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    • 专利摘要:
    The present invention relates to a process for synthesizing a compound of formula (I) below: in which: X denotes an oxygen atom, sulfur atom or an NH group, preferably an oxygen atom; R 1 represents a carbon chain optionally substituted or interrupted by one or more heteroatoms; n is an integer ranging from 0 to 4; - Sp represents an atom or a group of atoms.
    公开号:FR3037953A1
    申请号:FR1555822
    申请日:2015-06-24
    公开日:2016-12-30
    发明作者:Jean Luc Couturier；Philippe Leduc；Sergey Ivanov；Oleg Ugolnikov
    申请人:Michelin Recherche et Technique SA Switzerland ；Compagnie Generale des Etablissements Michelin SCA；Michelin Recherche et Technique SA France；Arkema France SA；
    IPC主号:
    专利说明:

    [0001] The present invention relates to the field of nitrogenous associative molecules comprising at least one unit making them capable of associating with each other or with a filler by non-covalent bonds, and comprising a functional group. capable of reacting with a polymer comprising unsaturations to form a covalent bond with said polymer. More specifically, the present invention relates to the molecules carrying a nitrile oxide function and an imidazolidinyl group. More specifically, the application relates to a method for synthesizing such molecules. In the industrial field, polymer blends with fillers are often used. In order for such mixtures to have good properties, means are constantly sought to improve the dispersion of the fillers within the polymers. One of the means to achieve this result is the use of coupling agents capable of establishing interactions between the polymer and the filler.
    [0002] Agents for coupling a polymer with a filler comprising nitrogen dipoles are described in the documents published under the numbers US7186845B2 and JP2008208163. These documents describe the modification of polymers comprising diene units by nitrogen-containing dipolar compounds further comprising a heterocycle, said heterocycle comprising itself a nitrogen atom, and an oxygen and / or sulfur atom. More particularly, the compounds described are nitrones carrying oxazoline and thiazoline functional groups, for example ((2-oxazolyl) -phenyl-N-methylnitrone).
    [0003] When diene polymers are reacted with such compounds, the resulting polymers will carry the oxazoline or thiazoline rings.
    [0004] These cycles present on the polymer are likely to react in turn, with surface function of the fillers, such as carbon black or silica, with which the polymers are mixed. This reaction leads to the establishment of covalent bonds between the coupling agent-modified polymer and the filler due to the opening of the oxazoline or thiazoline ring. Indeed, as described in US7186845B2, the oxazoline rings and / or thioazolines are likely to open in the presence of a nucleophile may for example be present on the surface of the charge. The establishment of such covalent bonds nevertheless has drawbacks in the preparation of mixtures comprising those polymers modified with coupling agents with fillers. In particular, the existence of these early covalent bonds between the polymer and the fillers renders these mixtures very viscous in the uncrosslinked state, which makes all the operations prior to the crosslinking (vulcanization) of the formulations difficult. rubber base, in particular the preparation of the mixtures of the components, and their shaping. These disadvantages have a strong impact on industrial productivity. It is therefore desirable to provide new molecules not having the above disadvantages, i.e., molecules that are capable, after reaction with a polymer and mixed with a filler, of not forming covalent bonds with the load and therefore not to cause too much increase in the viscosity of the mixture.
    [0005] Thus, the patent application WO 2012/007684 relates to a compound comprising at least one group Q, and at least one group A connected to one another by at least and preferably a Sp spacer group in which: - Q comprises a dipole containing at least and preferably a nitrogen atom; 5 - A comprises an associative group comprising at least one nitrogen atom; Sp is an atom or a group of atoms forming a bond between Q and A. When a polymer grafted with a compound as defined above is mixed with fillers, it only establishes labile bonds. with the charges, which ensures a good polymer-charge interaction, beneficial for the final properties of the polymer, but without the disadvantages that too much polymer interaction charge could cause.
    [0006] An example of such a compound is 24242-oxoimidazolidin-1-yl) ethoxy] benzonitrile oxide. This compound can be prepared from salicylic aldehyde and 1- (2-chloroethyl) imidazolidinone. 2-one.
    [0007] In a first step, 1- (2-chloroethyl) imidazolidin-2-one is obtained from 1- (2-hydroxyethyl) imidazolidin-2-one which reacts with thionyl chloride in dichloromethane. In a second step, 242- (2-oxoimidazolidin-1-yl) ethoxy] benzaldehyde is obtained from 1- (2-chloroethyl) imidazolidin-2-one which reacts with salicylic aldehyde in dimethylformamide ( DMF) in the presence of potassium carbonate.
    [0008] In a third step, 242- (2-oxoimidazolidin-1-yl) ethoxy] benzaldehyde oxime is obtained by reacting 2- [2- (2-oxoimidazolidin-1-yl) ethoxy] benzaldehyde with the hydroxylamine in ethanol.
    [0009] Finally, in a fourth step, the 24242-oxoimidazolidin-1-yl) ethoxy] benzonitrile oxide is obtained by reacting 2- [2- (2-oxoimidazolidin-1-yl) ethoxy] benzaldehyde oxime with sodium hypochlorite in dichloromethane. Thus, the method described above comprises a relatively large number of steps. The multiplication of the steps has an impact on the overall yield of the synthesis process of the desired compound but also on the investment costs and associated production costs. Furthermore, another concern in the synthesis of molecules carrying a nitrile oxide function is to minimize the number and the amount of solvents used in the preparation process, in order to facilitate the treatment of the effluents, to reduce the costs of investment and associated production, of course without affecting neither the yield nor the purity of said molecules. The object of the present invention is to provide a solution for solving all the problems mentioned above. According to the invention, a process for the synthesis of a compound of formula (I): ## STR1 ## in which: X represents an oxygen atom, a sulfur atom or an NH group; preferentially an oxygen atom; - R1 represents a carbon chain optionally substituted or interrupted by one or more heteroatoms; n is an integer ranging from 0 to 4; (I) 3037953 5 - Sp represents an atom or a group of atoms, comprises two successive steps (b 1) and (b2) according to a monotopic synthesis: - (b1) the reaction of a compound of formula (II) With a compound of formula (III): ZN NH Sp X (III) wherein Z is a nucleofugal group; in the presence of: - at least one polar solvent Si; At least one base; at a temperature Ti ranging from 70 to 150 ° C, to form an ether; (b2) reacting said ether with an aqueous hydroxylamine solution at a temperature T2 ranging from 30 to 70 ° C, to obtain an oxime compound of formula (IV): HdN-X (Ri) n (IV) ; then: a step (c) of recovering said oxime compound of formula (IV); a step (d) of oxidation of the oxime compound of formula (IV) with an oxidizing agent, in the presence of at least one organic solvent S2.
