Next Article in Journal
New Scabimycins A-C Isolated from Streptomyces acidiscabies (Lu19992)
Next Article in Special Issue
Drug Design: Where We Are and Future Prospects
Previous Article in Journal
Role of Mono- and Disaccharide Combination in Cryoprotective Medium for Rooster Semen to Ensure Cryoresistance of Spermatozoa
Previous Article in Special Issue
The Role of Organic Small Molecules in Pain Management
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 26
Issue 19
10.3390/molecules26195921
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Selective Oxidation of Clopidogrel by Peroxymonosulfate (PMS) and Sodium Halide (NaX) System: An NMR Study

by
Everaldo F. Krake
and
Wolfgang Baumann
*
Leibniz-Institut für Katalyse e.V., Albert-Einstein-Straße 29a, 18059 Rostock, Germany
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(19), 5921; https://doi.org/10.3390/molecules26195921
Submission received: 20 August 2021 / Revised: 23 September 2021 / Accepted: 25 September 2021 / Published: 29 September 2021
(This article belongs to the Special Issue From a Molecule to a Drug: Chemical Features Enhancing Pharmacological Potential)
Browse Figures
Review Reports Versions Notes

Abstract

:
A selective transformation of clopidogrel hydrogen sulfate (CLP) by reactive halogen species (HOX) generated from peroxymonosulfate (PMS) and sodium halide (NaX) is described. Other sustainable oxidants as well as different solvents have also been investigated. As result of this study, for each sodium salt the reaction conditions were optimized, and four different degradation products were formed. Three products were halogenated at C-2 on the thiophene ring and have concomitant functional transformation, such as N-oxide in the piperidine group. A halogenated endo-iminium product was also observed. With this condition, a fast preparation of known endo-iminium clopidogrel impurity (new counterion) was reported as well. The progress of the reaction was monitored using nuclear magnetic resonance spectroscopy as an analytical tool and all the products were characterized by 1D-, 2D-NMR and HRMS.

1. Introduction

The direct insertion of halogens in (hetero)aromatic drugs, in a selective way, has been the object of much interest by the synthetic community [1]. The inclusion of a new C−X bond in these bioactive heterocyclic compounds can improve their physical and biological properties, increase potency, and be used as a handle in the further design and construction of pharmaceuticals [2]. Thiophene rings are five-membered heterocycles bearing sulfur atoms in their structure. Connected to a halogen, halothiophenes represent a class of bioactive molecules with extraordinary pharmacological properties [3,4], including the FDA-approved drugs Avatrombopag, Tioconazole, Lornoxicam, Rivaroxaban, and Brotizolam (Figure 1A).
In recent years, several methods of direct activation of halogens in organic compounds have been reported using safe halogen sources such as HX, NH4X and NaX (X = Cl, Br and I). To sustainably transform these halides into more reactive species, the use of oxidizing agents that conform to the principles of Green Chemistry is essential [1].
Like other green oxidants such as O2 and H2O2 [5], peroxymonosulfate (PMS, Oxone ®) has been widely used: (1) in the academia to develop new synthetic protocols [6]; (2) in pharmaceutical companies to promote oxidative stress testing of active pharmaceutical ingredients (API) to predict their degradation [7]; and (3) in hypersaline industrial wastewaters to remove organic contaminants [8,9,10]. This safe, sustainable, and inexpensive oxidant has shown extraordinary reactivity with alkaline metal halide salts [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27] and with hydrogen halides (HCl, HBr and HI) [28,29,30].
In our previous work, we documented the reactive sequence of the oxidation–chlorination of Ticlopidine hydrochloride using PMS. We observed the formation of the reactive intermediate species (DP-1) containing a chlorine group at the C-2 carbon of the thiophene and the oxidation of cyclic amine to N-oxide in the piperidinic structure (Figure 1B) [31].
Clopidogrel hydrogen sulfate (CLP, Plavix TM) is another thienopyridine drug that has powerful antiplatelet properties, and it plays an important role in the treatment of coronary, peripheral vascular and cerebrovascular diseases [32,33,34]. Several researchers have reported functional transformations of CLP using halogenated succinimide reagents (Figure 1C). Padi and coworkers have used N-bromosuccinimide (NBS) for the preparation of endo-iminium impurity DP-2 on a large scale [35]. Jiao and coworkers have developed an efficient method using N-chlorosuccinimide (NCS) and dimethyl sulfoxide (DMSO) as a catalyst for the preparation of 2-Cl-clopidogrel DP-3a [36].
Continuing our efforts in the development and optimization of sustainable prediction methods for degradation of active pharmaceutical ingredients, we wanted to understand the oxidative halogenation reaction of heterocycles containing non-hydrohalic acids with safe halogen sources. Here, we show the oxidation of CLP using PMS/sodium halides (NaX, X = Cl, Br and I; Figure 1D). We observed the formation of four interesting classes of products that can predict the degradation of thienopyridines under high salinity media. To the best of our knowledge, detection, characterization, and selective preparation of the products in this oxidative method are first reported herein.

