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CN-121990889-A - Preparation method of gamma, delta-unsaturated ketone by adopting continuous flow process

CN121990889ACN 121990889 ACN121990889 ACN 121990889ACN-121990889-A

Abstract

The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of gamma, delta-unsaturated ketone by adopting a continuous flow process. The invention improves the existing karl rearrangement reaction, provides a preparation method of gamma, delta-unsaturated ketone by adopting a continuous flow process, and successfully applies the preparation method to the synthesis of farnesyl acetone and teprenone. The preparation method can be safely and rapidly carried out continuously at high temperature and high pressure, greatly improves the reaction efficiency, reduces unnecessary heat energy loss, is green, environment-friendly and economical, and is more suitable for industrial production.

Inventors

  • CAI ANHUA
  • ZHANG JICHENG
  • TAO ANPING
  • HUANG LUNING
  • GU HONG

Assignees

  • 上海科胜药物研发有限公司
  • 浙江华海药业股份有限公司

Dates

Publication Date
20260508
Application Date
20251107
Priority Date
20241107

Claims (10)

  1. 1. A process for the preparation of a gamma, delta-unsaturated ketone comprising the steps of: In an organic solvent, the compounds shown in the formula I and the formula II react under the action of an organic aluminum catalyst to obtain a compound III, the reaction is carried out in a continuous flow reaction system, Wherein R 1 and R 2 are each independently of the other optionally substituted-C 1-20 alkyl or-C 2-20 alkyl, the substituted substituents being-C 1-6 alkyl, -C 2-10 alkyl, -C 1-10 alkynyl, -C 3-6 cycloalkyl, -C 3-6 heterocycloalkyl, -C 6-10 aryl, -C 5-10 heteroaryl, and R 3 is-C 1-5 alkyl.
  2. 2. The process according to claim 1, wherein the reaction temperature is at least 200 ℃, preferably at least 220 ℃, more preferably at least 240 ℃, and/or The reaction pressure is not less than 1.50MPa, preferably not less than 2.00MPa, more preferably not less than 2.10MPa, and/or One of R 1 or R 2 is-C 1-10 alkyl, one is-C 5-20 alkene having one or more double bonds, preferably one of R 1 or R 2 is-C 1-5 alkyl, one is-C 10-20 alkene having two or three double bonds, more preferably one of R 1 or R 2 is methyl, and the other is methyl And/or R 3 is methyl, ethyl, n-propyl or isopropyl, preferably methyl, and/or The organic aluminum catalyst is aluminum isopropoxide, aluminum sec-butoxide, aluminum acetylacetonate or aluminum ethylacetoacetate, preferably aluminum isopropoxide, and/or The continuous flow reaction system comprises a sample injector, a reaction device, a pressure controller and a receiver which are connected in series through pipelines, and the reaction system also comprises a heater for heating the reaction device.
  3. 3. The method of claim 1 or 2, wherein the reaction apparatus comprises one or more reactors; preferably, the reactor is a tubular reactor, preferably a stainless steel coil; more preferably, the stainless steel coil is an SS316 stainless steel coil, and/or More preferably, the stainless steel coil has an outside diameter of one-eighth inch to one-quarter inch, still more preferably one-eighth inch, and/or More preferably, the stainless steel coil has an internal volume of 50 to 150mL, still more preferably 60 to 140mL, still more preferably 60 to 135mL, and/or The sample injector connected in series through the pipeline comprises a pump, preferably a plunger pump, a diaphragm pump or a syringe pump, preferably a plunger pump, more preferably a tetrafluoro plunger pump, and/or The pressure controller is a back pressure valve, and/or The heater is an oil bath pot, a gas phase column temperature box or a heating inner tube, and is preferably an oil bath pot.
  4. 4. A process according to claim 1 to 3, wherein the molar ratio of the organoaluminum catalyst to the compound of formula I is from 0.03 to 0.20, preferably from 0.04 to 0.15, more preferably from 0.04 to 0.13, and/or The molar ratio of the compounds of the formulae II and I is from 1.0 to 3.0, preferably from 1.2 to 2.5, more preferably from 1.3 to 2.3, and/or The organic solvent is hydrocarbon solvent, preferably n-heptane, n-nonane, cyclohexane, toluene or xylene, more preferably n-heptane or xylene, still more preferably n-heptane, and/or The volume-mass ratio of the organic solvent to the compound shown in the formula I is 1-5mL/g, preferably 2-4mL/g.