    [0010] Steps (b1) and (b2) are "one pot" (a one-step two-step synthesis process), that is, without isolation of the intermediate ether. For the purposes of the present invention, the term "polar solvent" means a solvent having a dielectric constant greater than 2.2. Preferably, step (b2) is followed by a step (e) of recovering the compound of formula (I). For the purposes of the present invention, the term "nucleofuge group" is intended to mean a leaving group which carries its binding doublet.
    [0011] For the purposes of the present invention, the term "carbon chain" means a chain comprising one or more carbon atoms. It is specified that the expressions "from ... to ..." used in the present description must be understood as including each of the mentioned terminals.
    [0012] The process according to the invention makes it possible to synthesize the compound of formula (I) from the compound of formula (II) in a two-step monotopic synthesis followed by an oxidation step. According to the patent application WO 2012/007684, the compound of formula (I) is also obtained from the compound of formula (II) but the intermediate ether compound is isolated and purified at the end of the first step. Other advantages and features of the invention will become more apparent upon examination of the detailed description. The process according to the invention allows the synthesis of the compound of formula (I) mentioned above. Advantageously, the X group represents a 5- or 6-membered, preferably diazotized, di or tri-nitrogen heterocycle comprising at least one carbonyl, thiocarbonyl or imine functional group. According to a particular embodiment of the invention, X is the group in which X is selected from an oxygen atom and a sulfur atom, preferably an oxygen atom. The group Sp is a spacer group which makes it possible to connect the oxygen atom to the group X, in which X is as defined above, as indicated by the formula of the compound (I), and thus can be of any type known per se. The term associative functions in the sense of the present invention, functions capable of associating with each other by hydrogen bonds.
    [0013] Thus, each associative function comprises at least one donor "site" and one acceptor site with respect to the hydrogen bond so that two identical associative functions are self-complementary and can associate with one another by forming at least two hydrogen bonds.
    [0014] The group Sp is preferably a linear, branched or cyclic C1-C24 hydrocarbon chain which may contain one or more aromatic radicals and / or one or more heteroatoms. Said chain may optionally be substituted, provided that the N-substituent HNs do not react with the X group and the nitrile oxide function. Advantageously, the group Sp is a linear or branched C 1 -C 24, preferably C 1 -C 10, alkylene chain optionally interrupted by one or more nitrogen or oxygen atoms, more preferably a C 1 -C 6 linear alkylene chain.
    [0015] Preferably, the group Sp contains a unit selected from - (CH2) yi-, - [NH- (CH2) yz] X- and 40- (CE12) y3] .2-, y1, y2 and y3 representing, independently , an integer from 1 to 6, and x1 and x2 independently representing an integer of from 1 to 4. Preferably, R1 represents a saturated carbon chain, more preferably an alkyl group, preferentially a 3037953 alkyl group. C1-C12, more preferably C1-C6, even more preferably C1-C4, or OR ', R' being an alkyl group, preferentially a C1-C12 alkyl group, more preferably C1-C6, still more preferentially C 1 -C 4, still more preferably methyl, ethyl or OCH 3. Advantageously, n is an integer ranging from 0 to 3. Preferably, the compound of formula (I) is chosen from the following compounds of formula (V), (VI) and (VII): ## STR2 ## V) NH (VI) NH 0 (VII) As previously explained, the process according to the invention comprises a step (b1) of reaction of a compound of formula (II), as mentioned above, with a compound of formula (III), as mentioned above, carrying a group Z. Preferably, the group Z is chosen from chlorine, bromine, iodine, mesylate group, tosylate group, the group acetate and the trifluoromethylsulfonate group.
    [0016] Said step (1) 1) of the process according to the invention is carried out in the presence of at least one polar solvent Si, and at least one base, at a temperature Ti ranging from 70 to 150 ° C. According to a particular embodiment of the invention, the polar solvent Si is a polar solvent miscible in water, preferably a protic solvent. Dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone ( DMPU), isopropanol, acetonitrile, ethanol, n-butanol and n-propanol are examples of solvents which can be used in the process according to the invention. Preferably, the protic solvent is alcoholic. Advantageously, the compound of formula (II) represents from 5 to 40% by weight, preferably from 10 to 30% by weight, relative to the weight of the solvent. A base conventionally employed in the etherification reactions can be used during step (1) 1) of the process according to the invention. Because of the presence of the aldehyde function particularly subject to oxidation and nucleophilic reactions and the possible presence of other functions in the compound of formula (II), those skilled in the art choose the base to selectively orient the reaction towards obtaining the target ether. Preferably, the base is selected from alkali alkoxides, alkali carbonates, alkaline earth carbonates, alkali hydroxides, alkaline earth hydroxides and mixtures thereof. Advantageously, it is possible to add: one or more catalysts chosen from a catalyst of the silver salt type (I), a quaternary ammonium phase transfer catalyst, and mixtures thereof; one or more ionic liquids. Preferably, the base is chosen from sodium methanolate, potassium carbonate and sodium hydroxide, more preferably potassium carbonate.
    [0017] According to a particular embodiment of the invention, the amount of base is from 1.5 to 8 equivalents, preferably from 2 to 6 equivalents, relative to the amount of compound of formula (II). As explained above, step (b1) of the process according to the invention is carried out at a temperature T1 ranging from 70 to 150 ° C. Preferably, the temperature T1 is a temperature ranging from 70 to 120 ° C, more preferably from 80 to 110 ° C. As explained above, step (b1) of the process according to the invention is followed by step (b2) of adding to the reaction medium containing said ether an aqueous hydroxylamine solution at a temperature T2 ranging from from 30 to 70 ° C. Preferably, the addition of the aqueous solution of hydroxylamine is carried out when the conversion of the compound of formula (II) is at least 70%.
    [0018] Advantageously, the temperature T2 varies from 40 to 60 ° C. The process according to the invention also comprises a step (c) of recovery, as mentioned above, of the oxime compound of formula (IV). Preferably, the oxime compound of formula (IV) is recovered by precipitation with water, followed optionally by washing with water. The process according to the invention also comprises a step (d) of oxidizing the oxime compound of formula (IV) with an oxidizing agent, in the presence of at least one organic solvent S2.
    [0019] Preferably, said oxidizing agent is chosen from sodium hypochlorite, N-bromosuccinimide in the presence of a base, N-chlorosuccinimide in the presence of a base, and hydrogen peroxide in the presence of a catalyst. preferentially sodium hypochlorite.
