C7), 123.18 (C8), 68.12 (C5),
62.65 (q .sup.2J.sub.C-P=7.3 Hz, C6), 37.52 (C2), 28.43 (d,
.sup.1J.sub.C-P=1.45 Hz, C5), 25.02 (C3), 24.96 (C4), 16.46 (d,
.sup.3J.sub.C-P=5.20 Hz, C1) ppm; .sup.31P NMR (121.45 MHz,
CDCl.sub.3, .delta.): 24.64 ppm.
##STR00106##
Example 14
1-(diethoxyphosphoryl)-4-(1,3-dioxoisoindolin-2-yl)butyl
methanesulfonate (15)
To a flame dried and evacuated 50 mL round bottom flask, equipped
with a magnetic stir bar was added sequentially trimethylamine
hydrochloride (0.062 g, 0.62 mmol, 0.20 eq.), DCM (2 mL),
triethylamine (0.65 mL, 4.63 mmol, 1.5 eq.) and the alcohol (1.097
g, 3.09 mmol) and the solution was cooled to 0.degree. C. in an ice
bath. To the chilled stirred solution was added, dropwise, mesyl
chloride (0.25 mL, 3.70 mmol, 1.2 eq.) in anhydrous DCM (2 mL) and
the cloudy yellow mixture was stirred for 20 min at room
temperature at which point TLC showed disappearance of the starting
amine (10% MeOH in EtOAc, 10 mL). The reaction was diluted with
water (1.times.10 mL) and extracted with DCM (2.times.5 mL total),
the combined organic layers were dried over MgSO.sub.4, filtered
and evaporated to give a yellow oil. The crude product (1.409 g)
containing traces of DCM and excess mesyl chloride by .sup.1H NMR,
was placed under high vacuum at 60.degree. C. for 1 hr. Yield 93%
(1.2013 g); TLC (10% MeOH in EtOAc), R.sub.f=0.5; .sup.1H NMR (400
MHz, CDCl.sub.3, .delta.): 7.85-7.81 (m, 2H, H9), 7.73-7.70 (m, 2H,
H8), 4.94-4.88 (m, 1H, H7), 4.20-4.15 (m, 4H, H6), 3.77-3.70 (m,
2H, H5), 3.15 (s, 3H, H4), 1.95-1.82 (m, 4H, H2, H3), 1.41-1.25 (m,
6H, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, .delta.): 168.26
(C11), 133.98 (C10), 132.08 (C9), 123.22 (C8), 74.79 (C7), 63.31
(q, .sup.2J.sub.C-P=7.3 Hz, C6), 52.56 (C2), 39.11 (C4), 27.58
(C3), 24.45 (d, .sup.2J.sub.C-P=11.67 Hz C5), 16.45
(.sup.2J.sub.C-P=5.20 Hz, C1) ppm; .sup.31P NMR (121.45 MHz,
CDCl.sub.3, .delta.): 17.63 ppm.
##STR00107## Syntheses of Bisphosphonic Quats--Via Michael Addition
to a Vinylbisphosphonate.
##STR00108##
Example 15
Tetraethyl ethene-1,1-diylbis(phosphonate) (16)
This compound has been previously reported in: Gebbia, N., Simoni,
D., Dieli, F., Tolomeo, M. & Invidiata, F. P. Geminal
bisphosphonates, their preparation and their use in the field of
oncology. PCT Int. Appl., 38 (2009); and Simoni, D. et al. Design,
Synthesis, and Biological Evaluation of Novel Aminobisphosphonates
Possessing an in Vivo Antitumor Activity Through a T
Lymphocytes-Mediated Activation Mechanism. J. Med. Chem. 51,
6800-6807 (2008). A 50 mL round bottom flask was charged with
paraformaldehyde (6.3 g, 200 mmol, 4.0 eq.) and diethylamine (5.2
mL, 50 mmol, 1 eq.) in methanol (125 mL) and the mixture was
stirred under reflux until a clear solution was obtained (.about.5
min). Tetraethylmethylene bisphosphonate was added via syringe
(12.4 mL, 50 mmol, 1.0 eq.) and the solution was refluxed overnight
(24 hr). The clear solution was concentrated in vacuo and then
re-evaporated from toluene (2.times.10 mL) completely removing
residual MeOH to give the intermediate methyl ether as a clear oil.