2. Results and Discussion

2.1. Impact of Halides on the Transformation of Clopidogrel

2.1.1. Influence of Chloride

Our experimental work started with the optimization of conditions for the oxidative chlorination of CLP with sodium chloride (NaCl) as a chlorine source, and different oxidant agents (Table 1). We monitored the reaction by NMR and HPLC. In the initial experiments, the treatment of CLP with H2O2 or tert-butyl hydroperoxide (TBHP) in the presence of NaCl did not lead to the formation of products after 24 h at room temperature (Table 1, Entries 1 and 2). Using PMS in D2O, we observed the complete consumption of CLP and the formation of various degradation products after one minute. Inspired by our previous work [31], we decided to investigate the co-solvent effect for this reaction. We performed some experiments with dichloromethane-d2 (CD2Cl2), chloroform-d (CDCl3), dimethyl sulfoxide-d6 ((CD3)2SO), benzene-d6 (C6D6), and toluene-d8 (C7D8), but these deuterated co-solvents did not lead to the formation of any products. However, with acetone-d6, we observed the formation of an N-oxide product, DP-6 (48%), as well as the chlorinated products DP-3a (4%) and DP-4a (25%) after 5 h (Entry 4).
To investigate the selectivity between chlorinated products DP-3a and DP-4a, the same reaction was performed with other polar solvents (Entries 5–7): methanol-d4 (32%), THF-d8 (51%) and acetonitrile-d3 (51%). We observed increased formation of DP-4a, as well as small amounts of DP-3a. With the optimized solvent in hand, we extended the method to optimize DP-3a or DP-4a using varying amounts of PMS and NaCl (Entries 8–13). We did not obtain DP-3a with a conversion higher than 20%. Thus, our best conditions for DP-4a formation used a mixture of D2O:CD3CN (2:1), PMS (2.0 equiv), and NaCl (2.0 equiv; Entry 8).

2.1.2. Influence of Bromide

In parallel to the chlorination reaction, we submitted CLP to the oxidation process using NaBr as a bromine source (Table 2). We observed a quick conversion of the brominated products DP-3b and DP-5b with all solvents studied. Then, we extended our study varying the amount of PMS and NaBr. The best condition for the formation of DP-3b was with D2O:CD3CN (2:1), PMS (0.5 equiv), and NaBr (1.0 equiv; Table 2, Entry 6). The combination of PMS (1.5 equiv) and NaBr (1.0 equiv; Table 2, Entry 8) provided DP-5b in excellent yield.

2.1.3. Influence of Iodide

When we used the iodide reagent NaI and other co-solvents (Entries 1–3), solubility problems were observed after the in situ oxidative conversion of the iodide to the reactive iodine species was generated. With NaCl, NaBr and NaI, acetonitrile-d3 was the most efficient deuterated co-solvent. Unlike with the halides described above, no substitution at the thiophene ring occurred (no formation of DP-3c, entries 4 and 5). Instead, we discovered a fast method (as compared to Padi’s) [35] to prepare DP-2 in excellent yield by using the PMS/NaI system (Table 3, Entry 4).

2.2. Determination of Reaction Progress by NMR

2.2.1. With NaCl

In Figure 2, a compilation of the 1H NMR spectra on the main functional transformations that occurred in the oxidative process, which resulted in the formation of the products in high yields, is shown. In addition, the data of the starting materials (as reference) and non-chlorinated intermediates DP-6 (mixture of diastereomers) are also included in this compilation of spectra, as described in Figure 2A,B [37]. The main observation among the NMR spectra of this work is the disappearance of the doublet (δH ~6.7 ppm, CD3CN) of proton H-3 of the thiophene ring and a conversion into a singlet in that same region which results from the insertion of a heteroatom at carbon-2 of this heterocycle (Figure 2C).
Figure 2C represents the progress of oxidative chlorination of CLP and NaCl after two hours (Table 1, Entry 12). In the first two hours of reaction, we observed the appearance of non-halogenated diastereomers of intermediate DP-6 with a new N+-OH bond, as well as the mono-chlorinated compound DP-3a. As the reaction progressed towards the production of DP-4a, the signals of DP-6 and DP-3a decreased in the spectrum. This led us to conclude that the reaction pathway to obtain DP-4a occurred via two simultaneous processes: oxidation-chlorination via DP-6 and chlorination-oxidation via DP-3a (Figure 3). The final product, DP-4a, is represented in Figure 4D, and bears a chlorine on the thiophene ring and an N-oxide in the piperidine structure. The mechanism of this reaction was shown in our previous work [31].

2.2.2. With NaBr

Contrary to the PMS/NaCl process, the reaction with NaBr did not present N-oxide products, but a C-2 halogen/endo-iminium DP-5b when PMS (1.0 equiv) was used (Figure 4B,D). To understand the development of this reaction, we started with 0.5 equivalent of PMS (Table 2, Entry 6; Figure 4A) and observed a mixture between CLP and mono-brominated product DP-3b. In addition, we increased the amount of PMS to provide DP-5b in a quantitative yield (Table 2, Entry 8; Figure 4D).

2.2.3. With NaI

With NaI, we tried to obtain an iodinated product, DP-3c, under our experimental conditions. Instead, we observed the formation of endo-iminium DP-2 in high yield (Table 3, Entry 4; Figure 5B). Reducing the molar amounts of PMS, we detected a mixture between CLP and endo-iminium DP-2 (Table 3, Entry 5, Figure 5A).

2.3. Characterization of the Products

Degradation products DP-2, DP-3a, DP-4a, DP-3b and DP-5b were characterized directly from the reaction mixtures by HPLC-MS, HRMS, as well as by 1D- and 2D-NMR spectroscopy. Two-dimensional correlations 1H-1H COSY, 1H-13C HSQC and 1H-13C HMBC were used for the elucidation of the structure.

