Citation: Zhen Zhang, Rui Su, Xiongjun Xiao, Jiaxin Yang, Yuwei Li, Tiemin Sun, Yang Liu, Chengjun Wu. A continuous-flow process for the synthesis of balsalazide disodium[J]. Chinese Chemical Letters, ;2026, 37(7): 111965. doi: 10.1016/j.cclet.2025.111965 shu

A continuous-flow process for the synthesis of balsalazide disodium

Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, China

suntiemin@126.com

y.liu@syphu.edu.cn

wuchengjun@syphu.edu.cn

Received Date: 15 July 2025
Revised Date: 29 September 2025
Accepted Date: 13 October 2025
Available Online: 15 October 2025

Figures(8)

Balsalazide disodium is an effective drug for alleviating ulcerative colitis. It slowly releases 5-aminosalicylic acid in the intestine. The traditional synthesis methods of balsalazide disodium exhibit high risk, high pollution and low efficiency concern. Thus, we innovatively develop a four-step route for the large-scale production of balsalazide disodium in continuous flow. In this work, methyl 3-aminopropionate hydrochloride was subjected to acylation and hydrolysis reactions to obtain the nitro intermediate with a selectivity of 99.55%. Micro-hydrogenation reactor filled with Raney Ni catalyzed three-phase reaction improves conversion and selectivity. In the diazotization and azo coupling reactions, the optimal equivalents of salicylic acid and base were determined. With the aid of response surface methodology, the influences of reaction temperature and residence time on yield were systematically investigated. Under the optimum conditions, the experimental yields coincided with the predicted yields. Compared to batch experiments, the continuous process achieved a total yield of 66.1% and a purity of 99.63% in 13.1 min.
- Balsalazide disodium,
- Continuous hydrogenation,
- Flow chemistry,
- Industrial process
1. [1]
  C. Le Berre, S. Honap, L. Peyrin-Biroulet, Lancet 402 (2023) 571–584. doi: 10.1016/S0140-6736(23)00966-2
2. [2]
  L. Du, C. Ha, Gastroenterol. Clin. N. 49 (2020) 643–654. doi: 10.1016/j.gtc.2020.07.005
3. [3]
  S.A. Patil, A.C. Moss, Expert Rev. Gastroent. 2 (2008) 177–184. doi: 10.1586/17474124.2.2.177
4. [4]
  J. Zhao, B. Zhang, Q. Mao, et al., J. Med. Chem. 65 (2022) 4926–4948. doi: 10.1021/acs.jmedchem.1c02166
5. [5]
  A. Prakash, C.M. Spencer, Drugs 56 (1998) 83–89. doi: 10.2165/00003495-199856010-00008
6. [6]
  P.K. Chan, in: Patent, GB2080796, 1982.
7. [7]
  P.K. Chan, in: Patent, US4412992, 1983.
8. [8]
  M. Movsisyan, E.I.P. Delbeke, J.K.E.T. Berton, et al., Chem. Soc. Rev. 45 (2016) 4892–4928. doi: 10.1039/C5CS00902B
9. [9]
  H. Jin, Q. Cai, P. Liu, et al., Chin. Chem. Lett. 35 (2024) 108721. doi: 10.1016/j.cclet.2023.108721
10. [10]
  Y. Liu, X. Yang, T. Lin, et al., Chin. Chem. Lett. 36 (2025) 109747. doi: 10.1016/j.cclet.2024.109747
11. [11]
  T. Gong, F. Ji, Y. Shi, et al., Org. Process Res. Dev. 29 (2025) 146–154. doi: 10.1021/acs.oprd.4c00405
