阅读说明：本技术 一种2-(氯磺酰基)环己烷-1-烯甲酸乙酯衍生物的制备方法 (Preparation method of 2- (chlorosulfonyl) cyclohexane-1-ethyl olefin formate derivative ) 是由 王云 张宏伟 周治国 高强 郑保富 于 2021-08-24 设计创作，主要内容包括：本发明涉及一种2-(氯磺酰基)环己烷-1-烯甲酸乙酯衍生物的制备方法,包括以下步骤：1)将式III化合物溶于有机溶剂中,在碱的存在下,反应得通式IV化合物；2)将式IV化合物加入N-氯代丁二酰亚胺制备得到式I的化合物；其中R1为氢、C-(1-6)烷基或C-(3-6)环烷基；R2优选Tf三氟甲磺酰基,Ts对甲苯磺酰基或Ms甲磺酰基。本方法是一条全新的可工业化的合成路线,还提供式IV全新的中间体化合物。同时,该路线避免使用硫化氢和氯气,得到式I化合物纯度好,产品稳定性好,对制备Toll样受体4(TLR4)抑制剂药物具有很好的方法学意义。(The invention relates to a preparation method of a 2- (chlorosulfonyl) cyclohexane-1-ethyl enoate derivative, which comprises the following steps: 1) dissolving a compound shown in a formula III in an organic solvent, and reacting in the presence of alkali to obtain a compound shown in a general formula IV; 2) adding the compound shown in the formula IV into N-chlorosuccinimide to prepare a compound shown in the formula I; wherein R1 is hydrogen, C 1‑6 Alkyl or C 3‑6 A cycloalkyl group; r2 is preferably Tf trifluoromethanesulfonyl, Ts p-toluenesulfonyl or Ms methanesulfonyl. The method is a brand-new synthesis route which can be industrialized, and also provides a brand-new intermediate compound shown in a formula IV. Meanwhile, the route avoids using hydrogen sulfide and chlorine, the obtained compound of the formula I has good purity and good product stability, and the method has a good method for preparing Toll-like receptor 4(TLR4) inhibitor drugsThe meaning of learning.)

1. A preparation method of 2- (chlorosulfonyl) cyclohexane-1-ethyl enoate derivatives comprises the following steps:

1) dissolving a compound shown in a formula III in an organic solvent, and reacting in the presence of alkali to obtain a compound shown in a general formula IV;

2) adding the compound shown in the formula IV into N-chlorosuccinimide to prepare a compound shown in the formula I;

wherein R is₁Selected from hydrogen, C1-6 alkyl or C3-6 cycloalkyl;

R₂selected from trifluoromethanesulfonyl, p-toluenesulfonyl and methylsulfonyl.

2. According to the claimsThe process according to claim 1, wherein R is₁Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

3. The preparation method according to claim 1 or 2, characterized in that the base of step 1) is selected from one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, N-diisopropylethylamine or triethylamine; preferably potassium carbonate or sodium carbonate; more preferably potassium carbonate.

4. The method according to claim 1 or 2, wherein the organic solvent of step 1) is selected from acetonitrile, tetrahydrofuran, and dichloromethane; the molar ratio of the compound of the formula III to the benzylmercaptan is 1 (1-2); preferably 1 (1.2-1.8), more preferably 1: 1.2;

said step 1) is carried out at a reaction temperature of 0-40 ℃, preferably 20-40 ℃, more preferably 25 ℃;

the reaction of step 1) requires 4 to 24 hours, preferably 10 to 24 hours, more preferably 20 to 24 hours.

5. The preparation method according to claim 1 or 2, wherein the molar charge ratio of the compound of formula IV in step 2) to N-chlorosuccinimide is 1:1 to 5, preferably 1:2 to 4, and more preferably 1: 3.2.

