Preparation and characterization of impurities of Teriflunomide - An Immunomodulatory agent

doi:10.21203/rs.3.rs-3044351/v1

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Preparation and characterization of impurities of Teriflunomide - An Immunomodulatory agent

https://doi.org/10.21203/rs.3.rs-3044351/v1

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Teriflunomide is an Immunomodulatory agent used in the treatment of rheumatoid arthritis. Our present research work depicts the origin, preparation and characterization of impurities of Teriflunomide viz: (2Z)-4-chloro-2-cyano-N-[4-(Trifluoromethyl]phenyl]-3-hydroxy-2-butenamide (Chloromethyl Teriflunomide 2), (2Z)-2-cyano-3-hydroxy-N-[4-(Trifluoromethyl)phenyl]-2-pentenamide (Ethyl Teriflunomide 3), two positional isomers namely (2Z)-2-cyano-3-hydroxy-N-[2-(Trifluoromethyl)phenyl]-2-butenamide (2-Isomer of Teriflunomide 4) and (2Z)-2-cyano-3-hydroxy-N-[3-(Trifluoromethyl)phenyl]-2-butenamide (3-Isomer of Teriflunomide 5). These impurities are process related impurities which are useful to finalize the specifications of Teriflunomide drug substance. These synthesised impurities are characterised by ¹³C NMR, ¹H NMR, HRMS and HPLC analysis.

Teriflunomide

Chloromethyl Teriflunomide

Ethyl Teriflunomide

2-isomer of Teriflunomide &amp

3-isomer of Teriflunomide

Teriflunomide is an active metabolite of Leflunomide. It is used as an immunosuppressant agent with an anti-inflammatory property. Teriflunomide is an oral de novo pyrimidine synthesis inhibitor of the dihydroorotate dehydrogenase enzyme (DHO-DH). (Palle et al., 2020 & Chandrashekhar et al., 2017) It is used in the treatment of rheumatoid arthritis, autoimmune diseases and multiple sclerosis. Teriflunomide (1) is marketed under the trade name of AUBAGIO®. (Aly et al., 2017, Wei et al., 2017, Satyanarayana et al., 2017) Chemically it is known as (2Z)-2-cyano-3-hydroxy-N-[4-(Trifluoromethyl]-phenyl-2-butenamide. Teriflunomide was first disclosed and claimed in an US patent 5679709. (Aly et al., 2017, Wei et al., 2017, Satyanarayana et al., 2017, Palle et al., 2020) Teriflunomide is a pharmacopeial drug substance and it is listed in British and European Pharmacopoeial monographs. Various synthetic routes are available in the literature to synthesize Teriflunomide drug which involves the commercially available key raw materials (Scheme 1). In addition, Teriflunomide may exist in two geometric isomeric forms (Z) & (E) which are as shown below. (Rabie AM 2021, Rao et al., 2020)

Teriflunomide in the solid state is exists in Z-isomer only, we believed that this may be due to the intramolecular hydrogen bonding which renders its extra stability. (Rabie AM 2021, Rao et al., 2020)

During the process for the preparation of Teriflunomide (1) the formation of four impurities (two are positional isomers) were identified they are (2Z)-4-chloro-2-cyano-N-[4-(Trifluoromethyl]phenyl]-3-hydroxy-2-butenamide (Chloromethyl Teriflunomide 2), (2Z)-2-cyano-3-hydroxy-N-[4-(Trifluoromethyl)phenyl]-2-pentenamide (Ethyl Teriflunomide 3), (2Z)-2-cyano-3-hydroxy-N-[2-(Trifluoromethyl)phenyl]-2-butenamide (2-Isomer of Teriflunomide 4) and (2Z)-2-cyano-3-hydroxy-N-[3-(Trifluoromethyl)phenyl]-2-butenamide (3-Isomer of Teriflunomide 5). These impurities are present at a level of 0.1–0.3% in Teriflunomide. The presence of these impurities in drug substances will have a significant impact on the quality and safety of the drug substance. Hence assessment and control of the related substances is mandatory to obtain the approvals from various regulatory bodies. (ICH Q3A (R2) 2006, Validation of Analytical procedures 2006) As per ICH guidelines it is recommended that the impurities which are present in the level of ˂0.1% w/w by analytical results in API should be identified & characterized based on the fact that unknown impurities may cause health hazards by making the API (Active Pharmaceutical Ingredient) inferior in quality. (ICH Q3A (R2) 2006) To have a better understanding of impurity profile, the unknown impurities have to be identified, synthesized and controlled in the manufacturing process. (Validation of Analytical procedures 2006) Based on the above facts and their importance in the pharmaceutical industry, the synthesis and characterization of these impurities (2, 3, 4 & 5) is reported.