12. [12]
  D. Polterauer, K.M.P. van Eeten, W. Stam, et al., Org. Process Res. Dev. 28 (2024) 1903–1909. doi: 10.1021/acs.oprd.3c00448
13. [13]
  Y. Mao, C. Zhou, C. Wang, et al., Chin. Chem. Lett. 34 (2023) 108061. doi: 10.1016/j.cclet.2022.108061
14. [14]
  X. Duan, X. Wang, X. Chen, et al., Org. Process Res. Dev. 25 (2021) 2100–2109. doi: 10.1021/acs.oprd.1c00164
15. [15]
  Y. Zhang, M. Xiao, R. Feng, et al., Org. Process Res. Dev. 28 (2024) 1675–1682. doi: 10.1021/acs.oprd.3c00323
16. [16]
  Y. Liu, D. Wang, Y. Chen, et al., Org. Process Res. Dev. 29 (2025) 909–919. doi: 10.1021/acs.oprd.5c00006
17. [17]
  H. Pang, J. Huang, J. Wang, et al., J. Flow Chem. 14 (2024) 427–435. doi: 10.1007/s41981-024-00310-7
18. [18]
  J. Tu, L. Sang, H. Cheng, et al., Org. Process Res. Dev. 24 (2020) 59–66. doi: 10.1021/acs.oprd.9b00416
19. [19]
  S.K. Komati, A. Manda, S. Vasam, et al., Org. Process Res. Dev. 29 (2025) 155–172. doi: 10.1021/acs.oprd.4c00416
20. [20]
  A. Afshar, M. Rahimi, P. Salehi, et al., Org. Process Res. Dev. 29 (2024) 3171–3181. doi: 10.1021/acs.oprd.4c00086
21. [21]
  A. Kraš, D. Kramar, I. Milošev, et al., Corros. Sci. 242 (2025) 112551. doi: 10.1016/j.corsci.2024.112551
22. [22]
  M. Khan, A. Abdulhameed, H. Alshahrani, et al., Int. J. Biol. Macromol. 261 (2024) 129964. doi: 10.1016/j.ijbiomac.2024.129964
23. [23]
  F.Y. Zhang, H.Y. Zhou, J.Q. Yuan, et al., Org. Process Res. Dev. 26 (2022) 3051–3066. doi: 10.1021/acs.oprd.2c00132
24. [24]
  A. Nagababu, D.S. Reddy, G.V.K. Mohan, J. Ind. Eng. Chem. 114 (2022) 377–390. doi: 10.1016/j.jiec.2022.07.027
1. [1]
  Hui Jin , Qin Cai , Peiwen Liu , Yan Chen , Derong Wang , Weiping Zhu , Yufang Xu , Xuhong Qian . Multistep continuous flow synthesis of Erlotinib. Chinese Chemical Letters, 2024, 35(4): 108721-. doi: 10.1016/j.cclet.2023.108721
2. [2]
  Peiwen Liu , Fang Zhao , Jing Zhang , Yunpeng Bai , Jinxing Ye , Bo Bao , Xinggui Zhou , Li Zhang , Changlu Zhou , Xinhai Yu , Peng Zuo , Jianye Xia , Lian Cen , Yangyang Yang , Guoyue Shi , Lin Xu , Weiping Zhu , Yufang Xu , Xuhong Qian . Micro/nano flow chemistry by Beyond Limits Manufacturing. Chinese Chemical Letters, 2024, 35(5): 109020-. doi: 10.1016/j.cclet.2023.109020
3. [3]
  Rajamani Manju , Ganesh Masilamani , Bernaurdshaw Neppolian . From laboratory insights to industrial applications in continuous flow sonophotocatalytic abatement of persistent pollutants enabled by a broad-spectrum S-scheme photocatalyst. Chinese Journal of Structural Chemistry, 2026, 45(4): 100845-100845. doi: 10.1016/j.cjsc.2025.100845
4. [4]
  Liliang Chu , Xiaoyan Zhang , Jianing Li , Xuelei Deng , Miao Wu , Ya Cheng , Weiping Zhu , Xuhong Qian , Yunpeng Bai . Continuous-flow synthesis of polysubstituted γ-butyrolactones via enzymatic cascade catalysis. Chinese Chemical Letters, 2024, 35(4): 108896-. doi: 10.1016/j.cclet.2023.108896
