Preparation method of 2, 2-difluoro-N-methoxy-N-methylacetamide

Abstract

The invention belongs to the technical field of organic synthesis, and particularly provides a preparation method of 2, 2-difluoro-N-methoxy-N-methylacetamide. According to the preparation method provided by the embodiment of the invention, the preparation method comprises the following step: carrying out condensation reaction on 2, 2-difluoroacetyl chloride and N, O-dimethylhydroxylamine hydrochloride to generate 2, 2-difluoro-N-methoxy-N-methylacetamide. According to the preparation method disclosed by the embodiment of the invention, the 2, 2-difluoroacetyl chloride is taken as a starting raw material to react with the N, O-dimethylhydroxylamine hydrochloride to obtain the 2, 2-difluoro-N-methoxyl-N-methylacetamide, and compared with difluoroacetic anhydride, the 2, 2-difluoro-N-methoxyl-N-methylacetamide is higher in activity, high in yield and simple and convenient to operate.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and more specifically, relates to a method for preparing 2,2-difluoro-N-methoxy-N-methylacetamide. Background Art

[0002] 2,2-Difluoro-N-methoxy-N-methylacetamide is an important fluorinated organic building block with widespread applications in pharmaceuticals, pesticides, functional materials, and other fields. 2,2-Difluoro-N-methoxy-N-methylacetamide is composed of a geminal difluoromethyl group and a Weinreb amide. The geminal difluoromethyl group exhibits enhanced lipophilicity, improving the lipid solubility and bioavailability of drug molecules. It also serves as a bioisostere for groups such as hydroxymethyl and thiol. Furthermore, Weinreb amide can undergo controlled reactions with a variety of nucleophiles, especially organometallic reagents, to afford aldehydes and ketones with high selectivity, effectively preventing overaddition.

[0003] Currently, the synthesis method of 2,2-difluoro-N-methoxy-N-methylacetamide is reported to be synthesized from difluoroacetic anhydride as a raw material and N,O-dimethylhydroxylamine hydrochloride in the presence of pyridine and triethylamine (Lang, SB; Wiles, RJ; Kelly, CB and Molander, GA, Angew. Chem. Int. Ed., 2017, 56, 47), as shown in the following formula (1).

[0004]

[0005] However, this method has a low yield of only 45%. In addition, the difluoroacetic anhydride used is expensive, the amount of alkali used is large, the cost is high, and the post-processing is loaded down with trivial details and the operation is complicated. Summary of the Invention

[0006] In view of this, the object of the present invention is to provide a method for preparing 2,2-difluoro-N-methoxy-N-methylacetamide with high yield and simple post-treatment.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0008] The preparation method of 2,2-difluoro-N-methoxy-N-methylacetamide according to an embodiment of the present invention comprises:

[0009] 2,2-difluoroacetyl chloride is reacted with N,O-dimethylhydroxylamine hydrochloride to generate 2,2-difluoro-N-methoxy-N-methylacetamide.

[0010] In some embodiments of the present invention, the preparation method further comprises:

[0011] 2,2-difluoroacetic acid is reacted with a chlorinating agent in a solvent to obtain the 2,2-difluoroacetyl chloride.

[0012] Furthermore, the chlorination agent is one or more of oxalyl chloride, thionyl chloride, and phosphorus pentachloride.

[0013] Furthermore, the solvent is any one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and acetonitrile.

[0014] Furthermore, the molar ratio of the 2,2-difluoroacetic acid to the chlorination reagent is 1:(1-1.5); the reaction temperature is -5-25° C., and the reaction time is 1-5 hours.

[0015] Furthermore, after the chlorination reaction is completed, distillation is performed under normal pressure to obtain a mixed solution of the 2,2-difluoroacetyl chloride and the solvent.

[0016] In some embodiments of the present invention, the condensation reaction is carried out in the presence of a base, and the base is one or more of triethylamine, N,N,-diisopropylethylamine, and N-methylmorpholine.

