阅读说明：本技术 高质量的苯乙基异硫氰酸酯的制备方法 (Preparation method of high-quality phenethyl isothiocyanate ) 是由 何浩明 孙小强 钱春国 王亚夏 卞春亭 程景才 于 2021-09-02 设计创作，主要内容包括：本发明公开了一种高质量的苯乙基异硫氰酸酯的制备方法,包括以下步骤：①在反应瓶中加入苯乙胺和溶剂,再加入三乙胺；开始滴加二硫化碳溶液；加毕加入相转移催化剂苄基三乙基氯化铵的水溶液并搅拌；用GC检测,苯乙胺含量≤0.1%作为反应终点,以控制杂质Ⅰ的生成量；②向步骤①得到的反应物料中加入二碳酸二叔丁酯溶液,反应8～10小时,升温至50±5℃反应25～35min,再降至室温,用HPLC检测杂质Ⅱ的含量不超过0.5%作为反应终点,以控制杂质Ⅱ的含量；③对步骤②得到的反应液提纯得到苯乙基异硫氰酸酯。本发明严格控制杂质的产生,制备的苯乙基异硫氰酸酯纯度高,是高质量的苯乙基异硫氰酸酯,且本发明方法的收率高。(The invention discloses a preparation method of high-quality phenethyl isothiocyanate, which comprises the following steps: adding phenylethylamine and a solvent into a reaction bottle, and then adding triethylamine; dropping carbon disulfide solution; adding the aqueous solution of a phase transfer catalyst benzyltriethylammonium chloride and stirring; GC is used for detection, and the content of phenethylamine is less than or equal to 0.1 percent and is used as a reaction end point to control the generation amount of the impurity I; adding a di-tert-butyl dicarbonate solution into the reaction material obtained in the step I, reacting for 8-10 hours, heating to 50 +/-5 ℃, reacting for 25-35 min, cooling to room temperature, and detecting that the content of the impurity II is not more than 0.5% by using HPLC (high performance liquid chromatography) as a reaction end point to control the content of the impurity II; and thirdly, purifying the reaction liquid obtained in the step II to obtain the phenethyl isothiocyanate. The method strictly controls the generation of impurities, the prepared phenethyl isothiocyanate has high purity and high quality, and the method has high yield.)

1. A preparation method of high-quality phenethyl isothiocyanate is characterized by comprising the following steps:

adding phenylethylamine and an organic solvent into a reaction bottle, starting stirring, cooling to 5-10 ℃ in an ice bath, and then adding a triethylamine solution; dropping carbon disulfide solution, wherein the temperature in the bottle is controlled to be 10-20 ℃ in the dropping process; after the dropwise addition is finished, adding an aqueous solution of a phase transfer catalyst benzyltriethylammonium chloride and stirring; removing the ice bath, stirring for reaction at 10-35 ℃, detecting the reaction solution by using GC, and taking the phenylethylamine content of less than or equal to 0.1% as a reaction end point to control the content of the impurity I;

adding a di-tert-butyl dicarbonate solution into the reaction material obtained in the step I, controlling the temperature in the dropping process to be 5-10 ℃, reacting for 8-10 hours at 10-35 ℃, then heating to 50 +/-5 ℃, reacting for 25-35 min, then cooling to 10-35 ℃, and detecting the content of the impurity II to be not more than 0.5% by using HPLC (high performance liquid chromatography) as a reaction end point;

and thirdly, purifying the reaction liquid obtained in the step II to obtain the phenethyl isothiocyanate.

2. The method for producing high-quality phenethylisothiocyanate according to claim 1, characterized in that: the structural formula of the impurity I is as follows:

。

3. the method for producing high-quality phenethylisothiocyanate according to claim 1, characterized in that:

the structural formula of the impurity II is as follows:

。

4. the method for producing high-quality phenethylisothiocyanate according to claim 1, characterized in that:

in the step I, the feeding ratio of phenylethylamine to carbon disulfide is 1: 1.08-1.2.

