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    • 专利摘要:
    Deuterated compounds of flonicamide, procedure of preparation and use thereof. The invention relates to a deuterated compound of flonicamide, of formula (I) {image-01} Wherein r1 is a group selected from -ch2 -cn and -ch2 -cooh; and r2 is h, and wherein at least one hydrogen atom in r1 or in r2 is replaced by deuterium; to its obtaining procedure and its use as a standard for the detection and quantification of flonicamide and derivatives by chromatographic techniques coupled to mass spectrometry. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2644163A1
    申请号:ES201600466
    申请日:2016-05-27
    公开日:2017-11-27
    发明作者:Ignacio FERNÁNDEZ DE LAS NIEVES；Ana Belén RUIZ MUELLE；Rosalia LÓPEZ RUIZ；Antonia GARRIDO FRENICH；Roberto ROMERO GONZÁLEZ；José Luis MARTINEZ VIDAL
    申请人:Universidad de Almeria；
    IPC主号:
    专利说明:

    Deuterated flonicamide compounds, preparation procedure and use thereof.
    Sector
    Agrifood / Chemistry.
    10 Prior state of the art
    Flonicamide (parent product) is an insecticide usually applied in treatments against pests in various agricultural crops, of which three metabolites and / or transformation products are known:
    • (C9H7F3N2O3): N- (4-trifluoromethylnicotinoyl) glycine: TFNG
    • (C7H4F3NO2): 4-Trifluoromethyl Nicotinic Acid: TFNA
    20 • (C1H5F3N2O): 4-trifluoromethylnicotinamide: TFNA-AM
    Both the parent product and the different metabolites have been detected in different fruits and vegetables (Xu et al. Journal of Chromatography A 1218 (2011) 6663-6666), using the technique of liquid chromatography coupled to mass spectrometry. 25 However, one of the main problems of this technique is the presence of a matrix effect, that is, the variation in the chromatographic signals induced by the analysis matrices, which can hinder the process of quantification of the compounds under study. One of the solutions to solve this problem is the use of isotopically marked standards (Köck-Schulmeyer et al. Journal of Chromatography A 1305 30 (2013) 176-187). In general, said isotopically labeled compounds can be used in order to follow chemical or biochemical processes in which flonicamide participates. Although both flonicamide and its metabolites are on the market with a high degree of purity as "chemical standards," there is no history of the synthesis of any of these metabolites of deuterated flonicamide, and for the parent compound, flonicamide, the High Purity Compounds (HPC), sells the isotopically labeled compound exclusively in the three positions of the pyridine ring (see Formula 1), being therefore less chemically reactive, than those deuterium bonds present in the amide cluster , carboxylic acid group, or methylene in alpha, as are the compounds object of the present application
    40 patent.
    45 Formula 1. Structure of Flonicamide-d3 offered by HPC.
    Therefore, there is still a need to provide new deuterated flonicamide derivatives and metabolites for reliable and accurate detection / quantification thereof by liquid chromatography techniques coupled to mass spectrometry. One of these compounds is TFNG, of which no deuterated derivative is known
    5 of it.
    The present invention will allow the availability of the new compounds as "isotopically marked chemical standards" in agronomic studies and in the control of food safety, providing solutions in the monitoring of processes in which
    10 use flonicamide as a pesticide, as well as in studies where the reactivity of these molecules is evaluated.
    Description of the invention
    The present invention relates to deuterated derivatives of the pesticide flonicamide (C9H6F3N3O) and one of its metabolites, TFNG (C9H7F3N2O3), isotopically labeled with deuterium. The IUPAC name of flonicamide is N-cyanomethyl-4- trifluoromethylnicotinamide, and the IUPAC name of TFNG (C9H7F3N2O3) is N- (4trifluoromethylnicotinoyl) glycine.
    In this report the expression "flonicamide derivative compound" refers to a deuterated compound with flonicamide structure, or simply, deuterated flonicamide compound, and which may be flonicamide itself, a derivative or a metabolite. "Metabolite" should be understood with the usual meaning, as a derivative
    25, which is obtained from the metabolism of flonicamide.
