A method for synthesizing N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide

Abstract

The invention discloses a method for synthesizing N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide. The method comprises the following steps: adding 1,3,5-trimethoxybenzene to an organic solvent, adding a bromination reagent for reaction, adding water for crystallization, separating and drying after the reaction is completed to obtain 2,4,6-trimethoxybromobenzene; adding 2,4,6-trimethoxybromobenzene to an organic solvent, adding ammonia water, a base, a catalyst and a ligand, the reaction temperature is 90-120 DEG C, after the reaction is completed, extracting, salifying, filtering and drying to obtain 2-amino-1,3,5-trimethoxybenzene hydrochloride; and amidation reaction: adding 2-amino-1,3,5-trimethoxybenzene hydrochloride to an organic solvent, adding a base and oxalyl chloride, the reaction temperature is 0-30 DEG C, after the reaction is completed, filtering, concentrating, crystallizing, filtering and drying to obtain N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide. The invention avoids nitration reaction and hydrogenation reduction reaction, improves the safety of the reaction, avoids the generation of nitration waste acid, and is environmentally friendly; the reaction yield is increased to 66.1%.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis, and specifically relates to a method for synthesizing N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide. Background Art

[0002] N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide is a copper catalyst ligand and can be widely used in copper-catalyzed reactions such as chan-lam and Ullmannn.

[0003] N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide is generally prepared by reacting 2,4,6-trimethoxyaniline with oxalyl chloride. The synthesis of 2,4,6-trimethoxyaniline has the following routes:

[0004] Sankaraman, S.; Haney, WA; Kochi, JK et al. disclosed in Journal of the American Chemical Society, 1987, vol. 109, p. 5235 that 1,3,5-trichlorobenzene was used as a raw material for nitration reaction to obtain 2,4,6-trimethoxynitrobenzene with a yield of 18%; 2,4,6-trimethoxynitrobenzene was then reduced by hydrogenation to obtain 2,4,6-trimethoxyaniline.

[0005]

[0006] Kamer, Paul CJ; Nolte, Roeland JM; Drenth, Wiendelt et al. reported in Journal of the American Chemical Society, 1988, vol. 110, #20, p. 6818-6825 that 1,3,5-triphenol was used as a raw material for nitration reaction to obtain 2,4,6-trihydroxynitrobenzene with a yield of 62%, and 2,4,6-trihydroxynitrobenzene was reacted with dimethyl sulfate to obtain 2,4,6-trimethoxynitrobenzene with a yield of 68%; 2,4,6-trimethoxynitrobenzene was then reduced by hydrogenation to obtain 2,4,6-trimethoxyaniline.

[0007]

[0008] For the above two routes, both require nitration reaction, which is dangerous and produces a large amount of waste acid; secondly, it also needs to undergo hydrogenation reduction, which has high reaction cost and high risk; the other two routes have low yields and poor atomic economy; in summary, they are not suitable for industrial production. Summary of the invention

[0009] In view of the problems existing in the above-mentioned prior art, the purpose of the present invention is to provide a method for synthesizing N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide to solve the above-mentioned technical problems.

[0010] To achieve the above object, the present invention is implemented through the following technical solutions:

[0011] A method for synthesizing N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide, the synthetic route of which is as follows:

[0012]

[0013] The following steps are involved:

[0014] S1: Bromination reaction: Add 1,3,5-trimethoxybenzene to an organic solvent and a bromination reagent to carry out a bromination reaction at a temperature of 20-30°C. After the reaction is completed, add water to crystallize, separate and dry to obtain 2,4,6-trimethoxybromobenzene.

[0015] In step S1, the organic solvent is one of acetic acid, acetonitrile and acetone.

[0016] In step S1, the mass ratio of the organic solvent to 1,3,5-trimethoxybenzene is (5-10):1.

[0017] In step S1, the bromination reagent is one of bromine and NBS.

[0018] In step S1, the molar ratio of 1,3,5-trimethoxybenzene to the bromination reagent is 1:(0.9-1.1).

[0019] S2: Amination reaction: Add 2,4,6-trimethoxybromobenzene to an organic solvent, add ammonia water, alkali, catalyst, and ligand, and the reaction temperature is 90-120°C; after the reaction is completed, extract, form salt, filter, and dry to obtain 2-amino-1,3,5-trimethoxybenzene hydrochloride.

[0020] In step S2, the catalyst is one of copper oxide, cuprous iodide, and the like.

[0021] In step S2, the molar ratio of the catalyst to 2,4,6-trimethoxybromobenzene is (0.1-0.2):1.

[0022] In step S2, the organic solvent is one of DMSO, DMAc (N,N-dimethylacetamide), and DMF.