[0017] Furthermore, the molar ratio of the 2,2-difluoroacetic acid, N,O-dimethylhydroxylamine hydrochloride, and the base is 1:(0.9-1.5):(1.8-2.5).

[0018] Furthermore, the reaction temperature of the condensation reaction is 5 to 50° C., and the reaction time is 1 to 10 hours.

[0019] Furthermore, after the condensation reaction is completed, the product is washed with water, dried, and distilled under reduced pressure to obtain the 2,2-difluoro-N-methoxy-N-methylacetamide.

[0020] The above technical solution of the present invention has at least one of the following beneficial effects:

[0021] According to the preparation method of an embodiment of the present invention, 2,2-difluoroacetyl chloride is used as a starting material to react with N,O-dimethylhydroxylamine hydrochloride to obtain 2,2-difluoro-N-methoxy-N-methylacetamide. Compared with difluoroacetic anhydride, 2,2-difluoro-N-methoxy-N-methylacetamide has higher activity, high yield, and simple operation. DETAILED DESCRIPTION

[0022] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field are within the scope of protection of the present invention.

[0023] The following first describes in detail the preparation method of 2,2-difluoro-N-methoxy-N-methylacetamide according to an embodiment of the present invention.

[0024] The preparation method of 2,2-difluoro-N-methoxy-N-methylacetamide according to an embodiment of the present invention comprises:

[0025] 2,2-difluoroacetyl chloride is reacted with N,O-dimethylhydroxylamine hydrochloride to generate 2,2-difluoro-N-methoxy-N-methylacetamide.

[0026] That is, according to the preparation method of the present invention, 2,2-difluoroacetyl chloride is used as a starting material to react with N,O-dimethylhydroxylamine hydrochloride to obtain 2,2-difluoro-N-methoxy-N-methylacetamide. Compared with difluoroacetic anhydride, 2,2-difluoroacetyl chloride has higher activity, milder reaction conditions, simpler operation, and higher yield.

[0027] Wherein, 2,2-difluoroacetyl chloride can be used as a commercial product or can be prepared by the following method:

[0028] 2,2-difluoroacetic acid is reacted with a chlorinating agent in a solvent to obtain the 2,2-difluoroacetyl chloride.

[0029] That is, 2,2-difluoroacetic acid is used as a raw material and chlorinated with a chlorinating agent to produce 2,2-difluoroacetyl chloride.

[0030] Specifically, the preparation method of the present application has a synthetic route as shown in the following formula (2):

[0031]

[0032] Below, taking 2,2-difluoroacetic acid as the starting material, first undergoing a chlorination reaction with a chlorination reagent, and then undergoing a condensation reaction with N,O-dimethylhydroxylamine hydrochloride to obtain 2,2-difluoro-N-methoxy-N-methylacetamide as an example, each step is explained in detail.

[0033] (1) Chlorination reaction

[0034] That is, step S1: chlorination reaction is carried out on 2,2-difluoroacetic acid and a chlorination reagent in a solvent to obtain the 2,2-difluoroacetyl chloride.

[0035] Among them, as the chlorination agent, one or more of oxalyl chloride, thionyl chloride, and phosphorus pentachloride can be selected. Preferably, the chlorination agent is phosphorus pentachloride, which has a high boiling point and will not be distilled out with the product during atmospheric distillation, which can effectively reduce the difficulty of product purification.

[0036] As the reaction solvent, any one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and acetonitrile can be selected, preferably dichloromethane, which has a low boiling point and high distillation efficiency, thereby reducing the loss of intermediates.

[0037] Furthermore, the molar ratio of 2,2-difluoroacetic acid to the chlorination agent is 1:(1-1.5), preferably, the molar ratio is 1:1.1. That is, relative to 2,2-difluoroacetic acid, using a chlorination agent slightly higher than the chemical equivalent is more conducive to the reaction, while avoiding the interference of 2,2-difluoroacetic acid on the reaction purification, and will not cause a large amount of excess and waste of raw materials. Moreover, the reaction conditions of the reaction are mild and controllable.

