CN1176075C - Pyrrole derivatives preparation method - Google Patents

Pyrrole derivatives preparation method Download PDF

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CN1176075C
CN1176075C CNB011402350A CN01140235A CN1176075C CN 1176075 C CN1176075 C CN 1176075C CN B011402350 A CNB011402350 A CN B011402350A CN 01140235 A CN01140235 A CN 01140235A CN 1176075 C CN1176075 C CN 1176075C
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alkali metal
pyrrole
sodium
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CN1422846A (en
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栗同林
隋军龙
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北京燕山石油化工公司研究院
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Abstract

本发明涉及一种吡咯衍生物的制备方法,本发明的方法包括将一种酰酯化合物R The present invention relates to a method for preparing a pyrrole derivative, the method according to the present invention comprises bringing one acyl ester compound R

Description

吡咯衍生物的制备方法 Preparation of pyrrole derivatives

技术领域 FIELD

本发明涉及一种吡咯衍生物的制备方法,更具体地涉及一种甲酸酯基烷基取代的吡咯的制备方法。 The present invention relates to a method for preparing a pyrrole derivative, and more particularly to a method for preparing a carboxylate group substituted with an alkyl pyrrole.

背景技术 Background technique

甲酸酯基烷基取代的吡咯衍生物是制备烷基取代吡咯的重要中间体,而烷基取代吡咯如2,5-二甲基吡咯是一种重要的催化助剂。 Substituted alkyl formate derivative is an alkyl-substituted pyrrole preparing important intermediates, such as the alkyl substituted pyrrole-2,5-dimethylpyrrole is an important co-catalyst. 加拿大化学杂志(CANADIAN JOURNAL OF CHEMISTRY VOL.48P1689-1697,1970)公开了一种甲酸酯基烷基取代的吡咯衍生物的制备方法,该方法是将氨水加入酰酯化合物R2COCH2COOR和卤代化合物R4CHXCOH中,反应后得到甲酸酯基烷基取代的吡咯衍生物。 Canadian Journal of Chemistry (CANADIAN JOURNAL OF CHEMISTRY VOL.48P1689-1697,1970) discloses a method of preparing carboxylic acid esters of alkyl-substituted pyrrole derivatives, which is added to aqueous ammonia acid ester compound and a halogenated compound R4CHXCOH R2COCH2COOR in reaction to give alkyl substituted benzoates derivatives of pyrrole. 其缺点是反应产物收率低。 The disadvantage is the low yield of the reaction product.

发明内容 SUMMARY

本发明的目的在于提供一种吡咯衍生物的制备方法。 Object of the present invention to provide a method for preparing a pyrrole derivative. 用本发明的方法可以以高收率得到高纯度的吡咯衍生物。 Pyrrole derivatives can be obtained with high purity in high yield by the method of the present invention.

本发明提供一种具有如下通式的吡咯衍生物的制备方法, The present invention provides a method of preparing the pyrrole derivatives having the general formula, 包括将一种酰酯化合物R2COCH2COOR在存在碱或碱金属的极性溶剂中与卤代醛或卤代酮R4CHXCOR5反应得到甲酸酯取代的二酮R5COCH(R4)CH(COOR)COR2,然后再与氨水或加热时能释放出氨的铵盐在50-100℃下反应1-10小时,其中R、R2独立地为碳原子数为1-5的烷基,R4、R5独立地为氢或碳原子数为1-5的烷基,X为氯、溴或碘,优选氯或溴。 Acid ester comprising adding a compound R2COCH2COOR substituted halogenated formate to give haloketone R4CHXCOR5 aldehydes reacting with a base in a polar solvent or the presence of an alkali metal dione R5COCH (R4) CH (COOR) COR2, and then ammonia or ammonium salt when heated can release ammonia to react at 50-100 ℃ 1-10 hours, wherein R, R2 independently an alkyl group having 1-5 carbon atoms, R4, R5 is independently hydrogen or a C alkyl of 1 to 5 atoms, X is chlorine, bromine or iodine, preferably chlorine or bromine.

本发明的吡咯衍生物的制备方法包括β-取代反应、成环反应等。 Preparation of pyrrole derivatives of the present invention include β- substitution reaction, cyclization reaction and the like. 具体过程可表示如下:(1)酰酯化合物与碱或碱金属发生β-取代反应,生成酰酯碱金属或其用量为:碱或碱金属与酰酯化合物的摩尔比为1-5,以大致相等的摩尔数为最好。 The specific process may be as follows: (1) acid ester compound with a base or an alkali metal β- substitution reaction occurs to produce an acid or an alkali metal carbonate in an amount of: a molar ratio of alkali metal base or with an acid ester compound is 1-5, to substantially equal moles of the best.