The residue was dissolved in toluene (100 mL), treated with
p-toluenesulphonic acid (38 mg, 0.02 mmol), and refluxed through a
Dean-Stark trap overnight. The orange solution was concentrated in
vacuo, dissolved in chloroform (50 mL), washed with water
(2.times.10 mL), dried over MgSO.sub.4, and concentrated in vacuo.
A portion of the orange oil (6 g) was further distilled under high
vacuum. Yield 90% (5.4 g); TLC (EtOAc), R.sub.f=0.2; .sup.1H NMR
(400 MHz, CDCl.sub.3, .delta.): 7.02-6.86 (m, H3, 2H), 4.10-4.05
(m, H2, 8H), 1.34-1.21 (m, H1, 12H) ppm; .sup.13C NMR (100 MHz,
CDCl.sub.3, .delta.): 149.04 (m, C4), 133.77-129.71 (m, C3), 62.54
(t, .sup.2J.sub.C-P=2.88 Hz, C2), 16.17 (t, .sup.3J.sub.C-P=3.15
Hz, C1) ppm; .sup.31P NMR (121.45 MHz, CDCl.sub.3, .delta.): 21.0
ppm.
##STR00109## Syntheses of Bisphosphonic Quats--Via Phosphorylation
of a Mono-Phosphonate.
##STR00110##
Example 16
Diethyl (4-(1,3-dioxoisoindolin-2-yl)butyl)phosphonate (17)
This compound has been previously reported in Hara, T., Durell, S.
R., Myers, M. C. & Appella, D. H. Probing the Structural
Requirements of Peptoids That Inhibit HDM2-p53 Interactions. J. Am.
Chem. Soc. 128, 1995-2004 (2006). To a flame dried 50 mL round
bottom flask equipped with a reflux condenser was added
N-(4-Bromobutyl)-phthalimide (5 g, 17.7 mmol, 1.0 eq.) followed by
triethylphosphite (18.24 mL, 106.3 mmol, 6 eq.) and the mixture was
refluxed overnight (175.degree. C.) using a sand bath. The reaction
was then cooled to room temperature and excess triethylphosphite
was vacuum distilled using a shortpath distillation head attached
to a Schlenk line. Once all of the excess triethylphosphite stopped
distilling, the title compound was placed under high vacuum
(.about.30 min) until it solidified. Further recrystallization from
EtOAc (5 mL) at -20.degree. C. provided pure product. Colourless
crystals. Yield: 90% (5.4263 g). TLC (5% MeOH: EtOAc),
R.sub.f=0.90; .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.): 7.82-7.77
(m, 2H, H8), 7.70-7.66 (m, 2H, H7), 4.11-3.98 (m, 4H, H6), 3.66 (m,
J=7.0 Hz, 2H, H5), 1.81-1.71 (m, 4H, H4, H3), 1.67-1.56 (m, 2H,
H2), 1.27 (t, J=7.1 Hz, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3,
.delta.): 168.29 (C10), 133.91 (C9), 132.06 (C7), 123.18 (C8),
61.48 (d, .sup.2J.sub.C-P=6.5 Hz, C6), 37.23 (d,
.sup.1J.sub.C-P=1.33 Hz, C5), 29.25 (d, .sup.2J.sub.C-P=16.77 Hz
C4), 24.44 (C2), 19.81 (d, .sup.3J.sub.C-P=5.01 Hz, C3), 16.42 (d,
.sup.3J.sub.C-P=6.01 Hz, C1) ppm; .sup.31P NMR (121.45 MHz,
CDCl.sub.3, .delta.): 31.48 ppm.
