Synthesis process of 6-fluoro-2-methyl-1-indanone

Abstract

The invention provides a synthesis process of 6-fluoro-2-methyl-1-indanone, which comprises the following steps of: synthesizing 6-fluoro-2-methyl-1-indanone; the method mainly comprises the following steps: by taking p-fluorobenzaldehyde as a raw material, catalyzing by using a mixture of sodium propionate and pyridine in a condensation reaction of p-fluorobenzaldehyde and propionic anhydride, then recovering the auxiliary material pyridine through atmospheric distillation, recovering the auxiliary material sodium propionate through an acidification reaction system, and recrystallizing to obtain a compound A; the invention develops a process which is lower in reaction temperature, shorter in reaction time, higher in yield and less in wastewater, so that industrial and green production of 6-fluoro-2-methyl-1-indanone is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical pharmacy, and specifically relates to a synthesis process of 6-fluoro-2-methyl-1-indanone. Background Art

[0002] 6-Fluoro-2-methyl-1-indanone, molecular formula is C 10 H 9 FO is an important intermediate for the synthesis of sulindac. The main methods for synthesizing 6-fluoro-2-methyl-1-indanone reported publicly are:

[0003] (1) p-Fluorobenzaldehyde is used as a raw material, and malonic acid ester is subjected to condensation and decarboxylation reaction to obtain substituted acrylic acid, which is then subjected to hydrogenation, chlorination, and Friedel-Crafts reaction to synthesize 6-fluoro-2-methyl-1-indanone. The main patent disclosed is CN108329197 A. However, the malonic acid ester substitution product has poor selectivity in the reaction, resulting in a low condensation reaction yield; and the excess amount of acid and alkali used in the hydrolysis reaction is large, generating a large amount of wastewater, which is not conducive to environmental protection.

[0004] (2) Using p-fluorobenzaldehyde as the raw material, condensing and decarboxylating with propionic anhydride to obtain substituted acrylic acid, and then synthesizing 6-fluoro-2-methyl-1-indanone through hydrogenation, chlorination, and Friedel-Crafts reaction. The main patents disclosed are CN106916064A, US6538029, WO2003017999, WO201706520, etc. The reaction and post-treatment processes of these patents are basically the same. The reaction catalyst is a single sodium propionate, the reaction temperature is 140°C, and the reaction time is more than 20 hours. The reaction temperature is high, the time is long, and it is easy to overheat, and the production safety is poor; and the post-treatment uses a large amount of alkali and acid for refined extraction, which produces a large amount of wastewater and pollutes the environment; at the same time, the reaction yield is low, basically between 60% and 70%, and the economic benefit is not good.

[0005] (3) Using substituted benzyl halide as raw material, reacting with substituted malonic ester to generate substituted phenylpropionic acid compound, and then chlorinating and catalyzing with aluminum chloride to obtain 6-fluoro-2-methyl-1-indanone. The main patents disclosed are CN101337874A and CN1699335. However, these preparation processes are complicated, with many reaction steps and low overall yield. At the same time, a large amount of phosphorus-containing catalyst is used, which generates a large amount of wastewater, which is not conducive to environmental protection.

[0006] Therefore, in view of the disadvantages of high reaction temperature, long time, low yield, and much wastewater in the process reported in CN106916064A, etc., which uses p-fluorobenzaldehyde as a raw material, and performs a condensation reaction with propionic anhydride, and then performs hydrogenation, chlorination, and Friedel-Crafts reaction to synthesize 6-fluoro-2-methyl-1-indanone, the present invention uses p-fluorobenzaldehyde as a raw material, and uses a mixture of sodium propionate and pyridine for catalysis in the condensation reaction with propionic anhydride, and then recovers the auxiliary material pyridine by atmospheric distillation, recovers the auxiliary material sodium propionate by acidifying the reaction system, and then recrystallizes to obtain compound A. The present invention develops a process with lower reaction temperature, shorter reaction time, higher yield, and less wastewater, so as to produce 6-fluoro-2-methyl-1-indanone in an industrialized and green way.

