阅读说明：本技术 索非布韦杂质的制备方法 (Preparation method of sofosbuvir impurity ) 是由 史磊 游金宗 蔡金元 蒋善会 于 2020-12-31 设计创作，主要内容包括：本发明公开了索非布韦杂质的制备方法,所述索非布韦杂质为杂质SM1-Q7,其制备采用下述两种合成路线的其中一种。本发明原材料易得、反应条件温和、操作简单,所得SM1-Q7纯度较好并符合索非布韦杂质研究和控制的要求。(The invention discloses a preparation method of a Sofosbuvir impurity, wherein the Sofosbuvir impurity is an impurity SM1-Q7, and the preparation method adopts one of the following two synthetic routes. The method has the advantages of easily obtained raw materials, mild reaction conditions and simple operation, and the obtained SM1-Q7 has better purity and meets the requirements of research and control of Sofosbuvir impurities.)

1. A preparation method of Sofosbuvir impurities is characterized by comprising the following steps: the Sofosbuvir impurity is an impurity SM1-Q7, and the synthetic route is as follows:

2. the method for preparing sofosbuvir impurities as claimed in claim 1, wherein: the preparation method specifically comprises the following steps:

(1) mixing 2-methoxyethanol, DBU and a solvent in a reaction container, dropwise adding sulfonyl chloride, and stirring at 40-60 ℃ for reaction, wherein the solvent is one or a combination of DMF, tetrahydrofuran, acetonitrile, n-hexane and toluene;

(2) after the reaction is stopped, concentrating the solvent under reduced pressure, adding dichloromethane and water, stirring for 15-45 minutes, layering, washing an organic layer with water, and concentrating under reduced pressure to obtain a crude product;

(3) and (3) separating the crude product by silica gel column chromatography, wherein the eluent adopted by the silica gel column chromatography is a mixed solvent of ethyl acetate/n-hexane or dichloromethane/methanol to obtain the impurity SM 1-Q7.

3. The method of claim 2, wherein: in step (1), the solvent is selected from tetrahydrofuran or acetonitrile or n-hexane.

4. The method of claim 2, wherein: in the step (1), the molar ratio of DBU to sulfonyl chloride is 1-4, and the molar ratio of 2-methoxyethanol to sulfonyl chloride is 2-4.

5. The method of claim 2, wherein: in the step (3), the eluent is a mixed solvent of ethyl acetate/n-hexane with a volume ratio of 8:1, or a mixed solvent of dichloromethane/methanol with a volume ratio of 20: 1.

6. A preparation method of Sofosbuvir impurities is characterized by comprising the following steps: the Sofosbuvir impurity is an impurity SM1-Q7, and the synthetic route is as follows:

7. the method of claim 6, wherein: the preparation method comprises the following steps:

(a) mixing 2-methoxyethanol, DIPEA or TEA or DBU and a solvent in a reaction container, dripping sulfonyl chloride, and stirring for reaction at about 40-60 ℃, wherein the solvent is one or a combination of more of tetrahydrofuran, toluene, acetonitrile and n-hexane;

(b) after the reaction is stopped, concentrating the solvent under reduced pressure, adding dichloromethane and water, stirring for 15-45 minutes, layering, washing an organic layer with water, and concentrating under reduced pressure to obtain an intermediate;

(c) mixing the intermediate, DIPEA or TEA or DBU and a solvent in a reaction container, dropwise adding 2-bromoethyl methyl ether, and stirring at about 40-60 ℃ for reaction, wherein the solvent is one or a combination of more of tetrahydrofuran, toluene, acetonitrile and n-hexane;

(d) after the reaction is stopped, concentrating the solvent under reduced pressure, adding dichloromethane and water, stirring for 15-45 minutes, layering, washing an organic layer with water, and concentrating under reduced pressure to obtain a crude product;

(e) and (3) separating the crude product by silica gel column chromatography, wherein the eluent adopted by the silica gel column chromatography is a mixed solvent of ethyl acetate/n-hexane or dichloromethane/methanol to obtain the impurity SM 1-Q7.

8. The method of claim 7, wherein: in step (a) or (c), the solvent is selected from tetrahydrofuran or acetonitrile or n-hexane.