6. The method according to claim 1 or 2, wherein the step 2) is carried out in a reaction solvent selected from the group consisting of an acid, an acid and water, and an organic solvent, wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid and formic acid, and more preferably acetic acid; the organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, and dimethyl sulfoxide or any mixture thereof, preferably acetonitrile; the reaction solvent is most preferably acetic acid or an aqueous solution of acetic acid or acetic acid and water and acetonitrile, and the molar charge ratio of the acid to the N-chlorosuccinimide is (1-50: 1, preferably (1-25: 1);

the ratio of the dosage g of the compound shown in the formula IV in the step 2) to the volume mL of the reaction solvent is 1: (1-20) g/mL;

the step 2) is carried out at a reaction temperature of 0-30 ℃, preferably 5-10 ℃;

the reaction of step 2) requires 1 to 36 hours, preferably 1 to 10 hours, and further preferably 2 to 4 hours.

7. The method as claimed in claim 6, wherein the step 2) is carried out in a reaction solvent selected from acid and a mixed solvent of water and an organic solvent, wherein the volume ratio of the organic solvent to the water is 1 (0.1-1); preferably 1 (0.1-0.5); more preferably in a volume ratio of 1: 0.5.

8. The process according to claim 1 or 2, wherein the compound of formula III is prepared by:

adding alkali and a sulfonation reagent into the compound of the formula II in an inert solvent to obtain a compound of a general formula III;

wherein the base is selected from inorganic base or organic base, the inorganic base is selected from sodium hydrogen, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide; the organic base is selected from the group consisting of N, N-diisopropylethylamine, triethylamine, lithium diisopropylamide, lithium N- (C1-6 alkyl) disilazide, lithium hexamethyldisilazane, potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium tetramethylpiperidine, potassium butoxide, potassium pentoxide, potassium amylate, and mixtures thereof; still more preferably, the inorganic base is sodium hydrogen and the organic base is N, N-diisopropylethylamine or N-butyllithium;

the sulfonating agent is selected from trihalomethanesulfonic anhydride, p-toluenesulfonyl chloride, methanesulfonyl chloride and compounds having C₁～C₆Alkyl or C₆～C₁₈Aryl N-substituted trifluoromethanesulfonimides, preferably trifluoromethanesulfonic anhydride.

9. The process according to claim 8, wherein the base is used in an amount of 0.8 to 3 molar equivalents, preferably 0.8 to 1.5 molar equivalents, based on the compound of formula II; the molar ratio of the compound of formula II to the sulfonating reagent in the reaction is 1: (1-2); preferably 1 (1.2-1.5);

the inert solvent is selected from one or the combination of nitrile solvents, ether solvents, halogenated hydrocarbons, aromatic solvents, N-dimethylformamide and dimethyl sulfoxide; further preferred is one or a combination of acetonitrile, tetrahydrofuran, dichloromethane, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether or dimethyl sulfoxide.

10. An intermediate compound of formula IV having the structure:

wherein R is₁Is hydrogen, C_1-6Alkyl or C_3-6A cycloalkyl group; preferably, R₁Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

preferred compounds of formula IV are those having the structure:

Technical Field

The invention relates to a preparation method of a 2- (chlorosulfonyl) cyclohexane-1-ethyl enoate derivative, belonging to the technical field of synthesis of Toll-like receptor 4(TLR4) inhibitor drug intermediates.

Background

Yamada M et al, Journal of Medicinal Chemistry,2005,48(23):7457-7467, reported that ethyl 2- (2-chloro-4-fluorophenyl) sulfonylcyclohexane-1-enecarboxylate was most effective, and was synthesized from sulfonyl chloride and aniline by coupling of sulfonyl chloride and aniline in the presence of triethylamine and double bond migration reaction, according to the following reaction formula:

the most studied compounds currently are Tak-242/resortrovid compounds, which are Toll-like receptor 4(TLR4) inhibitors, believed to be potent inhibitors of congenital inflammation and have the structural formula:

michael A Plunk et al Med Chem Lett.2020Jan 3; 11(2) 141-146, the prodrug of Tak-242 (resortrovid) compound is designed, the structure is as follows:

therefore, the synthesis research of the 2- (chlorosulfonyl) cyclohexane-1-ethyl enoate derivative which is a key intermediate for preparing the Toll-like receptor 4(TLR4) inhibitor compound has important significance, and the 2- (chlorosulfonyl) cyclohexane-1-ethyl enoate derivative (the compound shown in the formula I) is mainly prepared by the following methods at present:

patent one JP2008260760A reports the synthesis of 6- (chlorosulfonyl) spiro [2.5] -5-ene-5-carboxylic acid ethyl ester, which is obtained by 5 steps of reaction by using 6-oxaspiro [2.5] octane-5-carboxylic acid ethyl ester as a raw material; the route is as follows (Scheme 2):

the route of the scheme is long, the overall yield is low and is only 22.74%, and the purification is very difficult.