2.3.1. Characterization of DP-2

Using NMR spectrometry (in CD3CN, see Table 4 and SI), fifteen protons were detected, a value consistent with the molecular formula of DP-2. In addition, the bidimensional 1H-1H COSY spectrum showed important correlations for structural elucidation of this molecule, including a cross peak between endo-iminium H-4 (δH 8.81, δC 162.40) and the singlet for H-10, which is part of a CH group (δH 6.39, δC 72.08). Shift data of the latter are similar to that observed for this position in the other molecules (Table 4). This feature proves that an endo-iminium compound, and not an exo-iminium one, is indeed formed. The edited HSQC exhibited the CH2 groups H-6 (δH 4.30–4.23 and 3.95–3.86, δC 49.94) and H-7 (δH 3.52–3.36, δC 24.04). With HRMS/ESI-TOF analysis, the molecular formula of DP-2 was determined as C16H15ClNO2S+, with m/z calculated at 320.0517, and m/z observed at 320.0516 (−0.3 ppm error), indicating loss of one hydrogen atom in the molecule and the formation of the endo-iminium product. These analyses do not show a halogenation bond in the molecule and confirm the structure of this degradation product.

2.3.2. Characterization of DP-3a

The molecular formula of product DP-3a was established as C16H11O2NSCl2 by HRMS/ESI-TOF data in which m/z of 356.0279 was observed and was calculated for [M + H]+ 356.0288 (2.5 ppm error), indicating the insertion of a new chlorine atom into the molecule. In the NMR spectrum (in CD3OD, see Table 4 and SI), the addition of the chlorine atom at carbon 2 resulted in an absence of the H-2 signal and the appearance of the singlet associated with H-3 (δH 6.50, δC 125.54) consistent with the molecular formula of DP-3a. 1H-13C HSQC edited indicated the methylene groups: H-4 (δH 3.64 and 3.54, δC 51.07), H-6 (δH 2.98–2.84, δC 49.21) and H-7 (δH 2.76–2.70, δC 25.78). The homonuclear correlation spectroscopy (1H-1H COSY) showed a correlation with the protons H-3/H-4 and H-3/H-7. This analysis was important to explain the structure elucidation of DP-3a. Also, 1H-13C HMBC correlations from proton signals for H-3, H-4, H-6 and H-10 were observed.

2.3.3. Characterization of DP-4a

The oxidative chlorinated product DP-4a was found to have the molecular formula C16H15O3NSCl2 by HRMS/ESI-TOF, in which m/z 372.0228 was observed and was calculated for [M + H]+ 372.0227 (−0.3 ppm error). This mass can also be seen in two retention times in the HPLC-MS chromatogram of Figures S1 and S2 (see SI) indicating the formation of two diastereomers with N+-OH bonds. In comparison to the data of 1H NMR with CLP, and based in our previous report about DP-6 (Figure 2B,D in CD3CN; also see ref. [37]), it is possible to notice a significant change in the chemical shift in H-4 (δH 6.62 and 6.52 ppm; δC 62.50, 62.27 ppm) due to the asymmetric electric field (AMEF) generated in the molecule. This electrical field is the result of the polarization of the molecule through the dipole N+-OH generated in this oxidative process.

2.3.4. Characterization of DP-3b

Similar to the results seen for the compound DP-3a, the product DP-3b showed the molecular formula C16H15O2NSClBr by HRMS/ESI-TOF, with m/z calculated 399.9774 and observed for [M + H]+ 399.9772 (−0.5 ppm error), specifying the insertion of a bromine atom into the molecule. In the NMR spectrum (in CD3OD, see Table 4 and SI), the inclusion of a bromine atom at carbon 2 resulted in an absence of the H-2 signal and the appearance of a signal associated with H-3 (δH 6.70, δC 129.36), consistent with the molecular formula of DP-3b. In addition, other changes in chemical shift in H-4 (δH 3.63 and 3.53, δC 51.10), H-6 (δH 2.95–2.80, δC 49.21) and H-7 (δH 2.77–2.74, δC 26.02) were noted. HMBC correlations from proton signals for H-3, H-4, H-6 and H-10 were observed.

2.3.5. Characterization of DP-5b

Finally, in the NMR spectrum (in CD3OD, see Table 4 and SI), fourteen protons were observed, a value consistent with the molecular formula of DP-5b. In addition, HSQC showed the existence of an endo-iminium group in the piperidine moiety as a singlet (δH 9.05, δC 162.47), two methylene groups in H-6 (δH 4.44–4.37 and 4.00–3.91, δC 49.65), H-7 (δH 3.59–3.40, δC 24.38) and H-10 protons (δH 6.62, δC 72.72). HMBC correlations from proton signals for H-3, H-4, H-6 and H-10 were observed. Also, the molecular formula of DP-5b was determined to be C16H14BrClNO2S+ by HRMS/ESI-TOF, with an observed m/z of 397.9622 and a calculated m/z of 397.9623 (0.3 ppm error) indicating the insertion of a bromine atom into the molecule, as well as the formation of the endo-iminium. This analysis corroborated with the data obtained from the NMR spectra.

3. Materials and Methods

3.1. Materials

Clopidogrel hydrogen sulphate (CLP) was kindly provided from RD&C Research, Development & Consulting GmbH, Vienna, Austria. Peroxymonosulfate (PMS, Oxone ®: 2KHSO5·KHSO4·K2SO4, MW = 614.74 g·mol−1) was purchased from TCI Deutschland. NaCl, NaBr and NaI were purchased from Sigma Aldrich, Inc. and used directly without further purification. All deuterated solvents were purchased from Deutero GmbH, Kastellaun, Germany.

