CN-121990890-A - Teprenone preparation method adopting continuous flow process

CN121990890ACN 121990890 ACN121990890 ACN 121990890ACN-121990890-A

Abstract

The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of teprenone by adopting a continuous flow process, which improves the existing teprenone synthesis process. The first continuous flow reaction system can safely and continuously carry out Carroll reaction at high temperature and high pressure, the system does not need to adopt a solvent with high boiling point, the reaction efficiency is greatly improved, the risk of bumping or flushing materials in the traditional kettle type reaction process is solved, the second continuous flow reaction system can seal the metal Grignard reagent in a pipeline and is not exposed outside, the reaction temperature is improved, the reaction residence time is shortened, and the safety of the Grignard reaction is ensured. The continuous synthesis method can realize safe, stable and continuous amplification reaction, and is more suitable for industrial production of teprenone.

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. The synthesis method of the teprenone is characterized by comprising the following steps of: A first step of pumping the compound 1, the compound 2, the organic aluminum catalyst and the hydrocarbon solvent into a first continuous reaction system for reaction, collecting a reaction liquid, and carrying out extraction and purification treatment to obtain a compound 4 Pumping a precooled vinyl Grignard reagent and an ether solvent into a second continuous reaction system, pumping a precooled compound 4 and an ether solvent for reaction at the same time after a period of time, collecting a reaction liquid, and performing quenching and extraction treatment to obtain a compound 5 Pumping the compound 5, the compound 2, the organic aluminum catalyst and the hydrocarbon solvent into a first continuous reaction system for reaction, collecting reaction liquid, and carrying out extraction and purification treatment to obtain a compound 6 The first continuous reaction system or the second continuous reaction system respectively and independently comprises a sample injector, a reaction device and a receiver which are connected in series through pipelines.
2. The process according to claim 1, wherein the hydrocarbon solvent is n-heptane, n-hexane, cyclohexane, toluene or xylene, more preferably n-heptane or xylene, still more preferably n-heptane, and/or The organoaluminum catalyst comprises aluminum isopropoxide, aluminum sec-butoxide, aluminum acetylacetonate or aluminum ethylacetoacetate, preferably aluminum isopropoxide, and/or The ether solvent is diethyl ether or tetrahydrofuran, preferably tetrahydrofuran, and/or The vinyl Grignard reagent is vinyl magnesium bromide or vinyl magnesium chloride, preferably vinyl magnesium chloride, and/or The sample injector comprises a pump, and/or The reaction device comprises one or more reactors, preferably the reactors are tubular reactors, more preferably the tubular reactors have an outer diameter of one-eighth inch to one-fourth inch, still more preferably one-eighth inch, and/or The molar ratio of the organoaluminum catalyst to compound 1 in the first step or the organoaluminum catalyst to compound 5 in the third step is each independently 0.03 to 0.20:1, preferably 0.04 to 0.15:1, more preferably 0.04 to 0.13:1, and/or The molar ratio of compound 2 to compound 1 in the first step or the molar ratio of compound 2 to compound 5 in the third step is each independently 1.0 to 3.0:1, preferably 1.2:1 to 2.5:1, more preferably 1.3:1 to 2.3:1, and/or The volume/mass ratio of the hydrocarbon solvent to the compound 1 in the first step or the hydrocarbon solvent to the compound 3 in the third step is 1 to 5mL/g, preferably 2 to 4mL/g.
3. The synthesis method according to claim 1 or 2, wherein the first continuous reaction system comprises a sample injector, a reaction device, a receiver, a pressure controller and a heater connected in series by a pipe; the sample injector of the first continuous reaction system is 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 of the first continuous reaction system is a back pressure valve, and/or The heater of the first continuous reaction system is an oil bath pot, a gas phase column temperature box or a heating inner tube, preferably an oil bath pot, and/or The reaction device of the first continuous reaction system comprises a reactor, and/or the reaction device of the first continuous reaction system is a stainless steel coil; Preferably, the reaction device is an SS316 stainless steel coil, and/or Preferably, the internal volume of the tube of the reaction device is 50-150mL, preferably 60-140mL, more preferably 60-135mL.