    [0020] Advantageously, the amount of oxidizing agent is from 1 to 5 equivalents, preferably from 1 to 2 equivalents, relative to the amount of oxime compound of formula (IV). Preferably, the organic solvent S 2 is an organic solvent chosen from chlorinated solvents and of ester, ether and alcohol type, more preferentially chosen from dichloromethane, ethyl acetate, butyl acetate and diethyl ether. , isopropanol and ethanol, more preferably chosen from ethyl acetate and butyl acetate.
    [0021] Preferably, the oxime compound of formula (IV) represents from 1 to 30% by weight, preferably from 1 to 20% by weight, relative to the total weight of the combination comprising said oxime compound of formula (IV), said organic solvent S2 and said oxidizing agent. Preferably, the process according to the invention comprises a step (e) of recovery, as mentioned above, of the compound of formula (I). Preferably, the compound of formula (I) is recovered by precipitation with water, optionally followed by washing with water. Preferably, the process according to the invention comprises a step (a1) of manufacture of the compound of formula (II), prior to step (b1), by reacting a compound of formula (VIII): OH (R1) n, / (VIII) with a formylating agent formed in situ or not and at least one Lewis acid in the presence of at least one organic solvent S3. Preferably, the Lewis acid is selected from TiCl4 and SnCl4, preferably TiCl4. Preferably, the amount of Lewis acid is from 0.5 to 4 equivalents, more preferably from 1 to 3 equivalents, based on the amount of compound of formula (VIII). Advantageously, the organic solvent S3 is a chlorinated organic solvent, preferably chosen from dichloromethane, chloroform and 1,2-dichloroethane, more preferably dichloromethane.
    [0022] As previously explained, the compound of formula (VIII) reacts with a formylating agent formed in situ or otherwise, according to a formylation reaction. Any type of formylating agent conventionally employed in the formylation reactions can be used. Preferably, the formylating agent is chosen from dichloromethyl methyl ether and dichloromethyl ethyl ether, more preferentially dichloromethyl methyl ether. According to a particular embodiment of the invention, the agent formed in situ is obtained by reaction of methyl or ethyl formate with a chlorinating agent, preferably phosphorus pentachloride.
    [0023] Advantageously, the compound of formula (VIII) represents from 5 to 15% by weight relative to the weight of the solvent. According to a particular embodiment of the invention, the process according to the invention comprises a step (a2) of manufacture of the compound of formula (III), prior to step (b1), by reacting a compound of formula (IX): ## STR2 ## with an agent allowing the formation of nucleofuge group Z. Preferably, said agent is thionyl chloride. Preferably, step (a2) is carried out in the absence or in the presence of at least one solvent, preferably a chlorinated solvent, more preferably dichloromethane. Advantageously, step (a2) is immediately followed by a step (a3) of recovering the compound of formula (III), preferably by purification with toluene, more preferably by crystallization of the compound of formula (III) in toluene. The present application also relates to the use of the compound of formula (I) obtained by the process according to the invention. The present invention is further illustrated by the following non-limiting examples.
    [0024] EXAMPLES The structural analysis as well as the determination of the molar purities of the synthetic molecules are carried out by NMR analysis. The spectra are acquired on a BRUKER 500 MHz Avance spectrometer equipped with a BBIz-grad 5 mm wideband probe. The quantitative 1E1 NMR experiment uses a 30 ° single pulse sequence and a 3 second repetition time between each of the 64 acquisitions. The samples are solubilized in deuterated dimethylsulfoxide (DMSO). This solvent is also used for the lock signal. Calibration is performed on the proton signal of DMSO deuterated at 2.44 ppm with respect to a TMS reference at 0 ppm. The 1E1 NMR spectrum coupled to the 2D experiments HSQC 1H / 13C and HMBC 1H / 13C allow the structural determination of the molecules 15 (see tables of attributions). The molar quantifications are made from the quantitative 1D 1E1 NMR spectrum. The mass spectrometry analysis is carried out by direct injection by an electrospray ionization mode (ID / ESI). The analyzes were performed on a Bruker HCT spectrometer (flow rate 600 20! AL / min, Nebulizer gas pressure 10 psi, nebulizer gas flow 4 L / min). Example 1: Synthesis of 2-12- (2-oxoimidazolidin-1-yl) ethoxylbenzonitrile oxide 2- [2- (2-Oxoimidazolidin-1-yl) ethoxy] benzonitrile oxide is synthesized from salicylaldehyde and 1- (2-chloroethyl) imidazolidin-2-one by two-step monotopic synthesis of 14 steps b1 and b2 (followed by a recovery step c) followed by an oxidation step d. An oxime can first be prepared independently according to the two protocols 1 and 2 indicated below before carrying out an oxidation step, according to protocol 3, in order to obtain said oxide. Two - step monotopic synthesis b1 and b2 followed by step c (in accordance with the invention): preparation of 24242 - oxoimidazolidin - 1 - (yl) ethoxy) benzaldehyde oxime Protocol 1 (according to the invention): a reactor of 1L, 30 g of sali-aldehyde (0.25 mol) and 200 g of ethanol are charged. 172.8 g of potassium carbonate (1.25 mol) are added and the mixture is refluxed. 92.8 g of 1- (2-chloroethyl) imidazolidin-2-one (0.63 mol) are then added in portions over a period of 5 hours. At the end of the addition, it is left to react for 2 hours at reflux. The mixture is cooled to 50 ° C. and 24.8 g of a 50% aqueous hydroxylamine solution (0.38 mol) are then added over a period of 15 minutes. Allowed to react for 2 hours at 50 ° C. The reaction mixture is concentrated to a volume of 50 mL and then 500 mL of water is added at room temperature. The precipitate obtained is filtered, washed with water and then with pentane, and dried under vacuum. A white solid (40.5 g, 65% mass yield) with a melting point of 88 ° C is obtained.