[0038] The reaction temperature of the chlorination reaction can be set to -5 to 25°C, preferably 0 to 10°C; the reaction time is 1 to 5 hours, preferably 2 hours. Too high a temperature or prolonged reaction time will increase the production of by-products.

[0039] Furthermore, after the chlorination reaction is completed, atmospheric distillation is performed to obtain a mixture of 2,2-difluoroacetyl chloride and a solvent, which can be directly used in a subsequent condensation reaction. In other words, after the chlorination reaction is completed, no complicated treatment is required, and the mixture can be directly used in a subsequent reaction by simple atmospheric distillation.

[0040] (2) Condensation reaction

[0041] That is, step S2: condensing 2,2-difluoroacetyl chloride and N,O-dimethylhydroxylamine hydrochloride to generate 2,2-difluoro-N-methoxy-N-methylacetamide.

[0042] In some embodiments of the present invention, the condensation reaction is carried out in the presence of a base, selected from the group consisting of triethylamine, N,N'-diisopropylethylamine, and N-methylmorpholine. The base acts to free N,O-dimethylhydroxylamine hydrochloride and serves as an acid-binding agent for the reaction. Preferably, the base is triethylamine, as the resulting salt solution is highly soluble and easily removed.

[0043] Furthermore, the molar ratio of the 2,2-difluoroacetic acid, N,O-dimethylhydroxylamine hydrochloride, and base is 1:(0.9-1.5):(1.8-2.5). Since 2,2-difluoroacetyl chloride evaporates with the solvent, it is difficult to directly use it to accurately calculate the feed ratio of the condensation reaction. The feed ratio in the condensation reaction is calculated based on the starting raw material 2,2-difluoroacetic acid. Preferably, the molar ratio of the 2,2-difluoroacetic acid, N,O-dimethylhydroxylamine hydrochloride, and base is 1:1.1:2.1. A slight excess of N,O-dimethylhydroxylamine hydrochloride and base can ensure the complete reaction of the acyl chloride. The amount of base used is much lower than that of the existing preparation method, greatly reducing the cost.

[0044] Furthermore, the reaction temperature of the condensation reaction is 5 to 50° C., preferably 25° C.; the reaction time is 1 to 10 hours, preferably 6 hours.

[0045] Furthermore, after the condensation reaction is completed, the product is washed with water, dried, and distilled under reduced pressure to obtain the 2,2-difluoro-N-methoxy-N-methylacetamide. In other words, the preparation method of the present invention is very simple in post-processing.

[0046] In summary, according to the preparation method of the embodiment of the present invention, 2,2-difluoroacetyl chloride is used as the starting raw material to react with N,O-dimethylhydroxylamine hydrochloride to obtain 2,2-difluoro-N-methoxy-N-methylacetamide. Compared with difluoroacetic anhydride, it has higher activity and is simple to operate. The experimental results show that its yield can reach more than 70%, which is much higher than 45% of the existing preparation method.

[0047] The preparation method of 2,2-difluoro-N-methoxy-N-methylacetamide of the present invention is further described in detail below through specific examples.

[0048] Example 1

[0049] (1) Preparation of 2,2-difluoroacetyl chloride

[0050] In a three-necked flask, 110 mL of dichloromethane and 107.34 g of phosphorus pentachloride were added in sequence, the temperature was lowered to 0°C and maintained below 10°C, 45.00 g of difluoroacetic acid was added dropwise, and the reaction was kept warm for 2 h after the addition was complete.

[0051] After the reaction was completed, distillation was carried out under normal pressure to collect the dichloromethane solution of 2,2-difluoroacetyl chloride.

[0052] (2) Preparation of 2,2-difluoro-N-methoxy-N-methylacetamide

[0053] In a three-necked flask, add 300 mL of dichloromethane and 45.71 g of N,O-dimethylhydroxylamine hydrochloride in sequence, cool to below 10°C, add a dichloromethane solution of 2,2-difluoroacetyl chloride dropwise, stir for 0.5 h, then add 99.58 g of triethylamine dropwise while controlling the temperature below 10°C. After the addition is complete, warm to room temperature (25°C) and react for 6 h.