4. A synthesis process according to claim 1 to 3, wherein the reaction temperature of the first continuous reaction system is at least 200 ℃, preferably at least 220 ℃, more preferably at least 240 ℃, and/or The reaction pressure of the first continuous reaction system is not less than 1.00MPa, preferably not less than 1.50MPa, more preferably not less than 2.00MPa, and/or The pump flow rate of the first continuous reaction system is 1-20mL/min, preferably 1.0-10mL/min, more preferably 3.0-7.0mL/min, and/or The reaction flux of the reaction in the first step or the third step is 1.0-2.0g/min, preferably 1.2-1.8g/min, and/or The first step or the third step further comprises pumping a hydrocarbon solvent to flush out all the reaction liquid, and/or The concentration of the vinyl grignard reagent in the precooled vinyl grignard reagent and the ether solvent is 1.2-2.0M, preferably 1.4-1.8M, more preferably 1.5-1.7M, and/or The molar ratio of vinyl Grignard reagent to compound 4 is 1.0 to 2.5, preferably 1.0 to 2.0, and/or The volume-mass ratio of ether solvent to compound 4 in the precooled compound 4 and ether solvent is 3-10mL/g, preferably 4-8mL/g, more preferably 5-7mL/g, and/or The quenching is to add the second reaction liquid into a quenching liquid, wherein the quenching liquid is acetic acid and n-heptane; preferably, the molar ratio of acetic acid to compound 4 is 3.0 to 5.0, more preferably 3.5 to 4.5, and/or Preferably, the volume to mass ratio of n-heptane to compound 4 is 2-5mL/g.
5. The synthesis process according to any one of claims 1 to 4, wherein the second continuous reaction system comprises a sample injector, a reaction device, a receiver, a mixer and a pre-cooling device connected in series by a pipe; preferably, the sample injector of the second continuous reaction system is a peristaltic pump or a syringe pump, more preferably a peristaltic pump, and/or Preferably, the receiver of the second continuous reaction system is filled with quench liquid.
6. The synthesis method according to any one of claims 1 to 5, wherein the reaction device of the second continuous reaction system comprises a pre-reactor and a post-reactor, and the post-injector of the second continuous reaction system is connected with a pre-cooling device; Preferably, the pre-cooling device comprises a pre-cooling tube; more preferably, the pre-cooling tube is a PFA coil, PTFE coil or FEP coil, still more preferably a PFA coil, and/or More preferably, the pre-cooling tube has an outside diameter of one-eighth inch to one-fourth inch, still more preferably one-eighth inch, and/or More preferably, the pre-cooling tube has an internal volume of 3 to 20mL, still more preferably 3 to 10mL, still more preferably 3 to 5mL, and/or The reaction device of the second continuous reaction system is a PFA coil, a PTFE coil or an FEP coil, preferably a PFA coil; preferably, the internal volume of the tube of the reaction device is 20-40mL, more preferably 30-40mL, still more preferably 30-35mL.
7. The synthesis process according to claim 6, wherein the temperature of the pre-cooling pipe, pre-reactor and receiver is controlled to be 0-10 ℃, preferably 0-5 ℃, and/or The temperature of the post-reactor is controlled to 15-30 ℃, preferably 15-25 ℃, more preferably 17-23 ℃.
8. The method according to any one of claims 1 to 7, wherein the pumping speed of the vinyl grignard reagent and the ether solvent is 2 to 10mL/min, preferably 3 to 7mL/min, more preferably 3 to 5mL/min, and/or The flow rate of the pumping compound 4 and the ether solvent is 5-15mL/min, preferably 7-13mL/min, and more preferably 8-12mL/min.
9. The method according to any one of claims 1 to 8, wherein the reaction flux of the reaction in the second step is 1.0 to 2.0g/min, preferably 1.0 to 1.5g/min, more preferably 1.3 to 1.5g/min, and/or The second step also includes pumping in ether solvent to flush out all the reaction liquid.
10. Teprenone, characterized in that it is prepared by the synthetic method according to any one of claims 1 to 18.

