CONTINUOUS-FLOW PREPARATION METHOD OF DIOL SULFONE

Abstract

A continuous-flow preparation method of diol sulfone using a two-stage micro-reaction system. The system includes a first micro-mixer, a first micro-channel reactor, a second micro-mixer, and a second micro-channel reactor communicated in sequence. The method includes: feeding hydrogen peroxide, a catalyst and a diol thioether solution simultaneously to the first micro-mixer followed by mixing; feeding the reaction mixture to the first micro-channel reactor for continuous oxidation; and feeding the reaction mixture and water simultaneously to the second micro-mixer and the second micro-channel reactor for continuous quenching and crystallization to obtain diol sulfone.

Claims

1. A continuous-flow preparation method of diol sulfone using a two-stage micro-reaction system, the two-stage micro-reaction system comprising a first micro-mixer, a first micro-channel reactor, a second micro-mixer, and a second micro-channel reactor communicated in sequence; and the method comprising: (S1) simultaneously feeding a hydrogen peroxide solution, a catalyst, and a solution of diol thioether (2) to the first micro-mixer followed by mixing to obtain a reaction mixture; and feeding the reaction mixture to the first micro-channel reactor to undergo a continuous oxidation reaction; and (S2) feeding the reaction mixture flowing out from the first micro-channel reactor and water to the second micro-mixer for mixing followed by continuous quenching and crystallization in the second micro-channel reactor to obtain diol sulfone (1); as shown in the following reaction scheme: ##STR00004## wherein R.sub.1 is ##STR00005## Y is nitrogen or sulfur; and R.sub.2 is a C.sub.1-C.sub.6 alkyl or phenyl.

2. The continuous-flow preparation method of claim 1, wherein in step (S1), the solution of diol thioether is a solution of diol thioether in an organic solvent; the organic solvent is selected from the group consisting of an alcohol, an ester, and a halogenated hydrocarbon; the alcohol is a C.sub.1-C.sub.6 monohydric alkyl alcohol or a C.sub.1-C.sub.6 polyhydric alkyl alcohol; the ester is selected from the group consisting of methyl acetate, ethyl acetate, and tert-butyl acetate; and the halogenated hydrocarbon is selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, dichloroethane, and chlorobenzene; the hydrogen peroxide solution comprises 10-50% by weight of hydrogen peroxide; and the catalyst is a metal catalyst or a non-metal catalyst; and the metal catalyst is selected from the group consisting of a tungsten catalyst, a molybdenum catalyst, a vanadium catalyst, a titanium catalyst, and an iron catalyst.

3. The continuous-flow preparation method of claim 1, wherein in step (S1), a flow ratio of the solution of diol thioether to the hydrogen peroxide solution is controlled such that a molar ratio of the diol thioether to hydrogen peroxide is 1:(2-10).

4. The continuous-flow preparation method of claim 3, wherein in step (S1), the first micro-channel reactor is controlled at 0-100° C.; and a residence time of the reaction mixture in the first micro-channel reactor is controlled to be 0.1-30 min.

5. The continuous-flow preparation method of claim 2, wherein in step (S2), a flow ratio of the reaction mixture to the water is controlled such that a molar ratio of the organic solvent to the water is 1:(0.5-5).

6. The continuous-flow preparation method of claim 5, wherein in step (S2), the second micro-channel reactor is controlled at −10-30° C.; and a residence time of the reaction mixture in the second micro-channel reactor is controlled to be 0.5-10 min.

7. The continuous-flow preparation method of claim 1, wherein the first micro-mixer and the second micro-mixer are independently selected from the group consisting of a static mixer, a T-type micro-mixer, a Y-type micro-mixer, a cross-type micro-mixer, a coaxial-flow micro-mixer, and a flow-focusing micro-mixer.

8. The continuous-flow preparation 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.

9. The continuous-flow preparation method of claim 8, wherein an inner diameter of the tubular micro-channel reactor is 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 successively 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. A continuous-flow preparation method of diol sulfone using a two-stage micro-reaction system. The system includes a first micro-mixer, a first micro-channel reactor, a second micro-mixer, and a second micro-channel reactor communicated in sequence. The method includes: feeding hydrogen peroxide, a catalyst and a diol thioether solution simultaneously to the first micro-mixer followed by mixing; feeding the reaction mixture to the first micro-channel reactor for continuous oxidation; and feeding the reaction mixture and water simultaneously to the second micro-mixer and the second micro-channel reactor for continuous quenching and crystallization to obtain diol sulfone.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] This FIGURE schematically illustrates a method for preparing diol sulfone according to an embodiment of the present disclosure.

DETAILED DESCRIPTION OF EMBODIMENTS

[0034] To describe the contents, features, objects and effects of the technical solutions in detail, this application will be described below with reference to the embodiments and drawing. It should be noted that the embodiments are merely illustrative to facilitate the understanding and implementation of the present disclosure, and are not intended to limit the present disclosure.

[0035] A micro-reaction system used herein is structurally depicted in the FIGURE, and operated as follows.

[0036] (A) An organic solution of compound (2), hydrogen peroxide and a catalyst solution are simultaneously fed into a first micro-channel reactor through a feeding pump to undergo continuous oxidation reaction to obtain a reaction mixture.