(2)酰酯碱金属与卤代醛或卤代酮反应,生成甲酸酯取代的二酮 (2) an alkali metal acid ester with a halogenated ketone or halogenated aldehydes, formate substituted generating dione 卤代醛或卤代酮的用量为:卤代醛或卤代酮与酰酯化合物的摩尔比为0.1-10,以大致相等的摩尔数为最好。 Halo aldehydes or halo ketones in an amount of: halo molar ratio of aldehyde or ketone and halogenated acid ester compound is 0.1 to 10, substantially equal to the number of moles for the best.

(3)甲酸酯取代的二酮直接和氨反应成环,生成甲酸酯基烷基取代的吡咯 (3) carboxylate substituted dione and ammonia to form a ring directly, generating an alkyl carboxylate group substituted pyrrole 由于氨易得、价格便宜且易挥发,所以,甲酸酯取代的二酮直接和氨反应成环过程中以氨过量为宜,以过量2倍以上为好,以过量2-10倍为最好。 Since ammonia is readily available, inexpensive and volatile, so formate substituted dione and ammonia to form a ring directly during the excess ammonia preferably to more than 2-fold excess as well, 2-10 times excess is most it is good.

本发明的酰酯钠可用《有机制备化学手册》(中卷、韩广甸等编译、1977年11月第一版、石油化学工业出版社、第158页)所公开的方法制得,也可由JP56-169639A所公开的方法制得。 Sodium acid esters of the present invention can be "prepared Organic Chemistry Handbook" (volumes, Han Guang Austin other compiler, November 1977 edition, Petroleum Chemical Industry Press, p. 158) prepared by the method disclosed, may also be the method disclosed in JP56-169639A prepared.

本发明的甲酸酯取代的二酮可用JP56-169639A方法制得。 A substituted ester of the present invention can be used dione JP56-169639A methods.

本发明所述的铵盐为碳酸铵或碳酸氢铵。 Ammonium salts of the present invention is ammonium carbonate or ammonium bicarbonate.

本发明所述的碱可以为通式MY所表示的碱金属化合物,M为碱金属,Y为氢原子、烷氧基。 The base of the present invention may be an alkali metal compound represented by the general formula MY, M being an alkali metal, Y is a hydrogen atom, an alkoxy group. 其中碱金属M为钠或钾;碱金属氢化物为氢化锂、氢化钠、氢化钾等碱金属氢化物;碱金属醇盐为甲醇钠、乙醇钠、丙醇钠、乙醇锂、异丙醇钾、丁醇钾等碱金属醇盐;优选氢化物和醇盐。 Wherein the alkali metal M is sodium or potassium; alkali metal hydrides, alkali metal hydrides of lithium, sodium hydride, potassium hydride and other hydride; alkali metal alkoxides are sodium methoxide, sodium ethoxide, sodium propoxide, lithium ethoxide, potassium isopropoxide , butoxide and the like alkali metal alkoxides; preferably hydrides and alkoxides. 从工业的取得容易及价格方面考虑,则以氢化钠、甲醇钠或乙醇钠为理想。 Easily acquired from the industrial viewpoint and price, places, sodium hydride, sodium methoxide or sodium ethoxide is preferable.

本发明所述的用于溶解原料及碱的极性溶剂,例如可为水与甲醇、乙醇、异丙醇等的醇类;二甲基甲酰胺、二甲亚砜、六甲基磷酰胺等的极性非质子性溶剂;二噁烷、四氢呋喃等的酯类。 A polar solvent and a base for dissolving the starting material according to the present invention, for example water and an alcohol as methanol, ethanol, isopropanol and the like; dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. polar aprotic solvents; esters dioxane, tetrahydrofuran and the like. 在以水为溶剂的场合,若使用的碱为碱金属氢化物或碱金属醇盐,则这类的碱与水反应生成氢氧化物,结果是以氢氧化物作为碱参与反应,招致反应的收率低下。 In the case of water as a solvent, if the base used is an alkali metal hydride or alkali metal alkoxides, such the base reacts with water hydroxides, alkali hydroxide as a result is involved in the reaction, the reaction is incurred the yield is low. 所以,溶剂以使用极性非水溶剂为好。 Therefore, a non-aqueous solvent is a polar solvent as well. 本发明的溶剂优选至少一种选自甲醇、乙醇、二甲基甲酰胺、二甲亚砜和六甲基磷酰胺的非水溶剂。 The solvent of the present invention is preferably at least one selected from non-aqueous solvent such as methanol, ethanol, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoramide is. 对其用量并无严格要求,以能使原料充分溶解并且能够搅拌充分为宜。 The amount thereof is not critical to make a raw material can be sufficiently dissolved and stirred sufficiently appropriate.

