UV cured benzophenone terminated quaternary ammonium antimicrobials for surfaces
10961401 ยท 2021-03-30
Assignee
Inventors
- Lukasz Porosa (Scarborough, CA)
- Amanda Mocella (Brampton, CA)
- Gideon Wolfaardt (Mississauga, CA)
- DANIEL FOUCHER (TORONTO, CA)
Cpc classification
A01N35/04
HUMAN NECESSITIES
C09D5/14
CHEMISTRY; METALLURGY
C07C217/22
CHEMISTRY; METALLURGY
International classification
C07C217/22
CHEMISTRY; METALLURGY
A01N35/04
HUMAN NECESSITIES
C07C311/41
CHEMISTRY; METALLURGY
Abstract
The invention relates to benzophenone-terminated quaternary ammonium compounds, processes for preparing benzophenone-terminated quaternary ammonium compounds, environmentally friendly antimicrobial formulations of said quaternary ammonium compounds and their use as durable antimicrobial surface coatings for surfaces.
Claims
1. An antimicrobial surface coating composition comprising a UV curable compound of formula (I) ##STR00063## wherein n is 3 or 4; R.sub.1 and R.sub.2 are independently methyl, ethyl, n-propyl or i-propyl; Z is ##STR00064## wherein m is selected from the group consisting of 12, 13, 14, 15, 16, 17 and 18, or ##STR00065## wherein R.sub.3, R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1-C.sub.6 linear or branched alkyl or C.sub.6-C.sub.10 aryl; and X is a halogen selected from the group consisting of chloro, bromo and iodo; and a carrier, wherein said carrier is a mixture of water and an alcohol, wherein said composition is UV curable upon application to said surface.
2. The composition of claim 1 wherein R.sub.1 and R.sub.2 are methyl.
3. The composition of claim 1 wherein X is bromo or iodo.
4. The composition of claim 1 wherein R.sub.3 and R.sub.4 are independently methyl, ethyl, n-propyl or isopropyl and R.sub.5 is hydrogen.
5. The composition of claim 1 wherein Z is ##STR00066##
6. The composition of claim 5 wherein m is 17.
7. The composition of claim 1 wherein Z is ##STR00067##
8. The composition of claim 1 wherein said alcohol is selected from the group consisting of methanol, ethanol, and isopropanol.
9. The composition of claim 8 wherein the alcohol is methanol.
10. The composition of claim 1 wherein the water is distilled water.
11. An antimicrobial surface coating composition comprising a UV curable compound of formula (I) ##STR00068## wherein n is 3 or 4; R.sub.1 and R.sub.2 are independently methyl, ethyl, n-propyl or i-propyl; Z is ##STR00069## wherein m is selected from the group consisting of 12, 13, 14, 15, 16, 17 and 18, or ##STR00070## wherein R.sub.3, R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1-C.sub.6 linear or branched alkyl or C.sub.6-C.sub.10 aryl; and X is a halogen selected from the group consisting of chloro, bromo and iodo; and a carrier, wherein said carrier is a mixture of water and an alcohol, wherein said composition is UV curable upon application to said surface, wherein a UV activatable moiety of the UV curable compound of formula (I) converts to a diradical species in the presence of UV light and reacts with any surface having CH bonds to form a covalent CC bond.
12. The antimicrobial surface coating composition of claim 1, wherein said compound of formula (I) is propyl-dimethyl (benzoylphenoxy) octadecylammonium bromide.
13. The antimicrobial surface coating composition of claim 11, wherein said compound of formula (I) is propyl-dimethyl (benzoylphenoxy) octadecylammonium bromide.
14. A method of treating a surface with an antimicrobial surface coating composition of claim 1, said method comprising: i) contacting the surface with said antimicrobial surface coating composition comprising the compound of formula (I) to form a coated surface; and ii) irradiating the coated surface.
15. The method of claim 14 wherein said compound of formula (I) is propyl-dimethyl (benzoylphenoxy) octadecylammonium bromide.
16. The method of claim 14 wherein the surface comprises a polymer or a fibre.
17. The method of claim 14 further comprising iii) a washing step wherein the washing step comprises the use of a water and isopropanol mixture.
18. The method of claim 14 wherein the irradiating step comprises irradiating the coated surface with UV light.
19. A method of treating a surface with an antimicrobial surface coating composition of claim 11, said method comprising: i) contacting the surface with said antimicrobial surface coating composition comprising the compound of formula (I) to form a coated surface; and ii) irradiating the coated surface.
20. The method of claim 19 wherein said compound of formula (I) is propyl-dimethyl (benzoylphenoxy) octadecylammonium bromide.
21. The method of claim 19 wherein the surface comprises a polymer or a fibre.
22. The method of claim 19 further comprising iii) a washing step wherein the washing step comprises the use of a water and isopropanol mixture.
23. The method of claim 19 wherein the irradiating step comprises irradiating the coated surface with UV light.
Description
DETAILED DESCRIPTION OF THE INVENTION
Brief Summary of Figures
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(51) The present invention is directed to novel quaternary ammonium compounds that are linked to a UV-activatable moiety, methods for manufacturing the compounds and treating surfaces with the compound to provide a durable, antimicrobial-treated article.
(52) The quaternary ammonium compound of the present invention comprises a positively charged nitrogen centre linked to two alkyl groups which are independently the same or different, a UV activatable moiety and a long alkyl chain and a halogen counterion. The two alkyl groups are independently methyl, ethyl, n-propyl or i-propyl, most preferably methyl. The alkyl chain is preferably at least 12, preferably between 12 and 36 and most preferably selected from the group consisting of 12, 13, 14, 15, 16, 17 and 18 carbon atoms long. The alkyl chain can be branched or linear and preferably linear. The UV activatable moiety is linked to the positively charged nitrogen centre via an alkyl chain of preferably three to six carbon atoms in length. The alkyl chain is preferably linear. The UV activatable moiety is preferably benzophenone. The halogen counterion is preferably selected from the group consisting of chloro, bromo and iodo, most preferably from chloro of bromo, with the proviso that when the halogen is bromo, the alkyl chain linking the UV activatable moiety to the nitrogen centre is three carbon atoms long and the two alkyl groups are methyl, the long alkyl chain cannot be 18 carbon atoms long.
(53) The quaternary ammonium compound of the present invention also comprises a positively charged nitrogen centre linked to two alkyl groups which are independently the same or different, a UV activatable moiety and a di-N-substituted-dialkylaminopropyl naphthalene-1-sulfonamide group of formula (VIb):
(54) ##STR00030##
wherein R.sub.3, R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1-C.sub.6 linear or branched alkyl or C.sub.6-C.sub.10 aryl, preferably R.sub.3 and R.sub.4 are methyl, ethyl, n-propyl or isopropyl and R.sub.5 is hydrogen. The two alkyl groups are independently methyl, ethyl, n-propyl or i-propyl, most preferably methyl. The UV activatable moiety is linked to the positively charged nitrogen centre via an alkyl chain of preferably three to six carbon atoms in length. The alkyl chain is preferably linear. The UV activatable moiety is preferably benzophenone. The di-N-substituted-dialkylaminopropyl naphthalene-1-sulfonamide group fluoresces under UV light and acts as an indicator of the presence of the quaternary ammonium compound.
(55) The quaternary ammonium compounds of the present invention can be prepared by modification of known synthetic techniques in the preparation of QACs. Generally, the first step involves reacting benzophenone with a dihaloalkane in the presence of an alkali metal carbonate in a polar, aprotic solvent under refluxing conditions. The dihaloalkane can have the same or different halogen groups, preferably selected from chloro, bromo and iodo. The dihaloalkane is from three to ten carbon atoms long, and is preferably four to nine carbon atoms long, more preferably five to eight carbon atoms long. The alkali metal carbonate is selected from the group consisting of sodium, potassium and cesium carbonate and most preferably potassium carbonate. The polar, aprotic solvent may be any suitable solvent; preferably it is selected from the group consisting of DMF, acetone, THF and acetonitrile. Most preferably the solvent is acetonitrile. The reaction mixture is heated until such time as the reaction mixture becomes substantially clear and a thin-layer chromatography (TLC) analysis shows the starting material has been consumed. Preferably the reaction mixture is heated to reflux. The final haloalkylbenzophenone product is isolated, preferably by filtration, preferably through Celite to remove the alkali metal halide by-product, which is further washed with a polar, aprotic solvent to extract any final product held in the Celite, evaporating the filtrate to dryness and purifying the final product preferably using a chromatographic method, most preferably column chromatography. The elution solvent is preferably a solvent mixture comprising ethyl acetate and hexanes. The final haloalkylbenzophenone product optionally can be further purified by recrystallization.