3.2. Nuclear Magnetic Resonance Spectroscopy

All NMR spectra were recorded on a Bruker AVANCE III HD 400 MHz spectrometer at 297 K in D2O/CD3OD or D2O/CD3CN (2:1, v/v) solvents. 19 mg of CLP were dissolved in 0.6 mL of deuterated solvent mixture and used for 1H, 13C NMR, 1H-1H COSY, HSQC and HMBC analysis. Chemical shifts are reported in ppm (δ) and residual CD3OD (δH = 3.31 ppm, δC = 49.0 ppm) or CD3CN (δH = 1.94 ppm, δC = 1.32 ppm). Processing of the raw data was performed using Bruker TOPSPIN software.

3.2.1. Recording of One-Dimensional NMR Spectra

The pulse conditions were as follows: 1H NMR, spectra (pulse sequence = zg30): number of data points (TD) = 43008, number of scans (NS) = 16, dummy scans (DS) = 2, spectra width (SWH) = 8012.820 Hz, acquisition time (AQ) = 2.6837 sec, spectrometer operating frequency (SFO1) = 400.13 MHz, π/2 pulse for 1H (P1) = 14.30 μs, relaxation delay (D1) = 1.27 s, line broadening (LB) = 0.10 Hz. 13C NMR spectra (pulse sequence = zgpg30): TD = 43702, NS = 256, DS = 2, SWH = 29411.766 Hz, AQ = 0.7429 sec, SFO1 = 100.626 MHz, LB = 1.00 Hz, D1 = 2.0 sec, P1 = 10.0 μs.

3.2.2. Recording of Two-Dimensional NMR Spectra

1H/1H COSY (pulse sequence = cosygpppqf): TD = 2048 (F2), TD = 256 (F1) NS = 2, DS = 16, SFO1 = 400.132 MHz, D1 = 2.00 sec. 1H–13C HSQC (pulse sequence = hsqcedetgp): TD = 1024 (F2), TD = 256 (F1) NS = 2, DS = 16, SFO1 = 400.132 (F2) MHz, SFO1 = 100.622 (F1) MHz, D1 = 2.00 sec. 1H–13C HMBC (pulse sequence = hmbcgpndqf): The parameters were very similar to those used in the HSQC experiment.

3.3. Mass Spectrometry

The compounds were dissolved (about 0.05 mg·mL−1) in acetonitrile, using a solvent system of acetonitrile: formic acid, 0.1% in water [90:10, v/v] at a flow rate of 0.5 mL·min−1. The mass spectrum of the isolated products was acquired on a Xevo G2-XS Tof Mass Spectrometry instrument from Waters (Wilmslow, UK) in positive spray ionization (ES+) mode. The column used was an ACQUITY UPLC BEH C18 1.7 µm and with the following dimensions: 2.1 mm × 50 mm. The ES+ capillary was set at 3.0 kV, the source temperature at 120 °C and the desolvation temperature at 500 °C. Mass range was scanned between 50 and 750 amu.

3.4. General Description of the Experiment

To a glass vial with a solution of CLP (19 mg; 45.49 µmol; 1.0 equiv) in D2O/CD3CN (0.6 mL, 2:1 v/v) was added the corresponding halide salt (1.0 equiv) and PMS (2KHSO5·KHSO4·K2SO4, MW = 614.74 g·mol−1)—see Table 1, Table 2 and Table 3 for specific data. The solution was stirred before being transferred to an NMR tube and continuously monitored by 1H NMR at room temperature. After complete conversion, the reaction mixture was quenched with sodium thiosulfate and extracted with dichloromethane (3×). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The desired halogenated products were then characterized without further purification. Characterization of the products by LC-MS is also possible directly from the reaction mixture.

4. Conclusions

In summary, we showed a selective transformation of clopidogrel hydrogen sulfate (CLP) by a PMS/halide system in aqueous acetonitrile media without employing a metal catalyst. With this method, we have prepared three major halogenated products using different halide salts. With this condition, a fast preparation of known endo-iminium clopidogrel impurity (DP-2, new counterion) was described as well. The new degradation products DP-3a–b, DP-4a and DP-5b were characterized using spectroscopic techniques (namely 1D-NMR, 2D-NMR and HRMS). We believe that this procedure is not only useful for generating clopidogrel derivatives but also very important to the study of drug degradation under hypersaline conditions. We are currently extending this study with other active pharmaceutical ingredients.

Supplementary Materials

The following are available online, Analytical data; Figures S1–S4: HPLC-MS chromatogram: PMS/NaCl; Figure S5: UV Spectrum; Figures S6–S32: HR-MS/NMR spectrum.

Author Contributions

E.F.K.: Conceptualization, Validation, Investigation, Visualization, Writing—Original Draft; W.B. Supervision, Writing—review & editing. All authors have read and agreed to the published version of the manuscript.

Funding

Financial support provided by Leibniz Association, project PHARMSAF (K136/2018).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in Supplementary Material.

Acknowledgments

We thank the analytical staff of the Leibniz-Institute for Catalysis, Rostock, for their excellent service.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