[0054] After the reaction, the reaction solution was poured into a beaker containing 90 mL of water, stirred for a while, transferred to a separatory funnel for extraction, and then washed once with 90 mL of water. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated. The crude product was distilled under reduced pressure to obtain 51.62 g of 2,2-difluoro-N-methoxy-N-methylacetamide with a yield of 79.2%.

[0055] 1H NMR (400 MHz, CDCl3) δ 6.32 (t, J = 53.7 Hz, 1H), 3.78 (s, 3H), 3.26 (s, 3H), consistent with the structure of 2,2-difluoro-N-methoxy-N-methylacetamide.

[0056] Example 2

[0057] (1) Preparation of 2,2-difluoroacetyl chloride

[0058] In a three-necked flask, add 110 mL of dichloromethane and 65.43 g of oxalyl chloride in sequence, cool to 0°C, control the temperature below 10°C, add 45.00 g of difluoroacetic acid dropwise, and keep the temperature for 2 h after the addition is complete.

[0059] After the reaction was completed, distillation was carried out under normal pressure to collect the dichloromethane solution of 2,2-difluoroacetyl chloride.

[0060] (2) Preparation of 2,2-difluoro-N-methoxy-N-methylacetamide

[0061] In a three-necked flask, add 300 mL of dichloromethane and 45.71 g of N,O-dimethylhydroxylamine hydrochloride in sequence, cool to below 10°C, add a dichloromethane solution of 2,2-difluoroacetyl chloride dropwise, stir for 0.5 h, then add 127.18 g of N,N,-diisopropylethylamine dropwise while controlling the temperature below 10°C. After the addition is complete, warm to room temperature (25°C) and react for 6 h.

[0062] After the reaction, the reaction solution was poured into a beaker containing 90 mL of water, stirred for a while, transferred to a separatory funnel for extraction, and then washed once with 90 mL of water. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated. The crude product was distilled under reduced pressure to obtain 47.52 g of 2,2-difluoro-N-methoxy-N-methylacetamide with a yield of 72.9%.

[0063] 1 H NMR (400 MHz, CDCl3) δ 6.32 (t, J = 53.7 Hz, 1H), 3.78 (s, 3H), 3.26 (s, 3H), consistent with the structure of 2,2-difluoro-N-methoxy-N-methylacetamide.

[0064] Example 3

[0065] (1) Preparation of 2,2-difluoroacetyl chloride

[0066] In a three-necked flask, add 110 mL of tetrahydrofuran and 107.34 g of phosphorus pentachloride in sequence, cool to 0°C, control the temperature below 10°C, add 45.00 g of difluoroacetic acid dropwise, and keep the temperature for reaction for 2 h after the addition is complete.

[0067] After the reaction was completed, distillation was carried out under normal pressure to collect the dichloromethane solution of 2,2-difluoroacetyl chloride.

[0068] (2) Preparation of 2,2-difluoro-N-methoxy-N-methylacetamide

[0069] In a three-necked flask, add 300 mL of tetrahydrofuran and 45.71 g of N,O-dimethylhydroxylamine hydrochloride in sequence, cool to below 10°C, add a dichloromethane solution of 2,2-difluoroacetyl chloride dropwise, stir for 0.5 h, then add 99.58 g of triethylamine dropwise while controlling the temperature below 10°C. After the addition is complete, warm to room temperature (25°C) and react for 6 h.

[0070] After the reaction, the reaction solution was poured into a beaker containing 90 mL of water, stirred for a while, transferred to a separatory funnel for extraction, and then washed once with 90 mL of water. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated. The crude product was distilled under reduced pressure to obtain 49.02 g of 2,2-difluoro-N-methoxy-N-methylacetamide with a yield of 75.2%.

[0071] 1 H NMR (400 MHz, CDCl3) δ 6.32 (t, J = 53.7 Hz, 1H), 3.78 (s, 3H), 3.26 (s, 3H), consistent with the structure of 2,2-difluoro-N-methoxy-N-methylacetamide.

