An Eco-Friendly Industrial Fischer Indole Cyclization Process

Aug 15, 2018 - Department of Synthetic Medicinal Chemistry, Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institut...
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An Eco-Friendly Industrial Fischer Indole Cyclization Process Xu Yang,‡ Xiang Zhang,*,‡ and Dali Yin†,‡ †

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Jia 2, Nanwei Road, Xicheng District, Beijing 100050, China ‡ Department of Synthetic Medicinal Chemistry, Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Jia 2, Nanwei Road, Xicheng District, Beijing 100050, China

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S Supporting Information *

ABSTRACT: We report an optimized Fischer indole cyclization process using toluene as both the cosolvent and extraction solvent. The process produced zero wastewater, and a high-purity product was obtained without further purification. The optimized route was applied to synthesize key intermediates of two MmpL3 inhibitors, NITD-304 and NITD-349, on a multikilogram scale. KEYWORDS: Fischer indole cyclization, improved process, multi-kilogram scale, MmpL3 inhibitors, NITD-304, NITD-349



INTRODUCTION The indole ring system is one of the most abundant and important aromatic heterocycles in nature.1−3 Over the past several decades, a diverse array of biologically significant natural compounds that contain the indole motif have been found.4 In addition, medicinal chemists have used the indole fragment in many synthetic drugs, including some blockbuster drugs.4 Indole construction is still an important field in organic synthesis and has been systemically summarized.4−10 Among those reviews, Taber and Tirunahari originally classified indole syntheses into nine strategic approaches based on the last bond formed of the four bonds in the five-membered indole ring.9 Although it might be unfashionable, the classic Fischer indole synthesis is still widely used because it addresses all the requirements of a modern indole synthesis and can conveniently and simply couple a monofunctionalized arene with a readily available aldehyde or ketone.4,11−13 Much effort has been made to improve the Fischer indole synthesis, and many catalysts such as p-toulenesulfonic acid, polyphosphoric acid (PPA), pyridine hydrochloride, anhydrous zinc chloride, and so forth have been developed to promote the reaction.11,12,14−19 Among these catalysts, PPA20 is the most common catalyst used in the Fischer indole synthesis in pilotplant scale due to its low price and convenient shipping and stock-keeping in large volumes.11 However, the workup with PPA, which involves pouring the reaction mixture into water, generates a large amount of wastewater. Moreover, the purity of the crude products is usually poor, and they are often brown to black and look like clay or tar; thus, further purification by column chromatography or other purification technologies is essential. These drawbacks make the process environmentally damaging and sharply increase the cost directly or indirectly, to some extent limiting the large-scale use of the reaction. In this study, we report a practical solution for preparing indole compounds on a pilot scale. The process provides highquality products and is much more eco-friendly than the conventional process. The reliability of the method was verified © XXXX American Chemical Society

with two indole pharmaceutical intermediates (1a and 1b) for the antitubercular drug candidates NITD-304 and NITD-349 (Scheme 1).21,22 Scheme 1. Preparation of Key Intermediate 1 for the Antitubercular Drug Candidates



RESULTS AND DISCUSSION The literature synthetic approach to intermediate 1 involves a conventional Fischer indole cyclization and suffers from problems with workup and purity.23,24 Adding a suitable cosolvent to the reaction mixture so that the reaction is heterogeneous reduces the PPA viscosity and makes the mixture easier to stir.12,25,26 Toluene was chosen as the cosolvent because of its appropriate boiling point and solubility. We assumed that the amount of PPA could be decreased when toluene was introduced. Actually, the study verified that the amount of PPA could be decreased to 3−5-times compared with the substrate when using toluene (Table 1). We achieved the best yield when the reaction was run with a PPA to reactant ratio of 3:1 w/w (Table 1, entry 3). The separation of the cosolvent and PPA led us to use the same cosolvent in the extraction during the Received: May 3, 2018 Published: August 15, 2018 A

DOI: 10.1021/acs.oprd.8b00144 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