(56) Optionally, the haloalkylbenzophenone product of the previous step can be converted to an iodoalkylbenzophenone by reacting the haloalkylbenzophenone with sodium iodide in a refluxing polar, aprotic solvent, preferably acetone.
(57) The second step in the preparation involves reacting the haloalkylbenzophenone of the previous step where the halo is selected from chloro, bromo or iodo with a trialkylamine in a refluxing polar solvent. One of the alkyl groups of the trialkylamine is preferably at least 12, preferably between 12 and 36 and most preferably selected from the group consisting of 12, 13, 14, 15, 16, 17 and 18 carbon atoms long. The alkyl chain can be branched or linear and preferably linear. The remaining two alkyl groups are independently methyl, ethyl, n-propyl or i-propyl, most preferably methyl. The solvent can be selected from DMF, acetone, THF, ethanol, methanol or acetonitrile. Most preferably the solvent is acetonitrile. The reaction is allowed to go until starting materials are substantially no longer present. One method of monitoring the progress of the reaction is via TLC. Other methods may be applied. The quaternary ammonium product is purified preferably by a chromatographic method, and most preferably by column chromatography. The elution solvent is preferably a solvent mixture comprising 6% sodium bromide in methanol and acetonitrile. The final quaternary ammonium product optionally can be further purified by recrystallization from a mixed solvent, preferably ethanol/acetone.
(58) Synthesis of quaternary ammonium compounds capped with a di-N-substituted-dialkylaminopropyl naphthalene-1-sulfonamide group of formula (VIb):
(59) ##STR00031##
wherein R.sub.3, R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1-C.sub.6 linear or branched alkyl or C.sub.6-C.sub.10 aryl, preferably R.sub.3 and R.sub.4 are methyl, ethyl, n-propyl or isopropyl and R.sub.5 is hydrogen can be carried out by reacting the haloalkylbenzophenone from the above step with a trialkylamine in which one of the alkyl groups is 5-dimethylaminonaphthalene-1-sulfonamidopropyl and the other two alkyl groups independently are selected from methyl, ethyl, n-propyl or i-propyl, preferably methyl. The halo group of the haloalkylbenzophenone can be chloro, bromo or iodo. The reaction can be carried out in refluxing polar solvent selected from DMF, acetone, THF, methanol, ethanol or acetonitrile. Most preferably the solvent is acetonitrile. The reaction is allowed to go until starting material are substantially no longer present. One method of monitoring the reaction is via TLC. The quaternary ammonium product is isolated by precipitation from the reaction mixture by addition of cold diethyl ether, more preferably diethyl ether at a temperature of about 10 C. to about 10 C. and most preferably at a temperature at about 0 C., and evaporation of the reaction solvent.
(60) The quaternary ammonium compounds of the present invention in another embodiment, can be used to antimicrobially treat hard surfaces. Without being bound by any particular theory, the UV activatable moiety of the quaternary ammonium compounds converts to a diradical species in the presence of UV light and reacts with any surface having CH bonds to form a covalent CC bond. The result is a fixed, durable antimicrobial coating of quaternary ammonium compounds.
(61) Treatment of articles, including hard surfaces can be done via dipping, painting, spraying or coating the surface with a solution of a quaternary ammonium compound of the present invention. A surface may be an inner and/or outer surface. The solution is environmentally friendly and comprises a water or a water-alcohol solvent mixture carrier, preferably water-methanol, water-ethanol or water-isopropanol, most preferably water or water-isopropanol. The amount of quaternary ammonium compound in the solution ranges from about 0.01% to about 1% and more preferably from about 0.05% to about 0.5% weight by volume. In one embodiment, polyvinylchloride previously washed with isopropanol and dried is treated with a 0.05% or a 0.5% solution of a C18 quaternary ammonium compound in which the UV activatable moiety is linked to the nitrogen centre with a C5 alkyl chain. The carrier is a water-methanol solvent mixture. The previously washed and dried polyvinylchloride (PVC) substrate is electrosprayed with the above solution followed by UV irradiation until a satisfactory coating is achieved. A typical UV wavelength of between about 200 and 400 nm, preferably between about 345 to about 365 nm is used. Optionally, the coated PVC substrate is rinsed with a water and isopropanol mixture and dried.
(62) With reference to
(63) With reference to
(64) With reference to
(65) The following non-limiting examples are provided.
(66) Materials. All reagents and solvents, unless otherwise specified were obtained from Sigma-Aldrich and used as received. Potassium carbonate was obtained from Fisher, N,N,-dimethyloctadecylamine was retrieved from Acros, and sodium iodide from BDH. 5-(dimethylamino)-N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide (compound 10) was prepared according to literature procedures: Wang, X. & Schneider, H. Binding of dansylamide derivatives to nucleotides and nucleic acids. J. Chem. Soc. Perkin Trans. 2, 1998, 1323-1328; Hillman G. R. et al., Effects of Dansylated Acetylcholine Analogs on Schistosoma a Mansoni, J. Pharm. Sci., 1980, 69(5), 516-520. Polyvinylchloride (PVC) was obtained from Oran Industries (Woodbridge ON), while silicone tubing was a VWR brand select silicone (0.0620.1250.032 cm). The UV fumehood used was equipped with a G30T8 30 W germicidal fluorescent bulb whereas the Hanovia utility UV quartz lamp was a 140 W source. Trypticase soy agar used in testing antimicrobial efficiency was provided by Bio Basic Canada Inc. Agar A.
(67) Instrumental Methods. Nuclear magnetic resonance (NMR) experiments were carried out on a 400 MHz Bruker Avance Spectrometer using deuterated chloroform (CDCl.sub.3) as the solvent. .sup.1H NMR (400 MHz) spectra were referenced to the residual protonated solvent resonance signal (CHCl.sub.3: 7.26 ppm) and the .sup.13C (100.6 MHz) to the central carbon resonance signal of the solvent (CDCl.sub.3: 77.0 ppm). All chemical shifts are given in (ppm) relative to the solvent. All thin layer chromatography (TLC) was performed using Silica gel 60 eluting with EtOAc/hexanes (20:80) solution unless otherwise noted. Melting points were measured using a Fischer Scientific melting point apparatus. The UV light source was a quartz mercury lamp with a power of 140 W.
Referential Example 1Synthesis of (1a-b; 2a-b; 3a-b)
(68) ##STR00032##
(69) In a 50 mL round bottom flask dihaloalkane (4 eq.) and potassium carbonate (2 eq.) were dissolved in acetonitrile (10 mL). A solution of 4-hydroxybenzophenone (1 eq.) dissolved in acetonitrile (10 mL) was prepared in a dropping funnel, and then added dropwise under reflux. The resultant yellow mixture was heated at reflux until a clear solution was obtained or until TLC showed the disappearance of starting material 4-hydroxybenzophenone. The excess potassium bromide salt was filtered off through Celite and washed with acetone (10 mL). The mixture was evaporated under reduced pressure to give a crude product.
(70) The crude product was packed onto silica and purified by dry column chromatography (4.5 cm5.0 cm frit, 40 g silica) eluting with EtOAc/hexanes (20:80) to afford the desired product and further recrystallized in toluene/hexanes (1:3).
Referential Example 2Synthesis of 4-O-(n-iodoalkyl)benzophenone precursors (1c, 2c, 3c)
(71) ##STR00033##
(72) In a 50 mL round bottom flask 4-O-(n-haloalkyl)benzophenone (1 eq.) and sodium iodide (3 eq.) were mixed in acetone (10 mL) and the resultant mixture was left to reflux for 24 hours or until TLC showed the disappearance of starting material (EtOAc/hexanes 20:80). Excess sodium iodide and sodium bromide salt were filtered through Celite, washing with cold hexanes. The solvent extracts were then evaporated under reduced pressure and the crude residue dry packed onto silica and purified by dry column chromatography (4.5 cm5.0 cm frit, 40 g silica), eluting with EtOAc/hexanes (20:80) to yield the desired product. Further recrystallization in toluene/hexanes (1:2) was undertaken.