References

  1. Larock, R.C.; Zhang, L. Aromatic Halogenation. In Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd ed.; Larock, R.C., Ed.; John Wiley & Sons, Inc.: Chichester, UK, 2018. [Google Scholar]
  2. Kosjek, T.; Heath, E. Halogenated Heterocycles as Pharmaceuticals; Springer: Berlin, Heidelberg, 2011; Volume 27. [Google Scholar]
  3. Gramec, D.; Mašič, P.L.; Dolenc, S.M. Bioactivation Potential of Thiophene-Containing Drugs. Chem. Res. Toxicol. 2014, 27, 1344–1358. [Google Scholar] [CrossRef]
  4. Shah, R.; Verma, P.K. Therapeutic importance of synthetic thiophene. Chem. Cent. J. 2018, 12, 137. [Google Scholar] [CrossRef] [Green Version]
  5. Podgoršek, A.; Zupan, M.; Iskra, J. Oxidative halogenation with “green” oxidants: Oxygen and hydrogen peroxide. Angew. Chem. Int. Ed. 2009, 48, 8424–8450. [Google Scholar] [CrossRef] [PubMed]
  6. Hussain, H.; Green, I.R.; Ahmed, I. Journey describing applications of oxone in synthetic chemistry. Chem. Rev. 2013, 113, 3329–3371. [Google Scholar] [CrossRef] [PubMed]
  7. Baertschi, S.W.; Alsante, K.M.; Reed, R.A. Pharmaceutical Stress Testing: Predicting Drug Degradation, 2nd ed.; Informa Healthcare: London, UK, 2011. [Google Scholar]
  8. Sheng, B.; Huang, Y.; Wang, Z.; Yang, F.; Ai, L.; Liu, J. On peroxymonosulfate-based treatment of saline wastewater: When phosphate and chloride co-exist. RSC Adv. 2018, 8, 13865–13870. [Google Scholar] [CrossRef] [Green Version]
  9. Lefebvre, O.; Moletta, R. Treatment of organic pollution in industrial saline wastewater: A literature review. Water Res. 2006, 40, 3671–3682. [Google Scholar] [CrossRef]
  10. Woolard, C.R.; Irvine, R.L. Treatment of hypersaline wastewater in the sequencing batch reactor. Water Res. 1995, 29, 1159–1168. [Google Scholar] [CrossRef]
  11. Kim, E.-H.; Koo, B.-S.; Song, C.-E.; Lee, K.-J. Halogenation of aromatic methyl ketones using Oxone® and sodium halide. Synth. Commun. 2001, 31, 3627–3632. [Google Scholar] [CrossRef]
  12. Tamhankar, B.V.; Desai, U.V.; Mane, R.B.; Wadgaonkar, P.P.; Bedekar, A.V. A simple and practical halogenation of activated arenes using potassium halide and Oxone® in water-acetonitrile medium. Synth. Commun. 2001, 31, 2021–2027. [Google Scholar] [CrossRef]
  13. Narender, N.; Srinivasu, P.; Kulkarni, S.J.; Raghavan, K.V. Highly efficient, para-selective oxychlorination of aromatic compounds using potassium chloride and oxone®. Synth. Commun. 2002, 32, 279–286. [Google Scholar] [CrossRef]
  14. Bovicelli, P.; Bernini, R.; Antoniolettia, R.; Mincione, E. Selective halogenation of flavanones. Tetrahedron Lett. 2002, 43, 5563–5567. [Google Scholar] [CrossRef]
  15. Desai, U.V.; Pore, D.M.; Tamhankar, B.V.; Jadhavb, S.A.; Wadgaonkar, P.P. An efficient deprotection of dithioacetals to carbonyls using Oxone–KBr in aqueous acetonitrile. Tetrahedron Lett. 2006, 47, 8559–8561. [Google Scholar] [CrossRef]
  16. Firouzabadi, H.; Iranpoor, N.; Kazemi, S. Direct halogenation of organic compounds with halides using oxone in water—A green protocol. Can. J. Chem. 2009, 87, 1675–1681. [Google Scholar] [CrossRef]
  17. Takada, Y.; Hanyu, M.; Nagatsu, K.; Fukumura, T. Radiolabeling of aromatic compounds using K[*Cl]Cl and OXONE®. J. Label. Compd. Radiopharm. 2012, 55, 383–386. [Google Scholar] [CrossRef]
  18. Ren, J.; Tong, R. Convenient in situ generation of various dichlorinating agents from oxone and chloride: Diastereoselective dichlorination of allylic and homoallylic alcohol derivatives. Org. Biomol. Chem. 2013, 11, 4312–4315. [Google Scholar] [CrossRef]
  19. Brucher, O.; Hartung, J. Oxidative chlorination of 4-pentenols and other functionalized hydrocarbons. Tetrahedron 2014, 70, 7950–7961. [Google Scholar] [CrossRef]
  20. Lai, L.; Wang, H.; Wu, J. Facile assembly of 1-(4-haloisoquinolin-1-yl) ureas via a reaction of 2-alkynylbenzaldoxime, carbodiimide, and halide in water. Tetrahedron 2014, 70, 2246–2250. [Google Scholar] [CrossRef]
  21. Wang, Y.; Wang, Y.; Jiang, K.; Zhang, Q.; Li, D. Transition-metal-free oxidative C5 C–H-halogenation of 8-aminoquinoline amides using sodium halides. Org. Biomol. Chem. 2016, 14, 10180–10184. [Google Scholar] [CrossRef]
