Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/10—Spiro-condensed systems

Definitions

• the invention relates generally to antimicrobial compounds and methods of their use for the control of microorganisms in aqueous or water-containing systems or in systems which are exposed to moisture.
• aqueous systems from microbial contamination is critical to the success of many industrial processes, including oil or natural gas production operations.
• microorganism contamination from both aerobic and anaerobic bacteria can cause serious problems such as reservoir souring (mainly caused by anaerobic sulfate-reducing bacteria (SRB)), microbiologically influenced corrosion (MIC) on metal surfaces of equipment and pipelines, and degradation of polymer additives.
• SRB anaerobic sulfate-reducing bacteria
• MIC microbiologically influenced corrosion
• Glutaraldehyde is a known antimicrobial compound that is used to control the growth of microorganisms in aqueous systems and fluids, including those found in oil and gas operations.
• Glutaraldehyde is susceptible to a number of drawbacks. For instance, it can degrade over time at the elevated temperatures often encountered in the oil and gas production environment. The material can also be inactivated by other common oilfield chemicals such as bisulfite salts and amines. These conditions can leave oilfield
• the problem addressed by this invention is the provision of antimicrobial systems with improved thermal and chemical stability.
• compounds of formula I as described herein are capable of controlling microorganisms in aqueous or water-containing systems or in systems which are exposed to moisture, including those found in oil and gas operations.
• the compounds of formula I are more stable at elevated temperatures, thus permitting extended control of microbial fouling.
• the compounds may exhibit improved stability in the presence of other chemical species that would otherwise degrade the free glutaraldehyde, such as reducing or oxidizing agents including bisulfites, and amines.
• the invention provides compounds of formula I:
• n is 0 or 1 ;
• R 1 , R 2 , and R 3 are independently H, linear or branched Ci-Cio alkyl, or C 3 -C 8 cycloalkyl, or R 2 and R 3 together with the carbon to which they are attached form C 3 -C 8 cycloalkyl; and
• X is O or NR 4 , wherein R 4 is H or Ci-C 6 alkyl.
• the invention provides methods for controlling microorganisms in aqueous or water-containing systems or in systems which are exposed to moisture.
• the system has a temperature of at least 40 °C.
• the method comprises contacting the system with a compound of formula I as described herein.
• Alkyl as used in this specification encompasses straight and branched chain aliphatic groups having the indicated number of carbon atoms.
• exemplary alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, hexyl, heptyl, and octyl.
• cycloalkyl refers to saturated and partially unsaturated cyclic hydrocarbon groups having the indicated number of ring carbon atoms.
• Preferred cycloalkyl groups include, without limitation, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• the cycloalkyl is optionally substituted with linear or branched Ci-C 6 alkyl.
• microorganism includes, but is not limited to, bacteria, fungi, algae, archaea, and viruses.
• control and
• control should be broadly construed to include within their meaning, and without being limited thereto, inhibiting the growth or propagation of microorganisms, killing
• the microorganisms are bacteria. In some embodiments, the microorganisms are aerobic bacteria. In some embodiments, the microorganisms are anaerobic bacteria. In some embodiments, the microorganisms are sulfate reducing bacteria (SRB). In some embodiments, the microorganisms are acid producing bacteria (APB). In some embodiments, the microorganisms are archaea.
• numeric ranges for instance as in “from 2 to 10,” are inclusive of the numbers defining the range (e.g., 2 and 10). Unless otherwise indicated, ratios, percentages, parts, and the like are by weight.
• the invention provides compounds and methods of using them for the control of microorganisms in aqueous or water-containing systems or in systems which are exposed to moisture, including those found in oil and gas operations.
• n is 0 or 1;
• R 1 , R 2 , and R 3 are independently H, linear or branched Ci-Cio alkyl, or C 3 -C 8 cycloalkyl, or R 2 and R 3 together with the carbon to which they are attached form C 3 -C 8 cycloalkyl; and
• X is O or NR 4 , wherein R 4 is H or Ci-C 6 alkyl.
• R 1 in the compounds of formula I is H.
• R 2 is H and R 3 is linear or branched C 1 -C 10 alkyl.