[0007] In order to achieve the above object, the present invention provides a synthesis process of 6-fluoro-2-methyl-1-indanone suitable for industrial large-scale production, which mainly comprises the following steps:

[0008] The synthetic process route is as follows:

[0009]

[0010] Step S10: using p-fluorobenzaldehyde SM1 as a starting material and reacting it with propionic anhydride, sodium propionate and pyridine to synthesize compound A.

[0011] The first condensation reaction is carried out by mixing p-fluorobenzaldehyde SM1 with propionic anhydride, sodium propionate and pyridine to obtain a mixed reaction liquid A; the mixed reaction liquid A contains compound A, propionic anhydride and sodium propionate; the temperature of the first condensation reaction is 80-120° C., and the time is 3-5 hours.

[0012] Acid is added to the mixed reaction liquid A for a second acidification reaction to obtain a mixed reaction liquid B, wherein the acid is sulfuric acid or hydrochloric acid; the mixed reaction liquid B contains compound A and propionic acid; the temperature of the second acidification reaction is 90-120° C., and the time is 1-5 hours.

[0013] Step S20: Compound A is subjected to hydrogenation reaction to obtain compound B.

[0014] In the process of obtaining compound B through hydrogenation reaction of compound A, palladium carbon is used as a reaction catalyst, the reaction temperature is 25-85°C, the time is 5-24h, and the pressure is 0.1-1.0MPa. In the reaction process, the reaction solvent includes any one or more of methanol, ethanol, and water.

[0015] Step S30: Compound B is subjected to Friedel-Crafts reaction to obtain 6-fluoro-2-methyl-1-indanone.

[0016] Compound B and thionyl chloride are subjected to a first acylation reaction to obtain 4-fluoro-2-methylphenylpropionyl chloride reaction solution A; the temperature of the first acylation reaction is 10-65° C. and the time is 1-8 hours.

[0017] The reaction solution of 4-fluoro-2-methylphenylpropionyl chloride is added dropwise to anhydrous aluminum chloride and a solvent to carry out a second Friedel-Crafts reaction to obtain a reaction solution B; the temperature of the second Friedel-Crafts reaction is -20 to 25°C and the time is 2 to 10 hours.

[0018] The reaction solution D is added dropwise to ice water to perform a third quenching reaction to obtain a reaction solution C containing 6-fluoro-2-methyl-1-indanone; the temperature of the third quenching reaction is -10 to 40°C, and the time is 2 to 5 hours.

[0019] The first acylation reaction and / or the second Friedel-Crafts reaction is carried out under an organic solvent condition, and the organic solvent is selected from any one or more of dichloromethane, chloroform, and DMF.

[0020] The embodiments of the present invention have at least the following beneficial effects:

[0021] The 6-fluoro-2-methyl-1-indanone synthesis process provided by the present invention has lower reaction temperature, shorter reaction time, higher product yield, less waste water, higher raw material recovery rate, simpler process steps, and is more in line with the requirements of large-scale industrial green production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and, together with the description, serve to explain the principles of the present application.

[0023] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0024] Figure 1 This is a schematic diagram of the HPLC product of Compound A in Example 1 provided in the present application.

[0025] Figure 2 This is a schematic diagram of the HPLC product of Compound B in Example 1 provided in this application.

[0026] Figure 3 This is a schematic diagram of the HPLC of the finished 6-fluoro-2-methyl-1-indanone of Example 1 provided in the present application. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0028] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other. The present invention will be described in detail below with reference to specific embodiments.

[0029] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0030] Example 1

[0031] A synthesis process of 6-fluoro-2-methyl-1-indanone comprises the following steps:

[0032] Step S10:

[0033] Reaction: Add 124g (1.0mol) p-fluorobenzaldehyde, 195.2g propionic anhydride (1.5mol), 67.2g sodium propionate (0.7mol), 23.7g pyridine (0.3mol) into a 500ml dry, clean three-necked flask, heat to 80-120°C, react for 3-5h, and monitor the reaction completion with liquid phase;

[0034] Auxiliary material 1 Pyridine recovery: 20.62 g of pyridine was distilled out of the reaction solution under normal pressure, with a pyridine recovery rate of 87%, and then the temperature was lowered to room temperature;

[0035] Auxiliary material 2 sodium propionate recovery: add 267.7 g of 30% hydrochloric acid to the reaction solution, raise the temperature to 90-120°C and stir for 1 hour, and distill under reduced pressure to obtain the solid in the kettle and the fraction propionic acid aqueous solution. The fraction propionic acid aqueous solution is adjusted to pH 8 with sodium hydroxide, and filtered at room temperature to obtain wet sodium propionate. The wet sodium propionate is dried to obtain 192.2 g of solid sodium propionate, with a molar yield of 91% (based on the amount of propionic anhydride and sodium propionate fed), and a purity of 99.8%.