  22. Bikshapathi, R.; Parvathaneni, S.P.; Rao, V.J. An atom-economical protocol for direct conversion of Baylis-Hillman alcohols to β-chloro aldehydes in water. Green Chem. 2017, 19, 4446–4450. [Google Scholar] [CrossRef]
  23. Olsen, K.L.; Jensen, M.R.; MacKay, J.A. A mild halogenation of pyrazoles using sodium halide salts and Oxone. Tetrahedron Lett. 2017, 58, 4111–4114. [Google Scholar] [CrossRef]
  24. Sriramoju, V.; Kurva, S.; Madabhushi, S. New method for the preparation of N-chloroamines by oxidative N-halogenation of amines using oxone-KCl. Synth. Commun. 2018, 48, 699–704. [Google Scholar] [CrossRef]
  25. Lakshmireddy, V.M.; Veera, Y.N.; Reddy, T.J.; Rao, V.J.; Raju, B.C. A Green and Sustainable Approach for Selective Halogenation of Anilides, Benzanilides, Sulphonamides and Heterocycles†. Asian J. Org. Chem. 2019, 8, 1380–1384. [Google Scholar] [CrossRef]
  26. Uyanik, M.; Sahara, N.; Ishihara, K. Regioselective oxidative chlorination of arenols using NaCl and oxone. Eur. J. Org. Chem. 2019, 27–31. [Google Scholar] [CrossRef]
  27. Semwal, R.; Ravi, C.; Kumar, R.; Meena, R.; Adimurthy, S. Sodium salts (NaI/NaBr/NaCl) for the halogenation of imidazo-fused heterocycles. J. Org. Chem. 2019, 84, 792–805. [Google Scholar] [CrossRef]
  28. Kim, K.-M.; Park, I.-H. A convenient halogenation of α, β-unsaturated carbonyl compounds with OXONE® and hydrohalic acid (HBr, HCl). Synthesis 2004, 16, 2641–2644. [Google Scholar] [CrossRef]
  29. Lee, H.S.; Lee, H.J.; Lee, K.Y.; Kim, J.N. Controlled C-5 Chlorination and Dichlorohydrin Formation of Uracil Ring with HCl/DMF/Oxone® System. Bull. Korean Chem. Soc. 2012, 33, 1357–1359. [Google Scholar] [CrossRef] [Green Version]
  30. Qiao, L.; Cao, X.; Chai, K.; Shen, J.; Xu, J.; Zhang, P. Remote radical halogenation of aminoquinolines with aqueous hydrogen halide (HX) and oxone. Tetrahedron Lett. 2018, 59, 2243–2247. [Google Scholar] [CrossRef]
  31. Krake, E.F.; Baumann, W. Unprecedented Formation of 2-Chloro-5-(2-chlorobenzyl)-4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine 5-oxide via Oxidation-Chlorination Reaction Using Oxone: A Combination of Synthesis and 1D-2D NMR Studies. ChemistrySelect 2019, 4, 13479–13484. [Google Scholar] [CrossRef]
  32. Wu, Y.J. Heterocycles and medicine: A survey of the heterocyclic drugs approved by the US FDA from 2000 to present. Prog. Heterocycl. Chem. 2012, 1–53. [Google Scholar]
  33. Herbert, J.M.; Frehel, D.; Vallée, E.; Kieffer, G.; Gouy, D.; Necciari, J.; Defreyn, G.; Maffrand, J.P. Clopidogrel, A Novel Antiplatelet and Antithrombotic Agent. Cardiovasc. Drug Rev. 1993, 11, 180–198. [Google Scholar] [CrossRef]
  34. Ferri, N.; Corsini, A.; Bellosta, S. Pharmacology of the new P2Y 12 receptor inhibitors: Insights on pharmacokinetic and pharmacodynamic properties. Drugs 2013, 73, 1681–1709. [Google Scholar] [CrossRef]
  35. Aalla, S.; Gilla, G.; Anumula, R.R.; Charagondla, K.; Vummenthala, P.R.; Padi, P.R. New and Efficient Synthetic Approaches for the Regioisomeric and Iminium Impurities of Clopidogrel Bisulfate. Org. Process Res. Dev. 2012, 16, 1523–1526. [Google Scholar] [CrossRef]
  36. Song, S.; Li, X.; Wei, J.; Wang, W.; Zhang, Y.; Ai, L.; Zhu, Y.; Shi, X.; Zhang, X.; Jiao, N. DMSO-catalysed late-stage chlorination of (hetero) arenes. Nat. Catal. 2020, 3, 107–115. [Google Scholar] [CrossRef]
  37. Krake, E.F.; Jiao, H.; Baumann, W. NMR and DFT analysis of the major diastereomeric degradation product of clopidogrel under oxidative stress conditions. J. Mol. Struct. 2022, 1247, 131309. [Google Scholar] [CrossRef]
Molecules 26 05921 g001 550
Figure 1. Halothiophene-containing pharmaceutical drugs and representative oxidation of CLP. (A) Examples of halothiophene-containing pharmaceutical drugs. (B) Our previous work: oxidative degradation of ticlopidine hydrochloride with PMS. (C) Previous work: treatment of CLP with halogenated succinimides. (D) This work: PMS-halide oxidation of CLP, anions may be halide or hydrogen sulfate.