##STR00111##
Example 17
2-(3-bromopropoxy)tetrahydro-2H-pyran (18)
This compound has been previously reported in: Pinchuk, A. N. et
al. Synthesis and Structure-Activity Relationship Effects on the
Tumor Avidity of Radioiodinated Phospholipid Ether Analogues. J.
Med. Chem. 49, 2155-2165 (2006). To a stirred solution inside a 125
mL round bottom flask containing 3-bromo-1-propanol (6.95 g, 50
mmol, 1 eq.) in DCM (25 mL) was added 3,4-dihydropyran (5.93 mL, 65
mmol, 1.3 eq.). The mixture was stirred overnight at room
temperature at which point TLC showed disappearance of
3-bromo-1-propanol (20% EtOAc in hexanes, 10 mL, KMnO.sub.4). The
reaction was evaporated and the crude material was purified by
flash chromatography on silica gel (20 g silica, 1.5 cm i.d)
eluting with 10% EtOAc: hexanes (100 mL) to obtain the title
compound as a clear oil. Yield 86.4% (9.637 g); TLC (20% EtOAc in
hexanes), R.sub.f=0.85; .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.):
4.59 (t, 1H, J=3.52 Hz, H7), 3.90-3.81 (m, 2H, H6), 3.55-3.47 (m,
4H, H4+H5), 2.16-2.08 (m, 2H, H3), 1.90-1.64 (m, 2H, H2), 1.57-1.50
(m, 4H, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, .delta.): 98.90
(C7), 64.88 (C6), 62.26 (C5), 32.90 (C3), 30.59 (d, .sup.2J=6.04
Hz, C4), 25.41 (C2), 19.48 (C1) ppm.
##STR00112##
Example 18
Diethyl (3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)phosphonate
(19)
This compound has been previously reported in: Voigt, M. et al.
Surface Functionalization of ZnO Nanorods with C60 Derivatives
Carrying Phosphonic Acid Functionalities. J. Phys. Chem. C 115,
5561-5565 (2011). To a 20 mL conical round bottom flask was added
the THP protected bromopropylalcohol (4.55 g, .about.20 mmol)
followed by excess triethyl phosphite (10.0 mL, 60.0 mmol, 3.0
eq.). The reaction was heated at reflux (175.degree. C.) overnight.
Excess triethyl phosphite was vacuum distilled at reduced pressure
providing the pure product as a clear, viscous oil. Yield 89% (5
g). .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.): 4.57 (t, 2H, J=3.54
Hz, H8), 4.17-4.04 (m, 4H, H7), 3.86-3.72 (m, 2H, H6), 3.52-3.40
(m, 2H, H5), 1.93-1.77 (m, 4H, H4+H3), 1.73-1.67 (m, 4H, H2), 1.31
(t, 6H, J=7.04 Hz, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3,
.delta.): 98.86 (C8), 64.85 (C6), 62.21 (C5), 32.90 (C3), 30.66
(C4), 25.43 (C2), 19.71 (C1) ppm.
##STR00113##
Example 19
Diethyl (4-(dimethylamino)butyl)phosphonate (20)
A mixture of diethyl (4-bromobutyl)phosphonate (5.0 g, 18.3 mmol)
with NHMe.sub.2 (5.6 M in EtOH, 10 mL, excess) was placed, with a
magnetic stirring bar, into a 20 ml glass reaction tube and sealed.