Referential Example 3Synthesis of N-(n-(4-benzoylphenoxy)alkyl)-N,N-dimethyloctadecan-1-ammonium halides
(73) ##STR00034##
(74) In a 20 mL screw cap vial N,N-dimethyloctadecylamine (1.1 eq.) and 4-O-(n-haloalkyl)benzophenone (1.0 eq.) were mixed in acetonitrile (1 mL). The resultant mixture was left to stir in a 100 C. sand bath for 24 hours or until TLC showed the disappearance of starting material (acetone/ammonia 15:1). The vial was then removed from heat and allowed to cool at ambient conditions and a crude product obtained. The crude product was recrystallized using ethanol/acetone (1:3) and evaporated under vacuum to obtain the desired product.
Referential Example 4Synthesis of n-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)propyl)-N,N-dimethylalkyl-1-ammonium halides
(75) ##STR00035##
(76) In a 20 mL screw cap vial 5-(dimethylamino)-N-(3-(dimethylamino)propyl)naphthalene-1-sulfonamide 10 (1.0 eq.) and haloalkoxy(phenyl)(phenyl)methanone (1.0 eq.) were dissolved in acetonitrile (2 mL). The resultant solution was left to stir in a 100 C. sand bath for 24 hours or until TLC showed the disappearance of starting material (EtOAc/hexanes 20:80). The residue was then precipitated from the resultant solution by the dropwise addition of cold diethyl ether (4 mL) and evaporated under vacuum to obtain the desired product.
Example 14-O-(3-bromopropyl)benzophenone 1a
(77) ##STR00036##
(78) According to the general procedure for the halide alkylation of 4-hydroxybenzopheonone derived from Saettone et al., International Journal of Cosmetic Sciences, 1988, 10, 99-109. 1,3-dibromopropane (60.5 mmol, 6.14 mL), potassium carbonate (30.2 mmol, 4.18 g) and 4-hydroxybenzophenone (15.1 mmol, 3.0 g) were stirred in acetonitrile (20 mL) under reflux for 24 hours to give a crude product of 4-O-(3-bromopropyl)benzophenone which was recrystallized in toluene/hexanes to yield compound 1a (3.22 g, 66.7% yield). C.sub.16H.sub.15BrO.sub.2; off white powder, mp 54-66 C.; .sup.1H NMR (CDCl.sub.3, 400 MHz) 2.35 (m, CH.sub.2, 2H), 3.62 (m, CH.sub.2, 2H), 4.21 (m, CH.sub.2, 2H), 6.95 (s, Ar, 2H), 7.55 (m, Ar, 2H), 7.60 (m, Ar, 1H), 7.75 (m, Ar, 2H), 7.80 (m, Ar, 2H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.52 (C5), 162.31 (C9), 138.24 (C4), 132.58 (C3), 129.74 (C1), 129.73 (C6), 128.21 (C2), 114.04 (C8), 65.53 (C10), 32.14 (C12), 29.74 (C11) ppm. HRMS-DART (m/z): [M.sup.+] calcd. for C.sub.16H.sub.15BrO.sub.2, 319.0334; found, 319.0329.
Example 24-O-(3-chloropropyl)benzophenone 1b
(79) ##STR00037##
(80) According to the general method derived from this group, 1-bromo-3-chloropropane (50.4 mmol, 5.00 mL), potassium carbonate (25.3 mmol, 3.49 g) and 4-hydroxybenzophenone (12.6 mmol, 2.50 g) were stirred in acetonitrile (20 mL) under reflux for 24 hours to give a crude product of 4-O-(3-chloropropyl)benzophenone which was recrystallized in toluene/hexanes to yield compound 1b (1.21 g, 34.9% yield). C.sub.16H.sub.15ClO.sub.2; off white powder; .sup.1H NMR (CDCl.sub.3, 400 MHz) =2.29 (m, CH.sub.2, 2H), 3.79 (m, ClCH.sub.2, 2H), 4.23 (m, OCH.sub.2, 2H), 6.98 (m, Ar, 2H), 7.45 (m, Ar, 2H), 7.60 (m, Ar, 1H), 7.75 (m, Ar, 2H), 7.82 (m, Ar, 2H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.52 (C5), 162.31 (C9), 138.24 (C4), 132.54 (C3), 130.38 (7), 129.74 (C1), 128.21 (C2), 114.04 (C8), 65.53 (C10), 32.14 (C12), 29.73 (C11) ppm. Note: Chemical properties agree with that of the compounds as prepared previously by Saettone et al., International Journal of Cosmetic Sciences, 1988, 10, 99-109.
Example 34-O-(4-bromobutyl)benzophenone 2a
(81) ##STR00038##
(82) According to the general procedure for the halide alkylation of 4-hydroxybenzophenone derived from Saettone et al., International Journal of Cosmetic Sciences, 1988, 10, 99-109, 1,4-dibromobutane (50.4 mmol, 6.02 mL), potassium carbonate (25.3 mmol, 3.49 g) and 4-hydroxybenzophenone (12.6 mmol, 2.50 g) were stirred in acetonitrile (20 mL) under reflux for 24 hours to give a crude product of 4-O-(4-bromobutyl)benzophenone which was recrystallized in toluene/hexanes to yield compound 2a (3.846 g, 91.6% yield). C.sub.17H.sub.17BrO.sub.2; pale yellow powder; .sup.1H NMR (CDCl.sub.3, 400 MHz) =1.99 (m, CH.sub.2, 2H), 2.09 (m, CH.sub.2, 2H), 3.51 (m, BrCH.sub.2, 2H), 4.09 (m, OCH.sub.2, 2H), 6.95 (m, Ar, 2H), 7.45 (m, Ar, 2H), 7.55 (m, Ar, 1H), 7.75 (m, Ar, 2H), 7.85 (m, Ar, 2H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.52 (C5), 162.51 (C9), 138.27 (C4), 132.57 (C3), 131.90 (1), 129.72 (C6), 128.20 (2), 113.99 (8), 67.13 (C10), 33.31 (C13), 29.36 (C11) 27.76 (C12) ppm. HRMS-DART (m/z): [M.sup.+] calcd. for C.sub.17H.sub.17BrO.sub.2, 333.0490 found, 333.0486.
Example 44-O-(6-bromohexyl)benzophenone 3a
(83) ##STR00039##
(84) According to the general procedure for the halide alkylation of 4-hydroxybenzopheonone derived from Saettone et al., International Journal of Cosmetic Sciences, 1988, 10, 99-109, 1,6-dibromohexane (40.4 mmol, 6.21 mL), potassium carbonate (20.2 mmol, 2.79 g) and 4-hydroxybenzophenone (10.1 mmol, 2.00 g) were stirred in acetonitrile (20 mL) under reflux for 24 hours to give a crude product of 4-O-(6-bromohexyl)benzophenone which was recrystallized in toluene/hexanes to yield compound 3a (1.495 g, 42.7% yield). C.sub.19H.sub.21BrO.sub.2; white powder; 1H NMR (CDCl.sub.3, 400 MHz) =1.55 (m, CH.sub.2, 4H), 1.88 (m, CH.sub.2, 4H), 3.45 (m, BrCH.sub.2, 2H), 4.09 (m, OCH.sub.2, 2H), 6.95 (m, Ar, 2H), 7.45 (m, Ar, 2H), 7.55 (m, Ar, 1H), 7.79 (m, Ar, 4H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.52 (C5), 162.75 (C9), 138.22 (C4), 132.57 (C3), 129.98 (C7), 129.72 (C1), 128.18 (C2), 114.00 (C8), 67.99 (C10), 33.78 (C15), 32.63 (C14), 28.94 (C11), 27.88 (C13), 25.25 (C12) ppm. HRMS-DART (m/z): [M.sup.+] calcd. for C.sub.19H.sub.21BrO.sub.2, 361.0803; found, 361.0796.
