• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a process for monomethylation of a nitrogen-containing heterocycle by reaction of a dimethyl carbonate with a nitrogen-containing heterocycle comprising at least one nitrogen atom bonded to a hydrogen atom. The reaction is carried out at a temperature of 100 ° C. to 200 ° C. and a pressure of 0.93 × 10 5 Pa to 1.07 × 10 5 Pa. Methanol produced during the reaction is distilled off as soon as it is formed.
    公开号:KR20040012495A
    申请号:KR1020030051061
    申请日:2003-07-24
    公开日:2004-02-11
    发明作者:보레동엘리자베뜨；샤보베르나르；가세앙또앙；욱크삼뒤；띠이에보-루소피
    申请人:에스엔피이；
    IPC主号:
    专利说明:

    Process for the monomethylation of nitrogenous heterocycles
    [1] The present invention relates to a process for monomethylation of nitrogen-containing heterocycles. Such heterocycles, such as azoles, find application in a variety of fields such as pesticides, pharmaceuticals, biotechnology, paints and dyes.
    [2] One skilled in the art already knows how to N-methylate nitrogen-containing heterocycles. Some methods are alkylation of nitrogen-containing heterocycles with alkyl halides or alkyl sulfates; These methods present a number of disadvantages. Some reactants, such as dimethyl sulfate, are quite toxic. In addition, the products obtained require complex purification processes. Thus, methods have been provided for using reactants that are less toxic to the environment. Thus, several methylation methods using dimethyl carbonate have been envisioned.
    [3] [Reference: Liebigs Ann. Chem., 1987, 1, 77], the authors describe the reaction of nitrogen-containing heterocycles with dimethyl carbonate in the presence of a base (potassium carbonate) and a phase transfer catalyst (crown ether 18-crown-6). , Benzimidazole and derivatives thereof have been described. This synthesis has the disadvantages of high cost and toxicity of the crown ethers. In addition, the termination of the reaction requires a separate operation of the catalyst from the reaction medium.
    [4] Subsequently, a method is provided which does not comprise the crown ethers described in patent WO 96/08537. This method is to prepare an organic pigment by methylating a heterocycle with dimethyl carbonate in the presence of alkaline carbonate or hydroxide. The reaction is carried out at temperatures between 80 ° C. and 150 ° C. and atmospheric pressure. In practice, the yield is low even in the presence of a catalyst.
    [5] Another method described in patent JP 9169737 provides a process for the synthesis of N-methylated imidazoles by reaction of imidazole with dimethyl carbonate at a temperature of from 120 ° C. to 200 ° C., preferably 160 ° C. The described method is limited only to the synthesis of methylimidazole derivatives from compounds having a boiling point of about 250 ° C. Tests conducted with heterocycles with lower boiling points showed that the process could not be generalized to all nitrogen-containing heterocycles and especially nitrogen-containing heterocycles with boiling points below 190 ° C.
    [6] Accordingly, those skilled in the art continue to search for methods of N-methylation of nitrogen-containing heterocycles that can be performed simply and generalized to various classes of nitrogen-containing heterocycles. In the case of nitrogen-containing heterocycles, each having several nitrogen atoms bonded to a hydrogen atom, one of ordinary skill in the art is searching for an optional method, i.e., a method in which only monomethylated products can be synthesized.
    [7] The present invention relates to such a method.
    [8] The present invention relates to a process for monomethylation of such nitrogen-containing heterocycles by reaction of nitrogen-containing heterocycles with dimethyl carbonate comprising at least one nitrogen atom bonded to a hydrogen atom, which is a temperature of 100 ° C to 200 ° C. And performing the reaction at a pressure of 0.93 × 10 5 Pa to 1.07 × 10 5 Pa, and continuously removing the methanol produced during the reaction.
    [9] The process, carried out at temperatures of 100 ° C. to 200 ° C. and at about atmospheric pressure, shows the advantage of being simple to carry out. In addition, the continuous removal of methanol, ie the fact that methanol is distilled off as soon as it is formed, makes it possible to control the temperature of the reaction medium. This has several advantages. Thus, the process can be applied to heterocycles having a high boiling point on the order of 250 ° C. as well as several classes of nitrogen-containing heterocycles. This also makes it possible to add large amounts of dimethyl carbonate thereto without lowering the temperature of the reaction medium. Since the reaction kinetics are a function of the amount of dimethyl carbonate in the reaction medium, the reaction is carried out with fairly good kinetics.