Literature survey revealed a number of different approaches to prepare Teriflunomide. We have reviewed all the approaches to prepare Teriflunomide reported in literature. (Bartlett et al., 1996, Uckun et al., 2002, Kuo et al., 1996, Schleyerbach et al., 1998 & Hachtel et al., 2005) Based on our literature review and feasibility studies, we found that the process described below will be suitable to manufacture Teriflunomide (1) from the commercially available raw materials namely cyanoacetic acid (6) and 4-(Trifluoromethyl)aniline (4-TFMA, 7).

In this process cyanoacetic acid (6) was reacted with PCl₅ in DCM to obtain cyanoacetyl chloride (A) intermediate as in situ. This intermediate was treated with 4-TFMA [4-(Trifluoromethyl)aniline] (7) to obtain Teriflunomide stage-I [2-Cyano-N-[4-(trifluoromethyl)phenyl]acetamide] (8). Compound 8 was treated with acetyl chloride using acetone as a solvent in the presence of 30% w/w aq NaOH solution to produce Teriflunomide crude product. Finally, Teriflunomide crude product (1) was purified by the acidification followed by basification to afford the Teriflunomide API.

We have synthesised the process related impurities of Teriflunomide (1) are 2, 3 and positional isomers 4, 5 using a very simple synthetic strategy, as shown in the schemes 2–4. Chloromethyl Teriflunomide (2) originates due to the presence of chloroacetyl chloride impurity in acetyl chloride raw material. This contaminates the Teriflunomide API at a level of 0.1–0.3%.

To prepare Chloromethyl Teriflunomide (2), Teriflunomide stage-I (8) was reacted with chloroacetyl chloride in acetone as a solvent in the presence of 30% w/w aq NaOH solution to obtain Chloromethyl Teriflunomide crude material which was subsequently purified from acetone to yield pure Chloromethyl Teriflunomide (2).

Ethyl Teriflunomide (3) originates due to the presence of propionyl chloride impurity in acetyl chloride raw material which results in the formation of 3 during the preparation of Teriflunomide in the level of 0.1–0.3%. To prepare Ethyl Teriflunomide (3), Teriflunomide Stage-I (8) was reacted with propionyl chloride in acetone in the presence of 30% w/w aq NaOH solution to get Ethyl Teriflunomide (3) crude which was subsequently purified from acetone to get pure Ethyl Teriflunomide (3).

Positional isomer (2-Isomer) of Teriflunomide (4) may originate due to the presence of traces of 2-(Trifluoromethyl)aniline (9) impurity in 4-TFMA (7) raw material which results in the formation of 4 during the preparation of Teriflunomide (1) in the level of 0.1–0.3% by HPLC. To prepare 2-Isomer of Teriflunomide (4), Cyanoacetic acid (6) was reacted with PCl₅ in DCM to obtain cyanoacetyl chloride (A) intermediate in situ. Cyanoacetyl chloride intermediate (A) was reacted with 2-TFMA (9) leads to the formation of 2-cyano-N-[2-(trifluoromethyl)phenylacetamide (10). Finally, 10 was reacted with acetyl chloride in acetone in the presence of 30% w/w aq NaOH solution to get 2-Isomer of Teriflunomide (4) crude which was subsequently purified by using column chromatography to get a pure positional isomer (2-Isomer) of Teriflunomide (4).