The reaction mixture was heated in the Biotage.RTM. Initiator
Microwave Synthesizer at 110.degree. C. (5 min). Volatiles were
removed on a rotovap and the crude material was purified by Dry
Column Vacuum Chromatography (DCVC) on silica gel (50 g silica, 3.5
cm.times.5.5 cm) eluting first with 150 mL (10% MeOH/acetone)
collecting 250 mL (10% MeOH/10% NH.sub.4.sup.+OH.sup.-/80%
acetone). Yield 81% (3.55 g); TLC (20%
NH.sub.4.sup.+OH.sup.-/acetone), Rf=0.50; .sup.1H NMR (400 MHz,
CDCl.sub.3, .delta.): 4.06-3.92 (m, 4H, H7), 2.85 (t, 2H, J=7.96
Hz, H6), 2.62 (s, 6H, H5), 1.83-1.53 (m, 6H, H4-H2 overlap), 1.22
(t, 6H, J=7.04 Hz, H1) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3,
.delta.): 61.71 (d, .sup.2J.sub.CP=6.60 Hz, C7), 57.68 (C6), 43.58
(C5), 25.68 (t, .sup.1J.sub.CP=14.07 Hz, C2), 24.13 (C4), 19.90 (d,
.sup.2J.sub.CP=4.60 Hz, C3), 16.41 (d, .sup.3J.sub.CP=6.22 Hz, C1)
ppm; .sup.31P NMR (121.45 MHz, CDCl.sub.3, .delta.): 30.89 ppm.
##STR00114## Syntheses of Bisphosphonic Quats--Via
Triethylorthoformate.
##STR00115##
Example 20
Tetraethyl dimethylaminomethylenediphosphonate (21)
This compound has been previously reported in: O'Boyle, N. M. et
al. Synthesis, evaluation and structural studies of
antiproliferative tubulin-targeting azetidin-2-ones. Bioorg. Med.
Chem. 19, 2306-2325 (2011). To a chilled solution of
dimethylformamide (3.87 mL, 50 mmol) in DCM (75 mL) was added
dropwise with stirring a solution of oxalyl chloride (25 mL, 2M in
DCM, 50 mmol). Following addition, the mixture was allowed to warm
to room temperature and stirred for 1 h. Triethyl phosphite (18.77
mL, 109.5 mmol, 2.19 eq.) was then added dropwise with stirring.
After 1 hr the mixture was concentrated under reduced pressure. The
product was obtained as a yellow oil in 75.5% yield. .sup.1H NMR
(400 MHz, CDCl.sub.3, .delta.): 4.21-4.14 (m, 8H, H4), 3.22 (dt,
1H, .sup.1J=24.98 Hz, .sup.2J=24.98 Hz, H3), 2.58 (s, 6H, H2), 3.18
(dt, 12H, J=7.07 Hz, J=7.06 Hz, 1H) ppm; .sup.13C NMR (100 MHz,
CDCl.sub.3, .delta.): 62.70 (t, .sup.1J.sub.C-P=3.05 Hz, C3), 62.40
(t, .sup.2J.sub.C-P=3.61 Hz, C4), 44.11 (t, .sup.3J.sub.C-P=4.71
Hz, C2), 16.39 (q, .sup.3J.sub.C-P=3.01 Hz, C1) ppm; .sup.31P NMR
(121.45 MHz, CDCl.sub.3, .delta.): 19.15 ppm.
Multidentate Phosphonic Acid Antimicrobial Structures Bisphosphonic
Acid Antimicrobials:
##STR00116##
N-(4,4-diphosphonobutyl)-N,N-dimethyloctadecan-1-aminium bromide.
(22)
##STR00117##
##STR00118##
N-(3-(bis(phosphonomethyl)amino)propyl)-N,N-dimethyloctadecan-1-aminium
bromide (23)
##STR00119##
N-(3-(bis(2-phosphonoethyl)amino)propyl)-N,N-dimethyloctadecan-1-aminium
bromide (24)
##STR00120## Trisphosphonic Acid Antimicrobials:
##STR00121##
N,N-dimethyl-N-(4,4,4-triphosphonobutyl)octadecan-1-aminium bromide
(25)
##STR00122##
##STR00123##
Tris ether phosphonic acid-1-N,N-dimethyloctadecan-1-aminium
bromide. (26)
##STR00124##
##STR00125##
N-(3-((1,3-bis(3-phosphonopropoxy)-2-((3-phosphonopropoxy)methyl)propan-2--
yl)amino)-3-oxopropyl)-N,N-dimethyloctadecan-1-aminium bromide.