    The term "protonation" may refer herein to both the introduction of a proton and a deuterium atom, since it is usually used interchangeably. It will be indicated however if it is a "protonation" with solvent
    30 protic (or protic type) or with a deuterated protic (or protic type) solvent. The term "deuteration" is also used in the latter case with the same meaning of "introduction of a deuterium atom".
    The present invention relates to a deuterated flonicamide compound of formula (I)
    wherein R1 is a group selected from -CH2-CN and -CH2-COOH; and R2 is H,
    40 and in which at least one hydrogen atom in R1 or R2 is substituted by deuterium. According to a specific embodiment, the deuterated compound has the formula (II) (also called flonicamide-d3)
    According to a further specific embodiment the deuterated compound has the formula (III) (also called flonicamide-d2)
    According to a further specific embodiment the deuterated compound is a TFNG compound having the formula (IV) (also called TFNG-d4)
    According to a further specific embodiment the deuterated compound is a TFNG compound having the formula (V) (also called TFNG-d2)
    The present invention also has as its object a process for the preparation of a compound of formula (1), defined above, characterized in that it comprises the deuteration of a precursor compound of formula (la)
    wherein R1 is a group selected from -CH2-CN and -CH2-COOH; and R2 is H, with a deuterated protic type solvent, in at least one of the different positions of the pyridine ring.
    5 According to particular embodiments, the process comprises the following steps: (a) selective abstraction of the two protons of the methylene group in alpha with respect to the amide group at a temperature of at least 40 ° C, preferably 60 ° C and more preferably at least 80 ° C; and (b) deuteration with a deuterated protic type solvent. A preferred embodiment results in the compound of formula (II).
    10 Scheme 1 shows the preferred method of obtaining the compound of formula (II).
    The solvent deuterated in the process of the invention can be any deuterated solvent of the prior art type, such as water (D2O), or any compound that contains in its structure an alcohol or carboxylic acid group, such as methanol ( MeOD), ethanol (EtOD), phenal (PhOD), acetic acid
    20 (MeCO2D), although it is preferably deuterated water.
    According to additional particular embodiments, the process further comprises a proton-deuterium exchange stage, thanks to the action of a protic type solvent. A protic solvent employed can be any protic type solvent of the state
    25 of the technique, such as water (H2O), methanol (MeOH), ethanol (EtOH), phenal (PhOH), acetic acid (MeCO2H), although the first one is preferred. A preferred embodiment for this alternative of the process results in the compound of formula (III).
    Scheme 2 shows an embodiment of the preferred method of obtaining the compound of formula (III).
    According to further particular embodiments of the process, the compound of formula
    35 (la) is a compound in which R1 is a -CH2-CN group, and the process comprises the following steps: (a) selective abstraction of the two protons of the methylene group in alpha with respect to the amide group at room temperature minus 40 ° C, preferably 60 ° C and more preferably at least 80 ° C; (b) deuteration with a deuterated protic type solvent, a step (c) of reaction of the product obtained in stage b) with a hydroxide type base that reacts with the nitrile group, and a subsequent stage (d) of deuteration with a deuterated protic type solvent. The base used can be a metal hydroxide selected from sodium hydroxide (NaOH) and potassium hydroxide (KOH), preferably it is sodium hydroxide.
    A preferred embodiment for this alternative of the process results in the compound of formula (IV).
    Scheme 3 shows an embodiment of the preferred method of obtaining the compound of formula (IV) from an embodiment of the compound (la):
    A further alternative of the process comprises steps (a) to (d) above.
    15 mentioned and also a proton-deuterium exchange stage, thanks to the action of a protic type solvent. A preferred embodiment for this alternative of the process results in the compound of formula (V) from the compound of formula (IV).
