CN115819318A

CN115819318A - Tetrafluorobenzoic acid intermediate impurity and preparation method thereof

Info

Publication number: CN115819318A
Application number: CN202211646171.2A
Authority: CN
Inventors: 年四昀; 李灵巧; 林勇利; 李奇彪; 尹晓萍; 周鸯飞; 刘楠; 安胡敏; 王新亮
Original assignee: Zhejiang Starry Pharmaceutical Co Ltd
Current assignee: Zhejiang Starry Pharmaceutical Co Ltd
Priority date: 2022-12-21
Filing date: 2022-12-21
Publication date: 2023-03-21

Abstract

The invention provides a preparation method of difluorodichlorobenzoyl imine as an impurity of a tetrafluorobenzoic acid intermediate, belonging to the technical field of synthesis and separation and comprising the following steps: the N-methyl tetrachlorophthalimide reacts with fluoride salt in a first solvent at a first temperature to obtain the impurity (1), and then the impurity is primarily purified by a silica gel column and then passes through a preparation column to obtain an impurity standard product with the purity of more than 95%. The impurity standard substance prepared by the method has high purity, meets the requirements of an impurity reference substance, and has instructive significance for impurity research of tetrafluorobenzoic acid and impurity research of levofloxacin.

Description

Tetrafluorobenzoic acid intermediate impurity and preparation method thereof

Technical Field

The invention belongs to the technical field of synthesis and separation, and particularly relates to a preparation method of difluorodichlorobenzoyl imine as an impurity of a tetrafluorobenzoic acid intermediate.

Background

Tetrafluorobenzoic acid is a white granular solid, is insoluble in water and is soluble in most organic solvents. The method is mainly used for fluoroquinolone drug intermediates, synthesis of fluorine-containing liquid crystals, synthesis of fluorine-containing resin and the like. The synthesis of the impurity has guiding significance for the impurity research of tetrafluorobenzoic acid and the impurity research of levofloxacin. The chemical structure is simply shown as follows:

disclosure of Invention

The invention aims to provide difluorodichlorobenzoyl imine serving as an impurity of a tetrafluorobenzoic acid intermediate and a preparation method thereof.

The tetrafluorobenzoic acid intermediate impurity difluorodichlorobenzoyl imine has a structural formula (1) shown as follows:

a preparation method of difluorodichlorobenzoyl imine as an impurity of a tetrafluorobenzoic acid intermediate comprises the following steps:

(1) Reacting N-methyl tetrachlorophthalimide with fluoride salt in a first solvent at a first temperature to prepare a crude compound of a formula (1);

(2) Post-treatment, namely, passing through a preparation column after preliminary purification of a silica gel column to obtain an impurity standard substance with the purity of more than 95%.

Wherein the fluoride salt is one of potassium fluoride or sodium fluoride, and the ratio of the added substances to the N-methyl tetrachlorophthalimide is 0.5-3.

Wherein the first solvent is one or more of dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N-dimethylformamide and N, N-dimethylacetamide, and the ratio of the added mass (m) to the added mass (m) of the N-methyl tetrachlorophthalimide (m) is 0.5-2.0.

Wherein the first temperature is 150-200 ℃.

The purification method of the crude product of the compound shown in the formula (1) comprises the following steps of firstly carrying out post-treatment on one of dichloromethane, trichloromethane, ethyl acetate and n-butyl alcohol, then carrying out primary purification by using a silica gel column through gradient elution of ethyl acetate/n-hexane, and then passing through a preparation column to obtain an impurity standard product with the purity of more than 95%.

Wherein, the silica gel is one of column chromatography silica gel, thin layer chromatography silica gel and modified silica gel, and the ratio of the added mass (m) to the crude product mass (m) is 10-30.

Preferably, the fluoride salt is potassium fluoride.

Preferably, the first solvent is sulfolane.

Preferably, the first extraction solvent, ethyl acetate, is worked up.

Preferably, the preparation column is separated and purified, and the preparation column is preferably a C18X 250mm 10 mu silica gel column; the mobile phase is preferably eluted with an acetonitrile/purified water gradient.

The difluorodichlorobenzoyl imine prepared by the method is simple and convenient to operate, the product purity is up to more than 95%, an impurity reference substance can be prepared, and the method is simple and convenient and fast.

