Identification and Quantification of Related Impurities in 2-Chloroethyl

Nov 25, 2009 - ... of all of these related impurities were analyzed, and some practical suggestions are put forward for their removal from or avoidanc...
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Ind. Eng. Chem. Res. 2010, 49, 443–447

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APPLIED CHEMISTRY Identification and Quantification of Related Impurities in 2-Chloroethyl Phenyl Sulfide for Industrial Use Jun-Qin Qiao, Yan-Chu Bao, Ji-Hong Yang, Qin Jiang, and Hong-Zhen Lian* Key Laboratory of Analytical Chemistry for Life Science (Ministry of Education of China), School of Chemistry & Chemical Engineering and Center of Materials Analysis, Nanjing UniVersity, 22 Hankou Road, Nanjing 210093, China

A combination of gas chromatography and mass spectrometry (GC-MS) was applied to separate and identify the relative substances in 2-chloroethyl phenyl sulfide (CEPS), an industrial intermediate formed in the synthesis of sulfinpyrazone. Six impurities, including 1,2-dichloroethane, thiophenol, diethylmalonate, tributylamine, diphenyl disulfide, and 1,2-dithiophenylethane, were verified. According to the production technique, the sources of all of these related impurities were analyzed, and some practical suggestions are put forward for their removal from or avoidance in CEPS. Furthermore, a technique involving high-performance liquid chromatography with UV detection (HPLC-UV) was developed to separate and determine thiophenol, the key impurity in CEPS. A linear standard curve was obtained for thiophenol in concentrations between 2.65 × 10-4 and 0.106 mg mL-1, and the detection limit of thiophenol was 1.32 × 10-4 mg mL-1. Excellent precision and accuracy were shown from the method validation, with relative standard deviations (RSDs) of less than 1.5% for both intra- and interday measurements, and recoveries between 95.4% and 97.0%. Based on the above merits, the proposed procedures of GC-MS and HPLC-UV can provide specific information on the impurities in CEPS, and therefore, these methods can be well applied to quality control in the industrial production of CEPS. 1. Introduction As a common medicine, sulfinpyrazone is usually utilized to treat chronic gout and alleviate or prevent the formation of tophus and the gouty lesions of arthrosis.1 In addition, sulfinpyrazone, like aspirin, can inhibit the aggregation or adhesion effects of platelets, increase the platelet survival time,2 and reduce the abrupt occurrence of myocardial infarction;3-5 therefore, sulfinpyrazone is used as a treatment for ischemic heart disease and cerebrovascular disease.6,7 Meanwhile, because of its ability to prevent artery embolization complications of valvular heart disease, sulfinpyrazone is also applied to patients who are given hemodialysis in order to prevent the occurrence of thrombosis.8 According to research on industrial synthesis, 2-chloroethyl phenyl sulfide (CEPS) is a pivotal intermediate in the preparation of sulfinpyrazone from thiophenol as the starting material.9 Some impurities in CEPS have severe effects on the quality of CEPS and its downstream products. Therefore, understanding the relative substances in CEPS intermediates is urgently necessary to provide valuable information for both quality control and technique improvement. Based on the production process (Figure 1), CEPS is synthesized with thiophenol and 1,2-dichloroethane through a phase-transfer catalysis reaction; consequently, the presence of residues of thiophenol and 1,2-dichloroethane in the product is likely. Compared with other potential impurities contained in CEPS, thiophenol is the one of greatest concern because it not only has very strong irritation and serious toxicity,10 but also more easily produces new impurities in subsequent reactions. Therefore, its residue will greatly affect the quality of CEPS and increase the costs for subsequent * To whom correspondence should be addressed. E-mail: hzlian@ nju.edu.cn. Tel.: +86-25-8368-6075. Fax.: +86-25-8332-5180.

