WO1994020415A1 - Procede de production d'oxyde nitrique gazeux utilisant des complexes d'oxyde nitrique - Google Patents

Procede de production d'oxyde nitrique gazeux utilisant des complexes d'oxyde nitrique Download PDF

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Publication number
WO1994020415A1
WO1994020415A1 PCT/US1993/002374 US9302374W WO9420415A1 WO 1994020415 A1 WO1994020415 A1 WO 1994020415A1 US 9302374 W US9302374 W US 9302374W WO 9420415 A1 WO9420415 A1 WO 9420415A1
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WIPO (PCT)
Prior art keywords
gas
nitric oxide
methyl
alkyl
adduct
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PCT/US1993/002374
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English (en)
Inventor
Joseph Anthony Hrabie
Larry Kay Keefer
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The United States Of America, Represented By The Secretary, Department Of Health And Human Services
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Filing date
Publication date
Priority claimed from US07/906,479 external-priority patent/US5250550A/en
Application filed by The United States Of America, Represented By The Secretary, Department Of Health And Human Services filed Critical The United States Of America, Represented By The Secretary, Department Of Health And Human Services
Priority to PCT/US1993/002374 priority Critical patent/WO1994020415A1/fr
Priority to US08/522,405 priority patent/US5683668A/en
Priority to AU38096/93A priority patent/AU3809693A/en
Publication of WO1994020415A1 publication Critical patent/WO1994020415A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B21/00—Nitrogen; Compounds thereof
    • C01B21/20—Nitrogen oxides; Oxyacids of nitrogen; Salts thereof
    • C01B21/24—Nitric oxide (NO)

Definitions

  • the present invention relates to the generation of nitric oxide gas using solid complexes of nitric oxide, in particular zwitterionic polyamine-nitric oxide adducts.
  • Nitric oxide has many important uses in biological, pharmaceutical, chemical, ⁇ and industrial applications.
  • NO is a key bioregulatory molecule that plays critical roles in the regulation of various biological processes, including the normal physiological control of blood pressure, macrophage- induced cytostasis and cytotoxicity, inhibition of platelet aggregation, and neurotransmission (Moncada et al., Pharmacological Reviews. 43(2), 109-142 (1991)).
  • NO has many other uses, particularly in chemical and industrial applications. NO is used extensively in both the laboratory and the industrial plant. For example, NO gas is used to directly effect desired chemical results, and the NO radical is involved in the formation of diazotizing/nitrosating agents, which are used to achieve a variety of chemical results. Free NO gas is used in the preparation of nitric acid, nitrosyl chloride, metal nitrosyls, and caprolactam, which, in turn, is used in the synthesis of nylon (McCleverty, Chem. Rev.. 79. 53-76 (1979)).
  • NO gas can be used to produce aryl bromides from aryl amines by a procedure which was developed as an alternative to traditional Sandmeyer reaction (Brackman and Smit, Reel. Trav. Chim. Pavs-Bas. 85. 857-864 (1966)).
  • the NO gas is used to produce cupric bromide nitrosyl jln situ, which converts the amine to a diazonium salt and then to the bromide.
  • NO is also used commercially as a polymerization inhibitor during the preparation of olefins (U.S. Patent 4,040,912 and French Patent 2,478,648) and to improve the properties of various polymers (German Patent 2,216,844).
  • NO is a highly poisonous and reactive gas. It is a strong irritant to the skin and mucous membranes. Moreover, NO is difficult to store in compact form, has a boiling point of -152°C, and is dangerous to transport. Also, NO gas cannot be manipulated in the presence of oxygen and will attack most metals and plastics. Consequently, NO is a difficult gas to handle, and the constraints on its use are compounded by the fact that, generally, NO can only be purchased in relatively low-pressure cylinders, thereby making its storage and distribution quite cumbersome and relatively expensive.
  • NO is either prepared on-site or shipped in heavy stainless steel cylinders at a pressure of 500 psig.