[0036] Extracting compound A: adding 600 g of ethanol to the solid in the kettle, heating to 50-60°C to dissolve most of the solid, hot filtering to obtain a mother liquor containing A and a salt-containing filter cake; cooling the mother liquor to -5-0°C to crystallize to obtain 155 g of finished compound A, with a molar yield of 86.1% and a purity of 98.47%.

[0037] Step S20: Add 180.2 g (1.0 mol) of the finished compound A, 9.0 g of Pd / C (palladium on carbon), 360.4 g of ethanol, and 900 g of water into a 2L hydrogenation kettle; replace with hydrogen 4 times, then set the hydrogen pressure in the kettle to 1.0 MPa, the temperature to 25°C, continue to pass hydrogen, and keep the reaction warm for about 20 hours. After the reaction is completed, monitor the liquid phase, cool and filter to recover the palladium on carbon, and concentrate the mother liquor under reduced pressure to obtain 179.7 g of a colorless transparent oil, which is compound B, with a molar yield of 98.63% and a purity of 96.39%.

[0038] Step S30: nitrogen replaced a 2000ml dry, clean three-necked flask three times, added compound B182.2g (1mol) and dichloromethane 911g under nitrogen protection, added thionyl chloride 238g (2.0mol) dropwise at a temperature of 15-25°C, reacted for 0.5h, and the reaction was completed after liquid phase monitoring. The reaction solution was concentrated under reduced pressure to obtain a crude product of 4-fluoro-2-methylphenylpropionyl chloride. Nitrogen was replaced in a 2000ml dry and clean three-necked flask for 3 times. Under nitrogen protection, 160g (1.2mol) of anhydrous aluminum chloride and 911g of dichloromethane were added, the temperature was lowered to -20~-15℃, 4-fluoro-2-methylphenylpropionyl chloride was slowly added dropwise, and after the addition was completed, the reaction was carried out at a temperature of -20~-15℃ for 6-10h. After the reaction was completed under liquid phase monitoring, the reaction solution was slowly added to ice water for quenching, and the temperature was controlled at -15~-10℃. After the addition was completed, the reaction was stirred for 0.5h, and the liquid was separated by standing. The organic phase was concentrated under reduced pressure to obtain 160.7g of brown oil, which was compound 6-fluoro-2-methyl-1-indanone, with a molar yield of 98.1% and a purity of 98.87%.

[0039] The embodiments described above are part of the embodiments of the present invention, rather than all of the embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A synthesis process for 6-fluoro-2-methyl-1-indanone, characterized in that: Compound B was subjected to Friedel-Crafts reaction to obtain 6-fluoro-2-methyl-1-indanone 2. The synthesis process according to claim 1, characterized in that: The compound B and thionyl chloride are subjected to a first acylation reaction to obtain a 4-fluoro-2-methylphenylpropionyl chloride reaction solution A; The 4-fluoro-2-methylphenylpropionyl chloride reaction solution was added dropwise to anhydrous aluminum chloride and a solvent to perform a second Friedel-Crafts reaction to obtain a reaction solution B; The reaction solution D was added dropwise into ice water to perform a third quenching reaction, thereby obtaining a reaction solution C containing 6-fluoro-2-methyl-1-indanone.

3. The synthesis process according to claim 2, characterized in that: The temperature of the first acylation reaction is 10-65°C and the time is 1-8h; the temperature of the second Friedel-Crafts reaction is -20-25°C and the time is 2-10h; the temperature of the third quenching reaction is -10-40°C and the time is 2-5h.