Patent II US 20090022706 reports that 2-cyclohexanone ethyl formate is used as a raw material to perform reduction reaction under the action of hydrogen sulfide gas to obtain a corresponding intermediate, and then chlorine is used to oxidize into sulfonyl chloride under the action of acetic acid; or oxidizing mercaptan into sulfonic acid and preparing the product of acyl chloride by using thionyl chloride. The reaction formula is (Scheme1):

the reaction uses hydrogen sulfide and chlorine gas respectively in two steps, the hydrogen sulfide is foul and toxic, the chlorine gas is high in toxicity, the cost of the chlorine gas for laboratories is very high, and the yield of the two steps is only 33.5%.

Disclosure of Invention

The invention aims to solve the technical problem of providing a preparation method of a 2- (chlorosulfonyl) cyclohexane-1-ethyl enoate derivative, wherein the compound is a key intermediate for preparing a Toll-like receptor 4(TLR4) inhibitor. The invention provides a preparation method of a brand new 2- (chlorosulfonyl) cyclohexane-1-ethyl olefin formate derivative, wherein the 2- (chlorosulfonyl) cyclohexane-1-ethyl olefin formate derivative shown in a general formula I is prepared by taking a 2-cyclohexanone ethyl olefin formate derivative as a raw material and carrying out esterification reaction, substitution reaction and oxidation reaction. The method of the invention adopts cheap raw materials, avoids using hydrogen sulfide and chlorine, has high reaction yield, low synthesis cost and good purity of the final product prepared by the reaction through searching and optimizing reaction conditions of each step, and is easy for industrial production.

The technical scheme for solving the technical problems is as follows:

the invention provides a preparation method of a 2- (chlorosulfonyl) cyclohexane-1-ethyl enoate derivative, which comprises the following steps:

1) dissolving a compound shown in a formula III in an organic solvent, and reacting in the presence of alkali to obtain a compound shown in a general formula IV;

2) adding the compound shown in the formula IV into N-chlorosuccinimide to prepare a compound shown in the formula I;

wherein R1 is hydrogen, C_1-6Alkyl or C_3-6A cycloalkyl group; preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; r2 is preferably Tf trifluoromethanesulfonyl, Ts p-toluenesulfonyl or Ms methanesulfonyl.

The step 1) of the present invention also provides a preferable technical scheme, the compound of formula III is dissolved in an organic solvent, and undergoes a substitution reaction with a nucleophile benzyl mercaptan in the presence of a base to obtain a compound of formula IV, wherein the reaction formula is as follows:

wherein R1 is hydrogen, C_1-6Alkyl or C_3-6A cycloalkyl group; preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; r2 is preferably Tf trifluoromethanesulfonyl, Ts p-toluenesulfonyl or Ms methanesulfonyl.

Examples of the base in step 1) of the present invention include one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, N-diisopropylethylamine, triethylamine, and the like; preferably potassium carbonate or sodium carbonate; more preferably potassium carbonate.

The molar ratio of the compound of the general formula III in the step 1) to the benzyl mercaptan is 1 (1-2); preferably 1 (1.2-1.8) or 1 (1.2-1.5), more preferably 1: 1.2. The organic solvent is selected from acetonitrile, tetrahydrofuran, dichloromethane and the like; acetonitrile is preferred.

The reaction temperature in step 1) of the present invention is 0 to 40 ℃, preferably 20 to 40 ℃, and more preferably 25 ℃.

The reaction time in step 1) of the present invention is 4 to 24 hours, preferably 10 to 24 hours, and more preferably 20 to 24 hours.

Step 2) of the present invention also provides a preferable technical scheme, wherein the compound of formula IV is dissolved in a mixed solvent of an organic solvent and water, and NCS (N-chlorosuccinimide) is added, wherein the reaction formula is as follows:

in the step 2), R1 is hydrogen or C_1-6Alkyl or C_3-6A cycloalkyl group; preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

The reaction temperature in step 2) of the present invention is preferably 0 to 30 ℃ and more preferably 5 to 10 ℃.