Positional isomer (3-Isomer) of Teriflunomide (5) may originate due to the presence of traces of 3-(Trifluoromethyl)aniline (11) impurity in 4-TFMA (7) raw material which results in the formation of 5 during the preparation of Teriflunomide (1) in the level of 0.1–0.3% by HPLC. To prepare positional isomer (3-Isomer) of Teriflunomide (5), Cyanoacetic acid (6) was reacted with PCl₅ in DCM to obtain cyanoacetyl chloride (A) intermediate in situ. Cyanoacetyl chloride intermediate (A) was reacted with 3-TFMA (11) leads to the formation of 2-cyano-N-[3-(trifluoromethyl)phenylacetamide (12). Finally, 12 was reacted with acetyl chloride in acetone in the presence of 30% w/w aq NaOH solution to get 3-Isomer of Teriflunomide (5) crude which was subsequently purified by using column chromatography to get a pure compound of 3-Isomer of Teriflunomide (5). Based on our literature search there is no reported synthesis available for the synthesis of potential impurities Chloromethyl Teriflunomide (2) & Ethyl Teriflunomide (3). The synthesis of positional isomers 2-isomer of Teriflunomide (4) & 3-isomer of Teriflunomide (5)) was disclosed in patents Faith et al., 2002 WO 02/34251 & Faith et al., 1999 WO 99/54286 using sodium hydride as a base and THF as a solvent.

Raw materials, reagents & solvents used in this process were obtained from the commercial sources and they are used without further purification. The ¹H NMR spectra were recorded on Bruker Avance 300 and 500 MHz spectrometers. The chemical shifts were reported in δ/ppm relative to TMS. Mass spectra were recorded on an API 2000 PerkinElmer PESciex mass spectrometer.

Preparation(2Z)-4-chloro-2-cyano-N-[4-(Trifluoromethyl]phenyl]-3-hydroxy-2-butenamide (Chloromethyl Teriflunomide 2)

Phosphorous pentachloride (22 g, 105.6 mmol) was slowly added by lot wise to a suspension of cyanoacetic acid 6 (7.92 g, 93.17 mmol) in DCM (80 ml) at 0–5°C. The reaction mass was slowly warmed to reflux temperature and stirred for 1 h to form cyanoacetyl chloride intermediate (A). Further, added 4-(Trifluoromethyl)aniline 7 (10 g, 62.11 mmol) dissolved in DCM (20 ml) to the resulting cyanoacetyl chloride intermediate (A) at 20–30°C slowly. The obtained suspension was heated to reflux and stirred for 5h at reflux temperature. After completion of the reaction, the mass was cooled to 20–30°C, the precipitated product was collected by filtration and dried to give Teriflunomide stage-I (8) (12.75 g, 90%) as an off-white solid.