5. [5]
  Runsheng Xu , Haotian Wu , Daoyuan Zu , Kui Yang , Xiangtong Kong , Jinxing Ma . Porous cathode enables continuous flow anodic oxidation for water purification: Performance and mechanisms. Chinese Chemical Letters, 2025, 36(8): 110517-. doi: 10.1016/j.cclet.2024.110517
6. [6]
  Pan Hu , Xiaofan Wu , Yi An , Xianjing Zheng , Liang Gao , Yuan Tao , Yajiao Zhang , Zedu Huang , Fener Chen . Batch and continuous-flow asymmetric synthesis of D-pantothenic acid precursor enabled by immobilized ketoreductase mutant. Chinese Chemical Letters, 2026, 37(2): 111945-. doi: 10.1016/j.cclet.2025.111945
7. [7]
  Bin Lei , Zongxing Tu , Dou Chen , Qin Luo , Xiaoying Peng , Suqin Wu , Guiming Peng . Nitrogen-defective carbon nitride nanorod arrays for continuous-flow photosynthesis of H₂O₂. Chinese Chemical Letters, 2026, 37(6): 112004-. doi: 10.1016/j.cclet.2025.112004
8. [8]
  Xia Jiang , Yan-Xin Chen , Rui Chen , Hao-Yan Shi , Ke-Xian Li , Wen-Ya Zhong , Jian-Feng Li , Can-Zhong Lu . Thermo-photocatalytic CO₂ conversion with H₂O to C₂ products in a continuous process by ZIF-67/biochar composites. Chinese Chemical Letters, 2026, 37(4): 111781-. doi: 10.1016/j.cclet.2025.111781
9. [9]
  Hang Wang , Qi Wang , Chuan-De Wu . Continuous synthesis of ammonia. Chinese Journal of Structural Chemistry, 2025, 44(3): 100437-100437. doi: 10.1016/j.cjsc.2024.100437
10. [10]
  Wei Chen , Pieter Cnudde . A minireview to ketene chemistry in zeolite catalysis. Chinese Journal of Structural Chemistry, 2024, 43(11): 100412-100412. doi: 10.1016/j.cjsc.2024.100412
11. [11]
  Ming Huang , Xiuju Cai , Yan Liu , Zhuofeng Ke . Base-controlled NHC-Ru-catalyzed transfer hydrogenation and α-methylation/transfer hydrogenation of ketones using methanol. Chinese Chemical Letters, 2024, 35(7): 109323-. doi: 10.1016/j.cclet.2023.109323
12. [12]
  Ziwang Liu , Xiaoqian Wang , Honglin Qin , Yan Chen , Ling Xia , Xuanjing Wang , Yanhua Lai , Gongke Li . Research progress of the Maillard reaction process monitoring. Chinese Chemical Letters, 2026, 37(4): 111742-. doi: 10.1016/j.cclet.2025.111742
13. [13]
  Yingnan Duan , Jinyu Liu , Qian Liu , Tianhao Li , Hexiang Zhao , Zhurui Shen . Remediation of characteristic contaminants in groundwater of chemical industrial by the activation of PMS: Recent developments and challenges-a mini-review. Chinese Chemical Letters, 2026, 37(1): 111120-. doi: 10.1016/j.cclet.2025.111120
14. [14]