Example 54-O-(6-chlorohexyl)benzophenone 3b
(85) ##STR00040##
(86) According to the general procedure for the halide alkylation of 4-hydroxybenzopheonone, 1-bromo-6-chlorohexane (13.9 mmol, 2.77 mL), potassium carbonate (25.2 mmol, 3.49 g) and 4-hydroxybenzophenone (12.6 mmol, 2.50 g) were stirred in acetonitrile (20.0 mL) under reflux for 24 hours to give a crude product of 4-O-(6-chlorohexyl)benzophenone which was recrystallized in toluene/hexanes to yield compound 3b (3.07 g, 76.8% yield). C.sub.19H.sub.21ClO.sub.2; off white powder, mp 64-67 C.; .sup.1H NMR (CDCl.sub.3, 400 MHz) =1.55 (m, CH.sub.2, 4H), 1.85 (m, CH.sub.2, 4H), 3.51 (m, ClCH.sub.2, 2H), 4.06 (m, OCH.sub.2, 2H), 6.95 (m, Ar, 2H), 7.49 (m, Ar, 2H), 7.52 (m, Ar, 1H), 7.77 (m, Ar, 4H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.54 (C5), 162.74 (C9), 138.34 (C4), 132.57 (C3), 129.72 (C1), 128.18 (C2), 114.00 (C8), 67.99 (C10), 30.32 (C15), 30.20 (C14), 28.92 (C11), 25.02 (C13) ppm. HRMS-DART (m/z): [M.sup.+] calcd. for C.sub.19H.sub.21ClO.sub.2, 317.1308; found, 317.1311.
Example 64-O-(3-iodopropyl)benzophenone 1c
(87) ##STR00041##
(88) According to the general procedure for the halide substitution of bromine for iodine in halo-alkoxy(phenyl)(phenyl)methanone compounds, 4-(3-bromopropoxy)(phenyl)(phenyl)methanone (3.13 mmol, 1.00 g) and sodium iodide (9.40 mmol, 1.41 g) were mixed in acetone (10.0 mL) under reflux for 24 hours to give crude product of 4-O-(3-iodopropyl)benzophenone which was recrystallized in toluene/hexanes (1:2) to obtain compound 1c (0.585 g, 51.0% yield). C.sub.15H.sub.16IO.sub.2; yellow powder; .sup.1H NMR (CDCl.sub.3, 400 MHz) =2.31 (m, CH.sub.2, 2H), 3.39 (m, CH.sub.2, 2H), 4.15 (m, ICH.sub.2, 2H), 6.95 (m, Ar, 2H), 7.51 (m, Ar, 3H), 7.70 (m, Ar, 4H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.47 (C5), 162.32 (C9), 138.27 (C4), 129.75 (C1), 128.28 (C2), 114.09 (C8), 67.54 (C10), 32.74 (C11), 2.19 (C12) ppm. HRMS-DART (m/z): [M.sup.+] calcd. for C.sub.16H.sub.15IO.sub.2, 367.0195 found, 367.0202.
Example 74-O-(4-iodobutyl)benzophenone 2c
(89) ##STR00042##
(90) The synthesis of compound 2c has been previously reported by Acosta et al., Polymer Degradation and Stability, 1996, 52, 11-17. An alternative synthetic approach, following the general procedure for the halide substitution of bromine for iodine in halo-alkoxy(phenyl)(phenyl)methanone compounds, 4-(4-bromobutoxy)(phenyl)(phenyl)methanone (3.00 mmol, 1.00 g) and sodium iodide (6.00 mmol, 0.900 g) were mixed in acetone (10.0 mL) under reflux for 24 hours to give crude product of 4-O-(4-iodobutyl)benzophenone which was recrystallized in toluene/hexanes (1:2) to obtain compound 2c (1.03 g, 90.2% yield). C.sub.15H.sub.16IO.sub.2; pale yellow powder; .sup.1H NMR (CDCl.sub.3, 400 MHz) =2.00 (m, CH.sub.2, 4H), 3.39 (m, ICH.sub.2, 2H), 4.05 (m, OCH.sub.2, 2H), 6.95 (m, Ar, 2H), 7.51 (m, Ar, 3H), 7.79 (m, Ar, 4H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) =195.52 (C5), 162.51 (C9), 138.27 (C4), 132.58 (C3), 131.90 (C7), 129.72 (C1), 128.20 (C2), 113.99 (C8), 66.92 (C10), 30.05 (C11), 30.01 (C12), 6.21 (C13) ppm. .sup.1H NMR chemical shifts agree with those reported by Acosta et al. above.
Example 84-O-(6-iodohexyl)benzophenone 3c
(91) ##STR00043##
(92) Previous synthesis of this compound has been reported by Acosta et al., Polymer Degradation and Stability, 1996, 52, 11-17. Following an alternative synthetic approach outlined in the general procedure for the halide substitution of bromine for iodine in halo-alkoxy(phenyl)(phenyl)methanone compounds, 4-((3-bromohexyl)oxy)phenyl)(phenyl) methanone (1.38 mmol, 0.500 g) and sodium iodide (4.15 mmol, 0.622 g) were mixed in acetone (10.0 mL) under reflux for 24 hours to give crude product of 4-O-(6-iodohexyl)benzophenone which was recrystallized in toluene/hexanes (1:2) to obtain compound 3c (0.480 g, 85.0% yield). C.sub.19H.sub.21IO.sub.2; off white powder; .sup.1H NMR (CDCl.sub.3, 400 MHz) =1.55 (m, CH.sub.2, 4H), 1.85 (m, CH.sub.2, 4H), 3.21 (m, ICH.sub.2, 2H), 4.05 (m, OCH.sub.2, 2H), 6.95 (m, Ar, 2H), 7.51 (m, Ar, 3H), 7.77 (m, Ar, 4H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.54 (C5), 162.74 (C9), 138.34 (C4), 132.57 (C3), 130.00 (C7), 129.72 (C1), 128.17 (C2), 114.00 (C8), 67.99 (C10), 33.32 (C14), 30.20 (C11), 28.92 (C13), 25.02 (C12), 6.89 (C15) ppm. .sup.1H NMR chemical shifts agree with those reported by Acosta et al. above.
Example 9Propyl-dimethyl (benzoylphenoxy)octadecylammonium bromide 4a
(93) ##STR00044##
(94) This compound has been previously reported by Saettone et al., International Journal of Cosmetic Sciences, 1988, 10, 99-109. According to the general procedure for the quaternization of N-dimethyloctadecylamine with 4-O-(n-haloalkyl)benzophenone, 4-O-(3-bromopropyl)benzophenone (0.313 mmol, 0.100 g) and N-dimethyloctadecylamine (0.345 mmol, 0.103 g) and acetonitrile (1 mL) were stirred in an 100 C. sand bath for 24 hours to give crude product of propyl-dimethyl (benzoylphenoxy)octadecylammonium bromide 4a (0.194 g, 101% crude yield). C.sub.36H.sub.58BrNO.sub.2; pale yellow solid; mp 58-68 C. (lit. mp 81-83 C.); .sup.1H-NMR 6=0.88 (m, CH.sub.3, 3H), 1.30 (m, CH.sub.2, 34H), 3.40 (s, NCH.sub.3, 6H), 3.45 (m, CH.sub.2, 2H), 3.75 (s, CH.sub.2, 2H), 4.13 (s, OCH.sub.2, 2H), 6.95 (m, Ar, 2H), 7.45 (m, Ar, 2H), 7.55 (m, Ar, 1H), 7.75 (m, Ar, 2H), 7.81 (m, Ar, 2H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.47 (C5), 161.58 (C9), 137.95 (C4), 132.48 (C3), 131.91 (C7), 130.75 (C1), 129.72 (C6), 128.17 (C2), 114.10 (C8), 68.90 (C10), 64.46 (C14), 61.14 (C12), 51.50 (C13), 31.90 (C23), 29.63 (C19), 29.39 (C17), 29.34 (C22), 27.36 (C16), 26.25 (C15), 23.16 (C11), 22.75 (C24), 14.11 (C25) ppm. HRMS-DART (m/z): [M.sup.+-Br] calcd. for C.sub.36H.sub.58BrNO.sub.2, 536.4478; found, 536.4462.