Drawings

FIG. 1 chemical structural formula of difluorodichlorobenzoyl imine

FIG. 2 Mass Spectroscopy of Difluoro-Dichlorobenzoyl-imine

FIG. 3 NMR spectra of difluorodichlorobenzoyl imine

FIG. 4 NMR carbon spectra of difluorodichlorobenzoyl imine

FIG. 5 NMR spectra of difluorodichlorobenzoyl imine

Detailed Description

The present invention is further illustrated by the following specific examples, which are not to be construed as limiting the invention thereto. .

Example 1

(1) Heating 60g of N-methyl tetrachlorophthalimide, 60g of sulfolane and 6g of potassium fluoride to 180 ℃, reacting, adding 3g of potassium fluoride, stirring at 180 ℃, reacting for 1 hour until TLC shows that the raw materials are completely reacted, finishing the reaction, and concentrating under reduced pressure.

(2) Extracting with ethyl acetate, and washing with drinking water; adding 2W 200-300 mesh column chromatography silica gel into the combined organic phase, concentrating under reduced pressure, mixing the sample, separating by 15W 200-300 mesh column chromatography silica gel and ethyl acetate/n-hexane 1/3 chromatography to obtain a target product point, concentrating under reduced pressure until the mixture is dried, adding a purified water filter membrane, filtering to obtain a filtrate upper column feed liquid after dissolving by using 40% acetonitrile aqueous solution, preparing a pre-column by using C18 silica gel with 250mm 10 mu, and selecting a gradient solvent for a mobile phase:

elution gradient:

the sample loading amount is 10 ml/time, and the sample loading flow rate is 10ml/min. Collecting main material section eluent with peak time of 28min to 33min to obtain more than 95.0 percent of single component, and then merging and concentrating the single component until the single component is dried to obtain the target product. m/z (APCI): 265. 267, 269 (9; ¹ H NMR(MeOD)δ：3.12(3H,s)； ¹³ C NMR(MeOD)δ：161.11(C-4)、159.05(C-5)、116.51-116.98(C-6)、118.31、118.14(C-7)、117.09(C-3)、129.82(C-8)、24.59(C-9)； ¹⁹ F NMR(MeOD)：-116.6(1F,d)、-105.4(1F,d)。

example 2

(1) Heating 60g of N-methyl tetrachlorophthalimide, 60g of sulfolane, 60g of N, N-dimethylacetamide and 9g of potassium fluoride to 150 ℃, reacting until TLC shows that the raw materials are completely reacted, finishing the reaction, and concentrating under reduced pressure.

(2) Extracting with dichloromethane, and washing with drinking water; separating with 25W silica gel column chromatography and sample mixing column; preparative column C850 × 650mm 30 μ was purified to obtain crude target.

The mobile phase is preferably a gradient solvent:

elution gradient:

the sample loading amount is 70 ml/time, and the sample loading flow rate is 70ml/min. Collecting eluate of the main material section at the peak time of 46min to 54min to obtain more than 95.0% of single components, and mixing and concentrating to dry to obtain the target product.

Example 3

(1) 60g of N-methyl tetrachlorophthalimide, 30g of dimethyl sulfoxide and 6g of potassium fluoride are heated to 160 ℃ for reaction until TLC shows that the raw materials are completely reacted, the reaction is finished, and the reaction is concentrated under reduced pressure.

(2) Extracting trichloromethane, and washing with drinking water; separating with 10W silica gel column chromatography and sample mixing column; purifying the preparative column to obtain a crude product of the target product.

The mobile phase is preferably a gradient solvent:

elution gradient:

the sample loading amount is 50 ml/time, and the sample loading flow rate is 50ml/min. Collecting main material section eluent at peak time of 53min to 62min to obtain more than 95.0 percent of single component, and then merging and concentrating the single component until the single component is dried to obtain the target product.

Example 4

(1) 60g of N-methyl tetrachlorophthalimide, 60g of dimethyl sulfoxide and 25g of sodium fluoride are heated to 170 ℃ for reaction until TLC shows that the raw materials are completely reacted, the reaction is finished, and the reaction is concentrated under reduced pressure.