[0072] Example 4

[0073] (1) Preparation of 2,2-difluoroacetyl chloride

[0074] In a three-necked flask, add 110 mL of dichloromethane and 107.34 g of phosphorus pentachloride in sequence, cool to 0°C, control the temperature below 10°C, add 45.00 g of difluoroacetic acid dropwise, and after the addition is complete, heat to about 15°C and react for 2 hours.

[0075] After the reaction was completed, distillation was carried out under normal pressure to collect the dichloromethane solution of 2,2-difluoroacetyl chloride.

[0076] (2) Preparation of 2,2-difluoro-N-methoxy-N-methylacetamide

[0077] In a three-necked flask, add 300 mL of dichloromethane and 45.71 g of N,O-dimethylhydroxylamine hydrochloride in sequence, cool to below 10°C, add a dichloromethane solution of 2,2-difluoroacetyl chloride dropwise, stir for 0.5 h, then add 99.58 g of triethylamine dropwise while controlling the temperature below 10°C. After the addition is complete, warm to room temperature (25°C) and react for 6 h.

[0078] After the reaction, the reaction solution was poured into a beaker containing 90 mL of water, stirred for a while, transferred to a separatory funnel for extraction, and then washed once with 90 mL of water. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated. The crude product was distilled under reduced pressure to obtain 48.62 g of 2,2-difluoro-N-methoxy-N-methylacetamide with a yield of 74.6%.

[0079] 1 H NMR (400 MHz, CDCl3) δ 6.32 (t, J = 53.7 Hz, 1H), 3.78 (s, 3H), 3.26 (s, 3H), consistent with the structure of 2,2-difluoro-N-methoxy-N-methylacetamide.

[0080] In summary, according to the preparation method of 2,2-difluoro-N-methoxy-N-methylacetamide of the present invention, 2,2-difluoroacetyl chloride is used as a starting material to react with N,O-dimethylhydroxylamine hydrochloride to obtain 2,2-difluoro-N-methoxy-N-methylacetamide. Compared with difluoroacetic anhydride, 2,2-difluoro-N-methoxy-N-methylacetamide has higher activity, high yield, and simple operation.

[0081] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing 2,2-difluoro-N-methoxy-N-methylacetamide, characterized in that: include: 2,2-difluoroacetyl chloride is reacted with N,O-dimethylhydroxylamine hydrochloride to generate 2,2-difluoro-N-methoxy-N-methylacetamide.

2. The preparation method according to claim 1, characterized in that Also includes: 2,2-difluoroacetic acid is reacted with a chlorinating agent in a solvent to obtain the 2,2-difluoroacetyl chloride.

3. The preparation method according to claim 2, characterized in that The chlorination agent is one or more of oxalyl chloride, thionyl chloride and phosphorus pentachloride.

4. The preparation method according to claim 3, characterized in that The solvent is any one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and acetonitrile.

5. The preparation method according to claim 3, characterized in that The molar ratio of the 2,2-difluoroacetic acid to the chlorination reagent is 1:(1-1.5); the reaction temperature is -5-25° C., and the reaction time is 1-5 hours.

6. The preparation method according to claim 2, characterized in that After the chlorination reaction is completed, distillation is performed under normal pressure to obtain a mixed solution of the 2,2-difluoroacetyl chloride and the solvent.

7. The preparation method according to claim 1, characterized in that The condensation reaction is carried out in the presence of a base, which is one or more of triethylamine, N,N,-diisopropylethylamine, and N-methylmorpholine.

8. The preparation method according to claim 7, characterized in that The molar ratio of the 2,2-difluoroacetic acid, N,O-dimethylhydroxylamine hydrochloride and the base is 1:(0.9-1.5):(1.8-2.5).

9. The preparation method according to claim 7, characterized in that The reaction temperature of the condensation reaction is 5 to 50° C., and the reaction time is 1 to 10 hours.

10. The preparation method according to claim 7, characterized in that After the condensation reaction is completed, the product is washed with water, dried, and distilled under reduced pressure to obtain the 2,2-difluoro-N-methoxy-N-methylacetamide.

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