5. The method for producing high-quality phenethylisothiocyanate according to claim 1, characterized in that:

in the second step, the molar ratio of the added di-tert-butyl dicarbonate to the phenylethylamine is 1.08-1.2: 1.

6. The method for producing high-quality phenethylisothiocyanate according to claim 1, characterized in that: the organic solvent in the step I, the solvent of triethylamine solution, the solvent of carbon disulfide solution and the solvent of di-tert-butyl dicarbonate solution in the step II are the same, and the solvents are organic solvents which are not mutually soluble with water and do not react with di-tert-butyl dicarbonate.

7. The method for producing high-quality phenethylisothiocyanate according to claim 6, characterized in that: the organic solvent used in the first step and the second step is one of dichloromethane, trichloromethane, benzene, toluene, methyl tert-butyl ether, cyclohexane and tetrahydrofuran.

8. The method for producing high-quality phenethylisothiocyanate according to claim 1, characterized in that: in the third step, the reaction liquid obtained in the second step is cooled to 5-10 ℃, deionized water is added, dilute hydrochloric acid is added dropwise to adjust the pH value to 6-7, the mixture is stirred and then stands for layering, the organic layer is washed by water, then is dried by anhydrous sodium sulfate, and is concentrated to be dry in vacuum in a water bath, so that an oily crude product is obtained; distilling and rectifying the oily crude product to obtain the high-quality phenethyl isothiocyanate.

Technical Field

The invention relates to a preparation method of high-quality phenethyl isothiocyanate.

Background

There are many methods for synthesizing isothiocyanates reported so far, including phosgene method, thiophosgene method, carbon disulfide method, bis (trichloromethyl) carbonate method, thiourea decomposition method, phenylthiocarbamate method, thiocyanate method, and the like.

The carbon disulfide method is that phenylethylamine (or other amine organic matters) and carbon disulfide and other raw materials are dissolved in an organic solvent, dithiocarbamate is synthesized under the catalysis of alkali, and isothiocyanate compounds are obtained through reaction under the action of a desulfurizer. As for the selection of the desulfurizing agent, many studies have been made, and methyl chloroformate, p-toluenesulfonyl chloride, phosgene solid, elemental iodine, chlorosilane, chlorophosphate, dicyclohexylcarbodiimide, or the like are mainly used. The method has the advantages of avoiding using highly toxic raw materials, but obtaining products with more impurities and low purity.

For example, chinese patent document CN 108503568A (application No. 201710108328.9) discloses a method for preparing high-purity isothiocyanate compounds suitable for industrial production, comprising the steps of: (1) reacting ANH2 with CS2 in an organic solvent in the presence of an organic base to obtain a first reaction mixture containing dithiocarbamate; (2) adding a desulfurizing agent into the first reaction mixture in the presence of an optional alkali catalyst to perform desulfurization reaction to obtain a second reaction mixture containing an isothiocyanate compound; (3) and (3) carrying out post-treatment purification on the second reaction mixture to obtain the isothiocyanate shown in the formula (I). The organic solvent is a solvent which can dissolve phenylethylamine and dithiocarbamate and is immiscible with water; preferably, the organic solvent is selected from the group consisting of: ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, butyl acetate, isobutyl acetate, pentyl propionate, butanol, isobutanol, pentanol, sec-pentanol, tert-pentanol, 3-methyl-2-butanol, hexanol, heptanol, dichloromethane, dichloroethane, chloroform, diethyl ether, petroleum ether, cyclohexane, or combinations thereof. The desulfurizing agent is selected from the following group: methyl chloroformate, p-toluenesulfonyl chloride, phosgene solids, elemental iodine, chlorosilane, chlorophosphate, dicyclohexylcarbodiimide, dicyandiamide, triphenylphosphine, di-tert-butyl dicarbonate, cyanuric chloride, or a combination thereof.