  • sodium nitrite which serves as the source of NO, is reacted with acidified iron sulfate to release NO gas, which then must be purified to remove higher oxides of nitrogen (Blanchard, Inorg. Synth.. 2., 126-128 (1946)).
  • the method employs a rather large apparatus to contain the slurry of salts used in the reaction and to ensure that pure NO gas is obtained.
  • Intermolecular salts have been prepared through the reaction of two diamines with NO (Longhi et al., supra) . These compounds, however, were apparently not stable enough to give good combustion analyses and therefore are likely unsuitable for the storage and generation of NO gas.
  • U.S. Patents 3,973,910, 3,996,002, 3,996,003, and 3,996,008 describe the generation of NO for the purpose of measuring the N-nitrosoamine content of a sample.
  • the NO gas is generated by heating N-nitrosoamine compounds of formula R- ⁇ NNO, wherein R ⁇ and R 2 are the same or different organic radicals, including those radicals which together with the nonnitroso N of N-NO constitute a nitrogen heterocyclic radical.
  • the heat 200-300 °C
  • This technique requires significant energy in the form of heat to yield NO gas.
  • U.S. Patents 4,256,462, 4,303,419, and 4,336,158 also describe the generation of NO for the purpose of measuring the N-nitrosoamine content of a sample. Instead of cleaving the N-NO bond by using heat energy, the N-NO bond is chemically cleaved.
  • NO gas is generated by reacting denitrosating agents with N- nitrosoamines of formula RR--.NN0, wherein R and ⁇ R ⁇ may be organic or substituted organic moieties.
  • the denitrosating agent is a mixture of glacial acetic acid and a concentrated inorganic acid, particularly phosphoric or sulfuric acid, in combination with an inorganic water-soluble bromide or iodide salt.
  • the present invention satisfies these long-standing needs for convenient NO storage, distribution, and generation and provides for the easy and inexpensive generation of NO gas in sufficient quantities for a variety of uses.
  • the present invention provides a method for the generation of NO gas by exposing a zwitterionic polyamine/NO adduct to suitable conditions to effect release of NO, such as by contacting the adduct with an acidic solvent, water of neutral or slightly alkaline pH, or a suitable catalyst in an alkaline solvent.
  • the zwitterionic polyamine/NO adducts Upon exposure to suitable conditions, the zwitterionic polyamine/NO adducts will release NO gas for any suitable purpose, e.g., biological, pharmaceutical, chemical, and industrial applications.
  • the zwitterionic polyamine/NO adducts can also be used in chemical processes wherein nitric oxide is generated in situ, by substituting an adduct for a reagent that produces nitric oxide in situ in a solvent in the chemical process.
  • the zwitterionic polyamine/NO adducts used in the present inventive method are very stable solids and contain as much as 45% NO by weight, which is capable of being released in solution in amounts and at rates that vary predictably with structure.
  • the present invention provides a method of generating NO gas.
  • the method involves exposing a zwitterionic polyamine/NO adduct to suitable conditions to effect the release of NO, such as by contacting the adduct with an acidic solvent, water of neutral or slightly alkaline pH, or a suitable catalyst in an alkaline solvent.
  • those zwitterionic polyamine/NO adducts of low molecular weight are preferred since such adducts, as compared to higher molecular weight adducts, typically have a higher water-solubility and a higher % NO yield by weight. Also, the lower molecular weight adducts typically are less expensive and have lower molecular weight by-products after release of NO which can be more readily disposed.
  • zwitterionic polyamine/NO adducts which are diamines and triamines are preferred inasmuch as adducts with fewer amine groups will be generally less cross-reactive with other possible species.
  • the zwitterionic polyamine/NO adducts may be prepared by any suitable process. The synthesis of the NO adducts is described in U.S. Patent 5,155,137, as well as in Example 1 herein.
  • the appropriate polyamines are preferably prepared first and then reacted with nitric oxide under suitable conditions to give the desired zwitterionic polyamine/NO adduct.
  • Many of the polyamines needed to prepare NO adducts using such a synthesis route are commercially available (e.g., from Aldrich Chemical Co., Milwaukee, WI) .