  5. 5. The method according to any one of claims 1 to 4, comprising the steps of: (1) The method comprises the steps of preparing a solution of an organic aluminum catalyst, a compound shown in a formula II and a compound shown in a formula I in an organic solvent as materials; (2) Setting the reaction temperature and the reaction pressure of a continuous flow reaction system, pumping materials into the continuous flow reaction system for reaction at a certain pump flow rate, and collecting effluent; (3) Suspending the pump, pumping the organic solvent at a certain pump flow rate, and collecting effluent; (4) All the effluent liquid obtained is extracted, dried and concentrated to obtain the compound shown in the formula III.
  6. 6. The process according to claim 5, wherein the pump flow rates in step (2) or step (3) are each independently 1-20mL/min, preferably 1.0-10mL/min, more preferably 3.0-7.0mL/min, and/or The reaction of step (2) has a reaction flux of 1.0 to 2.0g/min, preferably 1.2 to 1.8g/min, and/or The organic solvents in step (1) or step (3) are each independently a hydrocarbon solvent, preferably n-heptane, n-nonane, cyclohexane, toluene or xylene, more preferably n-heptane or xylene, still more preferably n-heptane.
  7. 7. The method of any one of claims 1-6, further comprising the steps of: (a1) At a certain pump flow rate, cleaning the pump and the pipeline by dilute hydrochloric acid and water in sequence; (a2) Cleaning the pump and the pipeline with an organic solvent at a certain pump flow rate; (a3) The flow rate of the pump is slowly reduced, the organic solvent is continuously pumped into the pump and the pipeline, the pump and the pipeline are cleaned, the reaction temperature is slowly heated, and the reaction pressure is set.
  8. 8. The method according to claim 7, wherein the pump flow rate in step (a 1) is 20-80mL/min, preferably 25-60mL/min, more preferably 30-50mL/min, and/or The dilute hydrochloric acid concentration in step (a 1) is in the range of 0.2 to 0.8M, preferably 0.3 to 0.7M, more preferably 0.4 to 0.6M, and/or The amount of dilute hydrochloric acid or water described in step (a 1) is each independently from 100 to 500mL, preferably from 200 to 400mL, and/or The pump flow rate in step (a 2) is 10-40mL/min, preferably 15-35mL/min, more preferably 20-30mL/min, and/or The organic solvent in step (a 2) is methanol, ethanol or acetone, preferably methanol or ethanol, more preferably ethanol, and/or The amount of the organic solvent in step (a 2) is 100-500mL, preferably 200-400mL, more preferably 250-350mL, and/or Step (a 3) wherein the pump flow rate is slowly reduced from the pump flow rate of step (a 2) by reducing the pump flow rate at intervals of from 1 to 5 minutes, more preferably from 2 to 4 minutes, and/or preferably wherein the reduced pump flow rate is from 1 to 5mL/min, more preferably from 1 to 3mL/min, and/or The organic solvent in step (a 3) is a hydrocarbon solvent, preferably n-heptane, n-nonane, cyclohexane, toluene or xylene, more preferably n-heptane or xylene, still more preferably n-heptane, and/or The amount of organic solvent in step (a 3) is >300mL, preferably >500mL, more preferably >600mL, and/or The time for the washing in the step (a 3) is 30 to 120min, preferably 40 to 100min, more preferably 50 to 80min.
  9. 9. A process for the preparation of teprenone intermediate compound 3, characterized by comprising the following step (a): (a) Preparation of compound 3 according to the preparation method of any one of claims 1-11 starting from compound 1 and compound 2 Preferably, the step (a) comprises the step of reacting the compound 1 and the compound 2 in n-heptane under the action of aluminum isopropoxide to obtain the compound 3, wherein the reaction is performed in a continuous flow reaction system, the reaction temperature is more than or equal to 200 ℃, the reaction pressure is more than or equal to 1.50MPa, more preferably the reaction temperature is more than or equal to 220 ℃, the reaction pressure is more than or equal to 2.00MPa, still more preferably the reaction temperature is more than or equal to 240 ℃, and the reaction pressure is more than or equal to 2.10MPa.
  10. 10. A process for the preparation of teprenone, characterized by comprising the following or step (b): (b) Preparation of compound 6 according to the preparation method of any one of claims 1-11 starting from compound 5 and compound 2 Preferably, step (b) comprises reacting compound 5 and compound 2 in n-heptane under the action of aluminum isopropoxide to give compound 6, the reaction being carried out in a continuous flow reaction system at a reaction temperature of 200 ℃ or more, at a reaction pressure of 1.50MPa or more, preferably at 220 ℃ or more, at 2.00MPa or more, more preferably at 240 ℃ or more, at 2.10MPa or more, and/or Preferably, the compound 5 is obtained by grignard reaction of the compound 4 More preferably, the compound 4 is obtained by crystallization of compound 3 Still more preferably, said compound 3 is obtained according to the preparation process of claim 12.