    [10] The method applies not only to heterocycles having a boiling point of about 190 ° C. or above 190 ° C. or about 250 ° C. but also to heterocycles having a lower boiling point of about 120 ° C.
    [11] In general, the method is applied to heterocycles having a boiling point of at least 120 ° C.
    [12] Preferably, the nitrogen-containing heterocycle is selected from azoles and benzene derivatives thereof, indolin, pyrazolidine, morpholine, piperazine and azepine.
    [13] The term "azole" is used to denote a 5-membered heterocyclic compound of one or more nitrogen atoms bonded to a hydrogen atom. Indole and carbazole may be mentioned as azoles containing one nitrogen atom, and imidazole, benzimidazole, pyrazole and indazole as azoles containing two nitrogen atoms. The azoles containing three nitrogen atoms are especially triazoles and benzotriazoles, and the azoles containing five nitrogen atoms are pentazoles.
    [14] The amount of dimethyl carbonate used is from 1 to 5 moles per mole of nitrogen-containing heterocycle and preferably from 1.2 to 3 moles per mole of nitrogen-containing heterocycle.
    [15] Dimethyl carbonate is generally added gradually to the reaction medium at a flow rate of 0.001 to 1 mole per mole of substrate that is a nitrogen-containing heterocycle per hour.
    [16] The reaction is carried out at a temperature of 100 ° C to 200 ° C and preferably 120 ° C to 180 ° C.
    [17] The reaction is carried out at a pressure of from 0.93 x 10 5 Pa to 1.07 x 10 5 Pa, ie from 700 mm Hg to 800 mm Hg. In general, the local atmospheric pressure is within this range and the reaction is carried out at this pressure.
    [18] Nitrogen-containing heterocycles are monomethylated on nitrogen atoms bonded to hydrogen atoms. The reaction is optional when the nitrogen-containing heterocycle comprises at least one nitrogen atom, ie at least two nitrogen atoms, wherein each nitrogen atom is bonded to a hydrogen atom. This means that the product undergoes single methylation, so that only monomethylated products are synthesized. To this end, the monomethylated product is removed continuously, ie from the reaction medium as soon as it is formed. If the nitrogen-containing heterocycle each comprises at least two nitrogen atoms bonded to a hydrogen atom, the process can be carried out in the presence of a solvent. The solvent is selected from the group consisting of methoxynaphthalene, anisole and trichlorobenzene.
    [19] In the following preferred embodiments of the present invention are provided. For this purpose, a reactor equipped with a stirring system and a thermometer, a distillation column in place and a reflux condenser is used.
    [20] First, a nitrogen-containing heterocycle is introduced alone or with a portion of the amount of dimethyl carbonate to be used during the reaction.
    [21] The reaction medium is then heated to a temperature of 100 ° C. to 200 ° C., preferably 120 ° C. to 180 ° C.
    [22] If the process is continuous or semicontinuous, dimethyl carbonate is subsequently introduced into the reaction medium at a flow rate of 0.001 to 1 mole per mole of substrate that is a nitrogen-containing heterocycle per hour.
    [23] The nitrogen-containing heterocycle may also be introduced continuously as a mixture with dimethyl carbonate in a molar ratio of dimethyl carbonate: nitrogen-containing heterocycle of 1 to 10, preferably 1 to 3.
    [24] Methanol produced during the reaction is distilled off as soon as it is formed.
    [25] At the end of the reaction, the reaction medium is cooled to ambient temperature and the methylated product is recovered.
    [26] If the nitrogen-containing heterocycle each comprises two or more nitrogen atoms bonded to a hydrogen atom, the resulting monomethylated product is also removed as soon as it is formed.
    [27] The following examples illustrate alternative aspects of the invention without limitation.
    [28] Example 1 Synthesis of 1-methylimidazole
    [29] The reaction is carried out in a 250 ml reactor. The reactor is equipped with a stirrer, a thermometer and an injection system for continuous injection throughout the reaction. The reactor is equipped with a distillation column, a reflux head and a reflux condenser.