[0023] In step S2, the mass ratio of the organic solvent to 2,4,6-trimethoxybromobenzene is (5-10):1.

[0024] In step S2, the ligand is N,N'-dimethylethylenediamine, L-proline, or L-hydroxyproline.

[0025] In step S2, the molar ratio of the ligand to 2,4,6-trimethoxybromobenzene is (0.2-0.4):1.

[0026] In step S2, the base is one of potassium carbonate, sodium carbonate and potassium phosphate.

[0027] In step S2, the molar ratio of the base to 2,4,6-trimethoxybromobenzene is 3:(1.8-2.2).

[0028] S3: Amidation reaction: add 2-amino-1,3,5-trimethoxybenzene hydrochloride to an organic solvent, add alkali and oxalyl chloride, and the reaction temperature is 0-30°C; after the reaction is completed, filter, concentrate, crystallize, filter, and dry to obtain N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide.

[0029] In step S3, the organic solvent is one of THF, dichloromethane and ethyl acetate.

[0030] In step S3, the volume ratio of the organic solvent to 2-amino-1,3,5-trimethoxybenzene hydrochloride is (5-10):1.

[0031] In step S3, the base is one of triethylamine, pyridine, DBU, triethylenediamine, and diisopropylethylamine.

[0032] In step S3, the molar ratio of the base to 2-amino-1,3,5-trimethoxybenzene hydrochloride is (2.5-3.5):1.

[0033] In step S3, the molar ratio of oxalyl chloride to 2-amino-1,3,5-trimethoxybenzene hydrochloride is (0.4-0.8):1.

[0034] Beneficial effects of the present invention:

[0035] The present invention avoids nitration reaction and hydrogenation reduction reaction, improves the safety of the reaction, avoids the generation of nitration waste acid, and is environmentally friendly; the reaction yield is increased to 66.1%, the atomic utilization rate is increased, and the production cost is reduced; at the same time, the post-reaction treatment process is optimized, the operation is simple, and it is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is a liquid chromatogram of 2,4,6-trimethoxybromobenzene prepared in Example 1;

[0037] Figure 2 This is the H NMR spectrum of 2,4,6-trimethoxybromobenzene prepared in Example 1;

[0038] Figure 3 The liquid phase chromatogram of 2-amino-1,3,5-trimethoxybenzene hydrochloride prepared in Example 6;

[0039] Figure 4 This is the H-NMR spectrum of 2-amino-1,3,5-trimethoxybenzene hydrochloride prepared in Example 6;

[0040] Figure 5 The mass spectrum of 2-amino-1,3,5-trimethoxybenzene hydrochloride prepared in Example 6;

[0041] Figure 6 The mass spectrum of N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide prepared in Example 14;

[0042] Figure 7 This is the liquid phase diagram of N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide prepared in Example 14. DETAILED DESCRIPTION

[0043] The present invention will be further described below in conjunction with embodiments, but the present invention is not limited to these embodiments.

[0044] S1 Bromination Reaction Example

[0045] Example 1

[0046] 1,3,5-trimethoxybenzene (200 g, 1.2 mol) was added to acetonitrile (2 L), and NBS was added in batches at 20-30 ° C (114 g for the first time, 60 g for the second time, 40 g for the third time, a total of 1.2 mol, and an interval of 15 min between batches). The temperature was controlled at 20-30 ° C for reaction for 0.5 h, and water (6 L) was added for crystallization. The mixture was centrifuged and washed with water (400 mL), and dried at 50 ° C to obtain 2,4,6-trimethoxybromobenzene (280 g, 1.1 mol). The yield was 95.3% and the purity was 98%.

[0047] 1 H NMR (DMSO; 400MHz) δ6.33 (s, 2H), 3.82 (s, 6H), 3.80 (s, 3H).

[0048] Example 2-5 is an example of preparing 2,4,6-trimethoxybromobenzene under different process parameters from Example 1, and the yields are shown in Table 1.

[0049] Table 1

[0050] test Process parameters different from Example 1 Yield / % Example 2 Replace the organic solvent acetonitrile with an equal volume of acetic acid 90.1 Example 3 Replace the organic solvent acetonitrile with an equal volume of acetone 87.4 Example 4 Replace NBS with bromine, and keep the addition method and equivalent unchanged 92.1 Example 5 Add NBS equivalent to replace 1.05 93.3