Example 10Propyl-dimethyl (benzoylphenoxy)octadecylammonium chloride 4b
(95) ##STR00045##
(96) According to the general procedure for the quaternization of N-dimethyloctadecylamine with 4-O-(n-haloalkyl)benzophenone, 4-O-(3-chloropropyl)benzophenone (0.910 mmol, 0.250 g) and N-dimethyloctadecylamine (1.00 mmol, 0.298 g) and acetonitrile (1 mL) were stirred in an 100 C. sand bath for 24 hours to give crude product of propyl-dimethyl (benzoylphenoxy)octadecylammonium chloride 4b (0.383 g, 77.0% crude yield) C.sub.36H.sub.58ClNO.sub.2; pale yellow powder; .sup.1H NMR (CDCl.sub.3, 400 MHz) =0.88 (m, CH.sub.3, 3H), 1.30 (m, CH.sub.2, 34H), 3.40 (6H, s), 3.45 (m, NCH.sub.3, 2H), 3.71 (s, CH.sub.2, 2H), 4.06 (s, OCH.sub.2, 2H), 6.95 (m, Ar, 2H), 7.45 (m, Ar, 2H), 7.55 (m, Ar, 1H), 7.75 (m, Ar, 2H), 7.81 (m, Ar, 2H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.47 (C5), 161.58 (C9), 137.95 (C4), 132.48 (C3), 131.91 (C7), 130.75 (C1), 129.72 (C6), 128.25 (C2), 114.10 (C8), 68.90 (C10), 64.46 (C14), 61.14 (C12), 51.50 (C13), 31.90 (C22), 29.63 (C18), 29.39 (C17), 29.34 (C21), 27.36 (C16), 26.25 (C15), 23.16 (C11), 22.75 (C23), 14.11 (C24) ppm. HRMS-DART (m/z): [M.sup.+-Cl] calcd. for C.sub.36H.sub.58ClNO.sub.2, 536.4461; found, 536.4462.
Example 11Propyl-dimethyl (benzoylphenoxy)octadecylammonium iodide 4c
(97) ##STR00046##
(98) According to the general procedure for the quaternization of N-dimethyloctadecylamine with 4-O-(n-haloalkyl)benzophenone, 4-O-(3-iodopropyl)benzophenone 1c (0.575 mmol, 0.211 g) and N-dimethyloctadecylamine (0.633 mmol, 0.188 g) were stirred in acetonitrile (1 mL) in an 100 C. sand bath for 24 hours to give crude product of propyl-dimethyl (benzoylphenoxy)octadecylammonium iodide to yield the desired product, 4c (0.363 g, 95.1% yield). C.sub.36H.sub.58INO.sub.2; white powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 0.87 (m, H20, 3H), 1.24 (m, H18-H16, 26H), 1.84 (m, H11, 2H), 3.37 (s, H13, 6H), 3.48 (m, H14, 2H), 4.05 (m, H10, 2H), 6.95 (m, Ar, 2H), 7.45 (m, Ar, 3H), 7.74 (m, Ar, 2H), 7.81 (m, Ar, 2H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 130.55 (C8), 124.53 (C9), 66.54 (C7), 64.01 (C6), 50.43 (C5), 31.91 (C2), 29.69-26.24 (C2, C14 OVERLAPPING), 26.26 (C3), 22.76 (C4), 14.11 (C1) ppm. HRMS-DART (m/z): [M.sup.+-I] calcd. for C.sub.36H.sub.58INO.sub.2, 536.4449; found, 536.4462.
Example 12Butyl-dimethyl (benzoylphenoxy)octadecylammonium bromide 5a
(99) ##STR00047##
(100) According to the general procedure for the quaternization of N-dimethyloctadecylamine with 4-O-(n-haloalkyl)benzophenone, 4-O-(4-bromobutyl)benzophenone (0.752 mmol, 0.251 g) and N-dimethyloctadecylamine (0.827 mmol, 0.246 g) and acetonitrile (1 mL) were stirred in an 100 C. sand bath for 24 hours to give crude product butyl-dimethyl (benzoylphenoxy)octadecylammonium bromide 5a (0.551 g, 100% crude yield). C.sub.37H.sub.61BrNO.sub.2; white powder; mp 83-87 C.; .sup.1H NMR (CDCl.sub.3, 400 MHz) =0.88 (m, CH.sub.3, 3H), 1.30 (m, CH.sub.2, 34H), 3.40 (6H, s), 3.45 (m, CH.sub.2, 2H), 3.71 (s, CH.sub.2, 2H), 4.06 (s, OCH.sub.2, 2H), 6.95 (m, Ar, 2H), 7.45 (m, Ar, 2H), 7.55 (m, Ar, 1H), 7.75 (m, Ar, 2H), 7.81 (m, Ar, 2H) ppm; .sup.13C NMR (CDCl.sub.3, 100 MHz) 195.49 (C5), 162.13 (C9), 138.07 (C4), 132.58 (C3), 132.02 (C7), 130.43 (C1), 129.71 (C6), 128.23 (C2), 114.06 (C8), 66.93 (C10), 64.11 (C13), 63.40 (C15), 51.19 (C14), 31.90 (C24), 29.69 (C23), 29.64 (C22), 29.58 (C21), 29.46 (C20), 29.39 (C19), 29.34 (C18), 29.22 (C11), 26.27 (C17), 25.81 (C16), 22.81 (C25), 22.67 (C26), 19.77 (C12), 14.12 (C27) ppm. HRMS-DART (m/z): [M.sup.+-Br] calcd. for C.sub.37H.sub.60BrNO.sub.2, 550.4632; found, 550.4618.
Example 13Butyl-dimethyl (benzoylphenoxy)octadecylammonium iodide 5c
(101) ##STR00048##
(102) According to the general procedure for the quaternization of N-dimethyloctadecylamine with 4-O-(n-haloalkyl)benzophenone, 4-O-(4-iodobutyl)benzophenone 2c (0.660 mmol, 0.250 g) and N-dimethyloctadecylamine (0.720 mmol, 0.215 g) were stirred in acetonitrile (1.00 mL) in an 100 C. sand bath for 24 hours to give crude product butyl-dimethyl (benzoylphenoxy)octadecylammonium iodide purified to give compound 5c (0.207 g, 46.3% yield). C.sub.37H.sub.60INO.sub.2; white powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 0.85 (m, H27, 3H), 1.21 (m, H26-H18, 29H), 1.71 (m, H12, 2H), 1.97 (m, H11, 3H), 3.36 (m, H14, 6H), 3.51 (m, H13, 2H), 3.74 (m, H15, 2H), 4.13 (m, H10, 2H), 6.96 (m, Ar, 2H), 7.42 (m, Ar, 2H), 7.52 (m, Ar, 1H), 7.70 (m, Ar, 2H), 7.77 (m, Ar, 2H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.51 (C5), 162.15 (C9), 138.06 (C4), 132.55 (C3), 132.03 (C7), 130.36 (C1), 129.70 (C6), 128.24 (C2), 114.16 (C8), 67.02 (C10), 64.51 (C13), 63.77 (C15), 51.48 (C14), 31.90 (C24), 29.69 (C23), 29.64 (C22), 29.61 (C21), 29.48 (C20), 29.40 (C19), 29.34 (C18), 29.21 (C11), 26.21 (C17), 25.70 (C16), 22.86 (C25), 22.67 (C26), 19.81 (C12), 14.11 (C27) ppm. HRMS-DART (m/z): [M.sup.+-Cl] calcd. for C.sub.37H.sub.60INO.sub.2, 550.4635; found, 550.4618.
Example 14Hexyl-dimethyl (benzoylphenoxy)octadecylammonium bromide 6a
(103) ##STR00049##
(104) According to the general procedure for the quaternization of N-dimethyloctadecylamine with 4-O-(n-haloalkyl)benzophenone, 4-O-(6-bromohexyl)benzophenone 3a (0.692 mmol, 0.250 g) and N-dimethyloctadecylamine (0.761 mmol, 0.227 g) were stirred in acetonitrile (1 mL) in an 100 C. sand bath for 24 hours to give crude product of hexyl-dimethyl (benzoylphenoxy)octadecylammonium bromide to yield the desired product, 6a (0.429 g, 94.1% yield). C.sub.39H.sub.64BrNO.sub.2; off white powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 0.89 (m, H25, 3H), 1.26 (m, H23-H19, H13, 32H), 1.58 (s, H24, H12, H18, H14, H11, 10H), 3.39 (s, H16, 6H), 3.50 (m, H15, 2H), 3.54 (m, H17, 2H), 4.07 (m, H10, 2H), 6.95 (m, Ar, 2H), 7.42 (m, Ar, 2H), 7.55 (m, Ar, 1H), 7.75 (m, Ar, 2H), 7.80 (m, Ar, 2H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.54 (C5), 162.63 (C9), 138.22 (C4), 132.53 (C3), 131.90 (C1, C7 OVERLAPPING), 129.68 (C6), 128.19 (C2), 114.03 (C8), 67.75 (C10, C15, C17 OVERLAPPING), 51.18 (C16), 31.90 (C23), 29.68 (C21), 29.63 (C20), 29.58 (C19), 29.38 (C11), 29.34 (C22), 26.27 (C13, C15 OVERLAPPING), 25.68 (C12), 25.36 (C18), 22.81 (C23), 22.68 (C24), 18.46 (C14), 14.12 (C25) ppm. HRMS-DART (m/z): [M.sup.+-Br] calcd. for C.sub.39H.sub.64BrNO.sub.2, 578.4958; found, 578.4931.
