CN116283635A - A method for synthesizing N,3,3-trimethyl-2-oxobutanamide - Google Patents

A method for synthesizing N,3,3-trimethyl-2-oxobutanamide Download PDF

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CN116283635A
CN116283635A CN202211732114.6A CN202211732114A CN116283635A CN 116283635 A CN116283635 A CN 116283635A CN 202211732114 A CN202211732114 A CN 202211732114A CN 116283635 A CN116283635 A CN 116283635A
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oxobutanamide
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黄林
施昌谷
陈彬
李原强
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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    • C07C231/00Preparation of carboxylic acid amides
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Abstract

The invention provides a method for synthesizing N, 3-trimethyl-2-oxo-butyramide. Taking 3, 3-dimethyl-2-oxo-butyric acid as a raw material, and performing condensation reaction with methylamine hydrochloride under the action of organic base and condensing agent to generate N, 3-trimethyl-2-oxo-butyramide. The N, 3-trimethyl-2-oxo-butyramide generated by the synthesis method has high yield which reaches 82%, mild reaction conditions, suitability for large-scale production, no adoption of high-toxicity raw materials, safety and environmental protection.

Description

一种合成N,3,3-三甲基-2-氧代丁酰胺的方法A method for synthesizing N,3,3-trimethyl-2-oxobutanamide

技术领域technical field

本发明涉及酰胺类技术领域,尤其涉及一种合成N,3,3-三甲基-2-氧代丁酰胺的方法。The invention relates to the technical field of amides, in particular to a method for synthesizing N,3,3-trimethyl-2-oxobutyramide.

背景技术Background technique

N,3,3-三甲基-2-氧代丁酰胺(3),英文名N,3,3-trimethyl-2-oxobutanamide,是合成高效不对称氢化反应中应用的tLANOP配体(N-(二苯基膦基)-2-[(二苯基膦基)氧]-3,3,N-三甲基丁酰胺)膦配体的关键中间体。文献High yield acyl anion trappingreactions:direct nucleophilic acylation of isocyanates and isothiocyanates.(Tetrahedron:Asymmetry 1998,9,4043–4054)公开了如下图的合成方法:N,3,3-trimethyl-2-oxobutanamide (3), English name N,3,3-trimethyl-2-oxobutanamide, is a tLANOP ligand (N- Key intermediate of (diphenylphosphino)-2-[(diphenylphosphino)oxy]-3,3,N-trimethylbutanamide)phosphine ligand. The document High yield acyl anion trapping reactions:direct nucleophilic acylation of isocyanates and isothiocyanates. (Tetrahedron:Asymmetry 1998,9,4043–4054) discloses the synthesis method as shown below:

Figure BDA0004031955120000011
Figure BDA0004031955120000011

已有的合成N,3,3-三甲基-2-氧代丁酰胺的文献和专利很少(TetrahedronLetters(1984),25(46),5251-4.;EP0798289A1)。具体的合成方法如下图:There are few literatures and patents on the synthesis of N,3,3-trimethyl-2-oxobutanamide (Tetrahedron Letters (1984), 25 (46), 5251-4.; EP0798289A1). The specific synthesis method is as follows:

Figure BDA0004031955120000012
Figure BDA0004031955120000012

在这种方法中,以高危险性的叔丁醇锂,高毒性的一氧化碳和活性的异氰酸酯为原料,在-110℃的低温条件下,以84%的收率合成了N,3,3-三甲基-2-氧代丁酰胺。应用高活性,高毒性的原料和超低温的条件,明显限制了该方法的广泛应用。尽管目前合成酰胺的手段多种多样,但是到目前为止,还没有一种温和高效的方法来合成N,3,3-三甲基-2-氧代丁酰胺这一重要的化合物。In this method, N,3,3-N,3,3- Trimethyl-2-oxobutanamide. The application of highly active, highly toxic raw materials and ultra-low temperature conditions obviously limit the wide application of this method. Although there are many ways to synthesize amides, so far, there is no mild and efficient method to synthesize N,3,3-trimethyl-2-oxobutyramide, an important compound.