For another example, chinese patent document CN110668986A (application No. 201911041422.2) discloses a method for preparing phenethyl isothiocyanate, under the protection of nitrogen, phenethylamine, triethylamine and tetrahydrofuran are mixed according to a molar ratio of 1: 1-4: 5-15 to obtain a mixture, and then in an ice water bath, mixing the mixture according to a molar ratio of phenylethylamine to carbon disulfide of 1: 1-2, dropwise adding carbon disulfide into the mixture by using a peristaltic pump, keeping the temperature at 0-5 ℃ for reaction, uniformly mixing, gradually heating to room temperature, and reacting at the temperature for 1-3 hours to obtain a reaction solution; dropwise adding p-toluenesulfonyl chloride into the reaction liquid in an ice water bath according to the molar ratio of phenethylamine to p-toluenesulfonyl chloride of 1: 1-1.5, uniformly mixing, heating to room temperature, reacting for 0.5-2.0 h at the temperature, and adding phenethylamine, hydrochloric acid and methyl tert-butyl ether into the obtained reaction liquid according to the molar ratio of 1: 0.8-1.2: and (3) adding hydrochloric acid and methyl tert-butyl ether to 8.0-12.0, mixing and extracting, desolventizing the extracted organic phase, and distilling to obtain the phenethyl isothiocyanate.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a preparation method of high-purity and high-yield high-quality phenethyl isothiocyanate.

The technical scheme for realizing the aim of the invention is a preparation method of high-quality phenethyl isothiocyanate, which comprises the following steps:

adding phenylethylamine and an organic solvent into a reaction bottle, starting stirring, cooling to 5-10 ℃ in an ice bath, and then adding a triethylamine solution; dropping carbon disulfide solution, wherein the temperature in the bottle is controlled to be 10-20 ℃ in the dropping process; after the dropwise addition is finished, adding an aqueous solution of a phase transfer catalyst benzyltriethylammonium chloride and stirring; removing the ice bath, stirring for reaction at 10-35 ℃, detecting the reaction solution by using GC, and taking the phenylethylamine content of less than or equal to 0.1% as a reaction end point to control the content of the impurity I.

Adding di-tert-butyl dicarbonate solution into the reaction material obtained in the step I, controlling the temperature in the dropping process to be 5-10 ℃, reacting for 8-10 hours at 10-35 ℃, then heating to 50 +/-5 ℃, reacting for 25-35 min, then cooling to 10-35 ℃, and detecting that the content of the impurity II does not exceed 0.5% by using HPLC (high performance liquid chromatography) to serve as a reaction end point.

And thirdly, purifying the reaction liquid obtained in the step II to obtain the phenethyl isothiocyanate.

The structural formula of the impurity I is as follows:

。

the structural formula of the impurity II is as follows:

。

further, in the step (i), the feeding ratio of phenylethylamine to carbon disulfide is 1: 1.08-1.2.

Further, in the second step, the molar ratio of the added di-tert-butyl dicarbonate to the phenylethylamine is 1.08-1.2: 1.

Further, the organic solvent in the step I, the solvent of triethylamine solution, the solvent of carbon disulfide solution and the solvent of di-tert-butyl dicarbonate solution in the step II are the same, and the solvents are organic solvents which are not mutually soluble with water and do not react with BOC anhydride.

Optionally, the organic solvent used in the first step and the second step is one of dichloromethane, chloroform, benzene, toluene, methyl tert-butyl ether, cyclohexane and tetrahydrofuran.

In the third step, the reaction liquid obtained in the second step is cooled to 5-10 ℃, deionized water is added, dilute hydrochloric acid is added dropwise to adjust the pH value to 6-7, the mixture is stirred and then stands for layering, the organic layer is washed by water, then is dried by anhydrous sodium sulfate, and is concentrated to be dry in a water bath vacuum manner, so that an oily crude product is obtained; distilling and rectifying the oily crude product to obtain the high-quality phenethyl isothiocyanate.

The invention has the positive effects that:

(1) the invention finds out and confirms the structure of the main impurities in the carbon disulfide route, researches the generation mechanism of the impurities I and II in the preparation process of the phenethyl isothiocyanate, and adopts a way and a method for eliminating and controlling the impurities I and II.