[0051] S2 Amination Reaction Example

[0052] Example 6

[0053] 2,4,6-trimethoxybromobenzene (100 g, 0.4 mol) was added to DMSO (500 mL), and aqueous ammonia (40 g, 0.6 mol), cuprous iodide (15.2 g, 0.08 mol), L-proline (18.4 g, 0.16 mol), and potassium carbonate (82 g, 0.6 mol) were added, and the mixture was reacted in a sealed tank at 90±5°C for 16 h. After the reaction was completed, the mixture was filtered, and water (500 mL) was added, and the mixture was extracted with dichloromethane (1000 mL). The organic phase was washed with water (500 mL), and 4M hydrochloric acid ethyl acetate (150 mL) was added, and the mixture was filtered, and the solid was collected and dried at 50°C to obtain 2,4,6-trimethoxyaniline hydrochloride (67.6 g, 0.31 mol) with a yield of 76% and a purity of 99.3%. 1 H NMR (DMSO; 400MHz) δ9.42(s,3H),6.40(s,2H),3.87(s,6H),3.81(s,3H). LC / MS: 184.21(M+1).

[0054] Examples 7-13 are examples of preparing 2,4,6-trimethoxyaniline hydrochloride under different process parameters from Example 6, and their yields and purities are shown in Table 2.

[0055] Table 2

[0056]

[0057] S3 Amidation Reaction Example

[0058] Embodiment 14

[0059] 2,4,6-Trimethoxyaniline hydrochloride (100 g, 0.46 mol) was added to THF (1 L), and triethylamine (147 g, 1.46 mol) was added. Oxalyl chloride (29.2 g, 0.23 mol) was added dropwise at a temperature of 0-5°C. After the addition was completed, the mixture was reacted at 25±5°C for 2 hours, filtered, and the solid was washed with THF (0.1 L). The filtrate was collected, concentrated, slurried with isopropanol (200 mL), filtered, and dried at 50±5°C to obtain N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide (122 g, 0.20 mol), with a yield of 90% and a purity of 99.2%. LC / MS: 443.39 (M+23).

[0060] Examples 15-19 are examples of preparing N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide under different process parameters from Example 14, and their yields and purities are shown in Table 3.

[0061] Table 3

[0062]

[0063] The water used in the present invention is deionized water.

[0064] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. However, any equivalent changes, modifications and evolutions made by ordinary technicians in the field without departing from the scope of the technical solution of the present invention by using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the technical solution of the present invention.

Claims

1. A method for synthesizing N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide, characterized in that: The following steps are involved: S1: Bromination reaction: Add 1.2 mol 1,3,5-trimethoxybenzene to 2 L acetonitrile, add NBS in batches at 20-30°C, add NBS 114g for the first time, 60g for the second time, and 40g for the third time, with a batch interval of 15 min; control the temperature at 20-30°C to react for 0.5 h, add 6 L water to crystallize, centrifuge and wash with 400 mL water, and dry at 50°C with forced air to obtain 2,4,6-trimethoxybromobenzene; S2: Amination reaction: Add 2,4,6-trimethoxy bromobenzene to an organic solvent, add ammonia water, a base, a catalyst, and a ligand, and the reaction temperature is 90-120° C. After the reaction is completed, extract, form salt, filter, and dry to obtain 2-amino-1,3,5-trimethoxybenzene hydrochloride; In step S2, the organic solvent is DMSO, the catalyst is copper oxide, the ligand is L-proline, and the base is potassium carbonate; S3: Amidation reaction: Add 2-amino-1,3,5-trimethoxybenzene hydrochloride to dichloromethane, add alkali and oxalyl chloride, and the reaction temperature is 0-30°C. After the reaction is completed, filter, concentrate, crystallize, filter, and dry to obtain N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide.

2. The method for synthesizing N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide according to claim 1, characterized in that: In step S2, the molar ratio of the copper oxide to 2,4,6-trimethoxybromobenzene is (0.1-0.2):1; the mass ratio of the DMSO to 2,4,6-trimethoxybromobenzene is (5-10):1; the molar ratio of the L-proline to 2,4,6-trimethoxybromobenzene is (0.2-0.4):1; the molar ratio of the potassium carbonate to 2,4,6-trimethoxybromobenzene is 3:(1.8-2.2).

3. The method for synthesizing N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide according to claim 1, characterized in that: In step S3, the mass ratio of dichloromethane to 2-amino-1,3,5-trimethoxybenzene hydrochloride is (5-10):

1.

4. The method for synthesizing N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide according to claim 1, characterized in that: In step S3, the base is one of triethylamine, pyridine, DBU, triethylenediamine, and diisopropylethylamine; the molar ratio of the base to 2-amino-1,3,5-trimethoxybenzene hydrochloride is (2.5-3.5):

1.

5. The method for synthesizing N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide according to claim 1, characterized in that: In step S3, the molar ratio of oxalyl chloride to 2-amino-1,3,5-trimethoxybenzene hydrochloride is (0.4-0.8):1.

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