发明内容Contents of the invention

针对现有技术中所存在的不足,本发明提供了一种合成N,3,3-三甲基-2-氧代丁酰胺的方法,其解决了现有技术中存在的高毒性的原料和超低温的条件导致方法应用受限的问题。Aiming at the deficiencies in the prior art, the invention provides a method for synthesizing N,3,3-trimethyl-2-oxobutyramide, which solves the problems of highly toxic raw materials and The ultra-low temperature condition leads to the problem of limited application of the method.

本发明一方面,提供一种合成N,3,3-三甲基-2-氧代丁酰胺的方法,以3,3-二甲基-2-氧代丁酸为原料,在有机碱和缩合剂作用下,与甲胺盐酸盐发生缩合反应,生成N,3,3-三甲基-2-氧代丁酰胺。One aspect of the present invention provides a method for synthesizing N,3,3-trimethyl-2-oxobutyramide, using 3,3-dimethyl-2-oxobutyric acid as a raw material in an organic base and Under the action of a condensing agent, it undergoes a condensation reaction with methylamine hydrochloride to generate N,3,3-trimethyl-2-oxobutyramide.

进一步地,该方法包括以下步骤:Further, the method includes the following steps:

S1:将3,3-二甲基-2-氧代丁酸溶解于有机溶剂中;S1: dissolving 3,3-dimethyl-2-oxobutanoic acid in an organic solvent;

S2:加入甲胺盐酸盐、有机碱和缩合剂,进行缩合反应。S2: adding methylamine hydrochloride, an organic base and a condensation agent to carry out condensation reaction.

进一步地,所述3,3-二甲基-2-氧代丁酸与有机溶剂的摩尔体积比为1:10-30。Further, the molar volume ratio of the 3,3-dimethyl-2-oxobutanoic acid to the organic solvent is 1:10-30.

进一步地,3,3-二甲基-2-氧代丁酸、甲胺盐酸盐、缩合剂、有机碱的摩尔比为1:2:2:1.21。Further, the molar ratio of 3,3-dimethyl-2-oxobutanoic acid, methylamine hydrochloride, condensing agent, and organic base is 1:2:2:1.21.

进一步地,所述有机碱为N-甲基吗啡啉。Further, the organic base is N-methylmorpholine.

进一步地,所述缩合剂为COMU。Further, the condensing agent is COMU.

进一步地,所用有机溶剂为二氯甲烷。Further, the organic solvent used is dichloromethane.

进一步地,缩合反应的温度为20-35℃,反应时间为9-12小时。Further, the temperature of the condensation reaction is 20-35° C., and the reaction time is 9-12 hours.

本文中术语“eq”或“equiv.”为摩尔当量,“V”为溶剂体积,比如10V代表溶剂体积为溶质摩尔当量的10倍,每摩尔对应每升。具体来说3,3-二甲基-2-羰基丁酸的摩尔当量为1eq.,二氯甲烷用量为10V,浓度为0.1mol/L。Herein, the term "eq" or "equiv." refers to the molar equivalent, and "V" refers to the volume of the solvent. For example, 10V means that the volume of the solvent is 10 times the molar equivalent of the solute, and each mole corresponds to each liter. Specifically, the molar equivalent of 3,3-dimethyl-2-oxobutanoic acid is 1 eq., the amount of methylene chloride is 10 V, and the concentration is 0.1 mol/L.

相比于现有技术,本发明具有如下有益效果:Compared with the prior art, the present invention has the following beneficial effects:

1)本发明的合成方法生成的N,3,3-三甲基-2-氧代丁酰胺的收率高,收率达到82%。1) The yield of N,3,3-trimethyl-2-oxobutyramide produced by the synthesis method of the present invention is high, and the yield reaches 82%.

2)本发明的反应条件温和,适合放大生产。2) The reaction conditions of the present invention are mild and suitable for scale-up production.

3)本发明安全环保,没有采用高毒性的原料。3) The present invention is safe and environment-friendly, and does not use highly toxic raw materials.

附图说明Description of drawings

图1为本发明实施例1中N,3,3-三甲基-2-氧代丁酰胺的1H-NMR图谱。Figure 1 is the 1 H-NMR spectrum of N,3,3-trimethyl-2-oxobutyramide in Example 1 of the present invention.

图2为本发明实施例1中N,3,3-三甲基-2-氧代丁酰胺的31P-NMR图谱。Fig. 2 is the 31 P-NMR spectrum of N,3,3-trimethyl-2-oxobutyramide in Example 1 of the present invention.

