Preparation method of senbacoxostat intermediate

Abstract

The invention relates to a preparation method of a senbacolide intermediate, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: dissolving o-chloroacetophenone in a solvent, adding copper bromide, heating to reflux, carrying out a reaction, filtering after the reaction is finished, adding a sulfite aqueous solution or a hydrosulfite aqueous solution, carrying out a stirring reaction, washing with water after the reaction is finished, and concentrating to obtain the senbacolide intermediate which is 2-bromo-2 '-chloroacetophenone. According to the method, copper bromide is used as a bromination reagent, so that the selectivity is good, and the yield and purity of the product are relatively high. According to the preparation method, bromine can be generated in situ for reaction by using copper bromide, so that direct use of bromine which is high in toxicity, strong in irritation and high in environmental pollution is avoided, and the process is safer and more suitable for the field of pharmacy. White precipitate cuprous bromide is generated in the reaction, so that the reaction process is convenient to observe, the cuprous bromide is easily removed by filtration, and the product is simple and convenient to purify.

Description

Technical Field

[0001] The invention relates to a method for preparing a sambacol intermediate, and belongs to the technical field of drug synthesis. Background Art

[0002] Cenobamate, also known as phenbarate or cinobamate, has a chemical name of (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate, and its chemical structure is shown in Formula I:

[0003]

[0005] There are few reports on the synthesis route of Cenobamate, mainly patents published by the original research company. Publication (Announcement) No. US20060258718A1 reports the synthesis route of racemic-Cenobamate as follows:

[0006]

[0007] 2-Bromo-2'-chloroacetophenone reacts with tetrazole, then the carbonyl group is reduced by sodium borohydride, and finally reacts with N,N'-carbonyldiimidazole (CDI) and ammonia to obtain the racemic form of Senbacolt. Subsequently, the company reported that the target configuration was selectively obtained by carbonyl reductase.

[0008] After research, it was found that 2-bromo-2'-chloroacetophenone is an important intermediate for the synthesis of Sambacot. The reaction principle is as follows:

[0009]

[0010] At present, most of 2-bromo-2'-chloroacetophenone is obtained by bromination of o-chloroacetophenone. If 2-bromo-2'-chloroacetophenone is obtained by α-bromination reaction of o-chloroacetophenone and bromine, the toxicity and irritation of liquid bromine are relatively large, and there are many by-products, and the reaction is difficult to control, which is not suitable for the pharmaceutical industry. The preparation method announced by Publication (Announcement) No. CN114901647B and Publication (Announcement) No. CN102803233B is to use N-bromosuccinimide (NBS) as a bromination reagent, but the product after the reaction of NBS is an imine structure, and tetrazole will be used in the synthesis route of Sambacot, in which the residual nitrite will have the risk of reacting with imine to generate nitrosamine impurities, and nitrosamine impurities are genotoxic impurities that the industry focuses on, and the risk is greater than the benefit.

[0011] Therefore, it is very necessary to provide a synthetic method for preparing sambacot intermediate 2-bromo-2'-chloroacetophenone with safe process and low risk of genotoxic impurities. Summary of the invention

[0012] In view of the shortcomings of the prior art, the present invention provides a method for preparing a sambacot intermediate, and the specific technical scheme is as follows:

[0013] A method for preparing a sambacot intermediate comprises the following steps:

[0014] The o-chloroacetophenone is dissolved in a solvent, copper bromide is added, and the temperature is raised to reflux for reaction. After the reaction is completed, the mixture is filtered, and then a sulfite aqueous solution or a bisulfite aqueous solution is added and stirred for reaction. After the reaction is completed, the mixture is washed with water and concentrated to obtain the sambacot intermediate, which is 2-bromo-2'-chloroacetophenone.

[0015] In a further improvement, the solvent is one or two of methanol, ethanol, ethyl acetate, dichloromethane, n-butyl acetate, acetonitrile, and tetrahydrofuran.

[0016] In a further improvement, the amount of copper bromide used is 2.0 to 4.0 times the equivalent of o-chloroacetophenone.