  • Polyamines useful in preparing the NO adducts can also be synthesized utilizing procedures well known by those of ordinary skill in the art (see, e.g., Garrido et al., J. Org. Chem.. 49. 2021-2023 (1984); Bergeron, Accts. Chem. Res.. 19. 105-113 (1986); Bergeron et al., J.
  • the NO adducts can be prepared by reacting these suitable polyamines with nitric oxide in a method similar to that taught in Drago et al., J. Am. Chem. Soc.. 83. 1819-1822 (1961). It is generally important that the amine starting materials are uncontaminated by absorbed C0 2 so as to optimize reaction yields and the stability or shelf-life of the products. There does appear to be a preference for NO attachment at secondary amines. Compounds which have primary and secondary nitrogen sites will typically react with NO gas so as to primarily result in the production of secondary amine/NO adducts.
  • reaction of N- isopropyl-l,3-propanediamine with NO can result in the formation of either an intermolecular salt (isopropyl- N(0)NO " (CH 2 ) 3 NH 2 «isopropyl-NH 2 + (CH 2 ) 3 NH 2 ) or a zwitterion (isopropyl-N[N(0)NO " ] (CH 2 ) 3 NH 3 + ) .
  • the zwitterionic polyamine/NO adducts used in the present inventive method form at room temperature in excellent yields with short (less than one day) reaction times.
  • the NO adducts are stable as solids for weeks at room temperature in closed containers and yet will release NO rapidly in acidic solutions or more slowly in buffered near-neutral media.
  • Contacting a zwitterionic polyamine/NO adduct of formula I with an acidic solvent or water (neutral or even slightly alkaline) allows for the spontaneous release of NO gas as desired with no contamination by other oxides of nitrogen. There is no need to heat the solution, subject it to other reagents, or utilize UV- radiation to generate the NO gas.
  • the acidic solvent may be any suitable organic solvent, preferably containing at least a minor amount of a mineral acid (e.g., hydrochloric acid, sulfuric acid, or the like) or a Lewis acid (e.g., CuBr 2 or the like).
  • the acidic solvent is preferably only mildly acidic and has a pH of about 5 up to about 7.
  • the water of slightly alkaline pH preferably has a pH of from about 7 to about 8.
  • the solvent may be any suitable solvent which is capable of wetting the zwitterionic polyamine/NO adduct. It is not necessary that the adduct dissolve fully for NO to be produced, although full dissolution is preferable.
  • the preferred solvent for the generation of NO is water.
  • the zwitterionic polyamine/NO adduct will also release NO gas when contacted with a suitable catalyst, such as copper, even in an alkaline solvent.
  • a suitable catalyst such as copper
  • Such catalyzed release of NO gas in an alkaline medium is particularly useful in the jLn situ generation and reaction of NO.
  • the preferred solvent is acetonitrile, although other organic solvents (such as ether, tetrahydrofuran, and the like) will suffice.
  • the present invention also provides an improved method of carrying out a chemical process that employs a reagent that produces NO in situ in a solvent, wherein the improvement comprises substituting for the reagent a zwitterionic polyamine/NO adduct of formula I.
  • these zwitterionic polyamine/NO adducts can substitute for a reagent that acts via the production of a nonaqueous diazotizing agent and, in particular, can be useful substitutes for the sodium nitrite or alkyl nitrites in any one of the following reactions: the Pschorr ring closure (Abramovitch, Adv. Free- Radical Chem.. 2., 87-138 (1966)) or modification thereof (Chauncy and Gellert, Aust.
  • NO complexes which contain the highest percentage of NO by weight. Such complexes are formed from the lowest molecular weight amines. Especially preferred examples of these NO complexes are set forth in Table I.
  • the NO complexes contain as much as 45% NO by weight and are capable of releasing NO in amounts and at rates that vary in a predictable way with structure. Accordingly, the selection of an appropriate zwitterionic polyamine/NO adduct allows for a wide range of desired NO generation rates to be achieved.
  • the NO released from the various adducts can be very rapid, such as 1-2 minutes, or very slow, such as several days.