Figure 1. Halothiophene-containing pharmaceutical drugs and representative oxidation of CLP. (A) Examples of halothiophene-containing pharmaceutical drugs. (B) Our previous work: oxidative degradation of ticlopidine hydrochloride with PMS. (C) Previous work: treatment of CLP with halogenated succinimides. (D) This work: PMS-halide oxidation of CLP, anions may be halide or hydrogen sulfate.
Molecules 26 05921 g001
Molecules 26 05921 g002 550
Figure 2. Compilation of 1H NMR spectra (400 MHz, CD3CN) of all compounds involved. Reaction conditions: (A) CLP (as 1H NMR reference); (B) Experiment performed using only CLP (1.0) and PMS (1.0); (C) Progress of reaction after 2 h (see Table 1, Entry 12); (D) Crude 1H NMR spectrum of diastereomers DP-4a after 12 h (see Table 1, Entry 8).
Figure 2. Compilation of 1H NMR spectra (400 MHz, CD3CN) of all compounds involved. Reaction conditions: (A) CLP (as 1H NMR reference); (B) Experiment performed using only CLP (1.0) and PMS (1.0); (C) Progress of reaction after 2 h (see Table 1, Entry 12); (D) Crude 1H NMR spectrum of diastereomers DP-4a after 12 h (see Table 1, Entry 8).
Molecules 26 05921 g002
Molecules 26 05921 g003 550
Figure 3. Reaction progress for oxidative chlorination reaction of CLP with PMS/NaCl system measured by 1H NMR (see Table 1, Entry 8).
Figure 3. Reaction progress for oxidative chlorination reaction of CLP with PMS/NaCl system measured by 1H NMR (see Table 1, Entry 8).
Molecules 26 05921 g003
Molecules 26 05921 g004 550
Figure 4. Compilation of crude 1H NMR spectra (400 MHz, CD3CN) of all compounds involved (CLP, DP-3b and DP-5b). Reaction conditions: (A) PMS (0.5), NaBr (1.0), see Table 2, Entry 6; (B) PMS (1.0), NaBr (1.0), see Table 2, Entry 3; (C) 1H NMR spectrum of DP-3b isolated; (D) PMS (1.5), NaBr (1.0), see Table 2, Entry 8.
Figure 4. Compilation of crude 1H NMR spectra (400 MHz, CD3CN) of all compounds involved (CLP, DP-3b and DP-5b). Reaction conditions: (A) PMS (0.5), NaBr (1.0), see Table 2, Entry 6; (B) PMS (1.0), NaBr (1.0), see Table 2, Entry 3; (C) 1H NMR spectrum of DP-3b isolated; (D) PMS (1.5), NaBr (1.0), see Table 2, Entry 8.
Molecules 26 05921 g004
Molecules 26 05921 g005 550
Figure 5. Compilation of crude 1H NMR spectra (400 MHz, CD3CN) of all compounds involved (CLP and DP-2). Reaction conditions: (A): PMS (0.5), NaI (1.0), see Table 3, Entry 5; (B) PMS (1.0), NaI (1.0), see Table 3, Entry 4.
Figure 5. Compilation of crude 1H NMR spectra (400 MHz, CD3CN) of all compounds involved (CLP and DP-2). Reaction conditions: (A): PMS (0.5), NaI (1.0), see Table 3, Entry 5; (B) PMS (1.0), NaI (1.0), see Table 3, Entry 4.
Molecules 26 05921 g005
Table
Table 1. Screening of conditions for oxidative chlorination reaction (a).
Table 1. Screening of conditions for oxidative chlorination reaction (a).
Molecules 26 05921 i001
EntryNaCl
(equiv)		Oxidant
(equiv)		Deuterated
Solvent (b)		Time
(h)		DP-3a
(%) (d)		DP-4a
(%) (d)		DP-6
(%) (d)
11.0H2O2 (30%)H2O2:CD3OD (2:1)24NRNRNR
21.0TBHP (70%)TBHP:CD3OD (2:1)24NRNRNR
31.0PMS (2.0)D2O (c)1 mindegrad.degrad.degrad.
41.0PMS (2.0)D2O:(CD3)2CO (2:1)542548
51.0PMS (2.0)D2O:CD3OD (2:1)5193224
61.0PMS (2.0)D2O:C4D8O (2:1)515145
71.0PMS (2.0)D2O:CD3CN (2:1)465136
82.0PMS (2.0)D2O:CD3CN (2:1)448510
91.0PMS (1.5)D2O:CD3CN (2:1)425242
102.0PMS (1.5)D2O:CD3CN (2:1)4175919
111.0PMS (1.0)D2O:CD3CN (2:1)452752
122.0PMS (1.0)D2O:CD3CN (2:1)4153233
131.0PMS (0.5)D2O:CD3CN (2:1)45742
(a) Reaction conditions: CLP (1.0 equiv), NaCl, PMS, 0.2 mL of co-solvent, 0.4 mL of D2O. (b) List of abbreviations: (TBHP) tert-butyl hydroperoxide; (CD3OD) methanol-d4; (D2O) water-d2; (CD3CN) acetonitrile-d3; ((CD3)2CO) acetone-d6; (C4D8O) tetrahydrofuran-d8; (NR) no reaction; (degrad.) degradation. (c) Only D2O was used (0.6 mL). (d) Conversion determined by HPLC analysis. Note: Entry 8 (in bold) refers to the best condition for the formation of DP-4a.
Table
Table 2. Screening of conditions for oxidative bromination reaction (a).
Table 2. Screening of conditions for oxidative bromination reaction (a).
Molecules 26 05921 i002
EntryNaBr
(equiv)		PMS
(equiv)		Deut. SolventTime
(min)		DP-3b
(%) (b)		DP-5b
(%) (b)
1NaBr (1.0)1.0D2O:CD3OD (2:1)16238
2NaBr (1.0)1.0D2O:C4D8O (2:1)1397
3NaBr (1.0)1.0D2O:(CD3)2CO (2:1)13466
4NaBr (1.0)1.0D2O:CD3CN (1:1)16039
