A kind of synthetic method of ethyl p-chlorophenoxyacetate

Abstract

The invention discloses a method for synthesizing ethyl p-chlorophenoxyacetate, comprising the following steps: synthesizing p-chlorophenoxyacetyl chloride; esterification reaction; separation and concentration; and crystallization. The invention uses p-chlorophenoxyacetic acid and oxalyl chloride as raw materials, first synthesizes p-chlorophenoxyacetyl chloride, and then reacts with anhydrous ethanol to generate ethyl p-chlorophenoxyacetate; the synthetic method has mild conditions, a simple process, high safety, and the obtained ethyl p-chlorophenoxyacetate has high purity, can effectively confirm its liquid chromatography peak, and lays a foundation for the impurity identification and purification of meclofenoxate hydrochloride, and has strong practicality.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, in particular to a method for synthesizing ethyl p-chlorophenoxyacetate. Background Art

[0002] Meclofenoxate hydrochloride is an organic substance that can promote the redox of brain cells, regulate the metabolism of nerve cells, increase the utilization of sugars, and have an excitatory effect on the suppressed central nervous system. Meclofenoxate hydrochloride is used clinically as a central nervous system stimulant that can regulate the metabolism of nerve cells and promote their excitability. It is used to treat traumatic coma, enuresis in children, impaired consciousness, senile mental illness, various dementias, alcohol poisoning, etc.

[0003] Meclofenoxate hydrochloride is a clinical drug, and the content control requirements for impurities are relatively strict. Ethyl 4-chlorophenoxyacetate is a specific impurity in meclofenoxate hydrochloride, and the industry standard for its content control is different from that of ordinary impurities.

[0004] Currently, the industry still has a blank in the synthesis of ethyl 4-chlorophenoxyacetate. There is a lack of impurity standards for finished product testing, and its chromatographic characteristics cannot be effectively determined. As a result, meclofenoxate hydrochloride cannot be distinguished from other impurities during impurity identification, and its content cannot be determined. Summary of the invention

[0005] The invention provides a method for synthesizing ethyl 4-chlorophenoxyacetate, thereby solving the problem in the prior art that ethyl 4-chlorophenoxyacetate impurities in meclofenoxate hydrochloride cannot be effectively identified and the content thereof cannot be confirmed by liquid chromatography.

[0006] In order to solve the above technical problems, the present invention provides a method for synthesizing ethyl 4-chlorophenoxyacetate, comprising the following steps:

[0007] (1) Synthesis of p-chlorophenoxyacetyl chloride: p-chlorophenoxyacetic acid and oxalyl chloride are used as raw materials and reacted in an organic solvent to generate p-chlorophenoxyacetyl chloride;

[0008] (2) Esterification reaction: the reaction solution obtained in step (1) is concentrated under reduced pressure to a viscous liquid, cooled, and then anhydrous ethanol is added dropwise and refluxed to carry out an esterification reaction;

[0009] (3) separation and concentration: the reaction solution obtained in step (2) is concentrated under reduced pressure to a viscous liquid, dissolved, layered, washed, dried, filtered to remove inorganic salts, and then concentrated under reduced pressure;

[0010] (4) Crystallization: After the product concentrated under reduced pressure in step (4) is dissolved in anhydrous ethanol, the temperature is reduced for crystallization, and the crystals are filtered out, washed, and dried to obtain the ethyl p-chlorophenoxyacetate.

[0011] In a preferred embodiment of the present invention, in step (1), the mass ratio of p-chlorophenoxyacetic acid to oxalyl chloride is 2:1 to 1:1.

[0012] In a preferred embodiment of the present invention, in step (1), the process conditions of the reaction are: first react at 5-10°C for 30-60 minutes, and then reflux at 40-45°C for 1.5-3 hours.

[0013] In a preferred embodiment of the present invention, in step (2), the mass ratio of p-chlorophenoxyacetic acid to anhydrous ethanol is 3:1 to 5:1.

[0014] In a preferred embodiment of the present invention, in step (2), the conditions of the esterification reaction are: 75-80° C., reflux reaction for 4-6 hours.

[0015] In a preferred embodiment of the present invention, in step (3), the reagent for extracting the organic layer is a saturated solution of sodium bicarbonate.

[0016] In a preferred embodiment of the present invention, the process conditions for extracting the organic layer are: 20-30° C., stirring for 10-15 minutes.

[0017] In a preferred embodiment of the present invention, in step (4), the method of cooling and crystallizing is: first cooling to 30-35°C, keeping warm for crystallization for 2-3 hours, and then cooling to 10-15°C, keeping warm for crystallization for 1-1.5 hours.

[0018] In a preferred embodiment of the present invention, in step (4), the drying conditions are 30-35° C. and vacuum drying for 4-6 hours.

