A method for synthesizing N,3,3-trimethyl-2-oxobutyramide

Abstract

The invention provides a method for synthesizing N,3,3-trimethyl-2-oxobutyramide. 3,3-dimethyl-2-oxobutyric acid is used as a raw material, and methylamine hydrochloride is reacted with an organic base and a condensing agent to generate N,3,3-trimethyl-2-oxobutyramide. The yield of N,3,3-trimethyl-2-oxobutyramide generated by the synthesis method of the invention is high, the yield reaches 82%, the reaction conditions are mild, it is suitable for scaled-up production, and no highly toxic raw materials are used, which is safe and environmentally friendly.

Description

Technical Field

[0001] The invention relates to the technical field of amides, and in particular to a method for synthesizing N,3,3-trimethyl-2-oxobutyramide. Background Art

[0002] N,3,3-trimethyl-2-oxobutanamide (3), English name N,3,3-trimethyl-2-oxobutanamide, is a key intermediate of tLANOP ligand (N-(diphenylphosphino)-2-[(diphenylphosphino)oxy]-3,3,N-trimethylbutanamide) phosphine ligand used in the synthesis of high-efficiency asymmetric hydrogenation reaction. The literature 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 in the following figure:

[0003]

[0004] There are few existing literature and patents for the synthesis of N,3,3-trimethyl-2-oxobutyramide (Tetrahedron Letters (1984), 25 (46), 5251-4.; EP0798289A1). The specific synthesis method is shown in the figure below:

[0005]

[0006] In this method, N,3,3-trimethyl-2-oxobutyramide was synthesized with a yield of 84% at a low temperature of -110°C using highly dangerous lithium tert-butoxide, highly toxic carbon monoxide and active isocyanate as raw materials. The use of highly active and highly toxic raw materials and ultra-low temperature conditions significantly limits the wide application of this method. Although there are many ways to synthesize amides, there is no gentle and efficient method to synthesize this important compound, N,3,3-trimethyl-2-oxobutyramide. Summary of the invention

[0007] In view of the deficiencies in the prior art, the present invention provides a method for synthesizing N,3,3-trimethyl-2-oxobutyramide, which solves the problem that the highly toxic raw materials and ultra-low temperature conditions in the prior art limit the application of the method.

[0008] In one aspect, the present invention provides a method for synthesizing N,3,3-trimethyl-2-oxobutyramide, wherein 3,3-dimethyl-2-oxobutyric acid is used as a raw material, and methylamine hydrochloride is reacted with 3,3-dimethyl-2-oxobutyric acid to generate N,3,3-trimethyl-2-oxobutyramide under the action of an organic base and a condensing agent.

[0009] Further, the method comprises the following steps:

[0010] S1: dissolving 3,3-dimethyl-2-oxobutyric acid in an organic solvent;

[0011] S2: adding methylamine hydrochloride, an organic base and a condensation agent to carry out a condensation reaction.

[0012] Furthermore, the molar volume ratio of the 3,3-dimethyl-2-oxobutanoic acid to the organic solvent is 1:10-30.

[0013] Furthermore, the molar ratio of 3,3-dimethyl-2-oxobutyric acid, methylamine hydrochloride, condensing agent and organic base is 1:2:2:1.21.

[0014] Furthermore, the organic base is N-methylmorpholine.

[0015] Furthermore, the condensing agent is COMU.

[0016] Furthermore, the organic solvent used is dichloromethane.

[0017] Furthermore, the condensation reaction temperature is 20-35° C., and the reaction time is 9-12 hours.

[0018] The term "eq" or "equiv." herein refers to molar equivalents, and "V" refers to the volume of the solvent, such as 10V, which means that the volume of the solvent is 10 times the molar equivalent of the solute, with each mole corresponding to each liter. Specifically, the molar equivalent of 3,3-dimethyl-2-oxobutyric acid is 1 eq., the amount of dichloromethane is 10V, and the concentration is 0.1 mol / L.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1) The yield of N,3,3-trimethyl-2-oxobutyramide generated by the synthesis method of the present invention is high, and the yield reaches 82%.

[0021] 2) The reaction conditions of the present invention are mild and suitable for large-scale production.

[0022] 3) The present invention is safe and environmentally friendly, and does not use highly toxic raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1is N,3,3-trimethyl-2-oxobutyramide in Example 1 of the present invention 1 H-NMR spectrum.

[0024] Figure 2 is N,3,3-trimethyl-2-oxobutyramide in Example 1 of the present invention 31 P-NMR spectrum. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and embodiments.