Example 15Hexyl-dimethyl (benzoylphenoxy)octadecylammonium chloride 6b
(105) ##STR00050##
(106) According to the general procedure for the quaternization of N-dimethyloctadecylamine with 4-O-(n-haloalkyl)benzophenone, 4-O-(6-chlorohexyl)benzophenone 3b (0.789 mmol, 0.250 g) and N-dimethyloctadecylamine (0.868 mmol, 0.258 g) were stirred in acetonitrile (1 mL) in an 100 C. sand bath for 24 hours to give crude product of hexyl-dimethyl (benzoylphenoxy)octadecylammonium chloride purified to yield the desired product, 6b (0.311 g, 64.1% yield). C.sub.39H.sub.64ClNO.sub.2; pale yellow powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 0.86 (m, H25, 3H), 1.24 (m, H24-H18, 29H), 1.52 (m, H12, H13, 4H), 1.80 (m, H17, 2H), 2.29 (m, H14, 2H), 3.39 (m, H15, H17, 4H), 3.55 (m, H11, 2H), 4.03 (s, H10, 2H), 6.93 (m, Ar, 2H), 7.44 (m, Ar, 2H), 7.54 (m, Ar, 1H), 7.75 (m, Ar, 2H) 7.81 (m, Ar, 2H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.56 (C5), 162.75 (C9), 138.23 (C4), 132.56 (C3), 131.92 (C7), 131.86 (C1), 129.96 (C6), 128.19 (C2), 128.17 (C2), 114.00 (C8), 113.98 (C8), 67.99 (C10), 67.70 (C15), 59.90 (C16), 31.90 (C25), 29.69 (C23), 29.64 (C22), 29.58 (C21), 29.46 (C20), 29.39 (C19), 29.34 (C18), 29.22 (C11), 26.27 (C17), 25.36 (C16), 22.81 (C25), 22.68 (C20), 18.46 (C14), 14.12 (C27) ppm. HRMS-DART (m/z): [M.sup.+-Cl] calcd. for C.sub.39H.sub.64ClNO.sub.2, 578.4948; found, 578.4931.
Example 16Hexyl-dimethyl (benzoylphenoxy)octadecylammonium iodide 6c
(107) ##STR00051##
(108) According to the general procedure for the quaternization of N-dimethyloctadecylamine with 4-O-(n-haloalkyl)benzophenone, 4-O-(6-iodohexyl)benzophenone 3c (0.612 mmol, 0.250 g) and N-dimethyloctadecylamine (0.674 mmol, 0.200 g) were stirred in acetonitrile (1 mL) in an 100 C. sand bath for 24 hours to give crude product of hexyl-dimethyl (benzoylphenoxy)octadecylammonium iodide purified to yield the desired product 6c (0.373 g, 86.3% yield). C.sub.39H.sub.64INO.sub.2; white powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 0.86 (m, H21, 3H), 1.23 (m, H20-H18, H13-H11, 36H), 1.77 (m, H14, 2H), 2.36 (m, H17, 2H), 3.51 (s, H16, 6H), 3.84 (s, H15, 2H), 4.24 (s, H10, 2H), 6.95 (m, Ar, 2H), 7.45 (m, Ar, 2H), 7.55 (m, Ar, 1H), 7.78 (m, Ar, 4H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.56 (C5), 162.75 (C9), 138.23 (C4), 132.56 (C3), 131.92 (C7), 131.86 (C1), 129.96 (C6), 128.19 (C2), 128.17 (C2), 114.00 (C8), 113.98 (C8), 67.99 (C10), 67.70 (C15), 59.90 (C16), 31.90 (C25), 29.69 (C23), 29.64 (C22), 29.58 (C21), 29.46 (C20), 29.39 (C19), 29.34 (C18), 29.22 (C11), 26.27 (C17), 25.36 (C16), 22.81 (C25), 22.68 (C20), 18.46 (C14), 14.12 (C27) ppm. HRMS-DART (m/z): [M.sup.+-I] calcd. for C.sub.39H.sub.64INO.sub.2, 578.4938; found, 578.4931.
Example 173-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido) propyl)-N,N-dimethylpropan-1-ammonium bromide 7a
(109) ##STR00052##
(110) According to the general procedure of quaternization of compound 10 with 4-O-(n-haloalkyl)benzophenone, compound 10 (0.712 mmol, 0.239 g) and 4-O-(3-bromopropyl)benzophenone 1a (0.783 mmol, 0.250 g) were dissolved in acetonitrile (2 mL) and left to stir in a 100 C. sand bath for 24 hours. The resultant residue was precipitated using cold diethyl ether (4 mL) to obtain the desired product 3-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)propyl)-N,N-dimethylpropan-1-ammonium bromide, 7a (0.345 g, 74.0% yield). C.sub.33H.sub.40BrN.sub.3O.sub.4S; puffy yellow powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 1.78 (m, H15, H16, 4H), 2.22 (m, H11, 2H), 2.82 (s, H23, 6H), 3.10 (m, H17, 2H), 3.22 (m, H13, 6H), 3.62 (m, H14, 2H), 3.72 (m, H12, 2H), 4.07 (m, H10, 2H), 6.85 (m, Ar, 2H), 6.99 (m, Ar, 1H), 7.12 (m, Ar, 1H), 7.55 (m, Ar, 2H), 7.75 (m, Ar, 6H), 7.85 (m, Ar, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.48 (C5), 161.65 (C9), 137.98 (C4), 132.57 (C27), 132.44 (C3), 130.54 (C7), 130.39 (C1), 129.72 (C6), 128.71 (C2), 128.25 (C20), 128.20 (C25), 128.18 (C19), 123.35 (C26), 118.21 (C21), 115.32 (C24), 114.13 (C8), 68.92 (C10), 64.46 (C14), 62.09 (C12), 51.37 (C13), 45.36 (C23), 22.91 (C11) ppm. HRMS-DART (m/z): [M.sup.+-Br] calcd. for C.sub.33H.sub.40BrN.sub.3O.sub.4S, 574.2749; found, 574.2734.
Example 183-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido) propyl)-N,N-dimethylpropan-1-ammonium chloride 7b
(111) ##STR00053##
(112) According to the general procedure of quaternization of compound 10 with halo-alkoxy(phenyl)(phenyl)methanone, compound 10 (0.870 mmol, 0.291 g) and (4-(3-chloropropoxy)phenyl)(phenyl)methanone 1b (0.790 mmol, 0.250 g) were dissolved in acetonitrile (2 mL) and left to stir in a 100 C. sand bath for 24 hours. The resultant residue was precipitated using cold diethyl ether (4 mL) to obtain the desired product 3-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)propyl)-N,N-dimethylpropan-1-ammonium chloride, 7b (0.250 g, 51.9% yield). C.sub.33H.sub.40ClN.sub.3O.sub.4S; puffy yellow powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 1.55 (m, H16, H15, 4H), 1.99 (m, H11, 2H), 2.82 (m, H12, 2H), 2.85 (s, H23, 6H), 3.15 (m, H13, 6H), 4.21 (m, H10, 2H), 6.81 (m, Ar, 1H), 6.95 (m, Ar, 1H), 7.18 (m, Ar, 3H), 7.51 (m, Ar, 2H), 7.75 (m, Ar, 4H), 7.81 (m, Ar, 2H), 8.21 (m, Ar, 3H), 8.29 (m, Ar, 1H), 8.45 (m, Ar, 1H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.53 (C5), 162.33 (C9), 138.22 (C4), 132.57 (C27), 132.46 (C3), 130.32 (C7), 130.01 (C1), 129.88 (C6), 128.24 (C2), 128.20 (C20), 128.10 (C25), 123.17 (C26), 118.99 (C21), 115.01 (C24), 114.06 (C8), 64.49 (C14), 59.94 (C12), 59.49 (C13), 45.42 (C23), 32.05 (C16) 24.64 (C11), 24.61 (C15) ppm. HRMS-DART (m/z): [M.sup.+-Cl] calcd. for C.sub.33H.sub.40ClN.sub.3O.sub.4S, 574.2751; found, 574.2734.