[0037] (B) The reaction mixture flowing out from the first micro-channel reactor and water are simultaneously fed into the second micro-channel reactor to undergo continuous quenching, crystallization, and filtration to obtain diol sulfone.

Example 1

[0038] Provided herein was a method of continuously preparing tert-butyl 2-((4R,6S)-6-((benzothiazol-2-ylsulfonyl)methyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate.

[0039] A solution of tert-butyl 2-((4R,6S)-6-((benzothiazol-2-ylthio)methyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate (2) in isopropanol, a 30% (by weight) hydrogen peroxide solution, and an aqueous ammonium molybdate tetrahydrate solution were simultaneously fed into a T-type mixer for mixing, and then the reaction mixture was fed to a first tubular micro-channel reactor (with a reaction volume of 30 mL, and a diameter of 2 mm) and reacted at 70° C. for 8 minutes (namely, a residence time of the reaction mixture in the first tubular micro-channel reactor was 8 minutes), where flow rates of individual raw materials were adjusted such that a molar ratio of the compound (2) to hydrogen peroxide to the ammonium molybdate tetrahydrate was 1:3:0.05, and a back pressure of a back pressure valve was set to be 0.2 MPa. Then the reaction mixture flowing out from the outlet of the first tubular micro-channel reactor (the reaction mixture was sampled and detected, and the conversion rate of the compound (2) was 100%) and water were simultaneously fed into a Y-type micro-mixer for mixing, and then the reaction mixture was fed to a second tubular micro-channel reactor (with a reaction volume of 20 mL, and a diameter of 2 mm) and subjected to quenching and crystallization at 20° C. for 3 minutes (namely, a residence time of the second tubular micro-channel reactor was 3 minutes), where flow rates of the reaction mixture and the water were adjusted such that a volume ratio of isopropanol to the water was 1:1. The second micro-channel reactor was controlled at. The residence time of the reaction mixture in the second micro-channel reactor was. After that, the reaction mixture was allowed to flow out from an outlet of the second micro-channel reactor and filtered to obtain tert-butyl 2-((4R,6S)-6-((benzothiazol-2-ylsulfonyl)methyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate (1) which had a yield of 80% and a purity of 99% (HPLC).

Example 2

[0040] The preparation method provided in Example 2 was basically the same as that in Example 1 except that in this example, the compound (2) was tert-butyl 2-((4R,6S)-6-((1-methyl-1H-tetrazol-5-ylthio)methyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate. In this example, the substrate experienced a complete conversion, and the target product had a yield of 78% and a purity of 99% (HPLC).

Example 3

[0041] The preparation method provided in Example 3 was basically the same as that in Example 1 except that in this example, the compound (2) was tert-butyl 2-((4R,6S)-6-((1-tert-butyl-1H-tetrazol-5-ylthio)methyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate. In this example, the substrate experienced a complete conversion, and the target product had a yield of 83% and a purity of 99% (HPLC).

Example 4

[0042] The preparation method provided in Example 4 was basically the same as that in Example 1 except that in this example, the compound (2) was tert-butyl 2-((4R,6S)-6-((1-phenyl-1H-tetrazol-5-ylthio)methyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate. In this example, the substrate experienced a complete conversion, and the target product had a yield of 77% and a purity of 98% (HPLC).

Example 5

[0043] The preparation method provided in Example 5 was basically the same as that in Example 1 except that in this example, the solvent was ethanol. In this example, the substrate experienced a complete conversion, and the target product had a yield of 75% and a purity of 98% (HPLC).

Example 6

[0044] The preparation method provided in Example 6 was basically the same as that in Example 1 except that in this example, the catalyst was sodium tungstate dihydrate. In this example, the substrate experienced a complete conversion, and the target product had a yield of 78% and a purity of 99% (HPLC).

Example 7

[0045] The preparation method provided in Example 7 was basically the same as that in Example 1 except that in this example, the oxidation in the first tubular micro-channel reactor was performed at 60° C. In this example, the substrate experienced a complete conversion, and the target product had a yield of 82% and a purity of 99% (HPLC).

Example 8

[0046] The preparation method provided in Example 8 was basically the same as that in Example 1 except that in this example, the oxidation in the first tubular micro-channel reactor was performed at 90° C. In this example, the substrate experienced a complete conversion, and the target product had a yield of 78% and a purity of 98% (HPLC).

Example 9

[0047] The preparation method provided in Example 9 was basically the same as that in Example 1 except that in this example, the oxidation was performed under temperature gradient control. Specifically, the oxidation reaction was performed at 90° C. for 2 min with a reaction volume of 10 mL and a microchannel diameter of 2 mm, and then at 70° C. for 4 min with a reaction volume of 20 mL and a microchannel diameter of 4 mm. In this example, the substrate experienced a complete conversion, and the target product had a yield of 80% and a purity of 98% (HPLC).

[0048] It should be noted that the above examples are only used to illustrate the technical solutions of the disclosure, and are not intended to limit the disclosure. It should be understood that any changes, replacements and modifications made by those skilled in the art without departing from the spirit of the disclosure shall fall within the scope of the present disclosure defined by the appended claims.