although a further two extractions gave almost quantitative yields. The improved workup procedure, which was more environmentally friendly and cost-efficient, circumvented the problematic extraction and purification and increased the yield considerably. An in situ FTIR monitoring technique (ReactIR, Mettler Toledo RC1e) was used during the process study. IR analysis of identified components (Figure 1) showed that substrate 2 (red) and corresponding product 1 (blue) exhibit substantial differences between 1500 and 1700 cm−1. Compound 2 has an absorption at ∼1587 cm−1 corresponding to the CN stretching vibration of −CO−CN−N, whereas compound 1 does not, which can be used to monitor the reaction course. In addition, the peak height of 1700 cm−1 that represents the CO stretching vibration might assist us in identifying the end point of the reaction as well. Although the CO stretching vibration was contained both in the starting material and the corresponding product, the peak 1700 cm−1 of product 1 has a slight enhancement due to its bigger conjugated system. PPA is insoluble in toluene even when it is heated to the reaction temperature; therefore, it was not visible in the IR analysis. The plot of the components’ concentration versus time (Figure 2) showed that the reaction was complete after ∼1.5 h. The reaction was heated from room temperature to 95 °C in the first 10 min during which time compound 2 partitioned between the toluene and PPA phases. This was confirmed by the sharply increased peak height of 1570 cm−1, representing the CN stretching vibration of −CO−CN−N in compound 2. As the reaction proceeded, compound 2 contained in the toluene phase would be continually transferred into the PPA phase because the acid catalyzed the tautomerisation rearrangement of compound 2 to its ene tautomer then followed by a [3, 3] sigmatropic rearrangement to produce the corresponding product compound 1. Therefore, we could observe the relatively slow decreased peak height of 1570 cm−1 from 10 min to 1.5 h, which indicated the continual consumption of starting materials. Then, the peak height of 1570 cm−1 remained stable, which might

Table 1. Effect of the Amount of PPA on the Reaction with Cosolventa entry

PPA/substrate ratio (w/w)

yield (%)b

1 2 3 4

10 5 3 0.5

86.1 90.9 97.1 incomplete reaction

a

Experimental conditions: reactions were performed with 10 g of compound 2a as the substrate in 95 °C for 3 h. The amounts of PPA of entries 1−4 were 100, 50, 30, and 5 g, respectively. The amounts of toluene of entries 1−4 were 100, 5, 30, and 5 mL, respectively. b Isolated yield.

workup. The cascade reaction proceeded smoothly. The reaction mixture was left to stand until the layers separated, and then the upper toluene layer was transferred. Fresh toluene was added to the flask; the mixture was stirred for another 10 min and left to stand, and then the upper solvent layer was transferred. A high-performance liquid chromatography extraction efficiency study showed that the reaction mixtures gave the target product in >99% yield and >95% purity when it was extracted four times (Table 2). Two extractions were effective, Table 2. Extraction Efficiency of the Cosolventa entry

product weight (g)

extraction yield (%)b

1 2 3 4 subtotal

27.94 8.69 0.29 0.11 37.03

75.1 23.4 0.8 0.3 99.6

a Experimental conditions: reactions were performed with 40 g of (E/ Z)-ethyl 2-[(3,5-difluorophenyl)hydrazono]propanoate and 120 g of PPA in 120 mL fo toluene at 95 °C for 3 h. bIsolated yield.

Figure 1. IR analysis of compounds 1 and 2. The IR spectra were measured on Thermo Nicolet 5700 FT-IR-Microscope: the blue spectra represent product 1, and red represent substrate 2. B

DOI: 10.1021/acs.oprd.8b00144 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Figure 2. ConcIRT component profiles of Fisher indole cyclization reaction. Instrument information: ReactIR 15 (SN:3058) with MCT detector using HappGenzel apodization; DiComp (Diamond) probe (SN:7698) connected via AgX 9.5 mm × 1.5 m Fiber (Silver Halide); sampling 3000 to 650 at 8 wavenumber resolution; scan option: AutoSelect; gain: 1×.

then the combined organic solvents were concentrated to dryness under reduced pressure to give ethyl 4,6-dichloro-1Hindole-2-carboxylate (1a) (2.70 kg, 99.5%). Mp 187−188 °C; HRMS (ESI) m/z [M − H]− calcd for C11H8NO2Cl2 255.9927, found 255.9930; 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 4.43−4.30 (q, 2H), 1.34 (d, 3H); 13C NMR (151 MHz, CDCl3) δ 161.69, 137.08, 131.00, 128.45, 128.37, 125.31, 121.26, 110.52, 107.07, 61.56, 14.32; IR (cm−1) 3314.3, 2987.6, 1700.2, 1615.8, 1566.2, 1523.7, 1487.2, 1323.3, 1247.2, 1072.4, 840.1, 770.2. Ethyl 4,6-Difluoro-1H-indole-2-carboxylate (1b). A reactor was charged with PPA (9.6 kg) and heated to 70 °C. (E/Z)-Ethyl 2-[(3,5-difluorophenyl)hydrazono]propanoate (2b) (3.2 kg) and toluene (10.6 L) were added to the reactor sequentially under a N2 atmosphere. The mixture was heated to 90−100 °C for 2 h. The reaction mixture was left to stand until the layers separated, and then the upper toluene layer was transferred. The residue was cooled to 70 °C; toluene (10 L) was added to the reaction flask, and the mixture was stirred for 10 min followed by standing and transferring the top layer of solvent. This extraction was repeated a further three times, and then the combined organic solvents were concentrated to dryness under reduced pressure to give ethyl 4,6-difluoro-1Hindole-2-carboxylate (1b) (2.97 kg, 100%). Mp 154−155 °C; HRMS(ESI) m/z [M − H]− calcd for C11H8NO2F2 224.0518, found 224.0519; 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 7.17 (s, 1H), 7.06 (d, 1H), 7.00−6.89 (m, 1H), 4.52−4.30 (q, 2H), 1.34 (d, 3H); IR (cm−1) 3316.6, 2990.5, 1707.0, 1645.2, 1592.9, 1520.9, 1451.7, 1287.6, 1212.1, 826.2, 768.2.