    Scheme 4 shows an embodiment of the preferred method of obtaining the compound of formula (V) from the compound of formula (IV):
    25 Flonicamide is a pesticide that is interested in knowing its metabolites, in order to monitor it in the field of food safety control and in other types of studies in which this compound participates. The availability of "isotopically labeled chemical standards" of both flonicamide and its metabolites, allows its use in studies in the biotic or abiotic environment facilitating analytical control when
    30 employ mass spectrometry and nuclear magnetic resonance techniques, among others. The invention has industrial application in companies whose objective is to provide organic synthesis compounds with a high degree of purity to be sold as "isotopically marked chemical standards" for use in analysis laboratories. Additionally, in kinetic studies of isotopic effect, they are standards of a value
    35 added important since they allow access to mechanistic studies in which the reactive part is not that of the pyridine type ring but those of the protons in alpha with respect to the nitrile group and the amide group.
    The present invention also has the purpose of using a deuterated compound of formula (I) defined above as a standard for the detection and quantification of flonicamide or derivatives by chromatographic techniques coupled to mass spectrometry.
    A particular embodiment is the use of the deuterated compound of formula (II) for obtaining the deuterated compound of formula (III).
    A further particular embodiment is the use of the deuterated compound of formula (IV) for obtaining the deuterated compound of formula (V).
    Examples
    Synthesis of Flonicamide-d3. 3 mg of flonicamide are weighed into a vial and 0.5 mL of deuterated solvent is added. It dissolves with the help of a sonicator for 5 minutes. This solution is heated in an oil bath at a minimum temperature of 80 ° C for at least 5 hours. The resulting solution is lyophilized until the objective product is obtained. The solvent used will be any deuterated solvent of the prior art type, such as water (D2O), methanol (MeOD), or ethanol (EtOD), although the first one is preferred. The nuclear magnetic resonance (NMR) analysis of 1H and 2H confirms the formation of the desired product unequivocally. Thus, the absence of the 1H chemical shift signal of 4.38 ppm, and the appearance of two chemical shift signals of 4.41 and 8.55 ppm in the NMR-2H spectrum confirm the deuteration in the two positions and input of three atoms of deuterium. The high resolution mass spectrum of the isolated product confirms the increase in three units of atomic mass in relation to the compound without deuterating, obtaining in positive ionization the compound with a mass / charge ratio (m / z) of 233.0724 ([C9H3D3F3N3O3 + H] +, mass error <5 ppm), which again confirms the proposed structure.
    Synthesis of Flonicamide-d2 3 mg of flonicamide-d3 is weighed and 1 mL of protic solvent is added. Stir for 5 minutes with the help of a vortex. The solution is lyophilized until the objective product is obtained. The protic solvent used will be any protic type solvent of the state of the art, such as water (H2O), methanol (MeOH), or ethanol (EtOH), although the first one is preferred. The structure of the compound is checked by observing in the NMR-2H spectrum the disappearance of the chemical shift signal of 8.55 ppm and its appearance in the corresponding 1H NMR spectrum at a chemical shift of 8.53 ppm. Again, mass spectrometry shows an m / z of 230.0505 ([C9H4D2F3N3O3-H] -, mass error <5 ppm), when monitored in a negative mode, which verifies the presence of only two deuterium atoms .
    Synthesis of TFNG-d4. 3 mg of flonicamide are weighed into a vial and 0.5 mL of deuterated solvent is added. It dissolves with the help of the sonicator for 5 minutes. To this solution is added a catalytic amount (at least 1% in mol with respect to flonicamide) of 5N NaOH or stoichiometric base. The resulting solution is heated in an oil bath at 60 ° C for 5 h. The solution is neutralized with 7.6 N DCI to neutral pH and extracted into ethyl acetate. The solution is dried over anhydrous sodium sulfate and dried in the rotary evaporator, which results in obtaining the target product. The solvent used will be any deuterated solvent of the prior art type, such as water (D2O), methanol (MeOD), or ethanol (EtOD), although the first one is preferred. In the preferred embodiment of the process of the invention, the base employed is a metal hydroxide selected from sodium hydroxide (NaOH) and potassium hydroxide (KOH). The absence of the 1H chemical shift signal from
    4.09 ppm in its NMR spectrum, and the appearance of three signals at chemical shifts of 4.41, 8.12 and 11.44 ppm in the NMR-2H spectrum confirm the deuteration in the three positions and therefore entry of four deuterium atoms. The high resolution mass spectrum of the isolated product confirms the increase in four atomic mass units with an m / z of 253.0641 ([C9H3D4F3N2O3 + H] +, mass error <5 ppm) when the compound is monitored in positive mode.