本发明所述的R、R2独立地为碳原子数为1-3的烷基,更优选甲基、乙基,R4、R5独立地为氢或碳原子数为1-3的烷基,更优选氢、甲基、乙基。 According to the present invention, R, R2 is independently from 1 to 3 carbon atoms in the alkyl group, more preferably methyl, ethyl, R4, R5 is independently hydrogen or an alkyl group of 1-3 carbon atoms, more preferably hydrogen, methyl, ethyl. 最优选R为甲基或乙基,R2甲基,R4为氢,R5为甲基或氢。 Most preferably R is methyl or ethyl, R2 methyl, R4 is hydrogen, R5 is methyl or hydrogen.

本发明所述的酰酯化合物R2COCH2COOR与卤代醛或卤代酮R4CHXCOR5的反应温度为-10-100℃,优选-10-25℃。 R2COCH2COOR acid ester compound with a halogenated aldehyde or reaction temperature R4CHXCOR5 haloketone of the present invention is -10-100 ℃, preferably -10-25 ℃.

用本发明的方法制备甲酸酯烷基取代的吡咯时,具有易操作、产品收率高、纯度高的特点。 When an alkyl-substituted pyrrole carboxylate prepared by the method of the present invention is easy to operate, high yield and high purity characteristics.

具体实施方式 Detailed ways

下面的实施例将有助于说明本发明,但不局限其范围。 The following examples will help to illustrate the invention, but are not limited to the scope thereof.

实施例11、丙酮基乙酰乙酸乙酯的制备将带有搅拌装置的1000ml圆底烧瓶放置在水浴中,加入420ml无水N,N二甲基甲酰胺和102g(1.5mol)乙醇钠,在室温(20℃)、搅拌状态下,缓慢加入195g(1.5mol)乙酰乙酸乙酯,加料速率以物料温度不超过25℃为限,滴加完毕,再滴加140g(1.5mol)氯丙酮,加料速率仍以物料温度不超过25℃为限。 Example 11 Preparation of ethyl acetyl acetone 1000ml round-bottomed flask with a stirring apparatus is placed in a water bath, was added 420ml of anhydrous N, N-dimethylformamide and 102g (1.5mol) of sodium ethoxide at room temperature at (20 ℃), stirred, was slowly added 195g (1.5mol) of ethyl acetoacetate, feed rate of material temperature does not exceed 25 ℃ limited to, the addition was complete, then was added dropwise 140g (1.5mol) of chloroacetone, feed rate still the material temperature does not exceed 25 ℃ is limited. 然后,继续维持反应12小时,制得混浊状褐色反应液(1)。 Then, the continuation of the reaction for 12 hours to obtain a brown cloudy reaction solution (1).

将反应液(1)进行过滤,除去NaCl固体,得到紫红色液体650ml(2),经色谱-质谱联用仪定性分析、色谱定量分析,其中丙酮基乙酰乙酸乙酯的含量为33%。 The reaction solution (1) was filtered to remove solid NaCl to give a purple liquid 650ml (2), by chromatography - mass spectrometry analysis of the qualitative, quantitative chromatographic analysis, wherein the content of ethyl acetate in acetyl acetone 33%. 将紫红色液体(2)进行减压分馏,以除去反应溶剂和未反应的组分,收集温度80℃(3.3kpa)的馏分(3),其质量为220克,经色谱定量分析,其中丙酮基乙酰乙酸乙酯含量96wt.%(211克,1.13mol),其收率以氯丙酮为基础计算为75%。 The purple liquid (2) vacuum distillation to remove the reaction solvent and the fraction of unreacted components, collecting temperature 80 ℃ (3.3kpa) (3), a mass of 220 g, quantitative analysis by chromatography, wherein acetone ethyl acetoacetate group content of 96wt.% (211 g of, 1.13mol), the yield calculated on the basis of chloroacetone in 75%.