indicate completion of the reaction. Thus, the disappearance of the starting material can be monitored easily to determine the progress of the reaction. In addition, the trend of the peak height of 1730 cm−1 that represents the CO stretching vibration also gave us some clue in identifying the end point. We attributed the sharp increased peak height of 1730 cm−1 during the first 10 min to the dissolution of starting materials in the toluene phase. Then, its slight increasing trend from 10 min to 1.5 h might be a comprehensive result of the exchange of compounds 1 and 2 between the toluene and PPA phases. Finally, the peak height of 1730 cm−1 remained stable as the reaction arrived at the end point. The process was validated on a scale of more than 3 kg, demonstrating its good reproducibility and thus its robustness.



CONCLUSIONS We have developed an improved Fischer indole cyclization process that is suitable for industrial scale. Toluene was used as a cosolvent in the reaction and an extraction solvent in the workup. The optimized process did not produce wastewater, and the crude product was sufficiently pure without further purification. This method will reduce the environmental impact and cost of producing drugs containing the indole skeleton.



EXPERIMENTAL SECTION General Information. All the solvents and reagents were obtained from commercial sources and used without further purification. 1H and 13C NMR spectra were collected on a Bruker AVANCE III 400 MHz spectrometer and a Varian 600 MHz spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) from tetramethylsilane (TMS) using the residual solvent resonance. Multiplicities are abbreviated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br s (broad singlet). ESI-MS was recorded on Thermo Exactive Orbitrap plus spectrometer. Melting points were determined on a microscope melting point apparatus. Ethyl 4,6-Dichloro-1H-indole-2-carboxylate (1a). A reactor was charged with PPA (9 kg) and heated to 70 °C. (E/Z)-Ethyl 2-[(3,5-dichlorophenyl)hydrazono]propanoate (2a) (3 kg) and toluene (10 L) were added to the reactor sequentially under a N2 atmosphere. The mixture was heated to 90−100 °C for 2.5 h. The reaction mixture was left to stand until the layers separated, and then the upper toluene layer was transferred. The residue was cooled to 70 °C; toluene (10 L) was added to the reaction flask, and the mixture was stirred for 10 min followed by standing and transferring the top layer of solvent. This extraction was repeated a further three times, and



ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00144.



Optimized procedure making the process more suitable for manufacturing production after some fine-tuning to the workup procedure along with HPLC data of the purity of products and NMR data (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +86-10-63165248. ORCID

Xu Yang: 0000-0001-9289-7668 C

DOI: 10.1021/acs.oprd.8b00144 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Notes

Smith, P. W. Design, synthesis, and biological evaluation of indole-2carboxamides: a promising class of antituberculosis agents. J. Med. Chem. 2013, 56 (21), 8849−59. (23) Jiricek, J., Kondreddi, R. R., Smith, P. W. Indole carboxamide derivatives and uses thereof: WO, CA 2881351 A1[P]. 2014. (24) Köse, M.; Ritter, K.; Thiemke, K.; Gillard, M.; Kostenis, E.; Müller, C. E. Development of [3H] 2-Carboxy-4, 6-dichloro-1 Hindole-3-propionic Acid ([3H] PSB-12150): A Useful Tool for Studying GPR17. ACS Med. Chem. Lett. 2014, 5 (4), 326−330. (25) Watson, T. J.; Horgan, S. W.; Shah, R. S.; Farr, R. A.; Schnettler, R. A.; Nevill, C. R.; Weiberth, F. J.; Huber, E. W.; Baron, B. M.; Webster, M. E.; et al. Chemical development of MDL 103371: An Nmethyl-D-aspartate-type glycine receptor antagonist for the treatment of stroke. Org. Process Res. Dev. 2000, 4 (6), 477−487. (26) Guy, A.; Guetté, J.-P.; Lang, G. Utilization of polyphosphoric acid in the presence of a co-solvent. Synthesis 1980, 1980 (03), 222− 223.

The authors declare no competing financial interest.



ACKNOWLEDGMENTS We are grateful for financial support from the National Scientific & Technological Major Project on Major New Drug Innovation (2015ZX09102007-004) and CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-3-022).