The reaction time in step 2) of the present invention is preferably 1 to 36 hours, more preferably 1 to 10 hours, and most preferably 2 to 4 hours.

The molar charge ratio of the compound of formula IV to the compound NCS in step 2) of the present invention is 1:1-5, preferably 1:2-4, and more preferably 1: 3.2.

The solvent in step 2) of the invention is selected from acid or acid and water and organic solvent, wherein the acid is selected from hydrochloric acid, acetic acid or formic acid, preferably acetic acid; examples of the organic solvent include tetrahydrofuran, dichloromethane, acetonitrile, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl t-butyl ether, diethyl ether, and dimethyl sulfoxide, or any mixture of the above solvents, preferably acetonitrile; the solvent is most preferably acetic acid or an aqueous acetic acid solution or a mixed solvent system of acetic acid and water with acetonitrile. Wherein the molar charge ratio of the acid to the compound NCS is (1-50) to 1, preferably (1-25) to 1; wherein the ratio of the amount g of the compound of formula IV to the volume amount mL of the reaction solvent is 1: (1-50) g/mL, preferably 1: (2-15) g/m; when the reaction solvent is selected from the mixed solvent of acid, water and organic solvent, the reaction is carried out, wherein the volume ratio of the organic solvent to the water is 1 (0.1-1); preferably 1 (0.1-0.5); more preferably in a volume ratio of 1: 0.5.

The invention also provides a preferable technical scheme for preparing the compound in the formula III in the step 1), wherein the compound in the formula III is prepared by reacting a compound in the formula II with a sulfonating reagent under the action of alkali, and the reaction formula is as follows:

the enol sulfonate derivative of the compound of formula III is prepared by reacting the compound of formula II with a sulfonating agent in the presence of a base.

The base used in the reaction of the present invention includes inorganic bases or organic bases, and examples of the inorganic base used include sodium hydrogen, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like; examples of the organic base used in the reaction include N, N-diisopropylethylamine, triethylamine, lithium diisopropylamide LDA, N- (C)_1-6Alkyl) lithium (e.g., n-butyllithium), lithium hexamethyldisilazane LiHMDS, potassium hexamethyldisilazane KHMDS, sodium hexamethyldisilazane NaHMDS, lithium tetramethylpiperidine LiTMP, potassium butoxide, potassium pentoxide, potassium pentanolate, and mixtures thereof. More preferably, the inorganic base comprises sodium hydrogen and the organic base comprises n- (C)_1-6Alkyl) lithium (e.g., n-butyllithium);

the base is preferably used in an amount of 0.8 to 4 molar equivalents, preferably 0.8 to 2.5 molar equivalents, based on the compound of formula II.

The sulfonating agent used in the reaction includes trihalomethanesulfonic anhydride, p-toluenesulfonyl chloride, methanesulfonyl chloride and a compound having C₁～C₆Alkyl or C₆～C₁₈Aryl N-substituted trifluoromethanesulfonimides (e.g. N-phenyltrifluoromethanesulfonimide (PhNTf)₂) Trihalomethanesulphonic anhydride (e.g. trifluoromethanesulphonic anhydride) is preferred. The molar ratio of the compound of formula II to the sulfonating reagent in the reaction is 1: (1-2); preferably 1 (1.1-1.5).

Examples of the organic solvent used in the reaction include, but are not limited to, one or a combination of nitrile solvents, ether solvents (e.g., tetrahydrofuran), halogenated hydrocarbons (e.g., dichloromethane), aromatic hydrocarbon solvents, N-dimethylformamide, and dimethylsulfoxide; the solvent is further preferably one or the combination of acetonitrile, tetrahydrofuran, dichloromethane, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether or dimethyl sulfoxide.

The reaction can preferably be carried out as follows: dissolving a compound of formula II and a base in an organic solvent, followed by adding a sulfonating agent thereto; according to a further preferable technical scheme, under the condition of-20-5 ℃, adding an alkali (such as sodium hydride) into an organic solution of the compound 5-substituted-2-cyclohexanone ethyl formate of the formula II, stirring for about 30 minutes to 2 hours, then dropwise adding a sulfonation reagent into a reaction system, slowly heating to 0-30 ℃, and stirring until the detection reaction is completed to obtain the compound of the formula III.