9. The method of claim 7, wherein: the molar ratio of the DIPEA, the TEA or the DBU to the sulfonyl chloride is 1-2, the molar ratio of the DIPEA, the TEA or the DBU to the 2-bromoethyl methyl ether is 1-2, and the molar ratio of the 2-methoxyethanol or the 2-bromoethyl methyl ether to the sulfonyl chloride is 1-1.2.

10. The method of claim 7, wherein: the eluent is a mixed solvent of ethyl acetate/n-hexane with a volume ratio of 8:1, or a mixed solvent of dichloromethane/methanol with a volume ratio of 20: 1.

Technical Field

The invention relates to a preparation process of Sofosbuvir impurities, belonging to the technical field of drug synthesis.

Background

Sofosbuvir, known in the English name of Sofosbuir and sold under the trade name of Sovaldi, is in the form of a tablet (400mg), is approved by the FDA in the United states to be marketed in 12 months of 2013, is a Hepatitis C Virus (HCV) nucleotide analogue NS5B polymerase inhibitor developed by Gilidard (Gilead Sciences) company, is used for treating chronic Hepatitis C Virus (HCV) infection, is clinically used as a combined antiviral treatment scheme for treating Chronic Hepatitis C (CHC) infection, and achieves a good effect by Sofosbuvir treatment in HCV genotype 1, 2,3 or 4 infected subjects, including those suffering from hepatocellular carcinoma and HCV/HIV-1 co-infection. Clinical trials prove that the overall sustained virological response rate (SVR) of sofosbuvir combined with polyethylene glycol interferon and ribavirin is up to 90 percent against hepatitis C1 and 4; aiming at type 2 hepatitis C, the SVR of the medicine and ribavirin is 89-95 percent; aiming at type 3 hepatitis C, the SVR of the medicine and ribavirin is 61-63%; when the sofosbuvir is used for treating the specific genotype type chronic hepatitis C, the sofosbuvir can eliminate the requirement on the traditional injection medicine Interferon (IFN), reduce the adverse reaction of a patient and improve the compliance of the patient, and is widely considered as a breakthrough treatment medicine for the chronic hepatitis C. Since 2013, the sofosbuvir primary research drug has been approved to be marketed in the united states, european union, japan, china, and other countries.

Sofosbuvir is not currently registered by pharmacopoeia such as USP, EP, BP, JP, CHP, and the like, and is still in a new stage of a counterfeit drug research, and a quality control research is an important work in the new pharmaceutical research stage, particularly, a work of impurity research and control. A large number of researches or practices show that the existence of impurities can bring potential medication safety risks, and has certain side effects, even fatal side effects, so that effective control needs to be carried out on the basis of full research; among them, impurities having potential carcinogenicity are particularly important for research and control of impurities. Since 1994, ICH has successively issued guidelines for "impurities in new crude drugs" (Q3A), "impurities in new formulations" (Q3B), "guidance for residual solvents" (Q3C), which established a unified standard for the study and control of organic impurities and residual solvents to be followed in most countries and regions worldwide, and also mentions "for potential impurities that can produce strong pharmacological activity or toxicity, even if the content thereof is less than 0.1%, qualitative and quantitative studies for structural identification are recommended", and thereafter, further definition "concerning potential genotoxic impurities in crude drugs, and possibly making lower limits for very toxic impurities" is required.

Genotoxic impurities can induce gene mutation and cause chromosome breakage and rearrangement at very low concentration, so that the genotoxic impurities have potential carcinogenicity, the guide principles of genotoxic and carcinogenic impurities are sequentially issued by the European Union and the U.S. drug regulatory agency, and the guide principle of DNA activity (mutagenicity) impurities (M7) is also issued by ICH in 2014, which provides guide suggestions and technical requirements for the confirmation, research and control of genotoxic impurities. As can be seen from the relevant guidelines, "alert structures" are used as markers to distinguish between common and genotoxic impurities, and for impurities containing alert structures, (quantitative) conformational prediction and in vitro and in vivo genotoxic and carcinogenic studies should be performed, or impurity levels should be kept below toxicological concerns.