For impurity I, the impurity I is a byproduct generated by the reaction of the raw material phenylethylamine and di-tert-butyl dicarbonate, in order to reduce the content of the impurity I, on one hand, the adding amount of carbon disulfide in the preparation of dithiocarbamate is increased, and the molar ratio of the phenylethylamine to the carbon disulfide is increased from 1:1 to 1: 1.08 to 1.2; (ii) a On the other hand, detecting the content of the phenylethylamine by using a GC method, and taking the detected content of the phenylethylamine in the reaction liquid as the reaction end point of the first step when the content of the phenylethylamine in the reaction liquid is less than or equal to 0.1 percent; if the final impurity level is still exceeded, it is removed in the distillation step of the work-up process, and several means work together to control the impurity level.

For impurity II, impurity II is generated in the desulfurization step, and in order to reduce the content of impurity II, the measures adopted by the invention are as follows:

firstly, the feeding molar ratio of di-tert-butyl dicarbonate is increased, and the molar ratio of phenethylamine to di-tert-butyl dicarbonate is increased from 1:1 to 1: 1.08 to 1.2, and ensuring the excess of di-tert-butyl dicarbonate.

Secondly, changing the process to improve the reaction capability of the di-tert-butyl dicarbonate, monitoring the content change of the impurity II by using HPLC, and finally determining the process operation: dropping di-tert-butyl dicarbonate at 5-10 deg.C, reacting at 10-35 deg.C, heating to 50 + -5 deg.C, reacting again, and cooling to 10-35 deg.C.

Thirdly, if the final impurity II content is still exceeded, it is removed in post-treatment.

The content of the impurity I and the impurity II is strictly controlled in the reaction and the post-treatment, the content of the impurity I and the impurity II in the final product is extremely low, the content of the phenethyl isothiocyanate reaches more than 99.7 percent, and the prepared phenethyl isothiocyanate is high in quality.

(2) In the invention, a phase transfer catalyst benzyltriethylammonium chloride aqueous solution is added in the reaction, and a finished product phenethyl isothiocyanate generated after the dithiocarbamate in the water phase is subjected to desulfurization reaction is transferred to an organic phase, so that the reaction is promoted to be carried out in the direction of generating the phenethyl isothiocyanate, the complete reaction is ensured as far as possible, the yield is improved, and the reaction time is shortened.

(3) The preparation process of the invention uses an organic solvent in the whole course, and is convenient for recycling.

(4) The phenethyl isothiocyanate prepared by the method has high purity and high reaction yield.

Drawings

FIG. 1 is an HPLC chromatogram of the crude product of example 1.

FIG. 2 is a HPLC chromatogram of the final product of example 1.

FIG. 3 is a HPLC detection profile of the final product of example 2.

FIG. 4 is an HPLC detection profile of the crude product in comparative example 1.

FIG. 5 shows the TLC detection of a mixture containing impurity I.

FIG. 6 shows the NMR spectrum H of impurity I.

FIG. 7 shows the NMR spectrum C of impurity I.

FIG. 8 is a mass spectrum of impurity I.

FIG. 9 shows the NMR spectrum H of impurity II.

FIG. 10 shows the NMR spectrum C of impurity II.

FIG. 11 is a mass spectrum of impurity II.

FIG. 12 is a control of cis-trans isomers of impurity II.

FIG. 13 is a diagram showing a mechanism of producing impurity II.

Detailed Description

(example 1)

The preparation method of high-quality phenethyl isothiocyanate of this example adopts the following route:

；

the method specifically comprises the following steps:

preparation of dithiocarbamate.