    [0025] Protocol 2 (according to the invention): 30 g of sali-aldehyde (0.25 mol) and 300 g of acetonitrile are charged to a 1L reactor. 172.8 g of potassium carbonate (1.25 mol) are added and the mixture is refluxed. 109.5 g of 1- (2-chloroethyl) imidazolidin-2-one (0.74 mol) are then added in portions over a period of 6 hours. At the end of the addition, it is left to react for 2 hours at reflux. The mixture is cooled to 50 ° C. and 24.8 g of a 50% aqueous hydroxylamine solution (0.38 mol) are then added over a period of 15 minutes. It is allowed to react for 2 hours at 50 ° C. The reaction mixture is concentrated and then 500 ml of water are added at room temperature. The precipitate obtained is filtered, washed with water and then with pentane, and dried under vacuum. A white solid (41.8 g, 70% mass yield) with a melting point of 88 ° C is obtained. Step d: Preparation of 2-1-2- (2-oxoimidazolidin-3-ethoxybenzonitrile oxide) Protocol 3: In a 1L reactor, 30 g of 24242-oxoimidazolidin-1-yl) ethoxybenzaldehyde oxime are charged. (0.12 mol) and 300 g of ethyl acetate. It is cooled to 5 ° C. and 111.7 g of 12% bleach (0.18 mol) are added over a period of 15 minutes. Allowed to react for 3 hours at 5 ° C. The mixture is filtered and the solid obtained is washed with water and then with ethyl acetate. A white-yellow solid (17.8 g, 60% mass yield) with a melting point of 109 ° C is obtained.
    [0026] EXAMPLE 2 Synthesis of 2,4,6-trimethyl-3- [4- (2-oxoimidazolidin-1-yl) ethoxylbenzonitrile oxide 2,4,6-trimethyl-342- (2- oxoimidazolidin-1-yl) ethoxy] benzonitrile is prepared according to two synthetic routes. According to a first route, said oxide is synthesized in six steps, named step a1, step a2, step b1, step b2, step c and step d. The second synthetic route differs from the first route in that steps b1 and b2 are performed in a two-step monotopic synthesis.
    [0027] For each of the steps, the compounds can be synthesized independently according to several protocols. Step a1 is carried out according to various protocols 4 to 9, step a2 according to various protocols 10 to 12, step b 1 according to various protocols 13 to 15. Steps b2 and c are performed according to two protocols 16 and 17 The two-step monotopic synthesis b1 and b2 followed by step c are carried out according to various protocols 18 to 21. Step d is carried out according to various protocols 22 to 24.
    [0028] Step a: Preparation of 3-hydroxy-2,4,6-trimethylbenzaldehyde Protocol 4: 15 This compound can be obtained according to a protocol described in the patent application WO 2012/007684. Protocol 5: To a solution of TiCl4 (10.44 g, 0.055 mol) in dichloromethane (5 mL) cooled to 12 ° C was added for 10 minutes a mesitol solution (5.0 g, 0.037 mol) in dichloromethane (15 mL). After stirring for 5-10 minutes at 1015 ° C, a solution of dichloromethyl methyl ether (6.75 g, 0.059 mol) in dichloromethane (5 mL) is added over a period of 10-15 minutes. After 15 hours at room temperature, a mixture of 100 mL of water and 50 g of ice is poured into the reaction medium. After 30-40 minutes of stirring, the crude reaction product is filtered, washed with water (4 times per 10 ml) and dried under air. The target product (3.93 g) is obtained with a mass yield of 65%.
    [0029] The molar purity estimated by 1E1 NMR is greater than 90%. Thin layer chromatography (TLC): Rf = 0.87 (SiO2, EtOAc, 12 and UV revelation), or Rf = 0.35 (SiO2, heptane: EtOAc = 3: 1, UV reveal and 12).
    [0030] Protocol 6: To a solution of mesitol (6.0 g, 0.044 mol) in dichloromethane (30 mL) (under an inert atmosphere) at 2 ° C, TiCl 4 (15.04 g, 0.079 mol) was added dropwise. ) over 15-20 minutes keeping the temperature of the reaction medium below 8 ° C. After stirring for 5 minutes at 6 ° C., the dichloromethyl methyl ether (7.60 g, 0.066 mol) is added for 35-40 minutes. After 16 hours at room temperature, a mixture of 75 mL of water and 50 g of ice is poured into the reaction medium. After stirring for 1 hour and 30 minutes, the product is filtered, washed with water (4 x 5 mL), and dried under air. The target product (5.53 g, 0.034 mol) is obtained with a mass yield of 76%. The molar purity estimated by 1E1 NMR is greater than 98%.
    [0031] TLC: Rf = 0.87 (SiO2, EtOAc, 12 and UV revelation), or Rf = 0.35 (SiO2, heptane: EtOAc = 3: 1, UV reveal and 12). Protocol 7: To a solution of SnC14 (183.6 g, 0.705 mol) in dichloromethane (250 mL) cooled to 13 ° C was added over 20 minutes a solution of mesitol (40.0 g, 0.294 mol) in dichloromethane (250 mL). After stirring for 5 minutes at 13 ° C., a solution of dichloromethyl methyl ether (50.6 g, 0.441 mol) in dichloromethane (100 ml) is added for 30 minutes. The reaction medium is stirred for 15 hours at room temperature. The reaction medium is then poured into a water / ice mixture (800 ml of water and 0.7 kg of ice). After stirring for one hour, the organic phase is separated. The aqueous phase is extracted with CH 2 Cl 2 (2 times per 100 ml). The combined organic phases are washed with water (2 × 100 mL), dried with Na 2 SO 4 and concentrated under reduced pressure (10 mbar, 23 ° C.) to yield 53 g of an oil. An aqueous solution of dimethyl amine (500 mL, 40% in water) is added to the crude reaction product. The mixture is heated to 60 ° C and stirred at this temperature for 2.5 hours. Water (1.0 L) is added and the aqueous phase is extracted with dichloromethane (4 times per 100 mL). The combined organic phases are washed with a solution of HCl / water (1: 2) (three times per 100 ml) and with water (three times per 100 ml). After concentration under reduced pressure (150 mbar, 23 ° C), 40/60 petroleum ether (100 mL) is added. The solution is cooled to -18 ° C for 15 hours. The crystals obtained are filtered and washed with a mixture of dichloromethane (5 ml) and 40/60 petroleum ether (15 ml), then with 40/60 petroleum ether (twice with 20 ml), and finally dried under air. The solid (20.02 g) is obtained with a mass yield of 42%. After concentration of the filtrate under reduced pressure (60 mbar, 23 ° C.), 40/60 petroleum ether (70 ml) is added thereto. The solution is cooled to -18 ° C for 6 hours. The crystals obtained are filtered and washed with 40/60 petroleum ether (twice per 10 ml) and dried under air. The second product fraction (3.02 g) is obtained with a yield of 6.3%.
    [0032] Purification by trituration is carried out according to the protocol indicated below. The two solids fractions are combined and solubilized in a mixture of dichloromethane (150 mL) and 40/60 petroleum ether (100 mL). The solution is cooled to -18 ° C for 4 to 6 hours. The crystals are filtered, washed with 40/60 petroleum ether (twice 20 mL), and air dried. The product (11.9 g) is obtained with a mass yield of 25%. The molar purity estimated by 1E1 NMR is greater than 96%.