Example 193-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido) propyl)-N,N-dimethylpropan-1-ammonium iodide 7c
(113) ##STR00054##
(114) According to the general procedure of quaternization of compound 10 with halo-alkoxy(phenyl)(phenyl)methanone, compound 10 (0.750 mmol, 0.252 g) and (4-(3-iodopropoxy)phenyl)(phenyl)methanone 1c (0.680 mmol, 0.250 g) were dissolved in acetonitrile (2 mL) and left to stir in a 100 C. sand bath for 24 hours. The resultant residue was precipitated using cold di-ethyl ether (4 mL) to obtain the desired product 3-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)propyl)-N,N-dimethylpropan-1-ammonium iodide, 7c (0.267 g, 55.9% yield) C.sub.33H.sub.401 N.sub.3O.sub.4S; puffy yellow powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 1.99 (m, H15, 2H), 2.20 (m, H11, 2H), 2.80 (s, H22, 6H), 3.08 (m, H14, 2H), 3.15 (m, H13, 6H), 3.69 (m, H12, 2H), 3.71 (m, H16, 2H), 4.09 (m, H10, 2H), 6.95 (m, Ar, 2H), 7.18 (m, Ar, 3H), 7.45 (m, Ar, 2H), 7.55 (m, Ar, 1H), 7.75 (m, Ar, 2H), 7.85 (m, Ar, 2H), 8.21 (m, Ar, 3H), 8.29 (m, Ar, 1H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.48 (C5), 161.65 (C9), 137.98 (C4), 134.79 (C27), 132.57 (C3), 130.54 (C7), 130.39 (C1), 129.72 (C6), 128.71 (C2), 128.25 (C21), 128.20 (C26), 123.35 (C27), 118.21 (C22), 115.32 (C25), 114.13 (C8), 68.92 (C10), 64.46 (C14), 62.09 (C12), 51.37 (C13), 45.36 (C22), 22.91 (C15) ppm. HRMS-DART (m/z): [M.sup.+-I] calcd. for C.sub.33H.sub.40IN.sub.3O.sub.4S, 574.2753; found, 574.2734.
Example 204-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido) propyl)-N,N-dimethylbutan-1-ammonium bromide 8a
(115) ##STR00055##
(116) According to the general procedure of quaternization of compound 10 with halo-alkoxy(phenyl)(phenyl)methanone, compound 10 (0.717 mol, 0.240 g) and (4-(4-bromobutoxy)phenyl)(phenyl)methanone 2a (0.721 mmol, 0.240 g) were dissolved in acetonitrile (2 mL) and left to stir in a 100 C. sand bath for 24 hours. The resultant residue was precipitated using cold di-ethyl ether (4 mL) to obtain the desired product 4-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)propyl)-N,N-dimethylbutan-1-ammonium bromide, 8a (0.168 g, 35.0% yield). C.sub.34H.sub.42BrN.sub.3O.sub.4S; puffy yellow powder. mp 96-104 C. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 1.84 (m, H17, H16, H12, H11, 8H), 2.84 (s, H24, 6H), 3.14 (m, H15, H14, H13, 10H), 4.03 (m, H10, 2H), 6.90 (m, Ar, 2H), 7.12 (m, Ar, 1H), 7.45 (m, Ar, 3H), 7.56 (m, Ar, 2H), 7.75 (m, Ar, 4H), 8.20 (m, Ar, 1H), 8.47 (m, Ar, 2H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.56 (C5), 162.22 (C9), 151.83 (C24), 138.09 (C4), 132.51 (C28), 132.00 (C3), 130.38 (C7), 130.20 (C1), 129.74 (C6), 129.45 (C2), 129.27 (C21), 128.23 (C26), 123.33 (C19), 115.34 (C25), 114.11 (C8) 67.00 (C10), 51.11 (C14), 45.39 (C23), 39.81 (C17), 22.86 (C12) ppm. HRMS-DART (m/z): [M.sup.+-Br] calcd. for C.sub.34H.sub.42BrN.sub.3O.sub.4S, 588.2908; found, 588.2890.
Example 214-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido) propyl)-N,N-dimethylbutan-1-ammonium iodide 8c
(117) ##STR00056##
(118) According to the general procedure of quaternization of compound 10 with halo-alkoxy(phenyl)(phenyl)methanone, compound 10 (0.598 mmol, 0.201 g) and (4-(4-iodobutoxy)phenyl)(phenyl)methanone 2c (0.658 mmol, 0.250 g) were dissolved in acetonitrile (2 mL) and left to stir in a 100 C. sand bath for 24 hours. The resultant residue was precipitated using cold diethyl ether (4 mL) to obtain the desired product 4-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)propyl)-N,N-dimethylbutan-1-ammonium iodide, 8c (0.244 g, 56.9% yield). C.sub.34H.sub.421 N.sub.3O.sub.4S; puffy yellow powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 1.62 (m, H11, 2H), 1.97 (m, H16, H12, 4H), 2.84 (s, H24, 6H), 3.15 (m, H12, H14, 8H), 3.48 (m, H13, H15, 4H), 3.60 (m, H17, 2H), 4.07 (m, H10, 2H), 6.91 (m, Ar, 3H), 7.15 (m, Ar, 1H), 7.45 (m, Ar, 3H), 7.57 (m, Ar, 2H), 7.75 (m, Ar, 4H), 8.19 (m, Ar, 1H), 8.42 (m, Ar, 1H), 8.50 (m, Ar, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.61 (C5), 162.22 (C9), 151.92 (C23), 138.06 (C4), 134.37 (C28), 132.52 (C3), 130.58 (C7), 130.19 (C1), 129.71 (C6), 129.32 (C2), 128.91 (C21), 128.26 (C26), 123.40 (C19), 114.20 (C8), 67.03 (C10), 51.39 (C14), 45.40 (C24), 30.04 (C11), 25.65 (C12), 19.65 (C15) ppm. HRMS-DART (m/z): [M.sup.+-I] calcd. for C.sub.34H.sub.421 N.sub.3O.sub.4S, 588.2904; found, 588.2890.
Example 226-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido) propyl)-N,N-dimethylhexan-1-ammonium bromide 9a
(119) ##STR00057##
(120) According to the general procedure of quaternization of compound 10 with halo-alkoxy(phenyl)(phenyl)methanone, compound 10 (0.629 mmol, 0.211 g) and (4-((6-bromohexyl)oxy)phenyl)(phenyl)methanone 3a (0.692 mmol, 0.250 g) were dissolved in acetonitrile (2 mL) and left to stir in a 100 C. sand bath for 24 hours. The resultant residue was precipitated using cold diethyl ether (4 mL) to obtain the desired product 6-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)propyl)-N,N-dimethylhexan-1-ammonium bromide, 9a (0.385 g, 87.8% yield). C.sub.34H.sub.42BrN.sub.3O.sub.4S; puffy yellow powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 1.36 (m, H13, 2H), 1.48 (m, H12, 2H), 1.76 (m, H18, H14, H11, 6H), 2.84 (s, H26, 6H), 3.12 (s, H17, 6H), 3.33 (m, H19, 2H), 3.63 (m, H16, 2H), 4.06 (m, H10, 2H), 6.95 (m, Ar, 1H), 7.10 (m, Ar, 2H), 7.40 (m, Ar, 1H), 7.60 (m, Ar, 4H), 7.80 (m, Ar, 3H), 8.20 (m, Ar, 1H), 8.45 (m, Ar, 2H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.58 (C5), 162.69 (C9), 151.79 (C26), 138.20 (C4), 134.94 (C30), 132.51 (C3), 131.92 (C7), 131.86 (C1), 129.87 (C6), 128.69 (C2), 128.21 (C22), 128.18 (C27), 123.33 (C21), 115.31 (C25), 114.00 (C8), 67.81 (C10), 51.04 (C17), 45.39 (C26), 33.77 (C19), 32.61 (C11), 28.92 (C11), 28.71 (C18), 27.86 (C13), 25.79 (C12), 25.43 (C14) ppm. HRMS-DART (m/z): [M.sup.+-Br] calcd. for C.sub.34H.sub.42BrN.sub.3O.sub.4S, 616.3224; found, 616.3203.