separation procedures. Therefore, as the prime impurity, thiophenol must be strictly controlled. CEPS was well documented merely as one of the H-agent simulants of mustard to study efficient extraction, removal, and decontamination of chemical war agents (CWAs) from water, soil, air, or other media.11-17 Some qualitative and quantitative analyses were performed to reflect the efficiency of these elimination methods for CWAs, among which the most commonly used technique for quantitative analysis was gas chromatography (GC). Gas chromatography-mass spectrometry (GC-MS) has primarily been utilized to identify CEPS or other simulacrums of CWAs. Additionally, UV-vis spectrophotometry and high-performance liquid chromatography (HPLC) have also been applied to perform quantitative analyses. Up to now, no quality control analysis of CEPS as a fine-chemical intermediate has been reported. In this work, a GC-MS method was developed to separate and identify the related impurities in industrial CEPS, and six compounds were verified. On this basis, the origination of these impurities during the synthesis procedure was further elucidated, and some suggestions were put forward for their avoidance or removal. Subsequently, a reliable HPLCUV method was established for the separation and quantification of thiophenol in industrial CEPS. 2. Experimental Section 2.1. Reagents and Materials. Reference substance (RS) of thiophenol (98.0%) was purchased from China Medicine Shanghai Chemical Reagent Factory (Shanghai, China). Industrial CEPS was supplied by Jiangsu Tianhe Medical Research Institution Co., Ltd. (Changzhou, China). 2-Chloromethane (99.8%) was purchased from Caledon Laboratories Ltd. (Georgetown, ON, Canada). Methanol (HPLC grade) was from Merck

10.1021/ie9014167  2010 American Chemical Society Published on Web 11/25/2009

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Figure 1. Reactions comprising sulfinpyrazone synthesis.

(Darmstadt, Germany). Acetic acid (g99.5%, analytical reagent) was from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Perchloric acid (70-72%, guaranteed reagent) was from Tianjin Third Reagent Factory (Tianjin, China). Wahaha purified water (Wahaha Group Co., Ltd., Hangzhou, China) was used throughout the experiments. 2.2. GC-MS. GC-MS analysis was accomplished on an Agilent 6890-5975 GC-MSD instrument with a DB-5 fusedsilica capillary column (30 m × 0.25 mm i.d., 0.25-µm film thickness). For GC separation, highly pure helium was employed as the carrier gas with a flow rate of 0.8 mL min-1. The inlet temperature was set at 250 °C, and the oven temperature program was that it was elevated at 10 °C min-1 from initial 60 to 290 °C and then held for 10 min. For MS analysis, an electron impact (EI) resource was used in positive-ion mode and an EI energy of 70 eV, and the ionization temperature was 230 °C. All components in CEPS were detected in full-scan mode with a mass range of 20-550 amu. Data were acquired and processed using Agilent GC/MSD ChemStation, and the NIST mass spectrum library was used for the identification of relative substances. 2.3. HPLC. HPLC instrumentation included a Waters Alliance 2695 separations module equipped with a vacuum degasser, a quaternary pump, an autosampler connected to a 996 UV-vis photodiode-array (PDA) detector, and an Empower chromatography manager system (Waters, Milford, MA). Separation was carried out on an Agela Venusil XBP-C18 column (250 × 4.6 mm i.d., 5 µm) (Agela Technology Inc., Tianjin, China) thermostatted at 30 °C. Elution was isocratic with a flow rate of 1.0 mL min-1 using a mixture of methanol and 1% aqueous acetic acid solution (80/20, v/v). The injection volume was 10 µL, and the detection wavelength was 240 nm. About 23.5 µL of thiophenol RS was accurately weighed and transferred into a 25-mL volumetric flask; after dilution with methanol, the solution was mixed well as the stock solution. About 21.0 µL of industrial CEPS sample was accurately weighed into a 25mL volumetric flask and then diluted with methanol.

