Method for preparing 3-chloro-4-oxopentyl acetate using fully continuous-flow micro-reaction system

Patent metadata

Field	Value
Publication number	US-11618727-B2
Application number	US-202117384747-A
Country	US
Kind code	B2
Filing date	Jul 24, 2021
Priority date	Feb 26, 2021
Publication date	Apr 4, 2023
Grant date	Apr 4, 2023

Abstract

This disclosure relates to organic synthesis, and more particularly to a method for preparing 3-chloro-4-oxopentyl acetate using a fully continuous-flow micro-reaction system. In this method, chlorine and an acetylbutyrolactone-containing liquid are simultaneously transported to a first micro-channel reactor for continuous chlorination to obtain α-acetyl-α-chloro-γ-butyrolactone. The reaction mixture is simultaneously transported to a micro-mixer and a second micro-channel reactor together with a mixed solution of glacial acetic acid, hydrochloric acid and water, and the continuous acylation is carried out to obtain 3-chloro-4-oxopentyl acetate. After quenched with a quenching agent, the reaction mixture was subjected to extraction and separation to obtain the 3-chloro-4-oxopentyl acetate.

First claim

What is claimed is:

1. A method for preparing 3-chloro-4-oxopentyl acetate using a fully continuous-flow micro-reaction system, the fully continuous-flow system comprising a first micro-channel reactor, a first micro-mixer, a second micro-channel reactor, a second micro-mixer and an extraction-separation unit communicated in sequence; the extraction-separation unit being composed of at least one extraction separator, and the method comprising:
(1) transporting chlorine gas and an acetylbutyrolactone-containing liquid simultaneously into the first micro-channel reactor followed by continuous chlorination;
(2) feeding the reaction mixture flowing out of the first micro-channel reactor and a mixed solution of glacial acetic acid, hydrochloric acid and water simultaneously into the first micro-mixer and the second micro-channel reactor in sequence for continuous acylation;
(3) transporting the reaction mixture flowing out of the second micro-channel reactor and an aqueous solution of an inorganic base into the second micro-mixer simultaneously, and transporting the reaction mixture flowing out of the second micro-mixer and an organic solvent to the extraction-separation unit for continuous quenching, extraction and separation; and
(4) concentrating the reaction mixture flowing out of the extraction-separation unit under vacuum to obtain a target product of 3-chloro-4-oxopentyl acetate;
as shown in the following reaction scheme:

wherein acetylbutyrolactone is shown in formula (3); the 3-chloro-4-oxopentyl acetate is shown in formula (1); and an intermediate α-acetyl-α-chloro-γ-butyrolactone formed from the chlorination is shown in the formula (2).

2. The method of claim 1 , wherein in step (1), the acetylbutyrolactone-containing liquid is a pure acetylbutyrolactone liquid, or a solution of acetylbutyrolactone dissolved in an organic solvent; the organic solvent is selected from the group consisting of alcohol, ether, ester and ketone; the alcohol is selected from the group consisting of methanol, ethanol, propanol, ethylene glycol, propylene glycol and benzyl alcohol; the ether is selected from the group consisting of isopropyl ether, tetrahydrofuran and 1,4-dioxane; the ester is selected from the group consisting of methyl acetate, ethyl acetate and tert-butyl acetate; and the ketone is selected from the group consisting of acetone, methyl butanone and methyl isobutyl ketone.

3. The method of claim 1 , wherein in step (1), flows of the chlorine and the acetylbutyrolactone-containing liquid are adjusted such that a molar ratio of the acetylbutyrolactone-containing liquid and chlorine in the first micro-channel reactor is 1:0.9-5.

4. The method of claim 1 , wherein in step (2), a temperature in the first micro-mixer is controlled at −20-50° C., and a residence time of the reaction mixture in the second micro-channel reactor is 0.1-30 min.

5. The method of claim 1 , wherein in step (2), the temperature in the first micro-mixer is controlled at 0-50° C.

6. The method of claim 1 , wherein in step (2), a molar ratio of glacial acetic acid to hydrochloric acid to water in the mixed solution of glacial acetic acid, hydrochloric acid and water is 1-10: 0-5:0.1-3.