Example 236-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido) propyl)-N,N-dimethylhexan-1-ammonium chloride 9b
(121) ##STR00058##
(122) According to the general procedure of quaternization of compound 10 with halo-alkoxy(phenyl)(phenyl)methanone, compound 10 (0.870 mmol, 0.291 g) and (4-(6-chlorohexyl(oxy))phenyl)(phenyl)methanone 3b (0.790 mmol, 0.250 g) were dissolved in acetonitrile (2 mL) and left to stir in a 100 C. sand bath for 24 hours. The resultant residue was precipitated using cold di-ethyl ether (4 mL) to obtain the desired product 6-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)propyl)-N,N-dimethylhexan-1-ammonium chloride, 9b (0.435 g, 84.5% yield). C.sub.36H.sub.46ClN.sub.3O.sub.4S; puffy yellow powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 1.18 (m, H13, 2H), 1.51 (m, H12, H19, 4H), 1.83 (m, H14, H18, 4H), 2.20 (m, H11, 2H), 2.81 (m, H15, H16, 4H), 2.87 (s, H26, 6H), 3.03 (s, H17, 6H), 4.03 (m, H10, 2H), 6.95 (m, Ar, 1H), 7.10 (m, Ar, 2H), 7.40 (m, Ar, 1H) 7.60 (m, Ar, 4H), 7.80 (m, Ar, 3H), 8.20 (m, Ar, 1H), 8.45 (m, Ar, 2H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.58 (C5), 162.76 (C9), 151.89 (C25), 138.31 (C4), 134.74 (C29), 132.57 (C3), 131.91 (C7), 131.87 (C1), 129.96 (C6), 129.62 (C2), 128.60 (C24), 128.20 (C28), 128.18 (C23), 115.29 (C27), 114.03 (C8), 68.00 (C10), 50.93 (C16), 45.42 (C26), 44.42 (C19), 32.46 (C11), 28.96 (C18), 28.72 (C13), 26.59 (C12), 25.82 (C14), 25.46 (C17) ppm. HRMS-DART (m/z): [M.sup.+-Cl] calcd. for C.sub.36H.sub.46ClN.sub.3O.sub.4S, 616.3221; found, 616.3203.
Example 246-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino)naphthalene-1-sulfonamido) propyl)-N,N-dimethylhexan-1-ammonium iodide 9c
(123) ##STR00059##
(124) According to the general procedure of quaternization of compound 10 with halo-alkoxy(phenyl)(phenyl)methanone, compound 10 (0.366 mmol, 0.272 g) and (4-((6-iodohexyl)oxy)phenyl)(phenyl)methanone 3c (0.333 mmol, 0.136 g) were dissolved in acetonitrile (2 mL) and left to stir in a 100 C. sand bath for 24 hours. The resultant residue was precipitated using cold diethyl ether (4 mL) to obtain the desired product 6-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino) naphthalene-1-sulfonamido)propyl)-N,N-dimethylhexan-1-ammonium iodide, 9c (0.232 g, 93.5% yield). C.sub.36H.sub.461 N.sub.3O.sub.4S; puffy yellow powder. .sup.1H NMR (400 MHz, CDCl.sub.3, ): 1.34 (m, H13, 2H), 1.46 (m, H18, 2H), 1.73 (m, H12, 2H), 2.00 (m, H11, 2H), 2.83 (s, H26, 6H), 3.10 (m, H16, 17, 8H), 3.29 (m, H15, 2H), 3.54 (m, H19, 2H), 3.95 (m, H10, 2H), 6.90 (m, Ar, 2H), 7.10 (m, Ar, 1H), 7.50 (m, Ar, 6H), 7.75 (m, Ar, 4H), 8.20 (m, Ar, 1H), 8.40 (m, Ar, 1H), 8.49 (m, Ar, 1H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3, ): 195.63 (C5), 162.69 (C9), 138.21 (C4), 134.45 (C30), 132.54 (C3), 131.95 (C7), 129.92 (C6), 129.74 (C2), 129.72 (C24), 128.22 (C27), 115.29 (C26), 114.11 (C8), 67.83 (C10), 51.35 (C17), 45.42 (C24), 28.96 (C11), 28.71 (C13), 25.47 (C14) ppm. HRMS-DART (m/z): [M.sup.+-I] calcd. for C.sub.36H.sub.46IN.sub.3O.sub.4S, 616.3217; found, 616.3203.
(125) TABLE-US-00001 TABLE 1 Physio-chemical data of 4-O-(n-haloalkyl)benzophenone derivatives
(126) TABLE-US-00002 TABLE 2 Physio-chemical data of alkyl-dimethyl(benzoylphenoxy) alkylammonium salts
(127) TABLE-US-00003 TABLE 3 Physio-chemical data of n-(4-benzoylphenoxy)-N-(3-(5-(dimethylamino) naphthalene-1-sulfonamido)propyl)-N,N-dimethylalkyl-1-ammonium halide derivatives
Preparation of Self Assembled Monolayers on Polyvinylchloride (PVC)
(128) PVC was cut into rectangles and substrates were rinsed in isopropyl alcohol (IPA) and water then dried in an oven for 30 minutes. A 0.05% and 0.5% (w/v) solution of 6a was made in H.sub.2O/MeOH and electrosprayed on the clean substrates three consecutive times with 5 minutes of irradiation time with UV in a fumehood in-between each spray. After the last spray substrates were irradiated once more for an additional 25 minutes. Unbound material was later rinsed from the substrates using H.sub.2O.
(129) Preparation of Self Assembled Monolayers on Silicone Tubing
(130) Using Peristaltic Pump
(131) Silicone tubing was rinsed with IPA and H.sub.2O using a peristaltic pump then dried by running air through the tubes. A 0.05% (w/v) solution of 8a in H.sub.2O and a 0.5% (w/v) solution of 4c in H.sub.2O/IPA were prepared. Tubes were coated using the peristaltic pump and filled tubes were irradiated using a UV fumehood for 25 minutes. Coated tubes were then rinsed with H.sub.2O to remove any unbound materials.
(132) Using a Syringe
(133) 1.5% (w/v) solutions of 8a and 4c in dichloromethane (DCM) were prepared. These solutions were pumped through clean silicone tubing using a syringe and irradiated using a UV quartz lamp for 30 minutes.
(134) Antimicrobial Test Method
(135) The antimicrobial efficacy was determined using a flow-cell method as described in Markison C and Swan J, The Effect of Humidity on the Survival of MRSA on Hard Surfaces, Indoor and Built Environment, 2006, 15(1), 85-91. A 1% tryptic soy broth and an inoculum of 1010.sup.4 cfu/mL of Pseudomonas spp. CTO7 were pumped through silicone tubing coated with 8a, 4c and a control tube for 30 hours. The tubes were then left stagnant for a period of 2 hours after which only the 1% TSB was allowed to flow through the tubes for 48 hours. During these 48 hours effluent samples of 100 L were collected periodically and plated on 10% trypticase soy agar (TSA) in a dilution series up to 1010.sup.4. Sampling periods were time zero, 3 hours, 6 hours, 24 hours, 27 hours, 30 hours, and 48 hours. The number of colonies grown on each plate was counted in order to determine antimicrobial activity.
(136) TABLE-US-00004 TABLE 4 Pseudomonas bacterial cell count on silicone tubing coated with 8a Concentration of samples (cfu/mL) Time (hr) 10.sup.0 10.sup.1 10.sup.2 10.sup.3 10.sup.4 0 0 0 0 0 0 3 15 0 0 0 0 6 6 0 0 0 0 24 0 0 0 0 0 27 30 0 0 0 0 30 18 4 0 0 0 48 27 1 0 0 0
(137) TABLE-US-00005 TABLE 5 Pseudomonas spp. CT07 bacterial cell count on silicone tubing coated with 4c Concentration of samples (cfu/mL) Time (hr) 10.sup.0 10.sup.1 10.sup.2 10.sup.3 10.sup.4 0 300 300 48 8 0 3 20 0 0 0 0 6 160 15 0 0 0 24 300 200 21 4 0 27 300 110 11 0 0 30 300 70 5 0 0 48 289 31 0 0 0
(138) 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.