as 1,2-dichloroethane (ClCH2CH2Cl), thiophenol (PhSH), diethylmalonate [CH2(CO2Et)2], tributylamine [N(C4H9)3], and diphenyl disulfide (PhSSPh), respectively, by comparing the mass spectral information of each compound with those of the standards in the NIST spectrum library. The fragmentation patterns of the five impurities were analyzed and are presented in Table 1. For impurity 6 (tR ) 17.9 min), no standard MS spectrum in the NIST library was found to match. Its mass spectrum gave rise to fragment ions of m/z (%) ) 246 (13), 137 (100), 123 (13), 109 (65), 77 (13), 65 (22), 45 (13), just different from that of CEPS, m/z ) 172, 137, 123, 109, 77, 65, 45, in the molecular ion. There might be a high similarity between impurity 6 and CEPS in chemical structure. The molecular ion [M]+ (m/z ) 246) of impurity 6 was present in a low abundance, whereas the next fragment ion (m/z 137), corresponding to [M - 109]+, was in a very high abundance (100%), implying that cleavage between them was dominant. In addition, the difference in m/z between them was coincident with the mass of -SPh, and m/z ) 77 showed a typical Ph+ ion. From the above information and according to the possible fragment ions of CEPS, we could deduced that impurity 6 was 1,2-dithiophenylethane (PhSCH2CH2SPh), and the corresponding fragmentation pattern is displayed in Figure 4. 3.2. Origins of Impurities and Suggestions for Their Elimination or Avoidance. The potential reasons for the existence of the six related impurities in CEPS were analyzed from the kinds of reactants, processes, and conditions of

3. Results and Discussion 3.1. Identification of Relative Substances in CEPS (GCMS). Considering the strong volatility of CEPS, GC-MS was chosen for the separation and identification of related impurities in industrial CEPS. Through optimization of the temperature gradient of the oven and the velocity of carrier gas, a good separation was accomplished. Figure 2 shows the total ionic current (TIC) chromatogram of CEPS sample. The relevant mass spectra of every impurity assigned to the corresponding peak in the TIC chromatogram are shown in Figure 3. The peaks eluted at retention times (tR) of 1.1 min (impurity 1), 3.8 min (impurity 2), 5.6 min (impurity 3), 7.3 min (impurity 4), and 15.1 min (impurity 5) during GC-MS were identified

Figure 2. Typical TIC chromatogram of CEPS sample. GC: Column, DB-5 fused-silica capillary column (30 m × 0.25 mm i.d., 0.25-µm film thickness); inlet temperature, 250 °C; programmed oven temperature, elevated at 10 °C min-1 from initial 60 to 290 °C and then held for 10 min; carrier gas, highly pure helium at a flow rate of 0.8 mL min-1. MS: Ionization mode, EI (+); electron impact energy, 70 eV; ionization temperature, 230 °C; scanning mass range, 20-550 amu.

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Figure 3. Mass spectra of the six relative impurities in the CEPS sample. GC-MS conditions were the same as in Figure 2.

reactions, followed by some practical suggestions proposed for the elimination or avoidance of these impurities. 1,2-Dichloroethane is utilized as the starting material and solvent of the first step reaction with an excess amount during the production of sulfinpyrazone. Even though vacuum distillation treatment for CEPS collection could realize isolation of 1,2-dichloroethane from the CEPS product, the residue was hard to avoid because of a failure of thoroughly cleaning the distillation tube before CEPS collection. A possible elimination method could be realized by strictly controlling the vacuum distillation temperature, with the sacrifice of some initial CEPS

product before final collection. Thiophenol is the other starting material of the overall reaction, and the incomplete transformation of thiophenol leads to its partial residue. Some methods can be tried to increase the input of 1,2-dichloroethane and optimize the reaction conditions, such as adding the proper amount for catalysis, adjusting a rational reaction temperature, and the like, all of which can be beneficial for accomplishing sufficient transformation of thiophenol and thereby reducing its residue. To our best knowledge, diethylmalonate, as the reagent of the second reaction step, should not be detected in the CEPS sample. Nevertheless, during the practical preparation of a

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Table 1. Fragmentation Patterns of the First Five Related Impurities Eluted by GC-MS peak 1 2 3