This reaction allows the compound of formula II enolsulfonate derivative to be readily prepared at-10 ℃ and higher without the use of column chromatography to obtain the compound of formula III in high yield.

The invention provides a preferable technical scheme, a preparation method of a 2- (chlorosulfonyl) cyclohexane-1-ethyl enoate derivative, which comprises the following synthetic route:

wherein R is₁Is hydrogen, C_1-6Alkyl or C_3-6A cycloalkyl group; preferably, R₁Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

wherein the reaction conditions of each step are as described above.

The invention also provides a novel intermediate compound shown in the formula IV, which has the following structure: :

wherein R is₁Is hydrogen、C_1-6Alkyl or C_3-6A cycloalkyl group; preferably, R₁Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

The invention also provides a preferred novel intermediate compound of formula IV, having the structure:

the method has the beneficial technical effects that:

1. the invention provides a brand-new industrialized route for synthesizing key intermediates of the cyclohexene derivatives containing the sulfonamide and ester groups, such as 2- (chlorosulfonyl) cyclohexane-1-ethyl enoate derivatives;

2. the synthetic route has short route and high yield, and the total yield of the three steps can reach more than 60 percent;

3. the synthetic route has cheap raw materials and convenient operation, does not use reaction reagents such as hydrogen sulfide or chlorine, and the like, uses the reagents which are environment-friendly and is suitable for industrial production;

4. a methodological reference was provided for the synthesis of similar compounds.

The method is a brand-new synthesis route which can be industrialized, and also provides a brand-new intermediate compound shown in a formula IV. Meanwhile, the compound of the formula I obtained by the route has good purity and good product stability, and has good methodological significance for preparing Toll-like receptor 4(TLR4) inhibitor medicines.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, which are not specified under specific conditions, are generally carried out under conventional conditions.

The starting materials or reagents used in the examples are, unless otherwise specified, commercially available.

The room temperatures stated in the examples are from 20 to 35 ℃. Unless otherwise indicated, the reagents were used without purification. All solvents were purchased from commercial suppliers, such as Aldrich (Aldrich), and used without treatment. The reaction was judged for termination by TLC analysis and/or by LC-MS analysis by consumption of starting material. Thin Layer Chromatography (TLC) for analysis was performed on glass plates (EMD Chemicals) precoated with silica gel 60F 2540.25 mm plates, visualized with UV light (254nm) and/or iodine on silica gel, and/or heated with TLC stains such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution, or ceric sulfate solution.

1H-NMR spectra were recorded on a Varian Mercury-VX400 instrument at 400MHz operation.

Abbreviations used in the present invention have the usual meaning in the art, such as: DCM represents dichloromethane and DMF represents N, N-dimethylformamide.

Example 1

To compound 1(1g,5.88mmol) in DCM (20mL) was added NaH (0.29g,12mmol) at 0 degrees. After nitrogen gas had been replaced, the mixture was stirred for 30 minutes to prepare trifluoromethanesulfonic anhydride Tf₂O (2.0g,7mmol) was added to the above reaction solution and slowly warmed to room temperature and stirred for 1-24 hours, after completion of the reaction, 20mL of water was added to quench, and then dichloromethane (20mL) was extracted twice, and the organic phase was dried. Spin-dry to give 2.0g of crude compound 2, the reaction is almost quantitative and can be used directly in the next step.

ESI/MS:m/z＝303(M+H)⁺.

Example 2

To the crude compound 2 obtained in all of example 1 and potassium carbonate (4g, 29mmol) in acetonitrile (40mL) was added benzyl mercaptan (1.38g, 11.11 mmol). The reaction was carried out at room temperature for 20-24 hours, and TLC showed completion of the reaction. The reaction was quenched by the addition of water (60mL), extracted twice with ethyl acetate (60mL), and dried over anhydrous sodium sulfate to give 1.46g of Compound 3 as a solid. The yield of the two steps is 89.8 percent, and the purity is 98.0 percent.