At present, the synthesis routes of sofosbuvir reported by domestic and foreign documents are many, and the most suitable industrial production route is that (2R) -2-deoxy-2-fluoro-2-methyl-D-erythro pentosan gamma-lactone 3, 5-dibenzoate is used as a main starting material, and the raw material is subjected to reduction, chlorination, substitution and deprotection, and finally undergoes a condensation reaction with N- [ (S) - (2,3,4,5, 6-pentafluorophenoxy) phenoxyphosphoryl ] -L-isopropyl alanine to obtain the sofosbuvir. In the synthesis process, sulfonyl substances with genetic toxicity impurity warning structures, such as sulfonyl chloride and the like, are very likely to be used; the most commonly used reagent of the reduction reaction is red aluminum, one of reduction byproducts is 2-methoxy ethanol, and genetic toxic impurities SM1-Q7 with a warning structure are easily generated by the reduction reaction and sulfonyl chloride and are remained in an intermediate or a finished product, so that great safety risk is brought to clinical medication. As can be seen from the literature search, the preparation method of the impurity SM1-Q7 is not reported in the substantive literature, so that the preparation method of the impurity needs to be invented to obtain the relevant impurity, thereby meeting the requirements of medicine research and quality control.

Wherein, the generation process and the structural formula of the impurities SM1-Q7 are as follows:

disclosure of Invention

The invention aims to provide a process for preparing SM1-Q7 by a chemical method, which has the advantages of easily obtained two raw materials, mild reaction conditions and simple operation, and the obtained SM1-Q7 has better purity and meets the requirements of research and control of Sofosbuvir impurities.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the invention provides a preparation method of a sofosbuvir impurity, wherein the sofosbuvir impurity is an impurity SM1-Q7, and the synthetic route is as follows:

preferably, the preparation method specifically comprises the following steps:

(1) mixing 2-methoxyethanol, DBU and a solvent in a reaction container, dropwise adding sulfonyl chloride, and stirring at 40-60 ℃ for reaction, wherein the solvent is one or a combination of DMF, tetrahydrofuran, acetonitrile, n-hexane and toluene;

(2) after the reaction is stopped, concentrating the solvent under reduced pressure, adding dichloromethane and water, stirring for 15-45 minutes, layering, washing an organic layer with water, and concentrating under reduced pressure to obtain a crude product;

(3) and (3) separating the crude product by silica gel column chromatography, wherein the eluent adopted by the silica gel column chromatography is a mixed solvent of ethyl acetate/n-hexane or dichloromethane/methanol to obtain the impurity SM 1-Q7.

As a further preference, in step (1), the solvent is selected from tetrahydrofuran or acetonitrile or n-hexane.

Further preferably, in the step (1), the molar ratio of DBU to sulfonyl chloride is 1-4.

In a further preferable mode, in the step (1), the molar ratio of the 2-methoxyethanol to the sulfonyl chloride is 2-4.

Further preferably, in the step (3), the eluent is a mixed solvent of ethyl acetate/n-hexane with a volume ratio of 8:1, or a mixed solvent of dichloromethane/methanol with a volume ratio of 20: 1.

In a second aspect, the invention provides a preparation method of a sofosbuvir impurity, wherein the sofosbuvir impurity is an impurity SM1-Q7, and the synthetic route is as follows:

preferably, the preparation method comprises the following steps:

(a) mixing 2-methoxyethanol, DIPEA or TEA or DBU and a solvent in a reaction container, dripping sulfonyl chloride, and stirring for reaction at about 40-60 ℃, wherein the solvent is one or a combination of more of tetrahydrofuran, toluene, acetonitrile and n-hexane;

(b) after the reaction is stopped, concentrating the solvent under reduced pressure, adding dichloromethane and water, stirring for 15-45 minutes, layering, washing an organic layer with water, and concentrating under reduced pressure to obtain an intermediate;

(c) mixing the intermediate, DIPEA or TEA or DBU and a solvent in a reaction container, dropwise adding 2-bromoethyl methyl ether, and stirring at about 40-60 ℃ for reaction, wherein the solvent is one or a combination of more of tetrahydrofuran, toluene, acetonitrile and n-hexane;

(d) after the reaction is stopped, concentrating the solvent under reduced pressure, adding dichloromethane and water, stirring for 15-45 minutes, layering, washing an organic layer with water, and concentrating under reduced pressure to obtain a crude product;

(e) and (3) separating the crude product by silica gel column chromatography, wherein the eluent adopted by the silica gel column chromatography is a mixed solvent of ethyl acetate/n-hexane or dichloromethane/methanol to obtain the impurity SM 1-Q7.

As a further preference, in step (a) or (c), the solvent is selected from tetrahydrofuran or acetonitrile or n-hexane.

Further preferably, the molar ratio of the DIPEA, TEA or DBU to the sulfonyl chloride is 1-2.