Description

Preparation method of gamma, delta-unsaturated ketone by adopting continuous flow process Technical Field The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of gamma, delta-unsaturated ketone by adopting a continuous flow process. Background The Carroll rearrangement is also called Carroll-Claisen rearrangement, and is found in 1940 at the earliest, and refers to the reaction of allyl tertiary alcohol compounds with a certain structure and acetoacetic acid esters under the action of a catalyst to obtain gamma, delta-unsaturated ketone, as shown below. Common catalysts are mainly organic aluminum salt systems, base catalytic systems and palladium noble metal systems. The karle rearrangement is widely used in industry. The allyl tertiary alcohol compound and methyl acetoacetate are subjected to Caroll rearrangement under the catalysis of aluminum isopropoxide, are the most commonly used preparation methods of important intermediates, namely farnesyl acetone 3, an anti-peptic gastric ulcer drug, namely teprenone 6 and the like in industry, and have the following structures: Slowly heating to 140-170 ℃ in CN103058839B, and then reacting for 10-14 hours to obtain the teprenone. In CN108047011B, (6E, 10E) -geranyl linalool and aluminum isopropoxide are stirred and heated to 170 ℃, methyl acetoacetate is added dropwise, the temperature is further raised to 200 ℃, and the temperature is kept for 2 hours to react to generate teprenone, which needs to be carried out in a distillation device. The high temperature of the reaction can generate lower alcohol, carbon dioxide and other gases, and the risk of bumping or flushing can be caused in the kettle type reaction process. Therefore, there is a need to develop a safe, efficient, green, and suitable amplified karle rearrangement reaction process to meet the industrial needs for the preparation of gamma, delta-unsaturated ketones. Disclosure of Invention The first aspect of the present invention provides a process for the preparation of a gamma, delta-unsaturated ketone comprising the steps of: In an organic solvent, the compounds shown in the formula I and the formula II react under the action of an organic aluminum catalyst to obtain a compound III, the reaction is carried out in a continuous flow reaction system, Wherein R 1 and R 2 are each independently of the other optionally substituted-C 1-20 alkyl or-C 2-20 alkyl, the substituted substituents being-C 1-6 alkyl, -C 2-10 alkyl, -C 1-10 alkynyl, -C 3-6 cycloalkyl, -C 3-6 heterocycloalkyl, -C 6-10 aryl, -C 5-10 heteroaryl, and R 3 is-C 1-5 alkyl. In some embodiments, the reaction temperature is greater than or equal to 200 ℃, preferably greater than or equal to 220 ℃, more preferably greater than or equal to 240 ℃, for example 245 ℃. In some embodiments, the reaction pressure is 1.50MPa or more, preferably 2.00MPa or more, more preferably 2.10MPa or more, for example 2.10, 2.20, 2.25, 2.30, 2.40, 2.50MPa or any value or range therebetween. In some embodiments, one of R 1 or R 2 is-C 1-10 alkyl and the other is-C 5-20 alkene having one or more double bonds thereon, preferably one of R 1 or R 2 is-C 1-5 alkyl and the other is-C 10-20 alkene having two or three double bonds thereon, more preferably one of R 1 or R 2 is methyl and the other is methyl In some embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl, preferably methyl. In some embodiments, the organoaluminum catalyst is aluminum isopropoxide, aluminum sec-butoxide, aluminum acetylacetonate, or aluminum ethylacetoacetate, preferably aluminum isopropoxide. In some embodiments, the continuous flow reaction system comprises a sample injector, a reaction device, a pressure controller, a receiver connected in series by a conduit, the reaction system further comprising a heater for heating the reaction device. In some embodiments, the reaction device comprises one or more reactors. In some embodiments, the reactor is a tubular reactor. In some embodiments, the reactor is a stainless steel coil; Preferably, the stainless steel coil is an SS316 stainless steel coil, and/or Preferably, the stainless steel coil has an outside diameter of one-eighth inch to one-quarter inch, more preferably one-eighth inch, and/or Preferably, the stainless steel coil has an internal volume of 50-150mL, preferably 60-140mL, more preferably 60-135mL, such as 64.2mL or 131.2mL. In some embodiments, the sample injector connected in series by a conduit comprises a pump. In some embodiments, the pump is a plunger pump, a diaphragm pump, or a syringe pump, preferably a plunger pump, more preferably a tetrafluoro plunger pump. In some embodiments, the pressure controller is a back pressure valve. In some embodiments, the heater is an oil bath, a gas column incubator, or a heated inner tube, preferably an oil bath. In some embodiments, the molar ratio of the organoaluminum catalyst to the compound of formula I is from 0.03 to 0.20, pref