(27)
##STR00126## Tetraphosphonic Acid Antimicrobials:
##STR00127##
N-(3-(bis(2,2-diphosphonoethyl)amino)propyl)-N,N-dimethyloctadecan-1-amini-
um bromide. (28)
##STR00128##
N-(3-(bis(2-(bis(2-phosphonoethyl)amino)ethyl)amino)propyl)-N,N-dimethyloc-
tadecan-1-aminium bromide. (29)
##STR00129## Dansyl-Phosphonic Acid Antimicrobials--UV
Detection.
##STR00130## Synthesis of Dansylphosphonic Acid Quats (DPQ).
##STR00131##
Example 21
5-(dimethylamino)-N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide
(30)
This compound has been previously reported in: Wang, X. &
Schneider, H. Binding of dansylamide derivatives to nucleotides and
nucleic acids. J. Chem. Soc., Perkin Trans. 2, 1323-1328 (1998). To
a flame dried 500 mL round bottom flask with a reflux condenser
connected to an inert atmosphere manifold anhydrous DCM (300 mL)
was added followed by dansyl chloride (10.0 g, 37.07 mmol),
triethylamine (.about.8 mL, 55.61 mmol). While the solution was
stirring at room temperature, 3-(dimethylamino)propylamine (7.0 ml,
55.61 mmol) was added drop wise via an inert syringe resulting in a
colour change from orange to lime-green. After stirring for 1
h--HCl (g) was bubbled through the solution until pH 2 was reached.
The resulting mixture was evaporated to dryness, then re-dissolved
in saturated brine water (100 mL) and basified to pH 11 with 6N
NaOH (15 mL) at 0.degree. C. until white-yellow precipitate was
observed. The mixture was refrigerated overnight enhancing further
precipitation of product. The precipitate was filtered washing with
water and the filtrate was extracted with DCM (500 mL) and
evaporated to dryness to afford a white solid in 97% yield (12.1
g). (Recrystallized using 80% EtOH/H.sub.2O). Mp=122-124.degree.
C.; TLC (5% NH.sub.4.sup.+OH.sup.-:Acetone), R.sub.f=0.72: .sup.1H
NMR (400 MHz, CDCl.sub.3, .delta.): 8.52 (ddd, .sup.1J=1.5 Hz,
.sup.2J=1.5 Hz, .sup.3J=8.5 Hz, 1H, H9), 8.31 (ddd, .sup.1J=1.0 Hz,
.sup.2J=1.0 Hz, .sup.3J=8.5 Hz, 1H, H6), 8.23 (dd, .sup.1J=1.5 Hz,
.sup.2J=7.0 Hz, 1H, H11), 7.50-7.58 (m, 2H, H(5, 10)), 7.18 (dd,
.sup.1J=1.0, .sup.2J=7.5, 1H, H4), 2.97 (t, J=5.5 Hz, 2H, H14),
2.90 (s, 6H, H(1,2)), 2.22 (t, J=5.5 Hz, 2H, H16), 2.14 (s, 6H,
H(17,18)), 1.57 (p, .sup.1J=5.8 Hz, 2H, H15) ppm; .sup.13C NMR (100
MHz, CDCl.sub.3, .delta.): 151.9 (C3), 134.7 (C12), 129.98-129.65
(m, overlap, C5, C7, C9, C10, C11), 123.1 (C6), 119.0 (C8), 115.0
(C4), 59.6 (C16), 45.4 (C1, C2, C17, C18), 44.5 (C14), 24.6 (C15)
ppm. HRMS-DART (m/z): [M.sup.+] calculated for
C.sub.17H.sub.26N.sub.3O.sub.2S.sub.1, 336.1736. found,
336.1745.