(2) Extracting with ethyl acetate, and washing with drinking water; separating by a 15W silica gel column chromatography sample mixing column; purifying the preparative column to obtain a crude product of the target product.

The mobile phase is preferably a gradient solvent:

elution gradient:

the sample loading amount is 5 ml/time, and the sample loading flow rate is 10ml/min. Collecting main material section eluent at the peak time of 38min to 43min to obtain more than 95.0 percent of single component, and then merging and concentrating the single component until the single component is dried to obtain the target product.

Example 5

(1) 60g of N-methyl tetrachlorophthalimide, 120g of N-methyl pyrrolidone and 15g of potassium fluoride are heated to 200 ℃ to react until TLC shows that the raw materials are reacted completely, the reaction is finished, and the reaction is concentrated under reduced pressure.

(2) Extracting with n-butyl alcohol, and washing with drinking water; carrying out chromatography and sample mixing column separation on a 30W silica gel column; purifying the preparative column to obtain a crude product of the target product.

The mobile phase is preferably a gradient solvent:

elution gradient:

the sample loading amount is 70 ml/time, and the sample loading flow rate is 70ml/min. Collecting main material section eluent at the peak time of 46min to 54min to obtain more than 95.0 percent of single component, and then merging and concentrating the single component until the single component is dried to obtain the target product.

Example 6

(1) 60g of N-methyl tetrachlorophthalimide, 72g of N, N-dimethylformamide and 9g of potassium fluoride are heated to 180 ℃ for reaction until TLC shows that the raw materials are completely reacted, the reaction is finished, and the reaction is concentrated under reduced pressure.

(2) Extracting trichloromethane, and washing with drinking water; separating with 25W silica gel column chromatography and sample mixing column; purifying the preparative column to obtain a crude product of the target product.

The mobile phase is preferably a gradient solvent:

elution gradient:

the sample loading amount is 10 ml/time, and the sample loading flow rate is 10ml/min. Collecting main material section eluent with peak time of 28min to 33min to obtain more than 95.0 percent of single component, and then merging and concentrating the single component until the single component is dried to obtain the target product.

Example 7 application of Tetrafluorobenzoic acid intermediate Difluorobenzoyl Imimine as impurity

Taking 25mg of tetrafluorobenzoic acid raw material, taking the product described in example 1 as a reference substance, detecting by using a tetrafluorobenzoic acid (internal control) detection method, and detecting that the content of the impurity in a crude product is less than 0.1%. Indicating that the impurities are well controlled in the intermediate of the product.

The impurity is mainly used as an impurity identification standard substance of a levofloxacin intermediate tetrafluorobenzoic acid raw material, is more beneficial to the control of the quality of subsequent products, and improves the quality of the products.

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A tetrafluorobenzoic acid intermediate impurity represented by the structural formula (1):

2. the process for preparing the intermediate impurity of claim 1, wherein the synthetic route is as follows:

3. the process of claim 2, comprising the steps of (1) reacting N-methyl tetrachlorophthalimide with a fluoride salt in a first solvent at a first temperature to produce a crude compound of formula (1);

4. The production method according to claim 2 or 3, wherein the fluoride salt is one of potassium fluoride and sodium fluoride, and the ratio of the amount of the added substance to N-methylchlorophthalimide is from 0.5.

5. The production method according to claim 2 or 3, wherein the first solvent is one or more of dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N-dimethylformamide, and N, N-dimethylacetamide, and the ratio of the mass (m) added to the N-methyltetrachlorophthalimide (m) is 0.5 to 2.0.

6. The method of claim 2 or 3, wherein the first temperature is 150 to 200 ℃.

7. The method according to claim 2 or 3, wherein the crude compound of formula (1) is purified by one of dichloromethane, chloroform, ethyl acetate and n-butanol, and then by silica gel column with ethyl acetate/n-hexane gradient elution for primary purification, and then by column preparation to obtain an impurity standard with purity of 95% or higher.

8. The preparation method according to claim 7, wherein the silica gel is one of column chromatography silica gel, thin layer chromatography silica gel and modified silica gel, and the ratio of the added mass (m) to the crude mass (m) is 10 to 1.

9. The method of claim 7, wherein the preparative column is a C1820 x 250mm 10 μ silica gel column and the mobile phase is methanol/purified water gradient elution.