[0019] The invention has the beneficial effects of: a method for synthesizing ethyl p-chlorophenoxyacetate, using p-chlorophenoxyacetic acid and oxalyl chloride as raw materials, first synthesizing p-chlorophenoxyacetyl chloride, and then reacting with anhydrous ethanol to generate ethyl p-chlorophenoxyacetate; the method has mild synthesis conditions, a simple synthesis process, high safety, high purity of the obtained ethyl p-chlorophenoxyacetate, and can effectively confirm its liquid chromatography peak, thereby laying a foundation for the impurity identification and purification of meclofenoxate hydrochloride, and having strong practicality. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is a liquid chromatogram of ethyl p-chlorophenoxyacetate prepared in a preferred embodiment 1 of a method for synthesizing ethyl p-chlorophenoxyacetate of the present invention;

[0021] Figure 2 This is a liquid chromatogram of meclofenoxate hydrochloride. DETAILED DESCRIPTION

[0022] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0023] The invention discloses a method for synthesizing ethyl p-chlorophenoxyacetate, and the reaction process is as follows:

[0024]

[0025] The specific steps include:

[0026] (1) Synthesis of p-chlorophenoxyacetyl chloride: p-chlorophenoxyacetic acid and oxalyl chloride are used as raw materials, and reacted in an organic solvent such as dichloromethane at a mass ratio of 2:1 to 1:1 at 5 to 10°C for 30 to 60 minutes, and then refluxed at 40 to 45°C for 1.5 to 3 hours to generate p-chlorophenoxyacetyl chloride; the waste gas generated by the reaction is absorbed by a sodium hydroxide solution with a mass concentration of 10 to 20% and then discharged;

[0027] (2) Esterification reaction: the reaction solution obtained in step (1) is concentrated under reduced pressure at 43-45° C. to a viscous liquid, cooled to 20-30° C., anhydrous ethanol is added dropwise in a mass ratio of 3:1 to 5:1 of p-chlorophenoxyacetic acid to anhydrous ethanol, the temperature is raised to 75-80° C. within 30-45 minutes, and refluxed for 4-6 hours to complete the esterification reaction;

[0028] (3) separation and concentration: the reaction solution obtained in step (2) is concentrated under reduced pressure to a viscous liquid, a saturated solution of sodium bicarbonate is added at 20 to 30° C., stirred for 10 to 15 minutes, the organic phase is extracted, washed, dried to remove water, filtered to remove inorganic salts, and then concentrated under reduced pressure;

[0029] (4) Crystallization: Add anhydrous ethanol to the product after reduced pressure concentration in step (4), heat to 60-65°C to dissolve, first cool to 30-35°C, keep warm for crystallization for 2-3 hours, then cool to 10-15°C, keep warm for crystallization for 1-1.5 hours, filter to obtain crystals, wash the obtained crystals with anhydrous ethanol below 10°C, filter by suction, and finally vacuum dry at 30-35°C for 4-6 hours to obtain the ethyl p-chlorophenoxyacetate.

[0030] Example 1

[0031] Add 20g of p-chlorophenoxyacetic acid and 100g of dichloromethane into a 250ml three-necked flask, stir to dissolve, cool to 8°C, and keep warm. Weigh 12g of oxalyl chloride, dilute with 30g of dichloromethane, and dropwise add into the above three-necked flask containing p-chlorophenoxyacetic acid within 40 minutes, keep warm for 30 minutes, then heat to 45°C and reflux for 2 hours, and the generated waste gas is absorbed by liquid sodium hydroxide with a mass concentration of 15% and then discharged.

[0032] The reaction solution was concentrated under reduced pressure at 45°C to a viscous liquid, cooled to 25°C, 50 g of anhydrous ethanol was slowly added dropwise thereto with stirring, and then the temperature was raised to 80°C within 40 minutes and the reflux reaction was maintained for 5 hours.

[0033] The reaction solution was concentrated under reduced pressure at 45°C to a viscous liquid, 100 g of dichloromethane was added to dissolve, 30 g of a saturated aqueous solution of sodium bicarbonate was added at 25°C, the dichloromethane layer was stirred and washed for 10 minutes, the dichloromethane layer was separated, and the dichloromethane layer was washed twice with 2×30 g of purified water, each time with stirring and washing for about 10 minutes. The dichloromethane layer obtained after the last water washing was dried with 10 g of anhydrous sodium sulfate for 5 hours. The inorganic salt was filtered off, and the dichloromethane solution was concentrated under reduced pressure at 45°C until there was no distillate.

[0034] Add 30g of anhydrous ethanol to the above concentrated solution, heat to 65°C to dissolve, slowly stir and cool to 35°C for crystallization for 3 hours, then cool to 10°C for crystallization for 1 hour, filter the crystal mixture, wash the obtained crystals twice with 5°C anhydrous ethanol, and filter to dryness. The filtered crystals are cold-dried for 1 hour under vacuum, then heated to 35°C and vacuum-dried for 5 hours to obtain 15g of ethyl p-chlorophenoxyacetate, with a yield of 65%.

[0035] The finished product of ethyl p-chlorophenoxyacetate obtained in Example 1 was subjected to liquid phase detection.