30% w/w aqueous sodium hydroxide solution (7 g NaOH in 16.4 mL water, 175.44 mmol) was added to a mixture of Teriflunomide stage-I (8) (10 g, 43.86 mmol) in acetone (60 ml) at 0–5°C. Chloroacetyl chloride (7.43g, 65.79 mmol) was added slowly to the reaction mass at 0–5°C. The resulting mass was stirred for 1 h at 0–5°C. After completion of the reaction added purified water (60 ml) and adjusted the pH of the mass to ~ 1.0 with HCl (11 ml, 35% w/w), stirred the mass for 15 min at 0–5°C. The obtained product was collected by filtration to get the crude wet material which was crystallized from acetone (40 ml) at 40–45°C, dried to give (Chloromethyl Teriflunomide) (2) as a white solid. Yield : 8 g (60%); HPLC Purity: 99.85%; ¹H-NMR (300 MHz, DMSO-d₆) δ: 4.22 (s, 2H), 7.56–7.59 (d, 2H, J = 8.4 Hz), 7.71–7.73 (d, 2H, J = 8.4 Hz), 11.76 (brs, 1H), 12.03 (s, 1H), ¹³C NMR (75 MHz, DMSO-d₆) δ: 46.1, 77.3, 118.9, 119.2, 121.4, 121.8, 121.9, 122.2, 122.7, 122.8, 125.97, 126.02, 126.07, 126.1, 126.4, 130.0, 143.4, 166.1, 182.3, coupling constants observed for the corresponding peaks are 121.4, 121.8, 122.2, 122.7 (q, J_CF = 31 Hz), 125.97, 126.02, 126.07, 126.1 (q, J_CF = 4 Hz), 119.2, 122.8, 126.4, 130.0 (q, J_CF = 269 Hz); HRMS (ESIQTOF) for C₁₂H₈ClF₃N₂O₂ [M - H] ⁻: m/z calcd: 303.0154, found: 303.1441 & 305.1389.

Preparation of (2 Z )-2-cyano-3-hydroxy- N -[4-(Trifluoromethyl)phenyl]-2-pentenamide (Ethyl Teriflunomide 3)

Phosphorous pentachloride (22 g, 105.6 mmol) was slowly added by lot wise to a suspension of cyanoacetic acid 6 (7.92 g, 93.17 mmol) in DCM (80 ml) at 0–5°C. The resulting reaction mass was slowly warmed to reflux temperature and stirred for 1 h to form cyanoacetyl chloride intermediate (A). Further, added 4-(Trifluoromethyl)aniline 7 (10 g, 62.11 mmol) dissolved in DCM (20 ml) to the resulting cyanoacetyl chloride intermediate (A) at 20–30°C. The obtained suspension was slowly heated to reflux and stirred for 5 h. After completion of the reaction, the mass was cooled to 20–30°C, the precipitated product was collected by filtration and dried to give Teriflunomide stage-I (8) (12.75 g, 90%) as an off-white solid.

30% w/w aqueous sodium hydroxide solution (7 g NaOH in 16.4 mL water, 175.44 mmol) was added to a mixture of Teriflunomide stage-I product (8) (10 g, 43.86 mmol) in acetone (60 ml) at 0–5°C. Further, propionyl chloride (6.09 g, 65.79 mmol) was added slowly to the reaction mass at 0–5°C. The resulting mixture was stirred for 1 h at 0–5°C. After completion of the reaction, added purified water (60 ml) and adjusted the pH of the mass to ~ 1.0 with HCl (10 ml, 35% w/w) and stirred for 30 min at 0–5°C. The obtained product was collected by filtration to get crude material and the crude wet material was purified from acetone (40 ml), dried to give Ethyl Teriflunomide (3) as a white solid. Yield 7 g (56%); HPLC Purity: 98.88%; ¹H-NMR (300 MHz, DMSO-d₆) δ: 1.09–1.14 (t, 3H, J = 7.5 Hz), 2.48–2.55 (m, 2H), 7.62–7.65 (d, 2H, J = 8.7 Hz), 7.74–7.77 (d, 2H, J = 8.7 Hz), 9.40–9.46 (brs, 1H), 11.24 (s, 1H), ¹³C NMR (125 MHz, DMSO-d₆) δ: 10.2, 29.1, 79.4, 117.2, 121.0, 121.5, 123.2, 123.9, 124.1, 124.4, 124.6, 125.3, 125.71, 125.74, 125.77, 125.80 (q, J_C2 = 3.75 Hz), 127.5, 141.2, 167.3, 191.8, coupling constants observed for the corresponding peaks are 123.9, 124.1, 124.4, 124.6 (q, J_CF = 32 Hz), 125.71, 125.74, 125.77, 125.80 (q, J_CF = 3.75 Hz), 121.0, 123.2, 125.3, 127.5 (q, J_CF = 270 Hz); HRMS (ESIQTOF) for C₁₃H₁₁F₃N₂O₂ [M - H]⁻: m/z calcd: 283.0700; found: 283.2039.