Further preferably, the molar ratio of the DIPEA, TEA or DBU to the 2-bromoethyl methyl ether is 1-2.

Further preferably, the molar ratio of the 2-methoxyethanol or 2-bromoethyl methyl ether to the sulfonyl chloride is 1 to 1.2.

More preferably, the eluent is a mixed solvent of ethyl acetate/n-hexane with a volume ratio of 8:1, or a mixed solvent of dichloromethane/methanol with a volume ratio of 20: 1.

Compared with the prior art, the invention has the beneficial effects that: the invention develops the method for preparing the impurities SM1-Q7 by adopting the chemical method, which has the advantages of easily obtained raw materials, mild reaction conditions and simple operation, and the obtained impurities have good purity and meet the requirements of research and control of Sofosbuvir impurities.

Drawings

FIG. 1 is a hydrogen spectrum of impurities SM1-Q7 prepared in example 3;

FIG. 2 is a gas mass spectrum of impurities SM1-Q7 prepared in example 6.

Detailed Description

For a better understanding of the present invention, the following detailed description is given in conjunction with specific examples, which are intended to illustrate, but not limit the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

Example 1

42g of 2-methoxyethanol, 85g DBU and 150g DMF are sequentially added into a 250mL reaction bottle, rapidly stirred for 15 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 40 ℃, the dropwise addition time is 30 minutes, after the dropwise addition is finished, the reaction is carried out for 3 hours at about 40 ℃, and the reaction is carried out for 3 hours at about 60 ℃. After the reaction is finished, concentrating under reduced pressure below 95 ℃ until no fraction is obtained, adding 150g of dichloromethane and 30g of water, stirring and dissolving for 30 minutes, layering, washing the organic layer twice with water, layering again, and concentrating the organic layer under reduced pressure below 50 ℃ until no fraction is obtained, thus obtaining a residue, namely a crude product SM 1-Q7. The crude product was subjected to flash chromatography on silica gel column (eluent: ethyl acetate/n-hexane: 8/1), and fractions were collected and concentrated to give about 23g of the objective SM1-Q7 as a colorless liquid with a purity of 93.2%.

Example 2

Adding 37g of 2-methoxyethanol, 37g of DBU37g and 100g of tetrahydrofuran into a 250mL reaction bottle in sequence, rapidly stirring for 15 minutes at room temperature, dropwise adding 30g of sulfonyl chloride, controlling the reaction temperature to be below 40 ℃, dropwise adding for 30 minutes, reacting for 3 hours at about 40 ℃ after dropwise adding, and heating to 50 ℃ for 3 hours. After the reaction is finished, concentrating under reduced pressure below 50 ℃ until no fraction is obtained, adding 150g of dichloromethane and 30g of water, stirring and dissolving for 40 minutes, layering, washing the organic layer twice with water, layering again, and concentrating the organic layer under reduced pressure below 50 ℃ until no fraction is obtained, thus obtaining a residue, namely a crude product SM 1-Q7. The crude product was subjected to flash chromatography on silica gel column (eluent: ethyl acetate/n-hexane: 8/1), fractions were collected and concentrated to give about 31g of SM1-Q7 as a colorless liquid target with a purity of 96.3%.

Example 3

Adding 37g of 2-methoxyethanol, 37g of DBU74g and 150g of acetonitrile into a 500mL reaction bottle in sequence, rapidly stirring for 15 minutes at room temperature, dropwise adding 30g of sulfonyl chloride, controlling the reaction temperature to be below 40 ℃, dropwise adding for 30 minutes, reacting for 3 hours at about 40 ℃ after dropwise adding, and heating to 50 ℃ for 3 hours. Working up as in example 2 (eluent: ethyl acetate/n-hexane: 8/1) gave the title SM1-Q7 as a colorless liquid, approximately 36g, with a purity of 98.9%.

The structure of the prepared compound is confirmed by a hydrogen spectrum, and the compound is identified as an impurity SM1-Q7, and is analyzed as follows:¹HNMR (500MHz, d-DMSO); 3.291(S,3H), corresponding to 6H, corresponding to the number of protons of two symmetric methyl groups in the molecule; delta 3.609-3.626(m,2H), corresponding to 4H, corresponding to the number of protons of two symmetric methylenes in the molecule; delta 4.357-4.374(m,2H), corresponding to 4H, corresponds to the proton of two symmetrical methylene groups in the moleculeAnd (4) counting.