  • An appropriate NO adduct therefore, can be chosen for a desired rate of release for most applications.
  • the release rate of NO can be varied by altering the length of the alkyl chain separating the nitrogen atoms, i.e., the value of x in the general structural formula I of the zwitterionic polyamine/NO adducts of interest.
  • the rate of release of NO may be increased by increasing the value of x.
  • the release rate of NO can be also varied by altering the size of the R group in the general formula I of the zwitterionic polyamine/NO adducts.
  • R group in the general formula I of the zwitterionic polyamine/NO adducts.
  • l-hydroxy-2-oxo-3-(2-aminoethyl)-3-meth ⁇ l-l-triazene, in which R is methyl has a half-life of 40 min
  • 1- hydroxy-2-oxo-3-(2-aminoethyl)-3-ethyl-l-triazene, in which R is ethyl has a half-life of 333 min.
  • half-lives in buffered aqueous solution at pH 7.4 and 22°C vary from extremely short (1.3 min for MeN[N(0)NO”] (CH 2 ) 4 NH 2 + Me) to very long (56 h for H 2 NCH 2 CH 2 N[N(0)NO " ]CH 2 CH 2 NH 3 + ) with the longest half-lives being achieved by triamine/NO adducts, in particular 1- hydroxy-2-oxo-3,3-di(2-aminoethyl)-l-triazene which has a half-life over 200 times that of the diethylamine/NO adduct. Stabilization of the zwitterionic polyamine/NO adducts by the R group may be due to changes in the electron distribution within the [N(0)NO ⁇ ] system.
  • R 1 does not appear to have any influence on half-life.
  • the overall amount of NO released can be also varied by choice of adduct.
  • adduct For example, l-hydroxy-2-oxo-3-(3- aminopropyl)-3-propyl-l-triazene, spermine/NO adduct, 1- hydroxy-2-oxo-3-(2-aminoethyl)-3-methyl-l-triazene, 1- hydroxy-2-oxo-3-(N-methyl-2-aminoethyl)-3-methyl-l- triazene, l-hydroxy-2-oxo-3-(N-ethyl-2-aminoethyl)-3- ethyl-1-triazene, and l-hydroxy-2-oxo-3,3-di(2- aminoethyl)-l-triazene all release two equivalents of NO at 22°C.
  • These zwitterionic polyamine/NO adducts are particularly useful for the storage and generation of NO gas.
  • These NO adducts are stable powders which may be shipped in glass or plastic bottles, in contrast to the steel cylinders used to ship NO gas.
  • the NO adducts not only can be handled in air without fear of exposure to toxic vapor, they provide a remarkably compact storage medium for NO gas.
  • l-hydroxy-2-oxo-3-(2- aminoethyl)-3-methyl-l-triazene is 45% NO by weight, and a 50 g bottle of this compound is equivalent to an entire lecture bottle of NO.
  • kits for the generation of NO gas comprises one or more of the zwitterionic polyamine/NO adducts and a suitable apparatus for contacting an adduct with an appropriate solvent such as an acidic solvent or water.
  • an apparatus will typically contain a reservoir to hold the adduct, a vessel in which to contact the adduct with solvent to effect generation of nitric oxide gas.
  • such a kit includes a mildly acidic solvent or a more concentrated acid which can be diluted with water prior to contact with the adduct.
  • Example 1 This example illustrates the preparation of various zwitterionic polyamine/NO adducts for use in conjunction with the present invention by using different amines as starting materials in the following general procedure.
  • Parr hydrogenation bottle was incorporated into a specially constructed reactor, which was modeled after the standard Parr 3911 hydrogenation apparatus (Parr
  • amines were purchased from either Carbolabs, Inc. (Bethany, CT) or Aldrich Chemical Co. (Milwaukee, WI) . Reaction solvents were anhydrous grade (Aldrich) but all others were reagent grade. NO was obtained from Matheson Gas Products and was used as received.