Preparation of (2 Z )-2-cyano-3-hydroxy- N -[2-(Trifluoromethyl)phenyl]-2-butenamide (2-isomer of Teriflunomide 4)

Phosphorous pentachloride (24.22 g, 116.16 mmol) was added slowly by lot wise to a suspension of cyanoacetic acid 6 (8.71 g, 102.47 mmol) in DCM (88 ml) at 0–5°C. The resulting reaction mass was heated to reflux and stirred for 1 h at reflux temperature to form cyanoacetyl chloride intermediate (A). Further, added 2-(Trifluoromethyl)aniline 7 (11 g, 68.32 mmol) dissolved in DCM (22 ml) to the resulting cyanoacetyl chloride intermediate (A) solution at 20–30°C. The suspension was slowly heated to reflux and stirred for 6 h. After completion of the reaction the resulting mixture was cooled to 25–30°C and obtained product was collected by filtration, dried to give 2-Cyano-N-[2-(trifluoromethyl)phenyl]acetamide (10) (13.2 g, 85%) as an off-white solid.

30% w/w aqueous sodium hydroxide solution (7.72 g NaOH in 18 mL water, 193 mmol) was added to a mixture of 2-Cyano-N-[2-(trifluoromethyl)phenyl]acetamide (10) (11 g, 48.25 mmol) in acetone (66 ml) at 0–5°C. Added acetyl chloride (5.68 g, 72.36 mmol) slowly to the reaction mass at 0–5°C. The resulting mixture was stirred for 2 h at 0–5°C. After completion of the reaction, added purified water (66 ml) and adjusted the pH of the mass to ~ 1.0 with HCl (11 ml, 35% w/w) and stirred for 30 min at 0–5°C. The obtained product was collected by filtration to get crude material and was purified by column chromatography to give pure compound of 2-isomer of Teriflunomide (4) as a white solid. Yield 7.8 g (60%); HPLC Purity: 99.75%; ¹H-NMR (300 MHz, DMSO-d₆) δ: 2.28 (s, 3H), 7.35–7.40 (t, 1H, J = 7. 5 Hz ), 7.64–7.73 (m, 2H), 7.93–7.96 (d, 1H, J = 8.1 Hz), 13.53 (brs, 1H) ppm; ¹³C NMR (75 MHz, DMSO-d₆) δ: 23.5, 82, 118.8, 119, 121.8, 122.2, 122.4, 122.6, 123.0, 125.9, 126.0, 126.5, 126.60, 126.67, 126.7, 127.6, 129.6, 133.6, 135.66, 135.68, 166.3, 186.0, coupling constants observed for the corresponding peaks are 118.8, 122.40, 126.0, 129.6 (J_CF = 271 Hz), 126.5, 126.6, 126.67, 126.74 (q, J_CF = 5 Hz), 121.8, 122.2, 122.6, 123.0 (q, J_CF = 29 Hz); HRMS (ESIQTOF) for C₁₂H₉F₃N₂O₂ [M - H]⁻: m/z calcd: 269.0543; found: 269.1931, [M + H]⁺: m/z calcd: 271.0689; found: 271.0713.

Preparation of (2 Z )-2-cyano-3-hydroxy- N -[3-(Trifluoromethyl)phenyl]-2-butenamide (3-isomer of Teriflunomide 5)

Phosphorous pentachloride (24.22 g, 116.16 mmol) was added slowly by lot wise to a suspension of cyanoacetic acid 6 (8.71 g, 102.47 mmol) in DCM (88 ml) at 0–5°C. The resulting reaction mass was heated to reflux and stirred for 1 h at reflux temperature. Further, added 3-(Trifluoromethyl)aniline 7 (11 g, 68.32 mmol) dissolved in DCM (22 ml) at 20–30°C. The suspension was heated to reflux and stirred for 6 h. After completion of the reaction, the mass was cooled to 20–30°C and the obtained product was collected by filtration, dried to give 2-Cyano-N-[3-(trifluoromethyl)phenyl]-acetamide (12) (13.2 g, 85%) as an off-white solid.