[0017] As a further improvement, the temperature when adding the sodium sulfite aqueous solution or the sodium bisulfite aqueous solution and stirring the reaction is room temperature.

[0018] As a further improvement, the mass fraction of the sulfite aqueous solution or the bisulfite aqueous solution is 5% to 26%.

[0019] In a further improvement, the molar ratio of the o-chloroacetophenone to copper bromide is 1:2.2, and the mass volume ratio of the o-chloroacetophenone to the solvent is 1:(7-9).

[0020] As a further improvement, the mass fraction of the sulfite aqueous solution is 10%, the volume ratio of the solvent to the sulfite aqueous solution is 1:1, and the mass volume ratio of o-chloroacetophenone to the solvent is 1:8.

[0021] As a further improvement, the mass fraction of the aqueous bisulfite solution is 10%, the volume ratio of the solvent to the aqueous bisulfite solution is 1:1, and the mass volume ratio of o-chloroacetophenone to the solvent is 1:9.

[0022] The reaction principle of the present invention is as follows:

[0023]

[0024] In a large number of experiments in the present invention, it is found that after the above reaction is completed, by adding a sulfite aqueous solution or a bisulfite aqueous solution to carry out a two-phase reaction, the two-phase reaction temperature can be reduced to room temperature, and the purity of the product can be further improved.

[0025] The inventors found in their research that the reaction solvent is crucial to the synthesis and quality control of the product. Using an appropriate solvent can achieve a purity of more than 90%. Using an inappropriate solvent not only slows the reaction rate, but also contains many impurities and low product purity. The amount of copper bromide used depends on the reaction mechanism and can be reacted when it is greater than 2 times the equivalent.

[0026] Beneficial effects of the present invention:

[0027] 1. The present invention uses copper bromide as a brominating reagent, has good selectivity, and has a high yield and purity of the product.

[0028] 2. The present invention uses copper bromide to generate bromine in situ for reaction, avoiding the direct use of bromine which is highly toxic, irritating and environmentally polluting, making the process safer and more suitable for the pharmaceutical field.

[0029] 3. The reaction generates white precipitate cuprous bromide, which is convenient for observing the reaction progress and can be easily removed by filtration, making the product purification simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is a curve graph between the mass fraction of sodium sulfite solution added in the reaction and the purity of the product. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0032] Example 1

[0033] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone, 44.0 mL of ethyl acetate, and 44.0 mL of dichloromethane to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, raise the temperature to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove the solid, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. Among them, the purity of 2-bromo-2'-chloroacetophenone is 78.19% (referring to the mass fraction of 2-bromo-2'-chloroacetophenone in the light yellow liquid is 78.19%; the same below).

[0034] Example 2

[0035] To a 100 mL reaction bottle, 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of dichloromethane were added, stirring was started, and 31.5 g (0.14 mol, 2.2 eq) of copper bromide was added. The temperature was raised to reflux, and the mixture was stirred and reacted at this temperature for 8 hours. No reaction was observed by TLC monitoring.

[0036] Example 3

[0037] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, raise the temperature to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lowers the system temperature to room temperature, filters, removes solids, washes the organic phase with water twice, and distills the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 82.61%.

[0038] Example 4

[0039] To a 100 mL reaction bottle, 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate were added, stirring was started, and 31.5 g (0.14 mol, 2.2 eq) of copper bromide was added. The temperature was raised to 60°C, and the mixture was stirred and reacted at this temperature for 8 hours. No reaction was observed by TLC monitoring.

[0040] Example 5

[0041] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of methanol to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, raise the temperature to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 63.35%.

[0042] Example 6

[0043] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethanol to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, raise the temperature to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 53.46%.

[0044] Example 7

[0045] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of n-butyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 80.87%.

[0046] Example 8

[0047] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of acetonitrile to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, raise the temperature to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 73.76%.

[0048] Example 9

[0049] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of tetrahydrofuran to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, raise the temperature to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 75.43%.

