Optimization of Ullmann Reaction Step in the Synthesis of Sertindole

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1 Advanced Materials Research Online: ISS: , Vols , pp doi:10.408/ 011 Trans Tech Publications, Switzerland Optimization of Ullmann Reaction Step in the Synthesis of Sertindole Wen Li 1, a, Xiaoqing Ma 1, b and Jianghe Yu, c 1 School of Chemical Engneering and Energy, Zhengzhou University, Zhengzhou, , China China Pharmaceutical University, anjing, 10009, China a liwen@zzu.edu.cn, b maxiaoqing69@16.com, c yujh849@yahoo.com.cn Keywords: sertindole, 5-chloro-1-(4-fluorophenyl) indole, Ullmann reaction, synthesis. Abstract. 5-chloro-1-(4- fluorophenyl)-indole is a key intermediate of sertindole. It can be synthesized from 4-fluoro-bromobenzene and 5-chloroindole by Ullmann reaction, but this step required significant optimization to improve yield and reproducibility for the purity processes of the syntheses that have been disclosed are quite complicated and the reaction proceeds usually can t go to completion. The Ullmann reaction step in the synthesis of sertidole was improved by using purified 5-chloroindole, suitable catalyst and solvent. A viable kilo-scale synthesis of the 5-chloro-1-(4- fluoro phenyl)-indole was described. Simple workup, economical, high yields and purity of product are some advantages of this method. Introduction Sertindole is a well-known antipsychotic drug having the formula 1. O H fomula 1 formula The compound was disclosed in US patent [1] and the antipsychotic activity thereof was described in US patent []. Sertindole is a potent centrally acting 5-HT receptor antagonist in vivo and has further been disclosed to be activity in models indicative of effect in the treatment of anxiety, hypertension, drug abuse and cognitive disorders. A number of syntheses of sertindole [1,3-7] have been disclosed. 5-chloro-1-(4-fluorophenyl) -indole (formula ) is a key intermediate in these syntheses. The syntheses of it as disclosed in US patent and WO require multiple steps from commercially available starting materials, are expensive, occupy production equipment for prolonged periods resulting in low production capacity and result in environment impact and safety. The synthesis which has been favored so far for industrial synthesis of sertindole comprises the multiple step synthesis of 5-chloro-1-(4-fluorophenyl) -indole as disclosed in WO The synthesis route was shown in Scheme 1. All rights reserved. o part of contents of this paper may be reproduced or transmitted in any form or by any means without the written permission of Trans Tech Publications, (ID: , Pennsylvania State University, University Park, USA-1/0/16,08:50:7)

2 Advanced Materials Research Vols COOH 3 4 HCH COOH Scheme 1 COOH CH COOH 5 total yield < 60% An alternative synthetic strategy [4, 8] for 1-aryl-indoles is the Ullmann arylation of -unsubstituted indoles with arylhalides catalyzed by large amounts of copper (Scheme ). However, during our development of the synthetic route into one which was sufficiently practical to provide kilo-scale quantities for studies, we encountered many challenges. irst, the purity of crude 5-chloro-indole (6) which was used in the reaction was 80%. After the reaction was completed, the crude product was purified by washed with base, distillated at normal pressure, stripped with 1-methyl--pyrrolidione, diluted with toluene and thin film distillation in turn. The whole purity process was quite complicated. Second, when toluene was used as the reaction solvent, the reaction mixture was heated at 130 for 36 hours and then the conversion checked by HPLC could reach 96%. The reaction proceed was very slowly and usually can t go to completion. Hence, this step required significant optimization to improve yield and reproducibility. H Br 6 7 PhCH 3 Cu(I) Scheme The conversion checked by GC was about 45% for 10h, 55% for 18h and 96% for 36h This paper describes the optimization of the synthesis of compound, involving significant experimentation on Ullmann reaction step. Results and Discussion irst, the reaction between 5-chloro-indole (6, purity 98%) and 4-fluoro- bromobenzene (7) in [bmin]b 4 chosen as the model reaction (Scheme 3) to detect weather the use of copper catalyst was different. The results are summarized in Table 1. It was found that the copper catalysts such as CuBr, CuBr /KI as well as the condition of no catalyst gave low yields of, whereas CuI, CuBr/KI, Cu/KI exhibited good catalytic effect with a good yield in a short reaction time. Considering the higher activity of CuI, it was chosen as the catalyst of choice. The reaction of 6 with 7 in the presence of 10mol% of CuI in [bmin]b 4 gave in 9.5%. H Br 6 7 [bmin]b 4 [bmin]b 4 CH 3 Cu(I) 10mol% Scheme 3 C 4 H 9.B 4 -