##STR00132##
Example 22
3-(diethoxyphosphoryl)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)pr-
opyl)-N,N-dimethylpropan-1-aminium bromide (31)
To a flame dried 20 mL glass vial, ACN (3 mL) was added followed by
5-(dimethylamino)-N-(3-(dimethylamino)propyl)-naphthalene-1-sulfonamide
(335.46 mg, 1 mmol). While stirring
diethyl(3-bromopropyl)phosphonate (=0.4 mL, 2 mmol) was added via
an inert syringe, and the vial was capped. The solution was stirred
for 48 hr at 110.degree. C., after which the solution turned to
pale-yellowish oil. The solution was cooled to room temperature,
washed with Et.sub.2O (3.times.10 mL) to remove soluble impurities
from the crude product. The product was further dried using rotary
evaporator resulting in orange gummy oil in 70% yield (416.5 mg)
Mp=34-36.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3, .delta.):
8.52 (ddd, .sup.1J=1.5 Hz, .sup.2J=1.5 Hz, .sup.3J=8.5 Hz, 1H, H9),
8.31 (ddd, 1 J=1.0 Hz, 2J=1.0 Hz, .sup.3J=8.5 Hz, 1H, H6), 8.23
(dd, .sup.1J=1.5 Hz, .sup.2J=7.0 Hz, 1H, H11), 7.50-7.58 (m, 2H,
H(5, 10)), 7.18 (dd, .sup.1J=1.0, .sup.2J=7.5, 1H, H4), 4.12-4.03
(m, 4H, H(22,23)), 3.68-3.57 (m, 4H, H(16,19)), 3.18 (s, 6H, H(17,
18)), 3.10-3.03 (m, 2H, H14), 2.87 (s, 6H, H(1, 2)), 2.02 (brs, 4H,
H(15,20)), 1.89-1.80 (m, 2H, H21), 1.29 (t, J=7.06 Hz, 6H,
H(24,25)); .sup.13C NMR (100 MHz, CDCl.sub.3, .delta.): 151.79
(C3), 134.62 (C12), 129.79-128.60 (m, overlap, C5, C7, C9, C10,
C11), 123.28 (C6), 119.28 (C8), 115.30 (C4), 62.23-62.16 (overlap,
C16, C19, C22, C23), 51.31 (C17, C18), 45.43 (C1, C2), 39.73 (C14),
24.75-22.83 (C15, C20, C21), 16.45 (.sup.2J=5.99, C24, C25) ppm;
HRMS-DART (m/z): [M.sup.+] calculated for
C.sub.24H.sub.41N.sub.3O.sub.5P.sub.1S.sub.1, 514.250. found,
514.251.
##STR00133##
Example 23
3-(5-(dimethylamino)naphthalene-1-sulfonamido)-N,N-dimethyl-N-(3-phosphono-
propyl)propan-1-aminium bromide (32)
Inside a flame dried and evacuated 20 mL screw cap vial
N-(3-(diethoxyphosphoryl)propyl)-N,N-dimethyloctadecan-1-ammonium
bromide (0.35 g, 0.58 mmol) was dissolved in anhydrous DCM (5 mL).
To the clear stirred solution was added TMSBr (0.23 mL, 1.76 mmol,
3.0 eq.) through a rubber septum via syringe and the reaction was
stirred at room temperature overnight. Completion of the reaction
was followed by .sup.31P after which the reaction was quenched with
EtOH (10 mL) and stirred for 1 h followed by addition of H.sub.2O
(1 mL). Volatiles were removed with a rotovap connected to a high
vacuum Schlenk line and the crude product was triturated with
Et.sub.2O (2.times.10 mL) to remove brown colored impurities.