    [30] 34.04 g of imidazole, or 0.5 mole, is introduced into the reactor. The medium is then heated to 170 ° C. and maintained at this temperature throughout the reaction.
    [31] Dimethyl carbonate is introduced into the reactor over 7 hours at a flow rate of 145 mmol / hour.
    [32] The resulting methanol is distilled off as soon as it is formed. After the introduction of all dimethyl carbonate, the reaction is continued at 170 ° C. for 2 hours. The reaction medium is then cooled to ambient temperature. 33.36 g of 1-methylimidazole, or 0.49 mole, is recovered, corresponding to a yield of 98%.
    [33] Example 2: Synthesis of N-methylmorpholine
    [34] The apparatus used is the same as that described in Example 1. After introducing 100 g of 2-methoxynaphthalene into the reactor, the medium is heated to 170 ° C. and maintained at this temperature throughout the reaction. The morpholine / dimethyl carbonate mixture is then introduced at a molar ratio of 1/2 and a morpholine flow rate of 72 mmol / hour. The introduction time of the morpholine / dimethyl carbonate mixture is 7 hours. Subsequently, only dimethyl carbonate is introduced into the reactor for 2 hours at a flow rate of 100 mmol / hr.
    [35] Methanol and N-methylmorpholine are recovered successively. 22.25 g of N-methylmorpholine, or 0.22 mol, are obtained, corresponding to a yield of 43%.
    [36] Example 3: Synthesis of N-methylpiperazine
    [37] The apparatus used is the same as that described in Example 1. 43.07 g of piperazine, or 0.5 mole, are introduced into the reactor. The medium is then heated to 110 ° C. and maintained at this temperature throughout the reaction.
    [38] Dimethyl carbonate is introduced into the reactor for 10 hours at a flow rate of 100 mmol / hour.
    [39] The resulting methanol is distilled off as soon as it is formed. Excess dimethyl carbonate is also distilled off to stabilize the temperature of the reaction medium to 110 ° C.
    [40] The reaction medium is subsequently cooled to ambient temperature. 14.52 g of 1-methylpiperazine, or 0.145 mol, is recovered, corresponding to a yield of 29%.
    [41] Example 4: Synthesis of N-methylpyrazole
    [42] The apparatus used is the same as that described in Example 1.
    [43] 20.64 g of pyrazole, i.e. 0.3 mole and 4.5 g of dimethyl carbonate, i.e. 0.05 mole, are introduced into the reactor.
    [44] The medium is then heated to 140 ° C. and maintained at this temperature throughout the reaction.
    [45] Dimethyl carbonate is introduced into the reactor for 8 hours at a flow rate of 60 mmol / hr.
    [46] The resulting methanol is distilled off as soon as it is formed.
    [47] The reaction medium is then cooled to ambient temperature. 17.24 g of N-methylpyrazole, or 0.21 mole, is recovered, corresponding to a 70% yield.
    [48] Example 5: Synthesis of 1,3,5-trimethylpyrazole from 3,5-dimethylpyrazole
    [49] The apparatus used is the same as that described in Example 1. 24.03 g of 3,5-dimethylpyrazole, i.e. 0.25 mole and 4.5 g of dimethyl carbonate, i.e. 0.05 mole, are introduced.
    [50] The reaction medium is heated to 140 ° C. and maintained at this temperature throughout the reaction.
    [51] Dimethyl carbonate is introduced for 8 hours at a flow rate of 50 mmol / hr.
    [52] The resulting methanol is distilled off as soon as it is formed. Excess dimethyl carbonate is also distilled off to stabilize the temperature of the reaction medium to 140 ° C.
    [53] After the introduction of all dimethyl carbonate, the reaction medium is cooled to ambient temperature. 15.41 g, or 0.14 mole, of 1,3,5-trimethylpyrazole is recovered, corresponding to a yield of 57%.
    [54] The following examples are not part of the invention. This was done to indicate that the process requires the continuous recovery of methanol produced during the reaction in order to be able to generalize the process to several classes of nitrogen-containing heterocycles and in particular nitrogen-containing heterocycles having boiling points below 190 ° C. .