3 596 Application of Chemical Engineering Table 1 The Ullmann reaction of compound 6 catalyzed by different catalysts in [bmin]b 4. a Entry Catalyst Time (h) Yield (%) b CuBr Cu CuI CuBr CuBr/KI Cu/KI CuBr /KI otes: a All reaction were carried out in [bmin]b 4 at 110 using 10 mol% catalyst. b Isolated yields. Establishing the higher catalytic activity of CuI among the tested copper catalysts in [bmin]b 4, optimization of reaction conditions using various solvents was undertaken. The model reaction was reaction carried out in solvents such as toluene, 1, -dichloroethane, DMSO, [bmin]br and [bmin]p 6 in order to determine weather the ionic liquid, [bmin]b 4, was an essential factor to promote the Ullmann reaction of compound 6. The results are summaried in Table. Table The Ullmann reaction of compound 6 catalyzed by CuI in different solvents. a Entry solvent Time (h) Yield (%) b 1 [bmin]b [bmin]p [bmin]oh [bmin]br DM DMSO CH 36 - c 8 Toluene TH 36 - c otes: a Reaction conditions: 5-chloro-indole (6, purity 98%,.8 mmol), 4-fluoro- bromobenzene (7,.9 mmol) and CuI (0.8 mmol, 10 mol %) at 110 or reflux. b Isolated yields. c o product formation was observed. The investigation of reaction medium for the process revealed the reaction solvents played a significant role in the model reaction. Ionic liquid was a type of feasible reaction medium for this arylation reaction. After screening a variety of reaction media, [bmin]b 4 was found to be the most effective medium for the generation of desired product in 9.5% yield. DM or toluene is also the effective solvent which could obtain good yield after increasing the reaction time. The reaction in DMSO resulted in poor yield of product along with uncharged starting material, whereas in ionic liquid [bmin]p 6,[bmin]OH and [bmin]br, it resulted in moderate yields. It is noteworthy to mention that there was no product formation in CH and TH even after 36h at reflux. The method here described could be carried out on a kilogram scale and thus 5mol of 5-chloro-indole (6, purity 98%) was quantitatively oxidized to 5-chloro-1-(4-fluorophenyl) -indole () with.5l [bmin]b 4 catalyzed by 0.5mol CuI in 8 hours at 130. The solid were filtered off and the [bmin]b 4 solution was added to cold water 3L whereupon 5-chloro-1-(4-fluorophenyl) -indole () precipitated as a crystal solid. (Yield 9.5%, purity 97.%). The reaction proceed is rapidly and the resulting 5-chloro-1-(4-fluorophenyl) -indole () is isolated after removal of the solvent. o significant amounts of side reaction products are found. High yields and high purity in most cases indicated by both the MR and HPLC analysis.

4 Advanced Materials Research Vols Conclusion In conclusion, we have presented an efficient, selective, practical and essential quantitative conversion of 5-chloro-indole to 5-chloro-1-(4-fluorophenyl) -indole () catalyzed by a copper salt in [bmin]b 4. Experimental All products are known compounds and were characterized by comparison of their physical and spectroscopic data with those of authentic samples. IR and 1 H-MR spectra were recorded on Perkin Elmer 781 and Brucker DPX400 instruments. HPLC was recorded on Shimadzu LC-10ATvp. General experimental procedure A suspension comprising 5-chloro-indole (30. g, 0. mol), K CO 3 (0.9 g, 0.15 mol), 4-fluorobromobenzene(38.3 g, 0. mol), CuI (3.8 g, 0.0 mol), ethylenediamine(3g, 0.05mol) and 100ml of [bmin]b 4 was heated at 130 under atmosphere for 6 hours and then cooled to ml water were added to the reaction mixture which. The mixture was added to cool under strring for 0.5 hour and filtered. The filter cake was washed with *5 ml water and dried under vacuum overnight to give as a fine, yellow crystalline solid (45.3g, 9.5% yield), mp HPLC-analysis: 97.5% w/w product. Spectroscopic data of 5-chloro-1-(4-fluorophenyl) -indole () 1 H MR(CD 3 ) δ: 7.71(1H, d, J=.0Hz); (3H,m); 7.31(1H, d, J=3.); (3H,m); 6.66(1H,d, J=3.). IR(KBr) ν/cm -1 : 963, 9, 895, 860, 1455, 1381, 136, 116; This data are in agreement with the structure of 5-chloro-1-(4-fluorophenyl)-indole. Acknowledgements This work was financially supported by the University Key Teacher by the Ministry of Education of Henan Province (o. 010GGJS-005), oundation of the Henan Education Committee (o. 010A350005) and Graduate Students Educational oundation Of Zhengzhou University (o ) References [1] J.K. Perregaard, U.S. Patent (1987) [] P. Jens, S. Torben, U.S. Patent (199) [3] B. Sommer, Michael, WO patent (1998) [4] J.Z. Venezia, M.V. Padova,. C. Padova, U.S. Patent (005) [5] J.Q. Li, X.J. Ye and L.Y. Huang, C patent A. (009) In Chinese [6] J.Q. Li, X.J. Ye and L.Y. Huang, C patent A. (009) In Chinese [7] Z. Jacopo, V. Marco, HK patent A1. (010) [8] P. Jens, A. Jorn and P.B. Klaus: J. Med. Chem. orum Vol. 35 (199), p

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