¹H NMR(400MHz,CDCl₃):7.20-7.40(m,5H),4.23(q,J＝7.2Hz,2H),4.05(s,2H),2.30-2.60(m.4H),1.60-1.80(4H,m),1.32(t,J＝7.2Hz,3H)；ESI/MS:m/z＝277(M+H)⁺.

Example 3

To compound 3(1g, 3.62mmol) in acetic acid (20mL) and water (2mL) under ice bath was added NCS (1.9g, 14.2mmol) in portions over 30 minutes. After stirring for 1-5 hours, TLC showed the reaction was substantially complete. After spin-drying, the crude product was washed with petroleum ether (30mL), filtered and the organic phase was spin-dried to give 0.73g of compound 4 as a colorless liquid in yield: 79.8 percent and the purity is 90.0 percent.

¹H NMR(400MHz,CDCl₃):4.31(q,J＝7.2Hz,2H),2.50-2.80(m,4H),1.70-1.95(m,4H),1.36(t,J＝7.2Hz,3H)；ESI/MS:m/z＝253(M+H)⁺.

Example 4

1(594g, 3.49mol) and NaH (168g, 6.98mol) were put into a dry four-necked bottle (10L). N is a radical of₂Replacement, adding dichloromethane (5L) for complete dissolution, stirring and cooling to 0 to-5 ℃, and slowly dripping Tf₂O (1478g, 5.2mol) and keeping the temperature of the reaction system between 0 and-5 ℃. After dropping, the temperature was naturally returned to room temperature (about 20 ℃ C.), and the mixture was stirred for 16 hours.

TLC monitoring reaction completion, H₂The excess NaH from the reaction was quenched with O (5L), the aqueous phase was back extracted with a little dichloromethane, the organic phases were combined and anhydrous NaSO was used₄Drying and rotary steaming to dry. 1014g of a tan-colored oily product are obtained. The product does not need to be purified except the yield, and can be directly used for the next reaction feeding.

Example 5

2(1014g) obtained in example 4 was put into a dry four-necked flask (10L), acetonitrile (5L) was added thereto and stirred to dissolve completely, and then potassium carbonate (1390g) was added thereto, followed by slowly adding benzyl mercaptan (500g) and stirring at room temperature for 24 hours.

TLC was used to monitor the completion of the reaction, the reaction solution was transferred to a single-neck flask, and after spin-drying under reduced pressure, ethyl acetate (5L) and H were added₂O (5L), washing off excess K₂CO₃Then, use Na₂SO₄The organic phase was dried and spin dried under reduced pressure to give 1500g of crude product as a pale yellow solid. Recrystallization from ethyl acetate/n-heptane gave 604g of pure product as a white solid in a two-step overall yield of 62.6% and 97.0% purity.

Example 6

3(548g, 1eq) was dissolved in acetic acid (5L), water (2.5L) was added and the temperature was reduced to between 5-10 ℃. NCS (848g, 3.2eq times molar equivalent) is slowly added in batches, and after the addition is finished, the temperature is kept between 5 and 10 ℃ and the mixture is stirred for 2 hours.

TLC is used for monitoring the reaction, after the reaction liquid is decompressed and dried in a rotating mode (the temperature does not exceed 35 ℃), petroleum ether or normal hexane is pulped, filtering is carried out, and the light yellow oily liquid 350g is obtained after drying in a rotating mode, and the yield is 69.8%.

Example 7

Following the procedure of example 4, 3000g of compound 1,2.1e qNaH and 1.5eq trifluoromethanesulfonic anhydride were charged to give 5327g of compound 2, which, disregarded yield and without purification, was used directly in the next reaction charge.

Example 8

According to the procedure of example 5, 5327g of compound 2 (from example 7) were charged to give 3410g of compound 3, in a total yield of 70.0% in two steps and with a purity of 96.5%.

Example 9

The synthesis of example 6 was carried out by dissolving 3(1095g, 1eq) in acetic acid (10L), adding water (5L) and cooling to between 5 and 10 ℃. NCS (1695g, 3.2eq) is slowly added in batches, and after the addition is finished, the temperature is kept between 5 and 10 ℃, and the mixture is stirred for 2 hours.