[0026] Example 1 Preparation of N,3,3-trimethyl-2-oxobutyramide

[0027] At room temperature, N-methylmorpholine (2 eq), methylamine hydrochloride (2 eq) and (ethyl 2-oxime-cyanoacetate)-N,N-dimethyl-morpholinyl uronium hexafluorophosphate (COMU) (1.21 eq) were slowly added to a reaction solution of 3,3-dimethyl-2-oxobutyric acid (1 eq) dissolved in dichloromethane (15 V) in sequence, and the reaction solution was stirred at room temperature for 10 hours. 82% of the final product N,3,3-trimethyl-2-oxobutanamide (3) was isolated. 1 H-NMR and 31 P-NMR spectrum Figure 1 , 2 The reaction formula is shown below:

[0028]

[0029] Example 2 Preparation of N,3,3-trimethyl-2-oxobutyramide

[0030] At room temperature, N-methylmorpholine (2 eq), methylamine hydrochloride (2 eq) and (ethyl 2-oxime-cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (COMU) (1.21 eq) were slowly added to a reaction solution of 3,3-dimethyl-2-oxobutyric acid (1 eq) dissolved in dichloromethane (10 V) in sequence, and the reaction solution was stirred at 20° C. for 12 hours. 80% of the final product N,3,3-trimethyl-2-oxobutanamide (3) was isolated.

[0031] Example 3 Preparation of N,3,3-trimethyl-2-oxobutyramide

[0032] At room temperature, N-methylmorpholine (2 eq), methylamine hydrochloride (2 eq) and (ethyl 2-oxime-cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (COMU) (1.21 eq) were slowly added to a reaction solution of 3,3-dimethyl-2-oxobutyric acid (1 eq) dissolved in dichloromethane (30 V) in sequence, and the reaction solution was stirred at 35° C. for 9 hours. 77% of the final product N,3,3-trimethyl-2-oxobutanamide (3) was isolated.

[0033] Comparative Example 1 Preparation of N,3,3-trimethyl-2-oxobutyramide

[0034] Similar to Example 1, except that COMU is replaced by EDCI and HOBt, N-methylmorpholine is replaced by DIPEA, and the optimal ratio and reaction temperature are adjusted. The reaction formula is as follows:

[0035]

[0036] According to the test, the yield of N,3,3-trimethyl-2-oxobutanamide is less than 15%.

[0037] Comparative Example 2 Preparation of N,3,3-trimethyl-2-oxobutyramide

[0038] Similar to Example 1, except that COMU is replaced by DCC and HOBt, N-methylmorpholine is replaced by DIPEA, DCM is replaced by THF, and the optimal ratio and reaction temperature are adjusted. The reaction formula is as follows:

[0039]

[0040] According to the test, the yield of N,3,3-trimethyl-2-oxobutanamide is less than 13%.

[0041] Comparative Example 3 Preparation of N,3,3-trimethyl-2-oxobutyramide

[0042] Similar to Example 1, except that COMU is replaced by HATU and HOAT, N-methylmorpholine is replaced by DIPEA, DCM is replaced by DMF, and the optimal ratio and reaction temperature are adjusted. The reaction formula is as follows:

[0043]

[0044] According to the test, the yield of N,3,3-trimethyl-2-oxobutyramide is less than 10%.

[0045] Comparative Example 4 Preparation of N,3,3-trimethyl-2-oxobutyramide

[0046] The reaction formula is as follows:

[0047]

[0048] According to the test, the yield of N,3,3-trimethyl-2-oxobutanamide is less than 5%.

[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing N,3,3-trimethyl-2-oxobutanamide, characterized in that: Using 3,3-dimethyl-2-oxobutyric acid as a raw material, a condensation reaction occurs with methylamine hydrochloride under the action of an organic base and a condensing agent to generate N,3,3-trimethyl-2-oxobutyramide, comprising the following steps: S1: dissolving 3,3-dimethyl-2-oxobutyric acid in an organic solvent; S2: adding methylamine hydrochloride, an organic base and a condensation agent to carry out a condensation reaction; Wherein, the organic solvent is dichloromethane; The organic base is N-methylmorpholine; The condensing agent is COMU; The molar equivalent ratio of 3,3-dimethyl-2-oxobutyric acid, methylamine hydrochloride, condensation agent and organic base is 1:2:2:1.

21.

2. A method for synthesizing N,3,3-trimethyl-2-oxobutyramide as claimed in claim 1, characterized in that: The volume of the organic solvent is 10-30V based on the molar equivalent of 3,3-dimethyl-2-oxobutanoic acid.

3. A method for synthesizing N,3,3-trimethyl-2-oxobutyramide as claimed in claim 1, characterized in that: The condensation reaction temperature is 20-35°C and the reaction time is 9-12 hours.

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