1104g (9.1 mol) of phenethylamine and 2.4L of dichloromethane are added into a 10L four-neck flask, stirring is started, and the temperature is reduced to 5-10 ℃ in an ice bath; 1010g (10 mol) of triethylamine were added thereto, at which time the internal temperature of the flask was 10 ℃. Beginning to dropwise add carbon disulfide 763g (10 mol) of dichloromethane (1L), and controlling the temperature in the bottle to be 10-20 ℃ in the dropwise adding process; after the dropwise addition, 20g of 50 mass percent aqueous solution of a phase transfer catalyst, namely benzyltriethylammonium chloride (TEBA) is added and stirred; removing the ice bath, stirring and reacting for 1 hour at room temperature (10-35 ℃), detecting the reaction liquid by GC, and taking the content of phenethylamine less than or equal to 0.1% as the reaction end point.

The amount of the phase transfer catalyst TEBA added was 5g to 20g, in this example 10 g.

The applicant researches and discovers that impurity I is generated in the process of preparing phenethyl isothiocyanate by adopting a carbon disulfide route (see a test example for specific discovery and identification), and the possible generation path of the impurity I is as follows:

。

therefore, the content of the impurity I can be controlled by effectively controlling the content of the phenethylamine.

In order to reduce the content of phenylethylamine, on one hand, the adding amount of carbon disulfide in the preparation of dithiocarbamate is increased, and the molar ratio of phenylethylamine to carbon disulfide is increased from 1:1 to 1: 1.08 to 1.2; and on the other hand, detecting the content of the phenethylamine by using a GC method, and taking the detected content of the phenethylamine in the reaction liquid as the reaction end point of the first step when the content of the phenethylamine in the reaction liquid is less than or equal to 0.1 percent. The content of impurity I is controlled by the above means.

And ② desulfurizing.

2188g (10 mol) of a dichloromethane (1L) solution of BOC anhydride (di-tert-butyl dicarbonate) is added into the reaction material obtained in the step I, the temperature in the dropping process is controlled to be 5-10 ℃, the reaction is carried out for 8-10 hours at room temperature (10-35 ℃), then the temperature is increased to 50 +/-5 ℃ for half an hour, the reaction is carried out to be cooled to room temperature, and HPLC is used for detecting that the content of the impurity II is not more than 0.5% to be used as a reaction end point.

In the above step, phenylethylamine: carbon disulfide: the feeding ratio of BOC anhydride is 1: 1.1.

The solvent used in the above step is dichloromethane, and besides dichloromethane, other solvents which are not miscible with water and do not react with BOC anhydride, such as one of chloroform, benzene, toluene, methyl tert-butyl ether, cyclohexane and tetrahydrofuran, can be used.

The impurities are studied and identified in the experimental examples.

Wherein the structure of impurity II is:

。

impurities II are generated in the desulfurization step, and in order to reduce the content of the impurities II, the measures are as follows:

firstly, the feeding molar ratio of di-tert-butyl dicarbonate is increased, and the molar ratio of phenethylamine to di-tert-butyl dicarbonate is increased from 1:1 to 1: 1.08 to 1.2, and ensuring the excess of di-tert-butyl dicarbonate.

Secondly, changing the process to improve the reaction capability of the di-tert-butyl dicarbonate, monitoring the content change of the impurity II by using HPLC, and finally determining the process operation: dropping di-tert-butyl dicarbonate at 5-10 deg.C, reacting at 10-35 deg.C, heating to 50 + -5 deg.C, reacting again, and cooling to 10-35 deg.C.

Thirdly, if the final impurity II content is still exceeded, it is removed in post-treatment.

And thirdly, post-processing.

Cooling the reaction liquid obtained in the second step to 5-10 ℃, adding 2000g of deionized water, then dropwise adding dilute hydrochloric acid to adjust the pH value to 6-7, stirring, standing for layering, washing an organic layer with water for three times, wherein each time is 300L, then drying with anhydrous sodium sulfate, and concentrating in vacuum in a water bath until the organic layer is dried to obtain 2044g of oily crude product, wherein the HPLC detection spectrum of the crude product is shown in figure 1, the content of the target product in the oily crude product is 76.37%, and the conversion rate is 99%.