Further purification entailed extraction with
NH.sub.4.sup.+OH.sup.-:H.sub.2O (1:10, 10 mL) and washing with
Et.sub.2O (1.times.5 mL). The aqueous fluorescent layer was
evaporated from ACN (1.times.50 mL) to give the pure product. Yield
(0.25 g, 79%). Light yellow solid. Mp=165-168.degree. C.; .sup.1H
NMR (400 MHz, MeOD, .delta.): 8.52 (ddd, 1J=1.5 Hz, 2J=1.5 Hz,
3J=8.5 Hz, 1H, H9), 8.31 (ddd, .sup.1J=1.0 Hz, .sup.2J=1.0 Hz,
.sup.3J=8.5 Hz, 1H, H6), 8.23 (dd, .sup.1J=1.5 Hz, .sup.2J=7.0 Hz,
1H, H11), 7.50-7.58 (m, 2H, H(5, 10)), 7.18 (dd, .sup.1J=1.0,
.sup.2J=7.5, 1H, H4), 3.36-3.26 (s, m overlap, 6H, H(17, 18,19)),
3.18-3.14 (m, 2H, H16), 2.97 (t, J=6.02 Hz, 2H, H14), 2.89 (s, 6H,
H(1, 2)), 1.93-1.86 (m, 4H, H(15,20)), 1.57-1.49 (m, 2H, H21), ppm;
.sup.13C NMR (100 MHz, MeOD, .delta.): 133.80 (C3), 129.76-128.40
(m, overlap, C5, C7, C9, C10, C11, C12), 124.54 (C6), 119.81 (C8),
116.59 (C4), 64.13 (C19), 61.33 (C16), 45.08 (C17, C18), 34.04 (C1,
C2), 24.77 (C14), 21.96 (C21), 16.85 (.sup.2J=3.24, C15) ppm;
.sup.31P NMR (121.45 MHz, MeOD, .delta.): 26.92 ppm; HRMS-DART
(m/z): [M.sup.+]+ calculated for C.sub.23H.sub.51NO.sub.3P,
420.3601. found, 420.3608.
Synthesis of Bisphosphonic Acid Dansylphosphonic Acid Quats
(BPDPQ)
##STR00134##
Example 24
Applying Phosphonate Antimicrobial Coatings
The following general procedure may be used to treat a surface with
a phosphonate antimicrobial coating:
1) Surface Pretreatment/Passivation modifies a metal surface by
creating a metal hydroxide layer to provide more binding sites on
the surface of the material to which phosphonic acid compounds can
bind can be achieved by mechanical means such as sanding, cleaning,
or degreasing; chemical means such as treatment with piranha
solution (a 3:1 H.sub.2SO.sub.4/H.sub.2O.sub.2 for about 10-30
minutes) or by activation by heating the surface (about 160.degree.
C. in air for about 1-2 hours). 2) Coating application by dip
coating at room temperature to about 50.degree. C. and about 1 to
about 10 mM solution of phosphonate/phosphonic acid in water or
alcohol; aerosol spraying an about 1 to about 10 mM solution of
phosphonate/phosphonic acid in water or alcohol solution; or by
vapor deposition of volatile phosphonate/phosphonic acid on the
passivated surface. 3) Annealing to create strong molecule-material
surface bonds by a thermal cure at about 100 to about 140.degree.
C. in an oven, or preferably, 120.degree. C. for about 18 hours
under about 0.1 Torr reduced pressure. 4) Washing the treated
surface to remove unbound phosphonate/phosphonic acid material via
immersion/dipping with alcohol or water often with the use of
sonication. 5) Repeating steps 2, 3 and 4 until such time as the
surface is sufficiently coated with the phosphonate antimicrobial
coating
The following are examples of pretreatment and coating procedures
for a given substrate that may be applicable to the present
invention:
Iron: grinding/polishing surface (600 grain size sand paper),
dipping into a solution of 10% HNO.sub.3 (4 min at room
temperature), followed by degreasing in ethanol. Dip coating of
phosphonate material (1 mM, 15 hrs, water). (Hanson, E. L.,
Schwartz, J., Nickel, B., Koch, N. & Danisman, M. F. Bonding
Self-Assembled, Compact Organophosphonate Monolayers to the Native
Oxide Surface of Silicon. J. Am. Chem. Soc. 125, 16074-16080
(2003); Harm et al., Novel protective coating for steel based on a
combination of SAM and conducting polymers Macromolecular Symposia.
187, 65-72 (2002)) Novel protective coating for steel based on a
combination of SAM and conducting polymers
Titanium foil: sanded, rinsed with hot methanol, and stored at
160.degree. C. in air, gives a surface coating of hydroxylated
titanium dioxide. Aerosol sprayed (0.75 mM in THF), annealed 18 hrs
at 120.degree. C., immersion in (dry THF twice, for 5 min each).