• R 2 is H and R 3 is C 3 -C 8 cycloalkyl.
• R 2 and R 3 are independently linear or branched C 1 -C 10 alkyl. In some embodiments, n is 0.
• X is O.
• X is NR 4 , wherein R 4 is H or Ci-C 6 alkyl. In some embodiments, R 4 is H.
• Exemplary compounds of formula I include the following:
• 2,3,4, 8,9,9a-hexahydropyrido[2,l-b][l,3]oxazine is excluded nd of the invention.
• Compounds of formula I may be prepared, for example, as depicted in Scheme I.
• the glutaraldehyde is mixed with amine compound A in a suitable solvent, such as water.
• the mixture may be stirred for sufficient time to allow the reaction to occur and the desired compound of formula I to form.
• the product may be used as is, or optionally further purified using techniques well known to those skilled in the art, such as crystallization, chromatography, distillation, extraction, etc.
• the compound A used in the synthesis described above is generally an amine compound that contains an additional amine or hydroxyl group.
• Examples include: 3- aminooctan-4-ol, 2-amino-4-ethyloctan-3-ol, (l-aminocyclohexyl)methanol, 2-amino-2- methylpropan-l-ol, 3-aminobutan-2-ol, 3-amino-l-propanol, pentane- 1,3 -diamine, or 2- amino-4-isopropylheptan-3-ol.
• Such compounds may be commercially available and/or may be readily prepared by those skilled in the art.
• the compounds of formula I be isolated or purified from the reaction mixture in which they were synthesized, and in some embodiments it may be preferred that the reaction mixture be used without purification for the control of microorganisms.
• Such mixture may contain isomers of the compound, or polymeric species or other byproducts that are inert or that may also provide microbial control.
• the compounds of formula I may release glutaraldehyde when heat-activated. Unlike the free aldehyde, however, the compounds are more stable at elevated temperatures thus permitting extended control of microbial fouling. In addition, the compounds may exhibit improved stability in the presence of other chemical species that would otherwise degrade the free aldehydes, such as bisulfites, and amines.
• the compounds of the invention are useful for controlling microorganisms for extended periods of time in aqueous or water-containing systems or in systems which are exposed to moisture, including those that are at elevated temperatures.
• the compounds of the invention are also useful for incorporation into products which are manufactured or stored at elevated temperatures.
• the compounds are also useful for controlling microorganisms aqueous or water-containing systems that may be present or used in oil or natural gas applications, paper machine white water, industrial recirculating water, starch solutions, latex or polymer emulsions, coatings or building products or household products or personal care products which are manufactured at elevated temperatures, plastics, hot rolling machining fluids, or industrial dishwashing or laundry fluids, animal biosecurity fluids, or high level disinfection fluids.
• the aqueous or water-containing system may be present or used in oil or natural gas applications. Examples of such systems include, but are not limited to, fracturing fluids, drilling fluids, water flood systems, oil field water, and produced fluids.
• the system may be at a temperature of 40 °C or greater, alternatively 55 °C or greater, alternatively 60 °C or greater, alternatively 70 °C or greater, or alternatively 80 °C or greater.
• the compounds may further be effective when a deactivating agent, such as a source of bisulfite ion or amines is present in the system.
• a deactivating agent such as a source of bisulfite ion or amines
• a suitable concentration based on the equivalent of glutaraldehyde that is potentially released (assuming 100 % release) by the formula I compound is typically at least about 1 ppm, alternatively at least about 5 ppm, alternatively at least about 50 ppm, or alternatively at least about 100 ppm by weight.
• the concentration is 2500 ppm or less, alternatively 1500 ppm or less, or alternatively 1000 ppm or less.
• the aldehyde equivalent concentration is about 100 ppm.
• the compounds of formula I may be used in the system with other additives such as, but not limited to, surfactants, ionic/nonionic polymers and scale and corrosion inhibitors, oxygen scavengers, nitrate or nitrite salts, and/or additional antimicrobial compounds.
• additives such as, but not limited to, surfactants, ionic/nonionic polymers and scale and corrosion inhibitors, oxygen scavengers, nitrate or nitrite salts, and/or additional antimicrobial compounds.