Example 4

51g of 2-methoxyethanol, 51g of DBU101g and 150g of n-hexane are sequentially added into a 500mL reaction bottle, the mixture is rapidly stirred for 15 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 40 ℃, the dropwise adding time is 30 minutes, after the dropwise adding is finished, the mixture reacts for 3 hours at about 40 ℃, and the temperature is raised to about 50 ℃ for 3 hours. Work-up as in example 2 (eluent: dichloromethane/methanol 20/1) gave the title SM1-Q7 as a colourless, liquid, approximately 39g, 97.7% pure.

Example 5

68g of 2-methoxyethanol, 135g of DBU135g and 150g of toluene are sequentially added into a 500mL reaction bottle, the mixture is rapidly stirred for 15 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 40 ℃, the dropwise addition time is 30 minutes, after the dropwise addition is finished, the reaction is carried out for 3 hours at about 40 ℃, and the reaction is carried out for 3 hours at about 50 ℃. After the reaction is finished, adding 30g of dichloromethane water, stirring and dissolving for 30 minutes, layering, washing the organic layer twice with water, layering, and concentrating the organic layer under reduced pressure below 80 ℃ until no fraction is produced to obtain a residue, namely a crude product SM 1-Q7. Further work-up was carried out as in example 2 (eluent: dichloromethane/methanol 20/1) to give the desired SM1-Q7 as a colorless liquid in a purity of about 34g and 94.9%.

Example 6

19g of 2-methoxy ethanol, 32g g of DIPEA and 150g of tetrahydrofuran are sequentially added into a 250mL reaction bottle, rapid stirring is carried out for 10 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 40 ℃, the dropwise addition time is 30 minutes, and after the dropwise addition is finished, the reaction is carried out for 3 hours at about 40 ℃. After the reaction is finished, concentrating under reduced pressure below 50 ℃ until no fraction is obtained, adding 150g of dichloromethane and 30g of water, stirring and dissolving for 30 minutes, layering, washing the organic layer twice with water, layering again, and concentrating under reduced pressure below 50 ℃ until no fraction is obtained, thus obtaining the intermediate.

The intermediate, DIPEA32g and tetrahydrofuran 150g were added to a 250mL reaction flask, rapidly stirred at room temperature for 10 minutes, and then added dropwise with 2-bromoethyl methyl ether 34g while controlling the reaction temperature below 40 ℃ for 30 minutes, and after the addition was completed, the reaction was carried out at about 40 ℃ for 3 hours. Work-up as in example 2 (eluent: dichloromethane/methanol-20/1) gave the title SM1-Q7 as a colourless, liquid, approximately 29g with a purity of 95.3%.

The structure of the prepared compound is confirmed by gas mass spectrometry, and the compound is identified as an impurity SM1-Q7, and is analyzed as follows: GC-MS m/z (%) 214, molecular weight corresponding to SM 1-Q7.

Example 7

19g of 2-methoxy ethanol, 43g g of DIPEA and 150g of toluene are sequentially added into a 250mL reaction bottle, rapid stirring is carried out for 10 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 55 ℃, the dropwise addition time is 30 minutes, and after the dropwise addition is finished, the reaction is carried out for 3 hours at about 40 ℃. After the reaction is finished, adding 30g of water, stirring and dissolving for 20 minutes, layering, washing the organic layer twice with water, layering, and concentrating the organic layer under reduced pressure below 80 ℃ until no fraction is produced to obtain an intermediate.

The intermediate, DIPEA43g and toluene 150g were added to a 250mL reaction flask, rapidly stirred at room temperature for 10 minutes, and then added dropwise with 2-bromoethyl methyl ether 34g while controlling the reaction temperature below 55 ℃ for 30 minutes, and after the addition was completed, the reaction was carried out at about 40 ℃ for 3 hours. Work-up as in example 5 (eluent: dichloromethane/methanol-20/1) gave the title SM1-Q7 as a colourless, liquid, approximately 23g, 93.9% pure.

Example 8

19g of 2-methoxy ethanol, 57g g of DIPEA and 150g of toluene are sequentially added into a 250mL reaction bottle, rapid stirring is carried out for 10 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 45 ℃, the dropwise addition time is 30 minutes, and after the dropwise addition is finished, the reaction is carried out for 3 hours at about 40 ℃. Work-up as in example 5 gave the intermediate.