{{5016 Gawalt, Ellen S. 2001;}} Similarly titanium disks were
wet-ground (220-4000 grit silicon carbide paper and further
polished with OPChem polishing cloths using OP-S colloidal silica
suspension) followed by ultrasonication (deionized water to
eliminate silica particles). Rinsed (acetone then ultrapure water)
and dried for a few minutes in an oven (80.degree. C.).
(Lecollinet, G. et al. Self-Assembled Monolayers of
Bisphosphonates: Influence of Side Chain Steric Hindrance. Langmuir
25, 7828-7835 (2009))
Stainless Steel: Mechanically Polished (220, 400, 800, and 1200
grit silicon carbide paper followed by a 1 um diamond suspension).
Ultrasonicated (MeOH, 15 min) or (DCM (10 min) then acetone (10
min)) and immersed (boiling MeOH to remove traces of organics and
metallic dust), storage (120.degree. C., oven). Dip coated (1 mM,
dry tetrahydrofuran (THF)) and reduced pressure annealed (0.1
Torr). (Raman, A., Dubey, M., Gouzman, I. & Gawalt, E. S.
Formation of Self-Assembled Monolayers of Alkylphosphonic Acid on
the Native Oxide Surface of SS316L. Langmuir 22, 6469-6472 (2006))
Similarly, oxidized SiO.sub.2/Si, TiO.sub.2/Ti and stainless steel
samples were dip coated (10 min) wash cautiously with acetone
followed by thermal annealing (24 hrs, 120 C). Weakly adsorbed
molecules were removed from all coupons by 10 min sonication in
acetone. Dipping, annealing, and sonicating steps were done twice.
Water soluble coatings were dip coated (3 hours in water), no
rinsing and annealed (120.degree. C., 20 h) and sonicated for 10
min in ultrapure water. Dipping, drying, and sonicating were
performed twice. (Lecollinet, G. et al. Self-Assembled Monolayers
of Bisphosphonates: Influence of Side Chain Steric Hindrance.
Langmuir 25, 7828-7835 (2009))
Silicon (100) wafer: cleaning by sonication in acetone (15 min).
oxidized (3:1, 30% H2O2:98% H2SO4 for 30 min), and rinsed
(ultrapure water) and immediately dip coated (25 .mu.M solution in
THF until the solvent evaporated at room temperature). Thermal
annealed (140 C 48 hrs). Three cycles of depositions with multiple
rinsing and sonication in THF and methanol was used to produce a
monolayer film. The films were stored in glass containers filled
with nitrogen until they were characterized. (Hanson, E. L.,
Schwartz, J., Nickel, B., Koch, N. & Danisman, M. F. Bonding
Self-Assembled, Compact Organophosphonate Monolayers to the Native
Oxide Surface of Silicon. J. Am. Chem. Soc. 125, 16074-16080
(2003))
Non thermal annealing: titanium samples dip coated (1 mM solution
in acetone, 3 hrs) decant solvent and reduced pressure anneal (15 h
at 50.degree. C.). The samples were ultrasonically washed with
acetone and then air-dried. (Lecollinet, G. et al. Self-Assembled
Monolayers of Bisphosphonates: Influence of Side Chain Steric
Hindrance. Langmuir 25, 7828-7835 (2009))
Example 25
Coating Composition of Compound (3) on TiO.sub.2
A one inch by inch TiO.sub.2 square was sanded with 600 grain size
sand paper, followed by an ethanol (EtOH) rinse. Samples were
stored in a 120.degree. C. oven prior to use. A 10 mM solution of
compound (3) in EtOH was aerosol spayed onto the TiO.sub.2 square,
allowed to air dry and placed into 120.degree. C. oven overnight to
anneal the compound followed by an EtOH rinse. Spaying, annealing
and rinsing were repeated two more times.
The scope of the claims should not be limited by the preferred
embodiments set forth in the examples, but should be given the
broadest interpretation consistent with the description as a
whole.
* * * * *