  • a solution of the appropriate amine in the desired solvent was placed into the standard Parr hydrogenation bottle. Nitrogen was passed through the apparatus and bubbled through the solution for 5-10 minutes. The bottle was clamped, and NO gas was admitted to a pressure of 5 atm. The solution was stirred for the indicated time with addition of NO as needed during the first 5-6 h to maintain the reservoir pressure. The reactions, which were neither heated nor cooled, appeared to warm only very slightly for the first hour, and then returned to room temperature. Excess NO was then vented, and N 2 was bubbled through the resulting white slurry for 5 min. The product was isolated by filtration, washed with the reaction solvent, washed with ether, and then dried in vacuo for several hours. All of the products were amorphous, voluminous powders which, except as indicated, were air-stable.
  • Kinetic data were obtained by diluting stock solutions (0.01 M NaOH) of each compound with pH 7.4 phosphate buffer (0.1 M) as needed to produce final solutions having compound concentrations in the range of 90-120 ⁇ M.
  • the rate of NO release was determined by following the disappearance of the characteristic UV absorption ( ⁇ - 250-252 nm) , which all of these compounds exhibit.
  • a plot of 1/(A-A,,,) vs. time was linear and was used to calculate the rate constant.
  • the temperature in the spectrophotometer cavity was 22 ⁇ 2°C and was not thermostated. Compound 14 was too stable to permit monitoring over a sufficient number of half-lives to guarantee the accuracy of the value obtained for its half-life.
  • Example 2 This example describes a preferred method of releasing NO gas from various zwitterionic polyamine/NO adducts. NO gas was generated from compounds 2, 6, 10, 11, and 14 of Example 1, as well as
  • the apparatus comprises a first vessel 10 having an inlet 11 and an outlet 12 and contains mineral oil (or other heavy liquid) to prevent backflow.
  • the outlet 12 of vessel 10 is connected to a first inlet 21 of second vessel 20, which also has a second inlet 22 and an outlet 23.
  • the second vessel 20 contained either the solid NO complex or an aqueous solution of the NO complex.
  • An addition funnel 30 is connected to the second inlet 22 of second vessel 20 so as to provide a means of introducing dilute aqueous HC1 into second vessel 20.
  • the outlet 23 of second vessel 20 is connected to the inlet 41 of condenser 40, and the outlet 42 of condenser 40 is connected to the inlet 51 of third vessel 50.
  • the condenser 40 and third vessel 50 function to capture any mist carried through the apparatus in the gas stream.
  • the outlet 52 of third vessel 50 is connected to drying towers 60 and 70 which contain desiccant such as calcium chloride or molecular sieves and contain an outlet 71 for gas passage.
  • nitrogen gas was passed through the apparatus through the inlet 11 of first vessel 10 to flush oxygen from the apparatus.
  • Acidic solution was then introduced into second vessel 20 by way of addition funnel 30, and NO gas was generated in second vessel 20.
  • the thus generated NO gas flowed through the outlet 23 of second vessel 20, through the condenser 40, into the third vessel 50, into the drying towers 60 and 70, and out the condenser outlet 71.
  • the NO gas released through the outlet 71 of drying column 70 was fed into a thermal energy analyzer (TEA) , which generates a signal proportional to the quantity of NO gas present.
  • TAA thermal energy analyzer
  • Example 3 This example illustrates the use of a zwitterionic polyamine/NO adduct in a chemical process , specifically the conversion of 2,3-dimethylaniline to 3-bromo-o- xylene.
  • This example illustrates the extended shelf-life and long-term stability of the zwitterionic polyamine/NO adducts used in the present invention.
  • Samples of compound 11 of Example 1 were stored in a refrigerator over the course of several months.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé pour la génération de NO gazeux consistant à exposer des additifs d'oxyde nitrique polyamine ampholytiques ayant la formule RN[N(O)NO-](CH2)xNH2+R', dans laquelle R = alkyle C¿1?-C6, aminoalkyle C1-C6, ou cyclohexyle, R' = hydrogène ou alkyle C1-C6, et x = 2-6, à des conditions adéquates pour effectuer la libération de NO, telles que par contact avec un solvant acide doux ou de l'eau ayant un pH neutre ou légèrement alcalin.