The intermediate, DIPEA57g and toluene 150g were added to a 250mL reaction flask, rapidly stirred at room temperature for 10 minutes, and then added dropwise with 2-bromoethyl methyl ether 34g while controlling the reaction temperature at 45 ℃ or lower for 30 minutes, and after the addition was completed, the reaction was carried out at about 40 ℃ for 3 hours. Working up as in example 5 (eluent: ethyl acetate/n-hexane: 8/1) gave the title SM1-Q7 as a colourless, liquid, approximately 23g, purity 94.3%.

Example 9

19g of 2-methoxyethanol, 36g g of TEA and 150g of acetonitrile are sequentially added into a 250mL reaction bottle, the mixture is rapidly stirred for 10 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 40 ℃, the dropwise addition time is 30 minutes, and after the dropwise addition is finished, the reaction is carried out for 3 hours at about 40 ℃. Work-up as in example 6 gave the intermediate.

The intermediate, TEA36g, and tetrahydrofuran 150g were added to a 250mL reaction flask, rapidly stirred at room temperature for 10 minutes, and then 34g of 2-bromoethyl methyl ether was added dropwise while controlling the reaction temperature below 40 ℃ for 30 minutes, and after the addition was completed, the reaction was carried out at about 40 ℃ for 3 hours. Working up as in example 2 (eluent: ethyl acetate/n-hexane: 8/1) gave the title SM1-Q7 as a colourless, liquid, approximately 33g, 97.6% pure.

Example 10

19g of 2-methoxyethanol, 45g of TEA45g and 150g of n-hexane are sequentially added into a 250mL reaction bottle, the mixture is rapidly stirred for 10 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 50 ℃, the dropwise addition time is 30 minutes, and after the dropwise addition is finished, the reaction is carried out for 3 hours at about 40 ℃. Work-up as in example 6 gave the intermediate.

The intermediate, TEA45g, and tetrahydrofuran 150g were added to a 250mL reaction flask, rapidly stirred at room temperature for 10 minutes, and then 34g of 2-bromoethyl methyl ether was added dropwise while controlling the reaction temperature below 50 ℃ for 30 minutes, and after the addition was completed, the reaction was carried out at about 40 ℃ for 3 hours. Working up as in example 2 (eluent: ethyl acetate/n-hexane: 8/1) gave the title SM1-Q7 as a colourless, liquid, approximately 35g, with a purity of 98.4%.

Example 11

19g of 2-methoxyethanol, 37g of DBU37g and 150g of tetrahydrofuran are sequentially added into a 250mL reaction bottle, the mixture is rapidly stirred for 10 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 45 ℃, the dropwise addition time is 30 minutes, and after the dropwise addition is finished, the reaction is carried out for 3 hours at about 40 ℃. Work-up as in example 6 gave the intermediate.

The intermediate, DBU37g and 150g of tetrahydrofuran were added to a 250mL reaction flask, rapidly stirred at room temperature for 10 minutes, 34g of 2-bromoethyl methyl ether was added dropwise while controlling the reaction temperature at 45 ℃ or lower for 30 minutes, and after the addition was completed, the reaction was carried out at about 40 ℃ for 3 hours. Work-up as in example 2 (eluent: dichloromethane/methanol-20/1) gave the title SM1-Q7 as a colourless, liquid, approximately 34g, with a purity of 99.1%.

Example 12

19g of 2-methoxyethanol, 51g of DBU51g and 150g of acetonitrile are sequentially added into a 250mL reaction bottle, the mixture is rapidly stirred for 10 minutes at room temperature, 30g of sulfonyl chloride is dropwise added, the reaction temperature is controlled below 40 ℃, the dropwise addition time is 30 minutes, and after the dropwise addition is finished, the reaction is carried out for 3 hours at about 40 ℃. Work-up as in example 6 gave the intermediate.

The intermediate, DBU51g and acetonitrile 150g were added to a 250mL reaction flask, rapidly stirred at room temperature for 10 minutes, and then 34g of 2-bromoethyl methyl ether was added dropwise while controlling the reaction temperature at 40 ℃ or lower for 30 minutes, and after the addition was completed, the reaction was carried out at about 40 ℃ for 3 hours. Working up as in example 2 (eluent: ethyl acetate/n-hexane: 8/1) gave the title SM1-Q7 as a colourless, liquid, approximately 38g, with a purity of 98.3%.