    [0033] TLC: Rf = 0.87 (SiO2, EtOAc, 12 and UV revelation), or Rf = 0.35 (SiO2, heptane: EtOAc = 3: 1, UV reveal and 12). Protocol 8: 5A of PC15 (91.7 g, 0.441 mol), under an inert atmosphere, is added at 22-29 ° C for 70 minutes of ethyl formate (34.8 g, 0.470 mol). The reaction being exothermic, the temperature of the medium can reach 40-60 ° C. The reaction medium is stirred for 1 hour at room temperature. Once the PC15 is completely solubilized, the reaction medium is stirred for a further 1-2 hours at room temperature. The formylating agent thus formed is used in the next step without further purification. To a solution of mesitol (40.0 g, 0.294 mol) in dichloromethane (100 mL) at 11 ° C is added TiCl4 (105.0 g, 0.529 mol) over 45 minutes. After 5 minutes at 12-13 ° C, the previously prepared formylating agent is added over 1.5-2.0 hours while maintaining the temperature between 9 and 22 ° C. The suspension obtained is stirred for 15 hours at room temperature. The reaction medium is then poured into a mixture of water (500 ml) and ice (500 g). After 15-20 minutes of stirring, the precipitate is filtered and washed with water (5 times per 50 ml). The crystals obtained are dried under air. The target product (27.5 g, 0.170 mol) is obtained with a mass yield of 58%.
    [0034] The molar purity estimated by 1 H NMR: 97 mol%. TLC: Rf = 0.35 (SiO2, heptane: EtOAc = 3: 1, UV reveal and 12). Protocol 9: In a 2 L reactor equipped with a condenser and purged with nitrogen, 105.8 g of titanium tetrachloride (0.56 mol) are charged. It is cooled to 15 ° C. and 40 g of mesitol (0.29 mol) dissolved in 400 g of dichloromethane are run over a period of 30 minutes. While maintaining the temperature at 15-20 ° C, 40.6 g of dichloromethyl methyl ether (0.35 mol) are then run over a period of one hour. At the end of the addition, it is left to react for 3 hours at room temperature. The reaction mixture is slowly transferred to a reactor containing 800 g of water and maintained at a temperature below 20 ° C. After stirring for 30 minutes, the mixture is decanted and the organic phase is recovered. The aqueous phase is extracted twice with 100 g of dichloromethane. The combined organic phases are washed with 200 g of water and then concentrated to a volume of 100 ml. 100 g of pentane are added and then cooled to -15 ° C. The crystals obtained are washed with 50 g of a 1/1 dichloromethane-pentane mixture and then dried under vacuum. A white-beige solid (45.4 g, 94% mass yield) with a melting point of 113 ° C. is obtained.
    [0035] Step a2: Preparation of 1- (2-chloroethyl) imidazolidin-2-one Protocol 10: This compound can be obtained according to a protocol described in patent application WO 2012/007684. Protocol 11: On 1- (2-hydroxyethyl) imidazolidin-2-one (dried under reduced pressure at 60 ° C) (5.0 g, 38.42 mmol) is added dropwise SOC12 (5, 0 mL, 69.34 mmol) for 2-3 minutes. The mixture is stirred at 80 ° C (Tbain) for 1 hour and 30 minutes then one hour and 30 minutes at 100 ° C (Tbain). After evaporation of the excess SOC12 under reduced pressure (Tbain 50 ° C, 8-9 mbar), the crude reaction product (7.53 g, yield 105.9%) is obtained in the form of a yellow oil.
    [0036] Water (10 mL) is added to the reaction crude and the pH of the aqueous phase is adjusted to 8 by addition of potassium carbonate.
    [0037] After crystallization at room temperature in water, the precipitate is filtered and washed with water (2-3 ml). The crystals are dried under air. The target product (2.87 g, 19.31 mol) is obtained with a mass yield of 50%. The molar purity estimated by 1F1 NMR is greater than 90%. Protocol 12: 120 g of HEIO ((1- (2-hydroxyethyl) imidazolidin-2-one), 0.92 mol) are charged into a 1L reactor equipped with a refrigerant and purged with nitrogen. It is heated to 90 ° C., and 120.4 g of thionyl chloride (1.02 mol) are added over a period of 30 minutes. Allowed to react for 2 hours at 90 ° C. 400 g of toluene are then added and heated at reflux for 2 hours. The reaction mixture is cooled to room temperature. The precipitate obtained is filtered, washed with toluene and then dried under vacuum. 123.2 g of a white solid are obtained (melting point of 93 ° C., mass yield of 90%). Step b1 (not according to the invention): Preparation of 2,4,6-trimethyl-3- (2- (2-oxoimidazolidin-1-yl) ethoxy) benzaldehyde Protocol 13: This compound can be obtained according to a protocol described in patent application WO 2012/007684. Protocol 14: A mixture of 3-hydroxy-2,4,6-trimethylbenzaldehyde (25.0 g, 0.152 mol) and K 2 CO 3 (126.3 g, 0.914 mol) in DMF (200 mL) is stirred at 30 ° C. -35 ° C for 5 to 10 minutes. Then 1- (2-chloroethyl) imidazolidin-2-one (33.9 g, 0.228 mol) is added. The temperature of the reaction medium is brought to 90 ° C (Tbain) for 2.5 to 3 hours. Then, a second portion of 1- (2-chloroethyl) imidazolidin-2-one (22.6 g, 0.152 mol) is added and the mixture is heated to 100 ° C (Tbain) for 3 hours. Finally, a third portion of 1- (2-chloroethyl) imidazolidin-2-one (22.6 g, 0.152 mol) is added and the mixture is brought to 110-115 ° C (Tbain) for 3 to 4 hours. After returning to 23 ° C., the reaction medium is diluted with water (4.0 L). The organic phase is extracted with CH2Cl2 (6 times per 200 mL). The combined organic phases are concentrated under reduced pressure (85 mbar, 36 ° C.). The residue obtained is taken up in Et 2 O (200 mL) and the mixture is stirred at room temperature for 2 hours. The precipitate obtained is filtered, washed on the filter with Et 2 O (25 mL) and dried at room temperature.