5NaBr (2.0)1.0D2O:CD3CN (1:1)13466
6NaBr (1.0)0.5D2O:CD3CN (1:1)1662
7NaBr (2.0)0.5D2O:CD3CN (1:1)16110
8NaBr (1.0)1.5D2O:CD3CN (1:1)1-99
9NaBr (2.0)1.5D2O:CD3CN (1:1)1-99
10NaBr (1.0)2.0D2O:CD3CN (1:1)1-99
(a) Reaction conditions: CLP (1.0 equiv), NaBr, PMS, 0.2 mL of co-solvent, 0.4 mL of D2O. (b) Conversion determined by HPLC analysis. Note: Entries 6 and 8 (in bold) refer to the best conditions for the formation of DP-3b and DP-5b, respectively.
Table
Table 3. Screening of conditions for oxidative iodination reaction (a).
Table 3. Screening of conditions for oxidative iodination reaction (a).
Molecules 26 05921 i003
EntryNaI
(equiv)		PMS
(equiv)		Deut. SolventTimeDP-2
(%) (b)		DP-3c
(%) (b)
1NaI (1.0)1.0D2O:CD3OD (2:1)12 h<1-
2NaI (1.0)1.0D2O:C4D8O (1:1)12 hNRNR
3NaI (1.0)1.0D2O:(CD3)2CO (1:1)12 hNRNR
4NaI (1.0)1.0D2O:CD3CN (1:1)10 min98-
5NaI (1.0)0.5D2O:CD3CN (1:1)10 min65-
(a) Reaction conditions: CLP (1.0 equiv), NaI, PMS, 0.2 mL of co-solvent, 0.4 mL of D2O. (b) Conversion determined by HPLC analysis. Note: Entry 4 (in bold) refers to the best condition for the formation of DP-2.
Table
Table 4. 1H and 13C assignments for all clopidogrel degradation products.
Table 4. 1H and 13C assignments for all clopidogrel degradation products.
Molecules 26 05921 i004
PositionX = H (DP-2)X = Cl (DP-3a)X = Cl, N-OH (DP-4a) (a)X = Cl, N-OH (DP-4a’) (a)X = Br (DP-3b)X = Br (DP-5a)
1H13C1H13C1H13C1H13C1H13C1H13C
2 (CX)-128.15-133.59-125.72-125.39-110.38-128.41
3 (CH)-129.446.50 s125.546.70 s125.266.60 s125.266.70 s129.36-133.01
4 (CH/H2)8.81 s162.403.64 d (14.5)
3.54 d (14.5)		51.075.09 d (15.5)
4.82 d (15.5)		62.504.65 (s)62.273.63 dt (14.4, 1.9)
3.53 dt (14.4, 1.9)		51.109.05 s162.46
6 (CH2)4.30–4.23 m
3.95–3.86 m		49.942.98–2.84 m49.214.22 dd (12.1, 5.3)
4.03 m		60.684.40 m
4.29 dd (9.2, 5.1)		61.992.95–2.80 m49.214.44–4.37 m
4.00–3.91 m		49.64
7 (CH2)3.52–3.36 m24.042.76–2.70 m25.783.04 m21.543.24 m22.192.77–2.74 m26.023.59–3.40 m24.38
8 (C)-156.50-128.22-130.56-130.48-136.39-158.09
9 (C)-129.02-133.28-130.39-130.18-135.32-130.19
10 (CH)6.40 s72.084.97 s68.556.19 (s)76.956.15 (s)74.934.93 s68.686.62 s72.72
11 (C(ipso))-129.35-134.13-134.58-134.55-134.76-115.56
12 (CArH)7.62–7.49 m133.817.44–7.41 m130.997.65–7.53 m129.207.65–7.53 m129.097.48–7.43 m131.027.68–7.56 m131.29
13 (CArH)-129.167.33–7.29 m128.487.65–7.53 m134.587.65–7.53 m134.547.37–7.31 m128.50129.61
14 (CArH)-132.86131.117.50–7.43 m131.917.50–7.43 m131.83131.05133.01
15 (CArH)-131.837.63–7.60 m130.997.73 dd (7.9, 1.6)133.937.77 dd (7.9, 1.6)133.937.66–7.61 m131.02132.08
16 (CCl)-136.18-135.80-137.59-137.17-135.91-136.54
17 (C=O)-167.81-172.10-166.27-166.17-172.76-168.20
18 (OCH3)3.89 s55.023.68 s52.843.75 (s)55.063.74 (s)55.063.70 s52.713.97 s54.85
Note: Positions show the number on the chemical structure above. Chemical shifts (δ) are reported in ppm relative to TMS (see Section 3.2). J- values are shown in Hz in parentheses. Abbreviations: d, doublet; dd, doublet doublet; dt, doublet triplet; m, multiplet; s, singlet; t, triplet. (a) 1H NMR (400 MHz, CD3CN) signals correspond to 56:44 mixture of diastereomers DP-4a and DP-4a’ (cf. ref. [37]).
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Krake, E.F.; Baumann, W. Selective Oxidation of Clopidogrel by Peroxymonosulfate (PMS) and Sodium Halide (NaX) System: An NMR Study. Molecules 2021, 26, 5921. https://doi.org/10.3390/molecules26195921

AMA Style

Krake EF, Baumann W. Selective Oxidation of Clopidogrel by Peroxymonosulfate (PMS) and Sodium Halide (NaX) System: An NMR Study. Molecules. 2021; 26(19):5921. https://doi.org/10.3390/molecules26195921

Chicago/Turabian Style

Krake, Everaldo F., and Wolfgang Baumann. 2021. "Selective Oxidation of Clopidogrel by Peroxymonosulfate (PMS) and Sodium Halide (NaX) System: An NMR Study" Molecules 26, no. 19: 5921. https://doi.org/10.3390/molecules26195921

APA Style

Krake, E. F., & Baumann, W. (2021). Selective Oxidation of Clopidogrel by Peroxymonosulfate (PMS) and Sodium Halide (NaX) System: An NMR Study. Molecules, 26(19), 5921. https://doi.org/10.3390/molecules26195921

Article Metrics

Back to TopTop