具体实施方式Detailed ways

下面结合附图及实施例对本发明中的技术方案进一步说明。The technical solutions in the present invention will be further described below in conjunction with the accompanying drawings and embodiments.

实施例1N,3,3-三甲基-2-氧代丁酰胺的制备Embodiment 1N, the preparation of 3,3-trimethyl-2-oxobutanamide

室温下,向溶于二氯甲烷(15V)的3,3-二甲基-2-羰基丁酸(1eq)的反应液中依次缓慢加入N-甲基吗啡啉(2eq),甲胺盐酸盐(2eq)和(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯(COMU)(1.21eq),反应液在室温下搅拌10小时。即可分离得到82%的终产物N,3,3-trimethyl-2-oxobutanamide(3)。终产物的1H-NMR和31P-NMR图谱如图1、2所示。反应式如下所示:At room temperature, slowly add N-methylmorpholine (2eq), methylamine hydrochloride to the reaction solution of 3,3-dimethyl-2-carbonylbutanoic acid (1eq) dissolved in dichloromethane (15V) Salt (2eq) and (2-oximino-ethyl cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (COMU) (1.21eq), the reaction solution was stirred at room temperature for 10 hours . That is to say, 82% of the final product N,3,3-trimethyl-2-oxobutanamide (3) can be isolated. The 1 H-NMR and 31 P-NMR spectra of the final product are shown in Figures 1 and 2 . The reaction formula is as follows:

Figure BDA0004031955120000031
Figure BDA0004031955120000031

实施例2N,3,3-三甲基-2-氧代丁酰胺的制备Embodiment 2N, the preparation of 3,3-trimethyl-2-oxobutanamide

室温下,向溶于二氯甲烷(10V)的3,3-二甲基-2-羰基丁酸(1eq)的反应液中依次缓慢加入N-甲基吗啡啉(2eq),甲胺盐酸盐(2eq)和(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯(COMU)(1.21eq),反应液在20℃下搅拌12小时。即可分离得到80%的终产物N,3,3-trimethyl-2-oxobutanamide(3)。At room temperature, slowly add N-methylmorpholine (2eq), methylamine hydrochloride to the reaction solution of 3,3-dimethyl-2-carbonylbutanoic acid (1eq) dissolved in dichloromethane (10V) Salt (2eq) and (2-oximino-ethyl cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (COMU) (1.21eq), the reaction solution was stirred at 20°C for 12 Hour. Then 80% of the final product N,3,3-trimethyl-2-oxobutanamide (3) can be isolated.

实施例3N,3,3-三甲基-2-氧代丁酰胺的制备Embodiment 3N, the preparation of 3,3-trimethyl-2-oxobutanamide

室温下,向溶于二氯甲烷(30V)的3,3-二甲基-2-羰基丁酸(1eq)的反应液中依次缓慢加入N-甲基吗啡啉(2eq),甲胺盐酸盐(2eq)和(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯(COMU)(1.21eq),反应液在35℃下搅拌9小时。即可分离得到77%的终产物N,3,3-trimethyl-2-oxobutanamide(3)。At room temperature, slowly add N-methylmorpholine (2eq), methylamine hydrochloride to the reaction solution of 3,3-dimethyl-2-carbonylbutanoic acid (1eq) dissolved in dichloromethane (30V) salt (2eq) and (2-oximino-ethyl cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (COMU) (1.21eq), the reaction solution was stirred at 35°C for 9 Hour. 77% of the final product N,3,3-trimethyl-2-oxobutanamide (3) can be isolated.

对比例1N,3,3-三甲基-2-氧代丁酰胺的制备Comparative example 1N, the preparation of 3,3-trimethyl-2-oxobutyramide

与实施例1类似,不同之处在于:将COMU替换为EDCI和HOBt,将N-甲基吗啡啉替换为DIPEA,并调整最佳配比和反应温度,反应式如下:Similar to Example 1, the difference is: COMU is replaced by EDCI and HOBt, N-methylmorpholine is replaced by DIPEA, and the optimum proportioning and reaction temperature are adjusted, the reaction formula is as follows:

Figure BDA0004031955120000032
Figure BDA0004031955120000032

经检测,N,3,3-三甲基-2-氧代丁酰胺的收率小于15%。After testing, the yield of N,3,3-trimethyl-2-oxobutanamide is less than 15%.