    [0038] A white solid (31.93 g, 76% mass yield) is obtained. The molar purity is greater than 82% (1H NMR). Protocol 15: 20 To a mixture of 3-hydroxy-2,4,6-trimethylbenzaldehyde (0.44 g, 3.3 mmol), 1- (2-hydroxyethyl) imidazolidin-2-one (0.64 g, 4.9 mmol) and triphenylphosphine (1.31 g, 5.0 mmol) in THF (30 mL) at room temperature is added a solution of diisopropyl azodicarboxylate (1.01 g, 5.0 mmol) in the THF (15 mL) for 5 to 10 minutes. The reaction medium is stirred for 15 hours at room temperature and water (15 ml) is then added thereto. The solvents are concentrated under reduced pressure (28 ° C., 50 mbar). The aqueous phase is extracted with ethyl acetate (three times with 25 ml). The combined organic phases are washed with a saturated aqueous solution of NaCl. The solvent is concentrated under reduced pressure to about 3 mL (30 ° C). After purification on a chromatographic column (0 1.5 cm, 11 cm H) (eluent: ethyl acetate: ethanol (10: 1)). The solvent is evaporated to dryness.
    [0039] A white solid (0.77 g, 84% mass yield) is obtained. The molar purity is greater than 78% (1H NMR).
    [0040] Steps b2 and c (not according to the invention): Preparation of 2,4,6-trimethyl-3- (2- (2-oxoimidazolidin-1-yl) ethoxy) benzaldehyde oxime The products isolated from Protocols 13, 14 and 15 are used in the following protocols (16, 17). The sequence of these steps is not in accordance with the invention because of the insulation of these products. Protocol 16: This compound can be obtained according to a protocol described in the patent application WO 2012/007684. Protocol 17: To a solution of 2,4,6-trimethyl-3- (2- (2-oxoimidazolidin-1-yl) ethoxy) benzaldehyde (31.5 g, 0.114 mol) in EtOH (300 mL) at room temperature. 44 ° C is added a solution of hydroxylamine (12.0 g, 0.182 mol., 50% in water, Aldrich) in EtOH (20 mL). The reaction medium is stirred for 4 hours at 50 ° C. Water (80 mL) is added to the solution. The reaction medium and concentrated under reduced pressure (80 mbar, 40 ° C). The resulting solution is cooled to 15-20 ° C and stirred for 5-10 minutes. The precipitate obtained is filtered, washed on the filter with an ethanol / water mixture (twice with 10/15 ml) and dried for 15-20 hours under atmospheric pressure at room temperature. A white solid (28.32 g, 85% mass yield) is obtained.
    [0041] The molar purity estimated by 1 H NMR is greater than 87%.
    [0042] TLC: Rf = 0.58 (SiO2, EtOAc: EtOH = 5: 1); revelation by UV and 12). Two-step monotopic synthesis b1 and b2 followed by step c (according to the invention): preparation of 2,4,6-trimethyl-3- (2- (2-oxoimidazolidin-1-yl) oxime ) ethoxy) benzaldehyde Protocol 18 (according to the invention): To a mixture of 3-hydroxy-2,4,6-trimethylbenzaldehyde (10.0 g, 0.061 mol) and K2CO3 (50.5 g, 0.365 g) mol) in DMF (100 mL) at 35 ° C is added 1- (2-chloroethyl) imidazolidin-2-one (13.55 g, 0.091 mol). The temperature of the reaction medium is brought to 90 ° C (Tbain) and it is stirred at this temperature for 2.5 to 3 hours. Then, a second portion of 1- (2-chloroethyl) imidazolidin-2-one (9.03 g, 0.061 mol) is added and the mixture is stirred at 100 ° C (Tbain) for 2.5 hours. Finally, the third portion of 1- (2-chloroethyl) imidazolidin-2-one (9.03 g, 0.061 mol, technical purity) is added and the mixture is stirred at 105 ° C (Tbain) for 4 hours. The temperature of the reaction medium is lowered to 43 ° C., and then a solution of hydroxylamine (6.84 g, 0.104 mol, 50% in water, Aldrich) is added. The reaction medium is stirred for 5 hours at 50-53 ° C. A second portion of hydroxylamine solution (about 3 g, 50% in water, Aldrich) is added. The reaction medium is stirred for 1.5 to 2 hours at 50-53 ° C. The mixture is then diluted with water (1.25 L). The suspension obtained is stirred for 15 hours at room temperature. The precipitate obtained is filtered, washed on the filter with water (4 times per 50 ml) and dried at room temperature. A light gray solid (12.87 g, 72% mass yield) is obtained.
    [0043] The molar purity estimated by 1F1 NMR is greater than 86%. Protocol 19 (according to the invention): 30 g of 3-hydroxy-2,4,6-trimethylbenzaldehyde (0.18 mol) and 200 g of DMF are charged to a 1L reactor. 126.5 g of potassium carbonate (0.92 mol) are added and heated to reflux. 67.9 g of 1- (2-chloroethyl) imidazolidin-2-one (0.46 mol) are then added in portions over a period of 6 hours. At the end of the addition, it is left to react for 2 hours at reflux. It is cooled to 50 ° C. and 14.3 g of a 50% aqueous hydroxylamine solution (0.22 mol) are then added over a period of 15 minutes. Allowed to react for 2 hours at 50 ° C. The reaction mixture is concentrated to a volume of 50 mL, then 500 mL of water is added at room temperature. The precipitate obtained is filtered, washed with water and then dried under vacuum.
    [0044] A white-beige solid (44.6 g, 85% mass yield) with a melting point of 167 ° C is obtained. Protocol 20 (according to the invention): To a mixture of 3-hydroxy-2,4,6-trimethylbenzaldehyde (22.8 g, 0.139 mol) and K 2 CO 3 (115.2 g, 0.833 mol) in isopropanol (160 mL) at 50 ° C is added 1- (2-chloroethyl) imidazolidin-2-one (30.9 g, 0.208 mol). The temperature of the reaction medium is brought to 100 ° C. (Tbain) and maintained for 3 to 4 hours. Then, a second portion of 1- (2-chloroethyl) imidazolidin-2-one (20.06 g, 0.139 mol, technical purity) is added and the mixture is stirred at 100 ° C (Tbain) for 5 hours. Finally, the third portion of 1- (2-chloroethyl) imidazolidin-2-one (20.06 g, 0.139 mol, technical purity) is added and the mixture is stirred at 100 ° C (Tbain) for 8 to 10 hours.
    [0045] The temperature of the reaction medium is lowered to room temperature, and then isopropanol (25 mL) is added to the reaction medium. The mixture is heated to 55 ° C and a solution of hydroxylamine (14.68 g, 0.222 mol, 50% in water, Aldrich) in isopropanol (25 mL) is added. The reaction medium is stirred for 7 hours at 50 ° C. The reaction medium is poured into water (3 L). After stirring for 5 hours, the precipitate obtained is filtered, washed on the filter with water (600 ml) and dried at room temperature. A light gray solid (30.35 g, 75% mass yield) is obtained.