REFERENCES

(1) Biswal, S.; Sahoo, U.; Sethy, S.; Kumar, H. K. S.; Banerjee, M. Indole: The molecule of diverse biological activities. Asian Journal of Pharmaceutical & Clinical Research 2012, 5 (1), 1−6. (2) Gribble, G. W. Indole ring synthesis: From natural products to drug discovery; John Wiley & Sons, 2016. (3) de Sa Alves, F.; Barreiro, E. J.; Manssour Fraga, C. From nature to drug discovery: the indole scaffold as a ‘privileged structure’. Mini-Rev. Med. Chem. 2009, 9 (7), 782−793. (4) Inman, M.; Moody, C. J. Indole synthesis − something old, something new. Chem. Sci. 2013, 4 (1), 29−41. (5) Gribble, G. W. Recent developments in indole ring synthesis methodology and applications. Journal of the Chemical Society, Perkin Transactions 1 2000, No. 7, 1045−1075. (6) Humphrey, G. R.; Kuethe, J. T. Practical methodologies for the synthesis of indoles. Chem. Rev. 2006, 106 (7), 2875−2911. (7) Patil, S. A.; Patil, R.; Miller, D. D. Microwave-assisted synthesis of medicinally relevant indoles. Curr. Med. Chem. 2011, 18 (4), 615−637. (8) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Copper catalysis in the construction of indole and benzo [b] furan rings. Org. Biomol. Chem. 2011, 9 (3), 641−652. (9) Taber, D. F.; Tirunahari, P. K. Indole synthesis: a review and proposed classification. Tetrahedron 2011, 67 (38), 7195−7210. (10) Cacchi, S.; Fabrizi, G. Synthesis and functionalization of indoles through palladium-catalyzed reactions. Chem. Rev. 2005, 105 (7), 2873−2920. (11) Robinson, B. The Fischer indole synthesis. Chem. Rev. 1963, 63 (4), 373−40. (12) Hughes, D. L. Progress in the Fischer indole reaction. A review. Org. Prep. Proced. Int. 1993, 25 (6), 607−632. (13) Li, J. J. Fischer indole synthesis. In Name Reactions; Springer, 2014; pp 253−254. (14) Köhling, P.; Schmidt, A. M.; Eilbracht, P. Tandem hydroformylation/Fischer indole synthesis: a novel and convenient approach to indoles from olefins. Org. Lett. 2003, 5 (18), 3213−3216. (15) Gore, S.; Baskaran, S.; König, B. Fischer indole synthesis in low melting mixtures. Org. Lett. 2012, 14 (17), 4568−4571. (16) Xu, D.-Q.; Wu, J.; Luo, S.-P.; Zhang, J.-X.; Wu, J.-Y.; Du, X.-H.; Xu, Z.-Y. Fischer indole synthesis catalyzed by novel SO 3 Hfunctionalized ionic liquids in water. Green Chem. 2009, 11 (8), 1239− 1246. (17) Xu, D. Q.; Yang, W. L.; Luo, S. P.; Wang, B. T.; Wu, J.; Xu, Z. Y. Fischer indole synthesis in brønsted acidic ionic liquids: a green, mild, and regiospecific reaction system. Eur. J. Org. Chem. 2007, 2007 (6), 1007−1012. (18) Haag, B. A.; Zhang, Z. G.; Li, J. S.; Knochel, P. Fischer Indole Synthesis with Organozinc Reagents. Angew. Chem., Int. Ed. 2010, 49 (49), 9513−9516. (19) Müller, S.; Webber, M. J.; List, B. The catalytic asymmetric Fischer indolization. J. Am. Chem. Soc. 2011, 133 (46), 18534−18537. (20) Popp, F. D.; McEwen, W. E. Polyphosphoric acids as a reagent in organic chemistry. Chem. Rev. 1958, 58 (2), 321−401. (21) Rao, S. P.; Lakshminarayana, S. B.; Kondreddi, R. R.; Herve, M.; Camacho, L. R.; Bifani, P.; Kalapala, S. K.; Jiricek, J.; Ma, N. L.; Tan, B. H. Indolcarboxamide is a preclinical candidate for treating multidrugresistant tuberculosis. Sci. Trans. Med. 2013, 5 (214), 214ra168. (22) Kondreddi, R. R.; Jiricek, J.; Rao, S. P.; Lakshminarayana, S. B.; Camacho, L. R.; Rao, R.; Herve, M.; Bifani, P.; Ma, N. L.; Kuhen, K.; Goh, A.; Chatterjee, A. K.; Dick, T.; Diagana, T. T.; Manjunatha, U. H.; D

DOI: 10.1021/acs.oprd.8b00144 Org. Process Res. Dev. XXXX, XXX, XXX−XXX