[0036] Specifically, the chromatographic conditions are: octadecylsilane bonded silica gel as filler (4.6mm×250mm, 5μm or chromatographic column of equivalent performance); 0.05mol / L sodium octane sulfonate (pH adjusted to 2.5 with phosphoric acid)-acetonitrile (65:35) as mobile phase, detection wavelength of 225nm, flow rate of 1ml / min.

[0037] Take about 5 mg of meclofenoxate hydrochloride and place it in a 50 ml volumetric flask. Take 5 mg of ethyl p-chlorophenoxyacetate and place it in a 50 ml volumetric flask. Add appropriate amount of solvent [water (pH adjusted to 2.5 with phosphoric acid)-acetonitrile (40:60)], shake to dissolve, and dilute to scale. Inject samples separately and record chromatograms.

[0038] The liquid chromatogram of ethyl p-chlorophenoxyacetate is shown in the attached figure. Figure 1 As shown, the main peak is ethyl 4-chlorophenoxyacetate, and the purity according to the area normalization method is about 96%, which can meet the needs of being used as an impurity control.

[0039] The peak area data are shown in Table 1 below.

[0040] Table 1

[0041]

[0042] The liquid chromatogram of meclofenoxate hydrochloride is shown in the attached figure. Figure 2 As shown, the main peak is meclofenoxate hydrochloride, and the impurity peak at about 43 minutes should be ethyl p-chlorophenoxyacetate. The peak area data is shown in Table 2 below.

[0043] Table 2

[0044]

[0045] The above-mentioned synthesis method of ethyl p-chlorophenoxyacetate uses p-chlorophenoxyacetic acid and oxalyl chloride as raw materials, first synthesizes p-chlorophenoxyacetyl chloride, and then reacts with anhydrous ethanol to generate ethyl p-chlorophenoxyacetate. The synthesized product ethyl p-chlorophenoxyacetate has a good yield and high purity, and its liquid chromatography peak can be effectively confirmed, laying a foundation for the impurity identification and purification of meclofenoxate hydrochloride.

[0046] In addition, the synthesis conditions of the synthesis method are mild, the synthesis process is simple, the safety is high, and it is suitable for industrial production.

[0047] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for synthesizing ethyl p-chlorophenoxyacetate, characterized in that: The steps include: (1) Synthesis of p-chlorophenoxyacetyl chloride: p-chlorophenoxyacetic acid and oxalyl chloride are used as raw materials and reacted in an organic solvent to generate p-chlorophenoxyacetyl chloride; (2) Esterification reaction: the reaction solution obtained in step (1) is concentrated under reduced pressure to a viscous liquid, cooled, and then anhydrous ethanol is added dropwise and refluxed to carry out an esterification reaction; (3) separation: the reaction solution obtained in step (2) is concentrated under reduced pressure to a viscous liquid, an organic solvent is added to dissolve it, the organic layer is extracted, washed, dried to remove water, filtered to remove inorganic salts, and finally concentrated under reduced pressure; (4) Crystallization: After the product concentrated under reduced pressure in step (4) is dissolved in anhydrous ethanol, the temperature is reduced for crystallization, and the crystals are filtered out, washed, and vacuum dried to obtain the ethyl p-chlorophenoxyacetate.

2. The method for synthesizing ethyl p-chlorophenoxyacetate according to claim 1, wherein: In step (1), the mass ratio of p-chlorophenoxyacetic acid to oxalyl chloride is 2:1 to 1:

1.

3. The method for synthesizing ethyl p-chlorophenoxyacetate according to claim 1, wherein: In step (1), the process conditions of the reaction are: first react at 5-10° C. for 30-60 min, and then reflux at 40-45° C. for 1.5-3 h.

4. The method for synthesizing ethyl p-chlorophenoxyacetate according to claim 1, wherein: In step (2), the mass ratio of p-chlorophenoxyacetic acid to anhydrous ethanol is 3:1 to 5:

1.

5. The method for synthesizing ethyl p-chlorophenoxyacetate according to claim 1, wherein: In step (2), the conditions of the esterification reaction are: 75-80° C., reflux reaction for 4-6 hours.

6. The method for synthesizing ethyl p-chlorophenoxyacetate according to claim 1, wherein: In step (3), the reagent for extracting the organic layer is a saturated solution of sodium bicarbonate.

7. The method for synthesizing ethyl p-chlorophenoxyacetate according to claim 6, wherein: The process conditions for extracting the organic layer are: 20-30° C., stirring for 10-15 minutes.

8. The method for synthesizing ethyl p-chlorophenoxyacetate according to claim 1, wherein: In step (3), the drying method is to add anhydrous sodium sulfate and dry for 4 to 6 hours.

9. The method for synthesizing ethyl p-chlorophenoxyacetate according to claim 1, characterized in that: In step (4), the method of cooling and crystallizing is: first cooling to 30-35°C, keeping warm for crystallization for 2-3 hours, and then cooling to 10-15°C, keeping warm for crystallization for 1-1.5 hours.

10. The method for synthesizing ethyl p-chlorophenoxyacetate according to claim 1, characterized in that: In step (4), the vacuum drying condition is 30-35° C., and the vacuum drying is 4-6 hours.

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