• a three neck 250 mL round bottom flask equipped with a stir bar, thermocouple, addition funnel capped with nitrogen inlet and condenser is charged with 3-aminooctan-4-ol (85%, 42.7 g, 0.25 mols, 1.0 equivalents).
• the flask is cooled down to approximately 10 °C under ice/water bath. Once the temperature is reached, glutaraldehyde (50%, 50.0 g, 0.25 mols, 1.0 equivalents) is added drop wise over a period of 45 minutes. The reaction temperature is maintained by cooling the bath and by controlled addition of glutaraldehyde.
• a three neck 50 mL round bottom flask equipped with a stir bar, thermocouple, addition funnel capped with nitrogen inlet and condenser is charged with 2-amino-4- ethyloctan-3-ol (100%, 8.7 g, 0.05 mols, 1.0 equivalents) and 10 mL of water.
• the flask is cooled down to approximately 10 °C under ice/water bath.
• glutaraldehyde (50%, 10.0 g, 0.05 mols, 1.0 equivalents) is added drop wise over a period of 15 minutes.
• the reaction temperature is maintained by cooling the bath and by controlled addition of glutaraldehyde.
• a three neck 50 mL round bottom flask equipped with a stir bar, thermocouple, addition funnel capped with nitrogen inlet and condenser is charged with (1- aminocyclohexyl)methanol (100%, 3.23 g, 0.025 mols, 1.0 equivalents) and 6 mL of water.
• the flask is cooled down to approximately 10 °C under ice/water bath.
• glutaraldehyde (50%, 5.0 g, 0.025 mols, 1.0 equivalents) is added drop wise over a period of 10 minutes.
• the reaction temperature is maintained by cooling the bath and by controlled addition of glutaraldehyde.
• a three neck 50 mL round bottom flask equipped with a stir bar, thermocouple, addition funnel capped with nitrogen inlet and condenser is charged with 2-amino-2- methylpropan-l-ol (95%, 7.8 g, 0.083 mols, 1.0 equivalents).
• the flask is cooled down to approximately 10 °C under ice/water bath. Once the temperature is reached, glutaraldehyde (50%, 16.7 g, 0.083 mols, 1.0 equivalents) is added drop wise over a period of 15-20 minutes. The reaction temperature is maintained by cooling the bath and by controlled addition of glutaraldehyde.
• the transparent reaction mixture turns milky/opaque and a viscous sticky solid starts forming making stirring difficult.
• the reaction is stopped and the GC of the material is taken and a peak at 11.99 minutes is observed which corresponds to compound (4).
• the GC has some minor impurities in the high retention region. 20 mL of ethyl acetate is added to the reaction mixture and vigorously stirred under nitrogen. The entire content of the flask dissolve in ethyl acetate. The ethyl acetate layer is washed twice with 25 mL of water and the organic layer dried in magnesium sulfate.
• a three neck 100 mL round bottom flask equipped with a stir bar, thermocouple, addition funnel capped with nitrogen inlet and condenser is charged with 3-aminobutan-2-ol (100%, 8.9 g, O. lmols, 1.0 equivalent).
• the flask is cooled to approximately 10 °C under ice/water bath.
• glutaraldehyde (50%, 20.0 g, 0.1 mols, 1.0 equivalents) is added drop wise over a period of 20 minutes.
• the reaction temperature is maintained by cooling the bath and by controlled addition of glutaraldehyde. After complete addition of glutaraldehyde, the transparent reaction mixture turns opaque and a viscous sticky solid starts forming making stirring difficult.
• the reaction is stopped and the GC of the material is taken and four isomeric peaks between 11.92 and 12.30 minutes are observed which corresponded to compound (5).
• the GC has some minor impurities in the high retention region.
• 20 mL of ethyl acetate is added to the reaction mixture and vigorously stirred under nitrogen. The entire content of the flask dissolves in ethyl acetate.
• the ethyl acetate layer is washed twice with 25 mL of water and the organic layer dried in magnesium sulfate. After filtering the MgS0 4 , the organic solvent is stripped off under a rotary evaporator and this results in approximately 7.1 g of crude material (46.4% yield).