[0050] Example 10

[0051] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone, 44.0 mL of ethyl acetate, and 44.0 mL of methanol to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, raise the temperature to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lowers the system temperature to room temperature, filters, removes solids, washes the organic phase with water twice, and distills the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. Among them, the purity of 2-bromo-2'-chloroacetophenone is 69.72%.

[0052] Embodiment 11

[0053] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone, 44.0 mL of ethyl acetate, and 44.0 mL of ethanol to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lowers the system temperature to room temperature, filters, removes solids, washes the organic phase with water twice, and distills the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 70.25%.

[0054] Example 12

[0055] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitoring shows that o-chloroacetophenone disappears, the system temperature is lowered to room temperature, filtered, solids are removed, 80.0 mL of saturated sodium sulfite solution is added, stirred for 2 hours, separated, the organic phase is washed twice with water, and the organic phase is distilled under reduced pressure until no fraction flows out to obtain a light yellow liquid. Among them, the purity of 2-bromo-2'-chloroacetophenone is 78.31%.

[0056] Example 13

[0057] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, add 80.0 mL of 15% sodium sulfite solution, stir for 2 hours, separate the liquids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. Among them, the purity of 2-bromo-2'-chloroacetophenone is 92.11%.

[0058] Embodiment 14

[0059] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, add 80.0 mL of 10% sodium sulfite solution, stir for 2 hours, separate the liquids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 98.99%.

[0060] Embodiment 15

[0061] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, add 80.0 mL of 5% sodium sulfite solution, stir for 2 hours, separate the liquids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 90.99%.

[0062] Example 16

[0063] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, heat to reflux, and stir and react at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, add 80.0 mL of 2% sodium sulfite solution, stir for 2 hours, separate the liquids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. Among them, the purity of 2-bromo-2'-chloroacetophenone is 83.18%.

[0064] Embodiment 17

[0065] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, raise the temperature to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove the solid, add 80.0 mL of 10% sodium bisulfite solution, stir for 2 hours, separate the liquids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. Among them, the purity of 2-bromo-2'-chloroacetophenone is 85.28%.

[0066] Embodiment 18

[0067] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitoring shows that o-chloroacetophenone disappears, the system temperature is lowered to room temperature, filtered, solids are removed, 80.0 mL of 10% sodium thiosulfate solution is added, stirred for 2 hours, separated, the organic phase is washed twice with water, and the organic phase is distilled under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 80.38%.

[0068] Embodiment 19

[0069] Add 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate to a 100 mL reaction bottle, start stirring, then add 31.5 g (0.14 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, add 80.0 mL of 10% sodium pyrosulfite solution, stir for 2 hours, separate the liquids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. Among them, the purity of 2-bromo-2'-chloroacetophenone is 81.18%.

[0070] Embodiment 20

[0071] Add 100.0 g (0.65 mol, 1.0 eq) of o-chloroacetophenone and 900.0 mL of ethyl acetate to a 2000 mL reaction bottle, start stirring, then add 315.0 g (1.4 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitors the disappearance of o-chloroacetophenone, lower the system temperature to room temperature, filter, remove solids, add 900.0 mL of 10% sodium bisulfite solution, stir for 2 hours, separate the liquids, wash the organic phase with water twice, and distill the organic phase under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 98.88%.

[0072] Embodiment 21

[0073] Add 100.0 g (0.65 mol, 1.0 eq) of o-chloroacetophenone and 750.0 mL of ethyl acetate to a 2000 mL reaction bottle, start stirring, then add 315.0 g (1.4 mol, 2.2 eq) of copper bromide, heat to reflux, and react by stirring at this temperature. TLC monitoring shows that o-chloroacetophenone disappears, the system temperature is lowered to room temperature, filtered, solids are removed, 750.0 mL of a 10% sodium bisulfite solution is added, stirred for 2 hours, separated, the organic phase is washed twice with water, and the organic phase is distilled under reduced pressure until no fraction flows out to obtain a light yellow liquid. The purity of 2-bromo-2'-chloroacetophenone is 97.22%.