4 5

mass peaks (m/z, %) +

+

C2H4Cl2 (98, 10), C2H3Cl (62, 100), CH2Cl+ (49, 35), C2H3+ (27, 35) C6H6S+ (110, 100; 84, 20), C6H5+ (77, 15; 66, 40), C4H3+ (51, 15), C3H3+ (39, 15) C7H12O4+ (160), C5H9O4+ (133, 70), C5H7O3+ (115, 100), C3H4O3+ (88, 35), C2H4O2+ (60, 30), C2H3O+ (43, 90), CHO+ (29, 90) C12H26N+ (185, 10), C9H19N+ (142, 100), C6H13N+ (100, 50), C3H7N+ (57, 15), C3H5+ (41, 18), C2H5+ (29, 15) C12H10S2+ (218, 70), 185 (18), C7H6S2+ (154, 20), C6H5S+ (109, 100), C6H5+ (77, 10), C5H5+ (65, 40), C3H3+ (39, 17)

assignment 1,2-dichloroethane thiophenol diethylmalonate

tributylamine diphenyl disulfide

product with multistep reactions in a plant, several reactions are always performed in the same reaction vessel. Therefore, the incomplete cleanness of the reaction vessel will result in inevitable residue of some reagents, such as diethylmalonate. However, a small quantity of diethylmalonate need not be removed from CEPS, considering that it will be used in the next reaction. Among onium salts used as catalysts, tetra-butyl ammonium chloride (TBACl), existing as one of the quaternary ammonium salts, is highly sensitive to temperature and inclined to decompose more easily in strong alkaline medium.18 As the phase-transfer catalyst in the first reaction step, TBACl can be partially turned into tetra-butyl ammonium hydroxide (TBAOH), because of the presence of NaOH. And the generated TBAOH immediately performs Hofmann’s degradation even under room temperature with the product tributylamine. The proposed removal method for tributylamine is listed below: The proper amount of 5% HCl aqueous solution was added into the sample to wash CEPS for three times consecutively, after which it was further washed with water three times to remove all of the soluble substances. Once catalysts, oxygen, and other oxidants exist, thiophenol could be easily transformed into diphenyl disulfide.19,20 In practical production, the presence of TBACl and atmosphere in the reaction medium could provide a possibility for generating diphenyl disulfide. 1,2-Dithiophenylethane can be produced through a nuclophilic substitution reaction between thiophenol and generated CEPS. The amount of 1,2dithiophenylethane can be reduced by increasing the amount of 1,2-dichloroethane, but the elimination of 1,2-dithiophenylethane is hard to realize. In addition, the phase-transfer catalyst plays a key role in the production of CEPS, determining not only the reaction velocity and degree, but also the occurrence or not of related side reactions. Therefore, special attention should be paid to its utility, including the ratio between catalyst and alkali and the mode and temperature of adding alkali, among other factors. 3.3. Determination of Thiophenol in Industrial CEPS by HPLC. The residue of thiophenol is critical to evaluating the quality of CEPS, implying that the measurement of thiophenol requires high sensitivity and accuracy. However, the poor stability and reliability of GC measurements make it

Figure 4. Fragmentation pattern of 2-dithiophenylethane.

Figure 5. HPLC separation of CEPS and its relative impurities. Column, Agela Venusil XBP-C18, 5 µm, 250 × 4.6 mm i.d.; column temperature, 30 °C; mobile phase, 80% CH3OH + 20% aqueous HAc solution (1%); flow rate, 1.0 mL/min; injection volume, 10 µL; wavelength for UV detection, 240 nm. Peaks: 1, thiophenol; 3, 2-chloroethyl phenyl sulfide; 2, 4, and 5, unknown impurities O, P, and Q, respectively.