• a three neck 100 mL round bottom flask equipped with a stir bar, thermocouple, addition funnel capped with nitrogen inlet and condenser is charged with 3-amino-l-propanol (100%, 7.52 g, O.lmols, 1.0 equivalent).
• the flask is cooled to approximately 10 °C under ice/water bath.
• glutaraldehyde (50%, 20.0 g, 0.1 mols, 1.0 equivalents) is added drop wise over a period of 20 minutes.
• the reaction temperature is maintained by cooling the bath and by controlled addition of glutaraldehyde. After complete addition of glutaraldehyde, the transparent reaction mixture turns viscous and yellow in color. There is no sign of any solid crashing out of solution.
• the reaction is allowed to stir under ice/water bath for 30 minutes and gradually warmed to room temperature. As the temperature of the reaction mixture increases, the yellow material turns brown. GC of the reaction mixture shows that all the starting material is consumed and a prominent peak is seen at retention time of 12.15 minutes.
• the reaction mixture is dissolved in 25 mL of ethyl acetate and vigorously stirred under nitrogen. The entire contents of the flask dissolves in ethyl acetate. The ethyl acetate layer is washed thrice with 25 mL of water and the organic layer dried in magnesium sulfate.
• a three neck 100 mL round bottom flask equipped with a stir bar, thermocouple, addition funnel capped with nitrogen inlet and condenser is charged with pentane- 1,3 -diamine (100%, 10.2 g, O.lmols, 1.0 equivalent).
• the flask is cooled to approximately 10 °C under ice/water bath. Once the temperature is reached, glutaraldehyde (50%, 20.0 g, 0.1 mols, 1.0
• Glutaraldehyde and Compounds 1 and 2 are tested for biocidal activity against a pool of aerobic organisms at room temperature and against sulfate reducing bacteria (SRB) at room temperature. Tests are performed as follows:
• Glutaraldehyde (50% in water) and Compounds 1 and 2 are each dissolved in DMSO to a concentration of 200 mM, which is equivalent to 20,000 ppm of free glutaraldehyde.
• Aerobic Bacteria a mixed pool of 6 bacterial species at ⁇ 5 x 10 6 CFU/mL in phosphate buffered saline is distributed into a 96-well plate. Each well receives an independent chemical treatment of glutaraldehyde or Compound 1 or 2 at concentrations ranging from 200 ppm to 12 ppm glutaraldehyde. A control treatment of DMSO alone is also included. Each condition is tested in triplicate. After set periods of incubation (1, 4, and 24h), the number of surviving cells in each well are enumerated by dilution to extinction in a medium containing resazurin dye as an indicator.
• SRB Sulfate Reducing Bacteria
• Compounds 1 and 2 do not show significant biocidal activity against aerobic bacteria at room temperature. They do show some activity against SRB, but are not as effective as glutaraldehyde.
• Compound 1 (208 mg) is dissolved in DMSO (5 mL) to yield a 200 mM solution such that the glutaraldehyde-equivalent concentration of the stock solution is 20,000 ppm.
• the bacterial strain Thermus thermophilus (ATCC 27634) is maintained at 70 °C.
• 10 mL of bacterial culture are harvested by spinning in a Beckman-Coulter benchtop centrifuge at 3000 rpm for 15 min.
• the cell pellet is resuspended in 100 mL of phosphate-buffered saline (PBS) to give approximately 5 x 10 5 CFU/mL and aliquoted into 10 mL portions in glass test tubes fitted with screw caps.
• PBS phosphate-buffered saline
• Samples are equilibrated to 37, 55, or 70 °C for 30 min and then treated with glutaraldehyde or Compound 1 at 50 ppm glutaraldehyde equivalent.
• the treated samples are returned to their respective equilibration temperatures for 4 h and then enumerated for surviving bacteria. After 24 h, the process is repeated by adding fresh grown bacteria to the samples to re-challenge the biocide. The samples are again enumerated after 4 h.
• Results are reported in terms of log kill of treated bacterial populations relative to an untreated control at each temperature. For values listed as ">x,” actual kill may have been higher but could not be detected by this assay.
• Compound 1 shows equivalent activity to glutaraldehyde at each 70 °C but is less effective at the lower temperatures.

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