Description

Teprenone preparation method adopting continuous flow process Technical Field The invention belongs to the field of organic chemistry, and particularly relates to a continuous synthesis method of teprenone. Background Teprenone (Teprenone), a terpene compound, with a chemical name of 6,10,14, 18-tetramethyl-5, 9,13, 17-nonatetralin-2-one, consisting of a mixture of two geometrical isomers (5Z, 9E, 13E) and (5E, 9E, 13E) in a 5Z:5E ratio of 0.6 to 0.7. Can promote synthesis and secretion of main regeneration defense factors, high molecular glycoprotein and phospholipid in gastric mucosa and gastric mucus, has effect of protecting gastric mucosa, and has good effects on acute gastritis, chronic gastritis and gastric ulcer. The structure is as follows: the preparation route of the common teprenone is described in the journal of Chinese medical industry, 2004,35 (8), 449-450, and mainly comprises the following steps: Wherein, trans-nerolidol 1 is taken as a raw material to react with methyl acetoacetate 2 through Carroll to obtain a cis-trans isomer compound 3, and then (5E, 9E) farnesyl acetone 4 is obtained after purification, and then the trans-nerolidol 1 and vinyl magnesium chloride undergo Grignard reaction to generate geranyl linalool 5, and then the geranyl linalool and the methyl acetoacetate 2 undergo Carroll reaction to prepare teprenone. The Carroll reaction is carried out at high temperature, methyl acetoacetate with high boiling point is generally adopted as a reaction reagent and a solvent, the reaction concentration is high during normal pressure reaction, the reaction temperature is limited by the reflux temperature of the solvent and is difficult to further increase, the catalyst aluminum isopropoxide has low solubility in methyl acetoacetate, the dosage is limited, the reaction time is longer, the reaction efficiency is lower, excessive methyl acetoacetate needs to be removed through complicated steps such as reduced pressure distillation or washing with a large amount of water after the reaction is finished, and the lower alcohol and carbon dioxide generated in the reaction process possibly cause the risk of bumping or flushing in the kettle type reaction process, the reaction condition of the Grignard reaction is harsh, the reaction time is longer, ethylene gas can be generated, and the process risk is higher. It is necessary to develop a safe, efficient and green industrial synthesis process of teprenone. Disclosure of Invention The first aspect of the invention provides a method for synthesizing teprenone, which comprises the following steps: A first step of pumping the compound 1, the compound 2, the organic aluminum catalyst and the hydrocarbon solvent into a first continuous reaction system for reaction, collecting a reaction liquid, and carrying out extraction and purification treatment to obtain a compound 4 Pumping a precooled vinyl Grignard reagent and an ether solvent into a second continuous reaction system, pumping a precooled compound 4 and an ether solvent for reaction at the same time after a period of time, collecting a reaction liquid, and performing quenching and extraction treatment to obtain a compound 5 Pumping the compound 5, the compound 2, the organic aluminum catalyst and the hydrocarbon solvent into a first continuous reaction system for reaction, collecting reaction liquid, and carrying out extraction and purification treatment to obtain a compound 6 The first continuous reaction system or the second continuous reaction system respectively and independently comprises a sample injector, a reaction device and a receiver which are connected in series through pipelines. In some embodiments, the hydrocarbon solvent is n-heptane, n-hexane, cyclohexane, toluene or xylene, more preferably n-heptane or xylene, still more preferably n-heptane. In some embodiments, the organoaluminum catalyst comprises aluminum isopropoxide, aluminum sec-butoxide, aluminum acetylacetonate, or aluminum ethylacetoacetate, preferably aluminum isopropoxide. In some embodiments, the ethereal solvent is diethyl ether or tetrahydrofuran, preferably tetrahydrofuran. In some embodiments, the vinyl grignard reagent is vinyl magnesium bromide or vinyl magnesium chloride, preferably vinyl magnesium chloride. In some embodiments, the purification treatment of the first step is crystallization, and the crystallization conditions are conventional in the art, and reference is made to CN108047011B. In some embodiments, the purification treatment of the third step is distillation, and the distillation conditions are conventional in the art, and reference is made to CN108047011B. In some embodiments, the sample injector comprises a pump. In some embodiments, the reaction device comprises one or more reactors; Preferably, the reactor is a tubular reactor; More preferably, the outer diameter of the tubular reactor is one-eighth inch to one-fourth inch, and still more preferably one-eighth inch. In some embodimen