7. The method of claim 1 , wherein in step (2), flows of the reaction mixture flowing out of the first micro-channel reactor and the mixed solution of glacial acetic acid, hydrochloric acid and water are adjusted such that a molar ratio of the intermediate α-acetyl-α-chloro-γ-butyrolactone (2) to acetic acid in the first micro-mixer is 1:1-10.

8. The method of claim 1 , wherein in step (2), a temperature in the second micro-channel reactor is controlled at 0-200° C.; and a residence time of the reaction mixture in the second micro-channel reactor is 1-100 min.

9. The method of claim 1 , wherein in step (3), the temperature in the second micro-mixer is controlled at −10-50° C.

10. The method of claim 1 , wherein in step (3), the organic solvent is selected from the group consisting of a halogenated hydrocarbon solvent, an acetate solvent, a substituted benzene solvent and an alkyl ether solvent; the extraction is performed at 10-50° C.; a residence time of the reaction mixture in each of the at least one extraction separator is 0.1-30 min.

11. The method of claim 1 , wherein in step (3), a mass percentage of the inorganic base in the aqueous solution of the inorganic base is 5-50%; and the inorganic base is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and a combination thereof.

12. The method of claim 1 , wherein the first micro-channel reactor and the second micro-channel reactor are independently a tubular micro-channel reactor or a plate-type micro-channel reactor;
the first micro-mixer and the second micro-mixer are independently a static mixer, a T-type micro-mixer, a Y-type micro-mixer, a cross-type micro-mixer, a coaxial flow micro-mixer or a flow-focusing micro-mixer; and
in step (3), the at least one extraction separator is each independently a plate-type micro-channel extraction separator, a membrane-type extraction separator or an annulus centrifugal extraction separator.

13. The method of claim 12 , wherein the tubular micro-channel reactor has an inner diameter of 50 μm-10 mm; the plate-type micro-channel reactor comprises a first heat exchange layer, a reaction layer, and a second heat exchange layer arranged from top to bottom; the reaction layer is provided with a reaction fluid channel, and a hydraulic diameter of the reaction fluid channel is 50 μm-10 mm; and
the plate-type extraction separator has an inner diameter of 100 μm-10 mm and comprises a mixing layer and a separation layer; a membrane of the membrane-type extraction separator is a hydrophobic membrane with a pore size of 0.1-4 μm; the annulus centrifugal extractor has a diameter of 10 cm-1 m; and the at least one extraction separator is connected in series to form the extraction-separation unit.

14. The method of claim 13 , wherein in step (1), the fully continuous-flow micro-reaction system further comprises a first feed pump, a gas mass flow controller, a gas-liquid separator, a buffer tank, a first back pressure valve and a second feed pump; the first feed pump is configured to feed the acetylbutyrolactone-containing liquid; one inlet of the first micro-channel reactor is connected to the first feed pump, and the other inlet of the first micro-channel reactor is connected to the gas mass flow controller; an outlet of the first micro-channel reactor is connected to a first port at a top of the gas-liquid separator, a second port at the top of the gas-liquid separator is configured to introduce nitrogen to provide a pressure in the gas-liquid separator; a pressure of the nitrogen is 0.01-2.5 MPa; a third port at the top of the gas-liquid separator is connected to the first back pressure valve; a back pressure of the first back pressure valve is 0.01-2 MPa; the pressure of the nitrogen is 0.02-0.5 MPa larger than the back pressure set by the first back pressure valve; a liquid outlet of the gas-liquid separator is connected to an inlet of the buffer tank, and an outlet of the buffer tank is connected to the second feed pump.

15. The method of claim 13 , wherein in step (2), the fully continuous-flow micro-reaction system further comprises a third feed pump and a second back pressure valve; the third feed pump is configured t

Assignees

• Univ Fudan

Inventors

• Chen Fener
• Jiang Meifen
• Liu Minjie
• Cheng Dang
• Yu Chao
• Huang Huashan

Classifications

• B01J19/0093 Primary

  Microreactors, e.g. miniaturised or microfabricated reactors (laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027) · CPC title

• C07D307/33

  in position 2, the oxygen atom being in its keto or unsubstituted enol form · CPC title

• B01J2219/00867

  Microreactors placed in series, on the same or on different supports · CPC title

• C07C67/31 Primary

  by introduction of functional groups containing oxygen only in singly bound form · CPC title

• B01J2219/00894

  More than two inlets · CPC title