    [0046] The molar purity estimated by 1H NMR is greater than 87%. Protocol 21 (according to the invention): 30 g of 3-hydroxy-2,4,6-trimethylbenzaldehyde (0.18 mol) and 200 g of isopropanol are charged to a 1L reactor. 126.5 g of potassium carbonate (0.92 mol) are added and the mixture is refluxed. 67.9 g of 1- (2-chloroethyl) imidazolidin-2-one (0.46 mol) are then added in portions over a period of 6 hours. At the end of the addition, it is left to react for 2 hours at reflux. The mixture is cooled to 50 ° C. and 14.3 g of a 50% aqueous hydroxylamine solution (0.22 mol) are then added over a period of 15 minutes. Allowed to react for 2 hours at 50 ° C. The reaction mixture is concentrated to a volume of 50 mL, then 500 mL of water is added at room temperature. The precipitate obtained is filtered, washed with water and then dried under vacuum.
    [0047] A white solid (43.0 g, 82% mass yield) with a melting point of 167 ° C is obtained. Step d: Preparation of 2,4,6-trimethyl-1,3-1-2- (2-oxoimidazolidin-1-yl) ethoxylbenzonitrile oxide Protocol 22: This compound can be obtained according to a protocol described in the patent application WO 2012 / Protocol 23: To a mixture of 2,4,6-trimethyl-3- (2- (2-oxoimidazolidin-1-yl) ethoxy) benzaldehyde oxime (9.7 g, 0.033 mol) in ethyl acetate (575 mL) at 1 ° C was added, dropwise, an aqueous solution of NaOCl (48% gCl / L) (73 mL) for 10 minutes. The reaction mixture is stirred for 1 hour and 30 minutes at 2-4 ° C. The precipitate obtained is filtered, washed on the filter with water (three times per 20 ml) and by ethyl acetate (three times 20 ml) and finally dried for 10 to 15 hours under atmospheric pressure at room temperature A white solid (8.63 g, 90% mass yield) is obtained.
    [0048] The molar purity estimated by 1 H NMR is greater than 94%. Protocol 24: In a 1L reactor, 40 g of 2,4,6-trimethyl-3- (2- (2-oxoimidazolidin-1-yl) ethoxy) benzaldehyde oxime (0.14 mol) are charged. and 280 g of ethyl acetate. The mixture is cooled to 5.degree. C. and 127.5 g of 12% bleach (0.17 mol) are added over a period of 15 minutes. Allowed to react for 3 hours at 5 ° C. The mixture is filtered and the solid obtained is washed with water and then with ethyl acetate. A white solid (33.7 g, 85% mass yield) with a melting point of 160 ° C is obtained. Thus, 2,4,6-trimethyl-342- (2-oxoimidazolidin-1-yl) ethoxy] benzonitrile oxide is obtained by two-step monotopic synthesis directly from 3-hydroxy-2,4, 6-trimethylbenzaldehyde, followed by an oxidation reaction.
    [0049] The process according to the invention therefore makes it possible to improve the overall yield of said process as well as a reduction in investment and production costs.
    [0050] EXAMPLE 3 Synthesis of 3-methoxy-4- (2- (2-oxoimidazolidin-1-yl) ethoxy) benzonitrile oxide JNH 5 Two-step monotopic synthesis b1 and b2 followed by step c (according to the invention): preparation of 3-methoxy-4- (2- (2-oxoimidazolidin-1-yl) ethoxy) benzaldehyde oxime Protocol (according to the invention): In a reactor of 1L, 30 g of vanillin (0.20 mol) and 200 g of isopropanol are charged. 138.2 g of potassium carbonate (1 mol) are added and the mixture is refluxed. 89.2 g of 1- (2-chloroethyl) imidazolidin-2-one (0.6 mol) are then added in portions over a period of 6 hours. At the end of the addition, it is allowed to react for 2 hours at reflux. It is cooled to 50 ° C. and 19.8 g of a 50% aqueous hydroxylamine solution (0.30 mol) are then added over a period of 15 minutes. Allowed to react for 2 hours at 50 ° C. The reaction mixture is concentrated to a volume of 50 mL, then 500 mL of water is added at room temperature. The precipitate obtained is filtered off, washed with water and then dried under vacuum. A white solid (33.5 g, 60% mass yield) with a melting point of 189 ° C is obtained.
    [0051] Step d: Preparation of 3-methoxy-4-1-2- (2-oxoimidazolidin-1-yl) ethoxylbenzonitrile oxide Protocol 26: 5 In a 1L reactor, 30 g of oxime are charged. 3-methoxy-4- (2- (2-oxoimidazolidin-1-yl) ethoxy) benzaldehyde (0.11 mol) and 300 g of dichloromethane. It is cooled to 5 ° C. and 102.4 g of 12% bleach (0.17 mol) are added over a period of 30 minutes. Allowed to react for 3 hours at 5 ° C. The mixture is filtered and the solid obtained is washed with water and then with pentane. A white solid (15.5 g, 52% mass yield) with a melting point of 111 ° C is obtained.
    权利要求:
    Claims (26)
    [0001]
    REVENDICATIONS1. Process for the synthesis of a compound of formula (I) below: ## STR2 ## in which: X represents an oxygen atom, a sulfur atom or an NH group, preferably an atom; oxygen; R 1 represents a carbon chain optionally substituted or interrupted by one or more heteroatoms; n is an integer ranging from 0 to 4; - Sp represents an atom or a group of atoms, comprising two successive steps (1) 1) and (b2) according to a monotopic synthesis: - (1) 1) the reaction of a compound of formula (II): (R 1) n with a compound of formula (III): ## STR2 ## wherein Z represents a nucleofugal group; in the presence of: - at least one polar solvent Si; - at least one base; At a temperature Ti ranging from 70 to 150 ° C, to form an ether; (b2) reacting said ether with an aqueous hydroxylamine solution at a temperature T2 ranging from 30 to 70 ° C, to obtain an oxime compound of formula (IV): ## STR2 ## ; then: a step (c) of recovering said oxime compound of formula (IV); a step (d) of oxidation of the oxime compound of formula (IV) with an oxidizing agent, in the presence of at least one organic solvent S2.
    [0002]
    2. The method of claim 1, wherein the group X is the group, wherein X is selected from an oxygen atom and a sulfur atom, preferably an oxygen atom.
