ANTIMICROBIAL COMPOSITIONS, METHODS OF MAKING, AND METHODS OF USE

Abstract

The invention provides a protected antimicrobial compound and methods of using the same.

Claims

1. A protected antimicrobial composition comprising: ##STR00010## wherein X is Cl, Br, I, tosyl, F, or a conjugate base of a strong acid; and, R.sub.1 and R.sub.2 are aliphatic or aromatic organic substituent groups independently having from 1-20 carbons or a polymerizable functional group selected from the group consisting of (meth)acrylate esters, (meth)acrylamides, and vinyl containing groups.

2. The protected antimicrobial composition of claim 1 comprising the following structure: ##STR00011## further wherein n is between 1 and 100.

3. The protected antimicrobial composition of claim 2 wherein n is between 2 and 5.

4. The protected antimicrobial composition of claim 2 wherein X is Br.

5. The protected antimicrobial composition of claim 2 wherein X is I.

6. The protected antimicrobial composition of claim 1 comprising the following structure: ##STR00012## wherein R is CH.sub.3 or H.

7. A formulation comprising the protected antimicrobial composition of claim 1.

8. A method of using the antimicrobial composition of claim 1 comprising: i. providing the protected antimicrobial composition of claim 1; and ii. contacting the protected antimicrobial composition with an environment having a pH of 7 or less to release acrolein.

9. The method of claim 8 wherein the temperature of the environment is from 0 to 200 C.

10. A method of using the compound of claim 1 wherein the protected antimicrobial composition of claim 1 is added to an oil well; water reservoir; natural gas reservoir; paint; film; pressure treated wood; coating; caulk; wall board; or plastic.

Description

EXAMPLES

[0011] ##STR00005##

Synthesis of Molecules

[0012] Materials: Unless otherwise noted, all the solvents were ACS reagent grade (conforms to specifications defined by the Committee on Analytical Reagents of the American Chemical Society) and purchased from Acros Organics, Fisher Scientific, Macron Fine Chemicals, or Sigma-Aldrich, and used without further purification. Acrolein was purchased from Thermo Fischer Scientific Chemicals INC/Alfa Aesar and used as received. Triethylene glycol monomethyl ether, TsOH.H.sub.2O, NaI were purchased from Aldrich and used as received. Bromotrimethylsilane (Oakwood Chemicals), and 1 M HCl in diethylether (Alfa Aesar) were used as received.

[0013] Compound 1: Into a 500 mL round bottom flask (RBF) was added 200 mL toluene, 50 mL diethyl ether, and 6.64 mL (0.1 mol) acrolein. The RBF was fitted with a liquid addition funnel under N.sub.2 atmosphere and 100 mL of 1 M HCl in diethyl ether was added dropwise over 1 h at room temperature (25 C.) while stirring. The crude reaction mixture indicated 99% conversion of the acrolein to 3-chloropropanaldehyde by .sup.1H NMR (500 MHz, CDCl.sub.3). Atmospheric distillation was used to remove 150 mL of diethyl ether from the reaction crude. To the RBF was added 40 mL (0.25 mol) triethylene glycol monomethyl ether and 230 mg (1.2 mmol) TsOH.H.sub.2O. The solution was refluxed for 24 h under Dean-stark conditions. At the end of the reaction, solvent was removed under reduced pressure, the crude was washed with 100 mL of hexane, and re-dissolved in 100 mL of ethyl acetate. This solution was washed with 300 mL of an aqueous solution containing 5 wt. % K.sub.2CO.sub.3 and 10 wt. % NaCl. The product was back extracted with 2100 mL of ethyl acetate. The organic layers were combined, washed with 150 mL brine, and dried over Na.sub.2SO.sub.4. The solution was vacuum filtered and concentrated under reduced pressure to obtain 26 g of 1 as crude product, 7 g of which was used directly in the Finkelstein reaction, and the remaining crude was purified by silica column chromatography using 30% acetone in petroleum ether (v/v) with <1% triethylamine to isolate yellow liquid product. Yield: 12.19 g, 30%.

[0014] Compound 2: 1 was converted to 2 via Finkelstein reaction. In a 100 ml round bottom flask with condenser, the precursor (7 g, 17.4 mmol) was dissolved in 60 mL of acetone and treated with 5.68 g, 2 equivalents, of NaI and 1 mol % triethylamine at 45 C. for 24 h. At the end of the reaction, the crude was transferred to a 250 mL Erlenmeyer flask and 60 mL of diethyl ether was added to this solution while cooling the solution at 20 C. to precipitate out most of the remaining NaI and NaCl. This cold solution was quickly filtered off through a sintered crucible. The filtrate was concentrated under reduced pressure, re-dissolved in 60 mL of ethyl acetate, and washed with 230 mL of 10% Na.sub.2S.sub.2O.sub.3 solution. The aqueous solution was back extracted with 30 mL ethyl acetate. All organic layers were combined, washed with 100 mL of brine, and dried over Na.sub.2SO.sub.4. The solution was vacuum filtered and concentrated under reduced pressure. The product was further purified by silica column chromatography using 30% acetone in petroleum ether (v/v) with <1% triethylamine to isolate yellow liquid product. Yield: 5.24 g, 61%.