    Synthesis of TFNG-d2. 3 mg of TFNG-d4 is weighed and 1 mL of protic solvent is added. Stir for 5 minutes with the help of a vortex. The solution is lyophilized until the objective product is obtained. The solvent used will be any protic type solvent of the state of the art, such as water (H2O), methanol (MeOH), or ethanol (EtOH), 10 although the first one is preferred. The structure of the compound is checked by observing in the NMR-2H spectrum the disappearance of the signals at chemical shift of 8.12 and 11.44 ppm and their appearance in the corresponding spectrum of NMR-1H at chemical shifts of 8.10 and 11.42 ppm. As in the previous cases, high resolution mass spectroscopy allows monitoring of the m / z ion
    15 249.0463, ([C9H4D2F3N2O3-H] -, mass error <5 ppm), in negative mode, which corroborates the increase in two units of atomic mass with respect to the mass of the undenutated TFNG, confirming the proposed structure.
    权利要求:
    Claims (11)
    [1]
    1. A deuterated flonicamide compound, of formula (I)
    wherein R1 is a group selected from -CH2-CN and -COOH; and R2 is H,and in which at least one hydrogen atom in R1 or R2 is substituted by deuterium.
    [2]
    2. Compound according to claim 1, having the formula (II)
    3. Compound according to claim 1, having the formula (III)
    [4]
    Four.  Compound according to claim 1 of TFNG, which has the formula (IV)
    [5]
    5.  Deuterated compound according to claim 1 of TFNG, which has the formula (V)
    [6]
    6.  Process for the preparation of a compound of formula (I), defined in claim 1, characterized in that it comprises the deuteration of a precursor compound of formula (la)
    wherein R1 is a group selected from -CH2-CN and -COOH; and R2 is H,
    with a deuterated protic type solvent, in at least one of the different positions 10 of the pyridine ring.
    [7]
    7. Method according to claim 6, comprising the following steps: (a) selective abstraction of the two protons of the methylene group in alpha with respect to the amide group, in the compound of formula (la) in which R1 is -CH2- CN, at the temperature of
    At least 40 ° C, preferably 80 ° C; and (b) deuteration with a deuterated protic type solvent.
    [8]
    8.  Process according to claim 7 wherein the compound of formula (II) is obtained.
    [9]
    9.  Process according to claim 7, further comprising a proton-deuterium exchange stage, thanks to the action of a protic type solvent, resulting in the compound of formula (III).
    Method according to claim 7, wherein the compound of formula (la) wherein R1 is a -CH2-CN group, and further comprising a reaction step (c) of the product obtained in step (b ) with a hydroxide type base that reacts with the nitrile group, and a subsequent step (d), of deuteration with a deuterated protic type solvent, obtaining the compound of formula (IV).
    [11]
    11. The method according to claim 10, further comprising a subsequent stage of proton-deuterium exchange, thanks to the action of a protic type solvent obtaining the compound of formula (V).
    12. Use of the deuterated compound of formula (I) defined in claim 1 as a standard for the detection and quantification of flonicamide or derivatives by chromatographic techniques coupled to mass spectrometry.
    [13]
    13. Use of the deuterated compound of formula (II) to obtain deuterated compound of formula (III).
    [14]
    14. Use of the deuterated compound of formula (IV) to obtain the deuterated compound of formula (V).
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