4. The synthesis process according to claim 2 or 3, characterized in that: The first acylation reaction and / or the second Friedel-Crafts reaction is carried out under an organic solvent condition, and the organic solvent is selected from any one or more of dichloromethane, chloroform, and DMF.

5. The synthesis process according to any one of claims 1 to 3, characterized in that: Compound A is hydrogenated to obtain compound B 6. The synthesis process according to claim 5, characterized in that: Compound A is subjected to hydrogenation reaction to obtain compound In process B, palladium carbon is used as a reaction catalyst, the reaction temperature is 25-85°C, the reaction time is 5-24h, and the pressure is 0.1-1.0MPa.

7. The synthesis process according to claim 5, characterized in that: Compound A is subjected to hydrogenation reaction to obtain compound In the reaction process of B, the reaction solvent includes any one or more of methanol, ethanol and water.

8. The synthesis process according to claim 5, characterized in that: Compound A was synthesized from p-fluorobenzaldehyde SM1 as the starting material with propionic anhydride, sodium propionate and pyridine.

9. The synthesis process according to claim 8, characterized in that: The p-fluorobenzaldehyde SM1 is mixed with propionic anhydride, sodium propionate and pyridine for a first condensation reaction to obtain a mixed reaction liquid A; the mixed reaction liquid A contains compound A, propionic anhydride and sodium propionate; the temperature of the first condensation reaction is 80-120° C., and the time is 3-5 hours; Acid is added to the mixed reaction liquid A for a second acidification reaction to obtain a mixed reaction liquid B, wherein the acid is sulfuric acid or hydrochloric acid; the mixed reaction liquid B contains compound A and propionic acid; the temperature of the second acidification reaction is 90-120° C., and the time is 1-5 hours.

10. A process for synthesizing 6-fluoro-2-methyl-1-indanone, characterized in that: The synthesis process is as follows: Step S10: using p-fluorobenzaldehyde SM1 as a starting material and synthesizing compound A with propionic anhydride, sodium propionate and pyridine; The p-fluorobenzaldehyde SM1 is mixed with propionic anhydride, sodium propionate and pyridine for a first condensation reaction to obtain a mixed reaction liquid A; the mixed reaction liquid A contains compound A, propionic anhydride and sodium propionate; the temperature of the first condensation reaction is 80-120° C., and the time is 3-5 hours; Adding an acid to the mixed reaction liquid A to perform a second acidification reaction to obtain a mixed reaction liquid B, wherein the acid is sulfuric acid or hydrochloric acid; the mixed reaction liquid B contains compound A and propionic acid; the temperature of the second acidification reaction is 90 to 120° C., and the time is 1 to 5 hours; Step S20: Compound A is subjected to hydrogenation reaction to obtain compound B; In the process of obtaining compound B by hydrogenation of compound A, palladium carbon is used as a reaction catalyst, the reaction temperature is 25 to 85° C., the reaction time is 5 to 24 hours, and the pressure is 0.1 to 1.0 MPa. In the reaction process, the reaction solvent includes any one or more of methanol, ethanol, and water; Step S30: Compound B is subjected to Friedel-Crafts reaction to obtain 6-fluoro-2-methyl-1-indanone; Compound B and thionyl chloride are subjected to a first acylation reaction to obtain 4-fluoro-2-methylphenylpropionyl chloride reaction solution A; the temperature of the first acylation reaction is 10 to 65° C., and the time is 1 to 8 hours; The 4-fluoro-2-methylphenylpropionyl chloride reaction solution is added dropwise to anhydrous aluminum chloride and a solvent to perform a second Friedel-Crafts reaction to obtain a reaction solution B; the temperature of the second Friedel-Crafts reaction is -20 to 25°C and the time is 2 to 10 hours; The reaction solution D is added dropwise to ice water to perform a third quenching reaction to obtain a reaction solution C containing 6-fluoro-2-methyl-1-indanone; the temperature of the third quenching reaction is -10 to 40°C and the time is 2 to 5 hours; The first acylation reaction and / or the second Friedel-Crafts reaction is carried out under an organic solvent condition, and the organic solvent is selected from any one or more of dichloromethane, chloroform, and DMF.

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