2、2,5-二甲基吡咯-3-甲酸乙酯的制备将溶液(3)置于水浴中1000ml三口瓶中,维持温度在60℃,搅拌,慢慢加入400ml 28%的氨水,2小时滴加完毕,60℃下继续反应1小时,然后自然冷却至室温,放置过夜。 2,2,5-dimethyl-pyrrole-3-carboxylic acid ethyl ester The solution of (3) in a 1000ml three-neck flask in a water bath, maintaining the temperature at 60 ℃, with stirring, was slowly added 400ml 28% aqueous ammonia, 2 h addition was complete, the reaction was continued for 1 hour at 60 ℃, then cooled to room temperature, allowed to stand overnight. 得到有金黄色沉淀的混合液(4)。 Gold yellow precipitate to obtain a mixture of (4). 将反应液(4)进行过滤,得到金黄色晶体(5),经质谱定性(5)为2,5-二甲基-3-甲酸乙酯基吡咯(161克,0.96mol),其收率为85%(以丙酮基乙酰乙酸乙酯为基础计算)。 The reaction solution (4) was filtered to give a golden yellow crystals (5), characterized by mass spectrometry (5) 2,5-dimethyl-pyrrole-3-carboxylate (161 g, 0.96mol), the yield 85% (to acetone, ethyl acetyl group basis).

实施例2用金属钠替代实施例1中的乙醇钠,其它条件同实施例1,试验结果见表1。 Example 2 Sodium metal sodium alternative embodiment of ethanol in Example 1, with the other conditions, see Table 1 1, the test results of Examples.

实施例3用乙醇替代实施例1中的二甲基甲酰胺,其它条件同实施例1,试验结果见表1。 Example 3 Alternative embodiments of dimethylformamide with ethanol in Example 1, other conditions were the same as in Example 1, the test results shown in Table 1.

实施例4用溴丙酮替代实施例1中的氯丙酮,其它条件同实施例1,试验结果见表1。 Example 4 substituting acetone with bromine in Example 1 chloroacetone embodiment, other conditions were the same as in Example 1, the test results shown in Table 1.

实施例5用500毫升50wt.%的碳酸铵水溶液替代实施例1中的氨水,成环反应温度为90℃,其它条件同实施例1,试验结果见表1。 Example 5 with 500 ml of 50wt.% Aqueous solution of ammonium carbonate aqueous ammonia alternate embodiment in Example 1, the cyclization reaction temperature is 90 ℃, other conditions were the same as in Example 1, the test results shown in Table 1.

实施例6用溴代乙醛替代实施例1中的氯丙酮,其它条件同实施例1,得到2-甲基-3-甲酸乙酯基吡咯,试验结果见表1。 Example 6 bromoacetaldehyde Example 1 in an alternative embodiment chloroacetone, other conditions were the same as in Example 1 to give 2-methyl-pyrrole-3-carboxylate, the test results shown in Table 1.

实施例7用乙酰乙酸甲酯替代实施例1的乙酰乙酸乙酯,其它条件同实施例1,得到2,5-二甲基-3-甲酸甲酯基吡咯,试验结果见表1。 Example 7 using ethyl acetoacetate, methyl acetoacetate alternative embodiment of Example 1, other conditions were the same as in Example 1, to give 2,5-dimethyl-pyrrole-3-carboxylate, the test results shown in Table 1.

对比例1将带有搅拌装置的1000ml的圆底烧瓶放置在水浴中,在室温下,加入65g(0.5mol)乙酰乙酸乙酯,46g(0.5mol)氯丙酮,250ml28%的氨水和250ml的蒸馏水。 Comparative Example 1 to 1000ml round-bottom flask with a stirring device placed in a water bath at room temperature, was added 65g (0.5mol) of ethyl acetoacetate, 46g (0.5mol) of chloroacetone, 250ml28% aqueous ammonia and 250ml of distilled water . 在水浴中维持60℃,反应2小时,然后自然冷却到室温,放置过夜。 In a water bath maintained at 60 ℃, reaction for 2 hours, then cooled to room temperature and stand overnight. 得到金黄色沉淀的混合反应液。 The reaction mixture obtained was golden yellow precipitate. 将反应液进行抽滤,得到金黄色晶体2,5-二甲基吡咯-3-甲酸乙酯36克,其收率为43%(以氯丙酮为基础计算)。 The reaction mixture was subjected to suction filtration to give golden yellow crystals of 2,5-dimethyl-pyrrole-3-carboxylate 36 g and the yield was 43% (based chloroacetone basis).