Crude oily product is subjected to coarse distillation to obtain 1510g, and is subjected to tertiary rectification (reflux ratio is 1: 5-10) to obtain 1351g of finished product, wherein HPLC detection spectrum is shown in figure 2, purity is 99.78%, and yield is 88%.

(example 2)

The preparation method of high-quality phenethyl isothiocyanate of this example was the same as that of example 1 except that: phenylethylamine: carbon disulfide: the feeding ratio of BOC anhydride is 1: 1.08.

The solvent used in steps (r) and (c) of this example was toluene.

The purity of the finished product obtained by post-treatment is 99.84% by HPLC detection, and the HPLC detection spectrum is shown in figure 3.

(example 3)

The preparation method of high-quality phenethyl isothiocyanate of this example was the same as that of example 1 except that: phenylethylamine: carbon disulfide: the feeding ratio of BOC anhydride is 1: 1.15: 15.

The solvent used in steps (r) and (c) of this example was methyl tert-butyl ether.

The purity of the finished product obtained by post-treatment is 99.75 percent by HPLC detection.

Comparative example 1

110g of phenethylamine and 240mL of absolute ethanol were placed in a 1L four-necked flask, and stirring was started, and then 101g of triethylamine was added thereto at an internal temperature of 15 ℃. A solution of carbon disulfide in ethanol (76 g of carbon disulfide dispersed in 100mL of ethanol) was started dropwise, the temperature being controlled between 10 ℃ and 20 ℃. After the addition, an ethanol solution of BOC anhydride (218 g of BOC anhydride dispersed in 100mL of ethanol) was added, the reaction was carried out at room temperature for 10 hours, and then the reaction was carried out at a temperature of 50 ℃ for half an hour.

And after the reaction is finished, distilling under reduced pressure to remove ethanol, extracting by using dichloromethane, adding dilute hydrochloric acid into an extracting solution to adjust the pH value to be 6-7, washing by using deionized water for three times, drying a dichloromethane solution by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude oily substance.

The crude product is subjected to HPLC detection, an HPLC spectrum is shown in figure 4, and two main peaks can be seen from figure 4, wherein one main peak is phenethyl isothiocyanate, and the other main peak is a reaction product of ethanol and BOC anhydride, and the separation is not performed due to the excessive content of byproducts.

(test examples, discovery and identification of impurities)

Structural determination of one, two main impurities

1. The impurity I can be separated through one-time column chromatography, and the specific experimental steps are as follows:

(1) a small amount of the mixture (crude phenethylisothiocyanate prepared according to the carbon disulfide route) was diluted with dichloromethane and dissolved, and the mixture was subjected to conventional TLC detection (developing solvent and ratio, V)_{(Petroleum ether)}：V_{(Ethyl acetate)}= 5: 1). By analysis, we consider the small spot on the TLC plate to be impurity I (see figure 5).

TLC detection of the mixture [ V ]_{(Petroleum ether)}：V_{(Ethyl acetate)} = 5：1]。

(2) Determining the proportion of column chromatography separating developing agent and the type of silica gel [ V ] according to the TLC detection condition_{(Petroleum ether)}：V_{(Ethyl acetate)}= 20: 1, silica gel (great, 200-mesh 300)]. 1.0 g of the mixture A was weighed out and subjected to column chromatography separation, and the objective product was collected and concentrated to obtain an objective substance, which was washed with n-hexane (5.0 mL. times.3), followed by filtration and drying to obtain 70 mg of an impurity I white solid, the isolation yield of the impurity I being 7%.

The high performance liquid chromatography detection of the impurity I shows that the impurity I generates a peak within 6.5 min, and the purity is 99%.