[0074] Embodiment 22

[0075] To a 200 mL reaction bottle, 10.0 g (0.065 mol, 1.0 eq) of o-chloroacetophenone and 80.0 mL of ethyl acetate were added, stirring was started, and 40.0 g (0.14 mol, 2.2 eq) of dibromohydantoin was added. The temperature was raised to reflux, and the mixture was stirred and reacted at this temperature for 8 hours. No reaction was observed by TLC monitoring.

[0076] In the above embodiments, the reflux temperature during reflux refers to 0-2° C. higher than the boiling point of the solvent.

[0077] According to the above examples, the effects of different solvents on product purity are shown in Table 1:

[0078] Table 1

[0079] Solvents purity(%) Ethyl acetate: dichloromethane (1:1, v / v) 78.19 Dichloromethane / Ethyl acetate 82.61 Methanol 63.35 Ethanol 53.46 n-Butyl acetate 80.87 Acetonitrile 73.76 Tetrahydrofuran 75.43 Ethyl acetate:methanol (1:1, v / v) 69.72 Ethyl acetate:ethanol (1:1, v / v) 70.25

[0080] According to the above embodiment, the relationship between the mass fraction of the sodium sulfite solution added in the reaction and the purity of the product is shown in FIG. Figure 1 ; It can be seen from this that, preferably, the mass fraction of the sodium sulfite solution added in the reaction is preferably 10%.

[0081] Moreover, as the same sulfur oxygen acid salt, compared with sodium sulfite, adding sodium thiosulfate solution or sodium metabisulfite solution to the reaction does not help to improve the purity of the product, but may cause a slight decrease in the purity of the product.

[0082] When investigating the effect of solvent dosage on product purity, it was found that when sodium sulfite solution was added, the mass volume ratio of o-chloroacetophenone to solvent was 1:8; when sodium bisulfite solution was added, the mass volume ratio of o-chloroacetophenone to solvent was 1:9. The mass volume ratio refers to the ratio between the mass of the solute and the volume of the solvent.

[0083] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a sambacot intermediate, characterized in that: The following steps are involved: The o-chloroacetophenone is dissolved in a solvent, copper bromide is added, and the temperature is raised to reflux for reaction. After the reaction is completed, the mixture is filtered, and then a sulfite aqueous solution or a bisulfite aqueous solution is added and stirred for reaction. After the reaction is completed, the mixture is washed with water and concentrated to obtain the sambacot intermediate, which is 2-bromo-2'-chloroacetophenone.

2. The method for preparing a sambacot intermediate according to claim 1, characterized in that: The solvent is one or two of methanol, ethanol, ethyl acetate, dichloromethane, n-butyl acetate, acetonitrile and tetrahydrofuran.

3. The method for preparing a sambacot intermediate according to claim 1, characterized in that: The amount of copper bromide used is 2.0 to 4.0 times the equivalent of o-chloroacetophenone.

4. The method for preparing a sambacot intermediate according to claim 1, characterized in that: The temperature when adding the sodium sulfite aqueous solution or the sodium bisulfite aqueous solution and stirring the reaction is room temperature.

5. The method for preparing a sambacot intermediate according to claim 1, characterized in that: The mass fraction of the sulfite aqueous solution or the bisulfite aqueous solution is 5% to 26%.

6. The method for preparing a sambacot intermediate according to claim 1, characterized in that: The molar ratio of the o-chloroacetophenone to copper bromide is 1:2.2, and the mass volume ratio of the o-chloroacetophenone to the solvent is 1:(7-9).

7. The method for preparing a Sambacot intermediate according to claim 1, characterized in that: The mass fraction of the sulfite aqueous solution is 10%, the volume ratio of the solvent to the sulfite aqueous solution is 1:1, and the mass volume ratio of o-chloroacetophenone to the solvent is 1:

8.

8. The method for preparing a sambacot intermediate according to claim 1, characterized in that: The mass fraction of the bisulfite aqueous solution is 10%, the volume ratio of the solvent to the bisulfite aqueous solution is 1:1, and the mass volume ratio of o-chloroacetophenone to the solvent is 1:9.

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