PCT/US1993/002374 1990-09-20 1993-03-12 Procede de production d'oxyde nitrique gazeux utilisant des complexes d'oxyde nitrique WO1994020415A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/US1993/002374 WO1994020415A1 (fr) 1992-06-30 1993-03-12 Procede de production d'oxyde nitrique gazeux utilisant des complexes d'oxyde nitrique
US08/522,405 US5683668A (en) 1990-09-20 1993-03-12 Method of generating nitric oxide gas using nitric oxide complexes
AU38096/93A AU3809693A (en) 1993-03-12 1993-03-12 Method of generating nitric oxide gas using nitric oxide complexes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/906,479 US5250550A (en) 1990-09-20 1992-06-30 Complexes of nitric oxide with polyamines
PCT/US1993/002374 WO1994020415A1 (fr) 1992-06-30 1993-03-12 Procede de production d'oxyde nitrique gazeux utilisant des complexes d'oxyde nitrique

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5683668A (en) * 1990-09-20 1997-11-04 The United States Of America As Represented By The Department Of Health And Human Services Method of generating nitric oxide gas using nitric oxide complexes
EP1903003A1 (fr) * 2006-07-05 2008-03-26 Christoph Suschek Dispositif et procede de production photolytique de monoxyde d'azote
CN103269973A (zh) * 2010-12-03 2013-08-28 皇家飞利浦电子股份有限公司 产生一氧化氮的方法和设置

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4256462A (en) * 1979-12-28 1981-03-17 University Of Iowa Research Foundation Method and composition for determination of n-nitrosamines
WO1990009785A1 (fr) * 1989-02-28 1990-09-07 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce Complexes stabilises d'oxyde nitrique-amines primaires utiles comme agents cardiovasculaires
WO1991004022A1 (fr) * 1989-09-15 1991-04-04 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce Compositions anti-hypertensives d'additifs d'oxyde aminonitrique secondaire et leur utilisation
WO1992005149A1 (fr) * 1990-09-20 1992-04-02 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce Complexes d'oxyde nitrique et de polyamines

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4256462A (en) * 1979-12-28 1981-03-17 University Of Iowa Research Foundation Method and composition for determination of n-nitrosamines
WO1990009785A1 (fr) * 1989-02-28 1990-09-07 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce Complexes stabilises d'oxyde nitrique-amines primaires utiles comme agents cardiovasculaires
WO1991004022A1 (fr) * 1989-09-15 1991-04-04 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce Compositions anti-hypertensives d'additifs d'oxyde aminonitrique secondaire et leur utilisation
WO1992005149A1 (fr) * 1990-09-20 1992-04-02 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce Complexes d'oxyde nitrique et de polyamines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. MED CHEM. vol. 34, no. 11, 1991, pages 3242 - 3247 C.M. MARGOS ET AL. 'Complexes of .NO with nucleophiles as agents for the controlled biological release of nitric oxide. Vasorelaxant effects.' cited in the application *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5683668A (en) * 1990-09-20 1997-11-04 The United States Of America As Represented By The Department Of Health And Human Services Method of generating nitric oxide gas using nitric oxide complexes
EP1903003A1 (fr) * 2006-07-05 2008-03-26 Christoph Suschek Dispositif et procede de production photolytique de monoxyde d'azote
EP3023389A1 (fr) * 2006-07-05 2016-05-25 BSN Medical GmbH Procede et dispositif de generation photolytique de monoxyde d'azote
CN103269973A (zh) * 2010-12-03 2013-08-28 皇家飞利浦电子股份有限公司 产生一氧化氮的方法和设置
CN103269973B (zh) * 2010-12-03 2016-03-23 皇家飞利浦电子股份有限公司 产生一氧化氮的方法和设置
US9776161B2 (en) 2010-12-03 2017-10-03 Koninklijke Philips N.V. Method and arrangement for generating nitric oxide

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