(3) Nuclear magnetic (hydrogen spectrum of fig. 6, carbon spectrum of fig. 7) and mass spectra (fig. 8) characterization of impurity I:

¹H NMR (300 MHz, CDCl₃) δ 7.48 – 7.07 (m, 5H), 4.54 (br, 1H), 3.37 (t, J = 7.0 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 1.43 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 155.92, 139.02, 128.84, 128.59, 126.42, 79.29, 41.88, 36.29, 28.43. MS (EI, m/z): calcd. for C₁₃H₁₉NO₂ [M]⁺: 221, found:221.

from nuclear and mass spectral data, simultaneous comparison literature (Tetrahedron, 2020,76131223) the structure of impurity I is presumed to be:

。

(4) possible generation routes of impurity I:

。

2. the impurity II can be separated through secondary column chromatography, and the specific experimental steps are as follows:

(1) the crude mixture (crude phenethylisothiocyanate prepared according to the carbon disulfide route) was dissolved by dilution with dichloromethane and the mixture was subjected to conventional TLC detection (developing solvent and ratio, V)_{(Petroleum ether)}：V_{(Ethyl acetate)}= 5: 1). Determining the proportion of column chromatography separating developing agent and the type of silica gel [ V ] according to the TLC detection condition_{(Petroleum ether)}：V_{(Ethyl acetate)}= 20: 1, silica gel (great, 200-mesh 300)]. 10g of the mixture was weighed out and subjected to column chromatography to obtain 3.0 g of an oily substance.

(2) Changing the type of developing agent (V)_{(Petroleum ether)}：V_{(methylene chloride)}= 5: 1) performing secondary TLC detection on 3.0 g of oily substance, and determining the proportion of column chromatography separation developing agent and the type of silica gel [ V ] according to TLC detection condition_{(Petroleum ether)}：V_{(methylene chloride)}= 20: 1, silica gel (great, 200-mesh 300)]. Column chromatography of 3.0 g of the oil gave 0.6 g of impurity II in a total separation yield of 6%.

High performance liquid chromatography detection of the impurity II shows that the peak is generated in 26.3 min, and the purity is 99.8%.

(3) Nuclear magnetic (hydrogen spectrum fig. 9, carbon spectrum fig. 10) and mass spectra (fig. 11) characterization of impurity II:

¹H NMR (300 MHz, CDCl₃) δ7.55 (br, 0.2H), 7.28 – 7.12 (m, 5H), 7.02 (br, 0.72H), 4.62 (s, 0.4H), 4.54 (s, 1.56H), 3.91 (q, J = 6.0, 1.56H), 3.60 (q, J = 6.0 Hz, 0.4H), 2.92 – 2.84 (m, 2H), 1.42 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 199.05, 195.92, 172.05, 168.71, 137.99, 137.04, 129.00, 128.87, 128.76, 128.71, 127.16, 126.88, 85.88, 48.25, 47.39, 37.86, 37.29, 34.88, 34.14, 28.22. HRMS (ESI, m/z): calcd. for C₁₅H₂₂NO₂S₃[M+H]⁺: 344.0807, found: 344.0803.

the nuclear magnetic spectrum shows that impurities II exist cis-trans isomers, the isomer structure is 4:1, wherein trans-configuration is a main product, and the trans-configuration of the impurities II is the main product due to steric hindrance of the structure of the compounds.

The structure of impurity II is:

a specific control of cis and trans isomers is shown in FIG. 12.

(4) A possible route for impurity II generation is shown in FIG. 13 (reference)Eur. J. Org. Chem. 2008, 519-523): firstly, phenylethylamine and carbon disulfide form a salt intermediate A under the action of triethylamine. Secondly, the intermediate A and solvent dichloromethane generate intermolecular nucleophilic substitution reaction to obtain chloromethyl intermediate B, and the intermediate B and the intermediate A rapidly generate secondary intermolecular nucleophilic substitution reaction to generate intermediate C and enol isomer D thereof. Then, the isomer D and BOC anhydride generate nucleophilic substitution reaction intermediate E under the action of triethylamine, and the intermediate E quickly forms intramolecular four-membered ring intermediate conversion product 2-phenylethyl isocyanate and intermediate F. The intermediate F is subjected to enol isomerization to obtain the corresponding impurity II (wherein the trans configuration is a main product, and the cis configuration is a minor product).