30% w/w aqueous sodium hydroxide solution (7.72 g NaOH in 18 mL water, 193 mmol) was added to a mixture of 2-Cyano-N-[3-(trifluoromethyl)phenyl]acetamide (12) (11 g, 48.25 mmol) in acetone (66 ml) at 0–5°C. Added acetyl chloride (5.68 g, 72.36 mmol) slowly to the reaction mass at 0–5°C. The resulting mixture was stirred for 2 h at 0–5°C. After completion of the reaction, purified water (66 ml) was added and the pH of the mass was adjusted to ~ 1.0 with HCl (11 ml, 35% w/w) and stirred for 30 min at 0–5°C. The precipitated product was collected by filtration, washed with precooled acetone (11 ml) to get crude compound and was purified by column chromatography to give pure compound of 3-isomer of Teriflunomide (5) as a white solid. Yield 7.8 g (60%); HPLC Purity: 94.28%; ¹H-NMR (300 MHz, DMSO-d₆) δ: 2.28 (s, 3H), 7.43–7.46 (d, 1H, J = 7.5 Hz), 7.53–7.58 (t, 1H, J = 7.8 Hz), 7.77–7.8 (d, 1H, J = 7.8 Hz), 8.05 (s, 1H), 10.16 (brs, 1H), 10.71 (s, 1H) ppm; ¹³C NMR (75 MHz, DMSO-d₆) δ: 23.2, 81.2, 118.1, 118.2, 119.1, 120.92, 120.97, 122.7, 125.5, 126.3, 129.2, 129.6, 129.9, 130.0, 130.2, 130.4, 138.9, 167.1, 187.7, coupling constants observed for the corresponding peaks are 118.1, 118.2(J_CF = 4.3 Hz), 120.92, 120.97 (J_CF = 3.7 Hz), 119.1, 122.7, 126.3, 129.9 (J_CF = 270 Hz); HRMS (ESIQTOF) for C₁₂H₉F₃N₂O₂ [M - H]⁻: m/z calcd: 269.0543; found: 269.1931.

We have prepared and characterized the four impurities of Teriflunomide by ¹³C NMR, ¹H NMR, HRMS and HPLC analysis. These impurities can be synthesised from the commercially available raw materials. Synthesis of these four impurities will be helpful to finalize the impurity profile of Teriflunomide, which is very essential in the generic pharmaceutical industry to address the regulatory requirements.

DCM

Dichloromethane

4-TFMA

4-(Trifluoromethyl)aniline

3-TFMA

3-(Trifluoromethyl)aniline

2-TFMA

2-(Trifluoromethyl)aniline

PCl₅

Phosphorous pentachloride

NaOH

Sodium hydroxide

ICH

International Council on Harmonization

API

Active Pharmaceutical Ingredient.

Acknowledgements

We are grateful to the management of Aurobindo Pharma Limited for accepting to publish our research work. We are indebted to the Analytical department for supporting the work.

Data Availability Statement

The required supporting analytical data for this paper is available in the supplementary material of this article.

Conflict of interest

The authors declare no conflict of interest.

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Scheme 1 to 4 are available in Supplementary Files section.

Scheme1.png
Scheme 1. Preparation of Teriflunomide (1)
Scheme2.png
Scheme 2. Preparation of Chloromethyl Teriflunomide (2) & Ethyl Teriflunomide (3)
Scheme3.png
Scheme 3. Preparation of 2-Isomer of Teriflunomide (4)
Schenme4.png
Scheme 4. Preparation of 3-Isomer of Teriflunomide (5)
SITeriflunomideSureshAPL.docx

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Preparation and characterization of impurities of Teriflunomide - An Immunomodulatory agent

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