difficult to use this technique for quantitative analysis of thiophenol. Compared with GC, HPLC has higher specificity and accuracy; therefore, a rapid HPLC method for determining thiophenol in CEPS was developed. 3.3.1. Optimization of HPLC Conditions. The CEPS sample solution spiked with thiophenol RS was analyzed, using methanol-water, methanol-perchloric acid (0.1%) aqueous solution, and methanol-acetic acid (1%) aqueous solution as mobile phases to perform isocratic elution. The results indicate that thiophenol can realize good separation from its adjacent impurities with all three mobile phases, but its peak would distort under the methanol-water system as thiophenol concentration increased. The higher the concentration of thiophenol, the greater distortion of the peak. This is because the partial dissociation of thiophenol containing hydroxy groups took place in the neutral aqueous mobile phase. Addition of some acids can lead to a sharper peak through the suppression of the dissociation of the weak acidic thiophenol. The separations under methanolperchloric acid (0.1%) aqueous solution and methanol-acetic acid (1%) aqueous solution at the same methanol ratio were compared further. Under the two conditions, CEPS and its impurities both had good resolution with sharp peaks when the ratio of methanol was 80%, and the retention times (tR) of each component in the two systems were almost the same. Considering the difference in retention mechanism between LC and GC, the LC-MS technique should be used in the future to verify the impurities on an LC chromatogram,21 because they might not be in full accordance with those appearing on the GC chromatogram. On the other hand, perchloric acid is not fit for LCMS analysis owing to its nonvolatility, so acetic acid was eventually chosen as the ion suppressor (Figure 5). The UV spectrum of thiophenol from the PDA detector gives maximum absorptions at 206.2 and 234.6 nm. However, acetic acid has a relatively strong absorption at wavelengths below 230 nm, resulting in an acute fluctuation of baseline. Therefore, 240 nm was selected as the detection wavelength owing to the best signal-to-noise ratio, which is beneficial to quantitative determinations. 3.3.2. Calibration Curve and Detection Limit. The concentration of thiophenol standard solution for HPLC analysis ranged from 6.62 × 10-5 to 0.106 mg mL-1 through step-bystep dilution of the stock solution with methanol. Linearity of the calibration curve was obtained from regression of the peak area (A, mV s) versus concentration (C, mg mL-1) of standards. The regression equation was A ) 3.6491 × 107C + 796.44, with a good linearity in concentrations between 2.65 × 10-4 and 0.106 mg mL-1, and the correlation coefficient was 0.9999.

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Table 2. Recovery of Thiophenol in CEPS for Industrial Use (n ) 3) original (mg L-1)

added (mg L-1)

found (mg L-1)

recovery (%)

RSD (%)

0.820 0.808 0.792

0.402 0.809 1.588

1.204 1.580 2.332

95.5 95.4 97.0

1.0 0.6 1.1

The limit of detection (LOD) was 1.32 × 10-4 mg mL-1, determined at S/N ) 3. 3.3.3. Sample Analysis. For intraday measurements, the CEPS sample solution was prepared in triplicate with every sample solution injected three times, and an external standard method was used for the determination of thiophenol. The same procedure was used to perform interday measurements. The intraday and interday results with their relative standard deviations (RSDs) were 0.0793% (1.0%) and 0.0795% (1.5%), respectively. Recoveries were obtained by spiking a known amount of thiophenol standard to the CEPS sample solution and performing the analysis under the above-mentioned HPLC conditions. Three replicates were performed for the test. The overall data in Table 2 indicate good accuracy of the method, with recoveries of thiophenol in the range of 95.4-97.0%. All RSDs of intraday, interday, and recovery measurements were less than 1.5%, indicating a good precision and stability of the established HPLC method. 4. Conclusions A tentative effort has been carried out for the quality control analysis of CEPS as a fine-chemical intermediate in the production of sulfinpyrazone. The accomplished work first used GC-MS to separate and identify the relative impurities in industrial CEPS. 1,2-Dichloroethane, thiophenol, diethylmalonate, tributylamine, diphenyl disulfide, and 1,2-dithiophenylethane were separated and identified; after which the origins of these impurities were analyzed and some promising and practicable protocols for elimination or avoidance of them were proposed. Furthermore, a stable and reliable HPLC-UV method was established subsequently for the rapid and accurate determination of thiophenol, the most influential impurity in CEPS. Based on GC-MS and HPLC-UV analyses, the quality of CEPS can be clearly affirmed, and quality control of CEPS can be effectively performed. Acknowledgment This work was supported by the National Basic Research Program of China (973 program, No. 2009CB421601), National Natural Science Foundation of China (20575027, 90913012), National Science Funds for Creative Research Groups (20821063), and Analysis & Test Fund of Nanjing University. We are grateful to Professor Wan-Fang Lu, School of Chemistry & Chemical Engineering, Nanjing University, for her helpful and instructive comments.

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ReceiVed for reView September 9, 2009 ReVised manuscript receiVed October 25, 2009 Accepted November 8, 2009 IE9014167