[0015] Compound 3: Into a 250 mL round bottom flask (RBF) cooled to 0 C. was added 125 mL dry benzene and 6.64 mL (0.1 mol) acrolein. The RBF was fitted with a septum and 15.8 mL (0.12 mol) trimethylsilyl bromide was added dropwise over 5 min. The solution stirred for 30 min at 0 C., warmed to room temperature, and stirred for an additional 2 h prior to the addition of 48 mL (0.30 mol) triethylene glycol monomethyl ether and 500 mg (2.6 mmol) TsOH.H.sub.2O. The mixture was refluxed under a Dean-Stark trap for 16 h, cooled, and evaporated. Chromatography of the residue on silica gel (elution with 3:1 petroleum ether/acetone) gave 3 as a yellow liquid. Yield: 9.5 g, 21%.

Synthesis of Compound III

[0016] ##STR00006##

where X is I and R is H.

[0017] In a 2 L round bottom flask with 100 g activated 3 molecular sieves, 900 mL HPLC-grade MeCN was added under N.sub.2. NaI (128 g, 0.85 mol) was added under N.sub.2, followed by addition of acrolein (52 mL, 0.78 mol). The solution was added to trimethylsilyl chloride (110 mL, 0.87 mnol) over 15 min. via an additional funnel. The solution was stirred at room temperature for 2 h, followed by addition of 2-hydroxyethyl acrylate (204.4 mL, 1.78 mol). The reaction was stirred for another 2 h.

[0018] The solution was filtered through sintered crucible, ethyl acetate was used to rinse the collected solids. The filtrate was rotovapped to dryness, pumped on high vacuum, and re-dissolved in 60% ethyl acetate/hexanes (500 mL). The solution was cooled to 20 C. for 2 h, filtered off solids in the suspension, and washed with saturated NaHCO.sub.3 (250 mL2), 10% w/v Na.sub.2S.sub.2O.sub.3 (250 mL2), DI H.sub.2O (250 mL3). The layers are separated and the aqueous layer was back extracted with 30% ethyl acetate/hexanes (250 mL1). The organic layers were combined, washed with brine (250 mL1), dried over Na.sub.2SO.sub.4 for 2 h, filtered to remove the drying agent, and evaporated on rotovap. The obtained oil was applied on top of a 20% ethyl acetate/hexanes-wetted plug consist of 50 mL celite at bottom and 50 mL basic alumina at top in a 200 mL sintered crucible. Vacuum was applied to elute the product with 1.5 L of 20% ethyl acetate/hexanes, until no intense product spot observed on thin-layer chromatography (TLC). The eluted solution was rotovapped and pumped on high vacuum to remove excess solvent.

Synthesis of an Acrylic Polymer Containing (III)

[0019] ##STR00007##

where X is I and R is H.

[0020] 3 g of a solution of 48% styrene, 40% butyl acrylate, 10% the compound above, and 2% acrylic acid were added to 7 g of a 1% sodium dodecyl sulfate in 0.1M phosphate buffer solution. The two phases were vortexed to form an emulsion. 200 mg of (NH.sub.4).sub.2S.sub.2O.sub.8 and 270 mg of (NH.sub.4).sub.2S.sub.2O.sub.5 were added to initiate polymerization. The reaction was allowed to proceed under nitrogen for 2 hrs. at room temperature followed by 2 hrs. at 70 C., yielding the polymer.

Degradation of Compound and Release of Acrolein

[0021] For compound

##STR00008##

n=3, X as defined in the table. Measured at 25 degrees Celsius (room temperature), tracked via NMR spectroscopy. All compounds were prepared at 50 mM in deuterated water, pH adjusted with deuterium chloride.

TABLE-US-00001 % % acrolein % acrolein % degraded pH degraded pH generated pH 7, generated pH 3, X 7, 7 days 3, 3 days 7 days 3 days Cl 0 50 0 1 Br 95 100 12 8 I 40 80 6 7

[0022] For compound

##STR00009##

n=3, X is Br. Measured at 25 or 70 degrees Celsius, tracked via NMR spectroscopy. All compounds were prepared at 50 mM in deuterated water at pH 7. Measurements were made after 4 hours.

TABLE-US-00002 % degraded % degraded % acrolein % acrolein 25 C. 70 C. generated 25 C. generated 70 C. 0 85 0 40