  Xin Li , Zhen Xu , Donglei Bu , Jinming Cai , Huamei Chen , Qi Chen , Ting Chen , Fang Cheng , Lifeng Chi , Wenjie Dong , Zhenchao Dong , Shixuan Du , Qitang Fan , Xing Fan , Qiang Fu , Song Gao , Jing Guo , Weijun Guo , Yang He , Shimin Hou , Ying Jiang , Huihui Kong , Baojun Li , Dengyuan Li , Jie Li , Qing Li , Ruoning Li , Shuying Li , Yuxuan Lin , Mengxi Liu , Peinian Liu , Yanyan Liu , Jingtao Lü , Chuanxu Ma , Haoyang Pan , JinLiang Pan , Minghu Pan , Xiaohui Qiu , Ziyong Shen , Shijing Tan , Bing Wang , Dong Wang , Li Wang , Lili Wang , Tao Wang , Xiang Wang , Xingyue Wang , Xueyan Wang , Yansong Wang , Yu Wang , Kai Wu , Wei Xu , Na Xue , Linghao Yan , Fan Yang , Zhiyong Yang , Chi Zhang , Xue Zhang , Yang Zhang , Yao Zhang , Xiong Zhou , Junfa Zhu , Yajie Zhang , Feixue Gao , Yongfeng Wang . Recent progress on surface chemistry Ⅰ: Assembly and reaction. Chinese Chemical Letters, 2024, 35(12): 110055-. doi: 10.1016/j.cclet.2024.110055
15. [15]
  Xin Li , Zhen Xu , Donglei Bu , Jinming Cai , Huamei Chen , Qi Chen , Ting Chen , Fang Cheng , Lifeng Chi , Wenjie Dong , Zhenchao Dong , Shixuan Du , Qitang Fan , Xing Fan , Qiang Fu , Song Gao , Jing Guo , Weijun Guo , Yang He , Shimin Hou , Ying Jiang , Huihui Kong , Baojun Li , Dengyuan Li , Jie Li , Qing Li , Ruoning Li , Shuying Li , Yuxuan Lin , Mengxi Liu , Peinian Liu , Yanyan Liu , Jingtao Lü , Chuanxu Ma , Haoyang Pan , JinLiang Pan , Minghu Pan , Xiaohui Qiu , Ziyong Shen , Qiang Sun , Shijing Tan , Bing Wang , Dong Wang , Li Wang , Lili Wang , Tao Wang , Xiang Wang , Xingyue Wang , Xueyan Wang , Yansong Wang , Yu Wang , Kai Wu , Wei Xu , Na Xue , Linghao Yan , Fan Yang , Zhiyong Yang , Chi Zhang , Xue Zhang , Yang Zhang , Yao Zhang , Xiong Zhou , Junfa Zhu , Yajie Zhang , Feixue Gao , Li Wang . Recent progress on surface chemistry Ⅱ: Property and characterization. Chinese Chemical Letters, 2025, 36(1): 110100-. doi: 10.1016/j.cclet.2024.110100
16. [16]
  Dongfang Liu , Zhouyu Wang , Junli Wang , Leyong Wang . The 5^th Xihua Chemistry and Biomedicine Forum. Chinese Chemical Letters, 2026, 37(2): 111925-. doi: 10.1016/j.cclet.2025.111925
17. [17]
  Tingting Du , Siyu Lu , Dong Wang , Jian Zhang , Jixiang Chen . Recent advances of imidazole derivatives in pesticide chemistry. Chinese Chemical Letters, 2026, 37(7): 112280-. doi: 10.1016/j.cclet.2025.112280
18. [18]
  Rui HUANG , Shengjie LIU , Qingyuan WU , Nanfeng ZHENG . Enhanced selectivity of catalytic hydrogenation of halogenated nitroaromatics by interfacial effects. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 201-212. doi: 10.11862/CJIC.20240356
19. [19]
  Minghui Zhang , Na Zhang , Qian Zhao , Chao Wang , Alexander Steiner , Jianliang Xiao , Weijun Tang . Cobalt pincer complex-catalyzed highly enantioselective hydrogenation of quinoxalines. Chinese Chemical Letters, 2025, 36(4): 110081-. doi: 10.1016/j.cclet.2024.110081
20. [20]
  Huihua GONG , Tianhua CUI , Li JI , Liyuan ZHANG , Xueli ZHENG , Haiyan FU , Hua CHEN , Jiawei MAO , Ruixiang LI . Efficient hydrogenation of CO₂ realized by Ru-NNN complex. Chinese Journal of Inorganic Chemistry, 2026, 42(5): 1085-1095. doi: 10.11862/CJIC.20250321

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(17)
HTML views(1)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142