    [0003]
    3. Method according to any one of claims 1 to 2, wherein the group Sp is a linear or branched alkylene chain C 1 -C 24, preferably C 1 -C 10, optionally interrupted by one or more nitrogen atoms or oxygen, more preferably a C1-C6 linear alkylene chain.
    [0004]
    4. A process according to any one of the preceding claims, wherein the Z group is selected from chlorine, bromine, iodine, mesylate group, tosylate group, acetate group and trifluoromethylsulfonate group.
    [0005]
    5. Method according to any one of the preceding claims, wherein the polar solvent Si is a polar solvent miscible in water, preferably a protic solvent. 3037953 32
    [0006]
    6. Method according to the preceding claim, wherein the protic solvent is alcoholic.
    [0007]
    7. Process according to any one of the preceding claims, in which the compound of formula (II) represents from 5 to 40% by weight, preferably from 10 to 30% by weight, relative to the weight of the solvent.
    [0008]
    8. A process according to any one of the preceding claims wherein the base is selected from alkali alkoxides, alkali carbonates, alkaline earth carbonates, alkali hydroxides, alkaline earth hydroxides and mixtures thereof.
    [0009]
    9. Process according to any one of the preceding claims, in which the base is chosen from sodium methanolate, potassium carbonate and sodium hydroxide, preferably potassium carbonate.
    [0010]
    10. Process according to any one of the preceding claims, in which the amount of base is from 1.5 to 8 equivalents, preferably from 2 to 6 equivalents, relative to the amount of compound of formula (II). 20
    [0011]
    11. A process according to any one of the preceding claims, wherein the addition of the aqueous hydroxylamine solution is carried out when the conversion of the compound of formula (II) is at least 70%.
    [0012]
    12. A process according to any one of the preceding claims, wherein said oxidizing agent is selected from sodium hypochlorite, N-bromosuccinimide in the presence of a base, N-chlorosuccinimide in the presence of a base, and oxygenated water in the presence of a catalyst, preferably sodium hypochlorite. 30
    [0013]
    13. Process according to any one of the preceding claims, in which the amount of oxidizing agent is from 1 to 5 equivalents, preferably from 1 to 2 equivalents, relative to the amount of oxime compound of formula (IV). 3037953 33
    [0014]
    14. Process according to any one of the preceding claims, in which the organic solvent S2 is an organic solvent chosen from chlorinated solvents and of ester, ether and alcohol type, more preferentially chosen from dichloromethane and ethyl acetate. , butyl acetate, diethyl ether, isopropanol and ethanol, more preferably chosen from ethyl acetate and butyl acetate.
    [0015]
    15. A process according to any one of the preceding claims wherein the oxime compound of formula (IV) is from 1 to 30% by weight, preferably from 1 to 20% by weight, based on the total weight of the set comprising said oxime compound of formula (IV), said organic solvent S2 and said oxidizing agent.
    [0016]
    16. A process according to any one of the preceding claims, comprising a step (e) of recovering the compound of formula (I).
    [0017]
    17. The process as claimed in any one of the preceding claims, wherein the process comprises a step (a1) of manufacturing the compound of formula (II), prior to step (1), by reacting a compound of formula (VIII): OH (R 1) n, / (VIII) with a formylating agent formed in situ or not and at least one Lewis acid, in the presence of at least one organic solvent S3.
    [0018]
    18. Process according to the preceding claim, in which the Lewis acid is chosen from TiCl4 and SnCl4, preferentially TiCl4.
    [0019]
    19. The process as claimed in any one of claims 17 to 18, in which the organic solvent S3 is a chlorinated organic solvent, preferably chosen from dichloromethane, chloroform and 1,2-dichloroethane, more preferably dichloromethane. 3037953 34
    [0020]
    20. Process according to any one of claims 17 to 19, wherein the formylating agent is chosen from dichloromethyl-methylether and dichloromethyl-ethylether, preferably dichloromethyl-methylether. 5
    [0021]
    21. Process according to any one of claims 17 to 20, wherein the agent formed in situ is obtained by reaction of methyl or ethyl formate with a chlorinating agent, preferably phosphorus pentachloride.
    [0022]
    22. A process according to any one of the preceding claims, wherein the process comprises a step (a2) of manufacturing the compound of formula (III), prior to step (1) 1), by reaction of a compound of formula (IX): ## STR2 ## with an agent allowing the formation of nucleofuge group Z.
    [0023]
    23. The process according to the preceding claim, wherein said agent is thionyl chloride.
    [0024]
    24. A process according to any one of claims 22 to 23, wherein step (a2) is carried out in the absence or in the presence of at least one solvent, preferably a chlorinated solvent, more preferably dichloromethane.
    [0025]
    25. A process according to any one of claims 22 to 24, wherein step (a2) is immediately followed by a step (a3) of recovering the compound of formula (III), preferably by toluene purification, plus preferentially by crystallization of the compound of formula (III) in toluene.
    [0026]
    26. Use of the compound of formula (I) obtained by the process as defined in any one of the preceding claims.
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    同族专利:
    公开号 | 公开日
    RU2724105C2|2020-06-22|
    RU2018101749A|2019-07-24|
    EP3313823A1|2018-05-02|
    WO2016207263A1|2016-12-29|
    RU2018101749A3|2019-11-14|
    CN107848982A|2018-03-27|
    FR3037953B1|2019-01-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CN101270071A|2008-04-21|2008-09-24|渤海大学|Method for synthesizing 1-alkyl-2-alkoxyl-3-indole aldoxime derivant|
    WO2012007684A1|2010-07-13|2012-01-19|Arkema France|Molecules having combinable groups|WO2021023840A1|2019-08-07|2021-02-11|Arkema France|Molecule having a nitrile oxide function|
    FR3068703A1|2017-07-04|2019-01-11|Compagnie Generale Des Etablissements Michelin|COMPOSITION BASED ON AT LEAST ONE PARTICULAR POLYAROMATIC COMPOUND|
    FR3068698A1|2017-07-04|2019-01-11|Compagnie Generale Des Etablissements Michelin|POLYMER CONTAINING PARTICULAR FUNCTIONAL PENDING GROUPS IMIDAZOLIDINONE|
    FR3068694B1|2017-07-04|2019-07-26|Arkema France|POLYAROMATIC MOLECULE WITH AN OXIDE FUNCTION OF NITRILE|
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    FR1555822A|FR3037953B1|2015-06-24|2015-06-24|PROCESS FOR THE SYNTHESIS OF MOLECULES CARRYING AN OXIDE FUNCTION OF NITRILE|
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