    [55] Example 6: Synthesis of N-methylpyrazole without recovery of methanol
    [56] The apparatus used is the same as that described in Example 1.
    [57] 20.64 g of pyrazole, i.e. 0.3 mole and 4.5 g of dimethyl carbonate, i.e. 0.05 mole, are introduced into the reactor.
    [58] The medium is then heated to 140 ° C. and then dimethyl carbonate is introduced into the reactor for 8 hours at a flow rate of 60 mmol / hr (ie 5.4 g / hr). No methanol formed is recovered.
    [59] It is found that the temperature of the reaction medium remains stable at 140 ° C. for 1 hour and then gradually decreases to 115 ° C. at the end of the reaction. The reaction medium is then cooled to ambient temperature. Only 3.53 g of N-methylpyrazole, or 0.042 mole, is recovered, corresponding to 14% yield.
    [60] Thus, N-methylpyrazole is obtained in a significantly lower yield (14%) than that obtained with the present method (70% yield, Example 4), which is the main subject of the present invention for recovering methanol.
    [61] As a method which can be generalized to several classes of nitrogen-containing heterocycles, nitrogen-containing heterocycles comprising at least one nitrogen atom bonded to a hydrogen atom can be reacted with dimethyl carbonate to monomethylate the nitrogen-containing heterocycle. .
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] A nitrogen-containing heterocycle comprising at least one nitrogen atom bonded to a hydrogen atom is reacted with dimethyl carbonate at a temperature between 100 ° C. and 200 ° C. and at a pressure between 0.93 × 10 5 Pa and 1.07 × 10 5 Pa and produced during the reaction. A method of monomethylation of a nitrogen-containing heterocycle, comprising continuously recovering the recovered methanol.
    [2" claim-type="Currently amended] The process of claim 1 wherein the nitrogen-containing heterocycle has a boiling point of at least 120 ° C. 3.
    [3" claim-type="Currently amended] The method of claim 2, wherein the nitrogen-containing heterocycle is selected from azoles, benzene derivatives of azoles, indolin, pyrazolidine, morpholine, piperazine and azepine.
    [4" claim-type="Currently amended] The process of claim 1 wherein the reaction is carried out at a temperature of 120 ° C. to 180 ° C. 7.
    [5" claim-type="Currently amended] The process of claim 1 wherein the amount of dimethyl carbonate is 1 to 5 moles per mole of nitrogen-containing heterocycle.
    [6" claim-type="Currently amended] The process of claim 1 wherein dimethyl carbonate is added gradually to the reaction medium.
    [7" claim-type="Currently amended] The process of claim 6, wherein dimethyl carbonate is introduced into the reaction medium at a flow rate of 0.001 to 1 mole per mole of nitrogen-containing heterocycle per hour.
    [8" claim-type="Currently amended] The method of claim 1, wherein the nitrogen-containing heterocycle comprises two or more nitrogen atoms each bonded to a hydrogen atom.
    [9" claim-type="Currently amended] The method of claim 8, wherein the monomethylated nitrogen-containing heterocycle is recovered continuously.
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    同族专利:
    公开号 | 公开日
    HU0302444A2|2004-05-28|
    EP1386916A1|2004-02-04|
    EP1386916B1|2006-01-18|
    DE60303273D1|2006-04-06|
    KR100532792B1|2005-12-02|
    IL156731D0|2004-02-08|
    US7022845B2|2006-04-04|
    ES2253647T3|2006-06-01|
    HU0302444D0|2003-10-28|
    DE60303273T2|2006-11-23|
    CA2434481A1|2004-02-01|
    JP2004067691A|2004-03-04|
    FR2843114A1|2004-02-06|
    AT316075T|2006-02-15|
    US20040024205A1|2004-02-05|
    FR2843114B1|2004-09-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2002-08-01|Priority to FR0209820
    2002-08-01|Priority to FR0209820A
    2003-07-24|Application filed by 에스엔피이
    2004-02-11|Publication of KR20040012495A
    2005-12-02|Application granted
    2005-12-02|Publication of KR100532792B1
    优先权:
    申请号 | 申请日 | 专利标题
    FR0209820|2002-08-01|
    FR0209820A|FR2843114B1|2002-08-01|2002-08-01|Process for monomethylation of nitrogen heterocycles|
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