表1 Table 1

*总收率为甲酸酯取代的二酮的收率(%)与甲酸酯基烷基取代的吡咯的收率之积。 * The total yield of product Yield carboxylate substituted dione Yield (%) with an alkyl formate group substituted pyrrole.

Claims (8)

1.一种具有如下通式的吡咯衍生物的制备方法, 1. A method of preparing the pyrrole derivatives having the general formula, 包括将一种酰酯化合物R2COCH2COOR在存在碱或碱金属M的极性溶剂中与卤代醛或卤代酮R4CHXCOR5反应得到甲酸酯取代的二酮R5COCH(R4)CH(COOR)COR2,然后再与氨水或加热时能释放出氨的铵盐在50-100℃下反应1-10小时,其中R、R2独立地为碳原子数为1-5的烷基,R4、R5独立地为氢或碳原子数为1-5的烷基,X为氯、溴或碘。 Acid ester comprising adding a compound R2COCH2COOR substituted halogenated formate to give aldehydes haloketone R4CHXCOR5 reaction in a polar solvent or presence of a base or an alkali metal M in dione R5COCH (R4) CH (COOR) COR2, then when heated with ammonia or ammonium salts can release ammonia to react at 50-100 ℃ 1-10 hours, wherein R, R2 independently an alkyl group having 1-5 carbon atoms, R4, R5 is independently hydrogen or 1-5 carbon atoms, an alkyl group, X is chlorine, bromine or iodine.
2.根据权利要求1所述的吡咯衍生物的制备方法,其特征在于所述的铵盐为碳酸铵或碳酸氢铵。 The method of preparing an azole derivative according to claim, wherein said ammonium salt is ammonium carbonate or ammonium bicarbonate.
3.根据权利要求1所述的吡咯衍生物的制备方法,其特征在于所述的碱为通式MY所表示的碱金属化合物,其中M为碱金属、Y为氢原子或烷氧基。 The method of preparing the pyrrole derivatives of claim 1, wherein said base is an alkali metal compound represented by the general formula MY, wherein M is an alkali metal, Y is a hydrogen atom or an alkoxy group.
4.根据权利要求1所述的吡咯衍生物的制备方法,其特征在于所述碱金属M为钾或钠;所述的碱金属氢化物为氢化锂、氢化钠或氢化钾;所述的碱金属醇盐为甲醇钠、乙醇钠、丙醇钠、乙醇锂、异丙醇钾、丁醇钾。 The production method according to claim 1 pyrrole derivatives, wherein the alkali metal M is sodium or potassium; the alkali metal hydride is lithium hydride, sodium hydride or potassium hydride; said base metal alkoxides are sodium methoxide, sodium ethoxide, sodium propoxide, lithium ethoxide, potassium isopropoxide, potassium butoxide.
5.根据权利要求1-4任一项所述的吡咯衍生物的制备方法,其特征在于所述的极性溶剂为至少一种选自甲醇、乙醇、二甲基甲酰胺、二甲亚砜和六甲基磷酰胺的非水溶剂。 5. The method of any of claims 1-4 Preparation of a pyrrole derivative according to claim, wherein said polar solvent is at least one selected from methanol, ethanol, dimethylformamide, dimethylsulfoxide and a nonaqueous solvent triamide six.
6.根据权利要求1-4任一项所述的吡咯衍生物的制备方法,其特征在于所述的R为甲基或乙基,R2为甲基,R4为氢,R5为甲基或氢。 6. The method of any of claims 1-4 Preparation of a pyrrole derivative according to claim, wherein said R is methyl or ethyl, R2 is methyl, R4 is hydrogen, R5 is methyl or hydrogen .
7.根据权利要求1-4任一项所述的吡咯衍生物的制备方法,其特征在于所述的X为氯或溴。 7. The production method according to any one of claims 1-4 pyrrole derivative according to claim, wherein said X is chlorine or bromine.
8.根据权利要求1-4任一项所述的吡咯衍生物的制备方法,其特征在于酰酯化合物R2COCH2COOR与卤代醛或卤代酮R4CHXCOR5的反应温度为-10-25℃。 8. A production method according to any one of claims 1-4 pyrrole derivative according to claim, characterized in that the acid ester with a halogenated compound R2COCH2COOR R4CHXCOR5 haloketone or aldehyde reaction temperature is -10-25 ℃.
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