TLC is used for monitoring the reaction, after the reaction liquid is decompressed and dried in a rotating mode (the temperature does not exceed 35 ℃), petroleum ether or normal hexane is pulped and filtered, and the light yellow oily liquid 648.76g is obtained after drying in a rotating mode, and the yield is 64.8%.

Example 10

The procedure and charge ratios of examples 1-3 were followed using 1a (10g) as starting material, p-toluenesulfonyl chloride (2eq) as sulfonation reagent and potassium carbonate (3eq) as base to give 3 a; dissolve 3a in dichloromethane and add NCS (2eq) to give 4a as a white solid 8.87g with 65.0% overall three step yield.

Intermediate 3a ESI/MS: M/z 333(M + H)⁺.

¹H-NMR(CDCl₃，400M)δ:0.92(9H,s),1.22-1.46(2H,m),1.36(3H,t,J＝7.2Hz),2.04-2.35(2H,m),2.45-2.65(2H,m),2.79-2.92(1H,m),4.31(2H,q,J＝7.2Hz)。

Example 11

To compound 1b (1.16g,5.91mmol) in DCM (20mL) was added N, N-diisopropylethylamine (1.90g,14.7mmol) at 0 degrees. After nitrogen is replaced, the mixture is stirred for 30 minutes, the temperature is reduced to-18 ℃, and the trifluoromethanesulfonic anhydride Tf is cooled₂O (2.0g,7.09mmol) was added to the reaction mixture, stirred for 10 minutes, slowly warmed to room temperature and stirred for 18 hours, crude LCMS showed reaction was substantially complete, after addition of 20mL water and quenching, dichloromethane (20mL) was extracted twice and the organic phase was dried. Spin-drying afforded 1.70g of compound 2b, 87.6% yield. ESI/MS, M/z 329(M + H) +.

Example 12

To a solution of compound 1b (1.16g,5.91mmol) in tetrahydrofuran (20mL) was added lithium hydroxide (0.57g,23.64mmol) at about 5 degrees. After nitrogen is replaced, the mixture is stirred for 30 minutes, the temperature is reduced to 0 ℃, and the trifluoromethanesulfonic anhydride Tf is cooled₂O (1.83g,6.49mmol) was added to the reaction mixture, stirred for 10 min, slowly warmed to room temperature and stirred for 16 h, crude TLC showed the reaction was substantially complete, quenched with 20mL water, extracted twice with dichloromethane (20mL) and the organic phase dried. Spin-dry to give 1.64g of compound 2b, 84.5% yield.

ESI/MS:m/z＝329(M+H)+.

Example 13

2b (1.50g,4.57mmol) from example 12 was put into a dry four-necked flask (50mL), tetrahydrofuran (15mL) was added, and after complete dissolution by stirring, N-diisopropylethylamine (1.77g, 13.70mmol) was added, followed by slow addition of benzyl mercaptan (0.85g, 6.84mmol), and stirring at 20 ℃ for 16-24 hours.

TLC was used to monitor the completion of the reaction, and the reaction solution was transferred to a single-necked flask, and after spin-drying under reduced pressure, ethyl acetate (30mL) and H were added₂O(30mL) By using Na₂SO₄The organic phase was dried and spin dried under reduced pressure to give 2g of crude product 3 b. Recrystallization from ethyl acetate/n-heptane gave 1.24g of pure product, 89.7% yield, 98.0% purity. ESI/MS: M/z 303(M + H) +.

Example 14

According to the synthesis of example 6, 3b (1g, 3.3mmol) was dissolved in acetonitrile (20mL) and NCS (2.20g, 16.5mmol) was added slowly. Then, aq 2M HCl (8.3mL) was added slowly. The reaction mixture was stirred at room temperature overnight with saturated Na₂CO₃The aqueous solution was quenched and extracted with EtOAc (3X 30 mL). The organic phase is passed through Na₂SO₄Drying, and vacuum concentrating to obtain colorless oily substance 4 b; yield: 0.77g (83.7%). ESI/MS: M/z 279(M + H) +.

¹H-NMR(CDCl₃,400MHz)δppm:4.28(2H,q,J＝7Hz),2.77-2.69(2H,m),2.43-2.38(2H,m),1.62(2H,t,J＝6Hz),1.33(3H,t,J＝7Hz),0.52-0.46(4H,m).