对比例2N,3,3-三甲基-2-氧代丁酰胺的制备Comparative Example 2N, the preparation of 3,3-trimethyl-2-oxobutyramide

与实施例1类似,不同之处在于:将COMU替换为DCC和HOBt,将N-甲基吗啡啉替换为DIPEA,将DCM替换为THF,并调整最佳配比和反应温度,反应式如下:Similar to Example 1, the difference is that COMU is replaced by DCC and HOBt, N-methylmorpholine is replaced by DIPEA, DCM is replaced by THF, and the optimal proportion and reaction temperature are adjusted. The reaction formula is as follows:

Figure BDA0004031955120000041
Figure BDA0004031955120000041

经检测,N,3,3-三甲基-2-氧代丁酰胺的收率小于13%。After testing, the yield of N,3,3-trimethyl-2-oxobutanamide is less than 13%.

对比例3N,3,3-三甲基-2-氧代丁酰胺的制备Comparative Example 3N, the preparation of 3,3-trimethyl-2-oxobutyramide

与实施例1类似,不同之处在于:将COMU替换为HATU和HOAT,将N-甲基吗啡啉替换为DIPEA,将DCM替换为DMF,并调整最佳配比和反应温度,反应式如下:Similar to Example 1, the difference is that COMU is replaced by HATU and HOAT, N-methylmorpholine is replaced by DIPEA, DCM is replaced by DMF, and the optimal proportioning and reaction temperature are adjusted. The reaction formula is as follows:

Figure BDA0004031955120000042
Figure BDA0004031955120000042

经检测,N,3,3-三甲基-2-氧代丁酰胺的收率小于10%。After testing, the yield of N,3,3-trimethyl-2-oxobutanamide is less than 10%.

对比例4N,3,3-三甲基-2-氧代丁酰胺的制备Comparative example 4N, the preparation of 3,3-trimethyl-2-oxobutyramide

反应式如下:The reaction formula is as follows:

Figure BDA0004031955120000043
Figure BDA0004031955120000043

经检测,N,3,3-三甲基-2-氧代丁酰胺的收率小于5%。After detection, the yield of N,3,3-trimethyl-2-oxobutyramide is less than 5%.

最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。Finally, it is noted that the above embodiments are only used to illustrate the technical solutions of the present invention without limitation. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be carried out Modifications or equivalent replacements without departing from the spirit and scope of the technical solution of the present invention shall be covered by the claims of the present invention.

Claims (8)

1. A method for synthesizing N, 3-trimethyl-2-oxobutanamide, which is characterized by comprising the following steps: taking 3, 3-dimethyl-2-oxo-butyric acid as a raw material, and performing condensation reaction with methylamine hydrochloride under the action of organic base and condensing agent to generate N, 3-trimethyl-2-oxo-butyramide.
2. A method of synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1, wherein: the method comprises the following steps:
s1: dissolving 3, 3-dimethyl-2-oxobutanoic acid in an organic solvent;
s2: adding methylamine hydrochloride, organic base and condensing agent to perform condensation reaction.
3. A method of synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 2, wherein: the volume of the organic solvent is 10-30V based on the molar equivalent of 3, 3-dimethyl-2-oxobutanoic acid.
4. A method for synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1 or 2, characterized in that: the molar equivalent ratio of the 3, 3-dimethyl-2-oxo-butyric acid to the methylamine hydrochloride to the condensing agent to the organic base is 1:2:2:1.21.
5. A method for synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1 or 2, characterized in that: the organic base is N-methyl morpholine.
6. A method for synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1 or 2, characterized in that: the condensing agent is COMU.
7. A method of synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 2, wherein: the organic solvent used was methylene chloride.
8. A method for synthesizing N, 3-trimethyl-2-oxobutanamide according to claim 1 or 2, characterized in that: the condensation reaction temperature is 20-35 ℃ and the reaction time is 9-12 hours.
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CN101519389A (en) * 2009-02-19 2009-09-02 苏州昊帆生物科技有限公司 Method for preparing N, N-dimethyl-4-morpholine carboxylic acid amide
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