-
E-mail
sales@morotchem.com
-
Phone
19884159221
-
Address
Ivy Health Industry Park, Yuhang District, Hangzhou City, Zhejiang Province
Hangzhou Borealis Chemical Technology Co., Ltd
It's done in 9 minutes! Continuous flow technology boosts the efficiency of life-saving antibiotic synthesis
Date: 2025-07-17Read: 4
1、 Research background and objectives
Ciprofloxacin is a fluoroquinolone antibiotic on the World Health Organization's (WHO) Essential Medicines List, widely used for the treatment of bacterial infections. Traditional synthesis methods have long reaction times (Bayer, 1980)The technology requires more than 24 hours, resin loading method requires more than 100 hours, and the efficiency is limited (total yield 49% -57%). This study aims to achieve rapid and efficient multi-step cascade synthesis of ciprofloxacin through continuous flow synthesis technology, shorten reaction time, and improve yield.
Figure 1 Reverse synthesis of ciprofloxacin hydrochloride
2、 Core achievements
1. Efficient and rapid synthesis: Starting from simple raw materials, 6 continuous chemical reactions are completed through 5 flow reactors, with a total residence time of only 9 minutes. After 2 subsequent offline treatments (acidification, filtration), ciprofloxacin and hydrochloride are obtained, with a total yield of 60% in 8 steps, which is comparable to traditional methods but significantly improves efficiency.
2. No need for intermediate separation: The entire synthesis process does not require intermediate separation, and only one acylation reaction is used to remove the main byproduct dimethylamine HNMe2, achieving efficient integration of the "telecontrol reaction" (series reaction) and making it the longest known continuous flow linear reaction sequence (uninterrupted).
3、 Technical details and key steps
1. Advantages of continuous flow synthesis:Rapid mixing in flow reactors, enhanced heat and mass transfer, and improved reaction selectivity (such as selective reduction of esters to aldehydes); Support safe operation under high temperature and high pressure conditions, suitable for high activity reactions such as rapid lithiation reactions.
2. Synthesis route design (Scheme 1-5):
Core steps: acylation reaction → cyclopropylamine substitution → two-stage region selective aromatic nucleophilic substitution of SNAr → ester hydrolysis → acidification.
Figure 2 Continuous flow synthesis of ciprofloxacin hydrochloride
Key optimization:
Selection of solvents and bases：Considering the FDA's restrictions on residual solvents (chloroform ≤ 60 ppm, acetonitrile ≤ 410 ppm), acetonitrile/N, N-diisopropylethylamine (DIEA) was ultimately selected to generate 98% of intermediate 6 within 1.5 minutes at 180 ℃ and 175 psi;
By product processing:By rapid acylation of acetyl chloride and DIEA at room temperature, the by-product dimethylamine is converted into interference free N, N-dimethylacetamide (DMA), ensuring uninterrupted continuous reaction;
Avoiding precipitation issues: Intermediate 2 and 3 have low solubility (e.g. 3<0.016 M in DMSO), and crystallization blockage of the reactor can be avoided by insulation.
3. Optimization of reaction conditions:One pot cyclization and SNAr reaction: by adjusting DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) andofpaiqinThe dosage is 3.0 equiv DBU+3.0 equiv）Achieve an 81% yield of target product 2 within 5 minutes at 180 ℃ (Table 1).
4、 Meaning and Value
1. Efficiency breakthrough: Shorten the traditional synthesis time from over 24 hours to 9 minutes, significantly reducing production time costs;
2. Green chemistry: Reduce intermediate separation steps, minimize waste generation, and align with the concept of sustainable synthesis;
3. Technical demonstration: The feasibility of continuous flow technology in multi-step complex synthesis has been verified, providing a reference template for the efficient synthesis of other drugs such as antibiotics and small molecule drugs.
5、 Conclusion
This study achieved rapid total synthesis of ciprofloxacin using continuous flow technology, with a total residence time of 9 minutes, a yield of 60%, and a series reaction mode without intermediate separation.
6、 Expand
Accurate delivery of reactants is the cornerstone for ensuring smooth reaction and stable product quality.Brilis' high-pressure constant current double plunger pump and high-pressure constant current explosion-proof PTFE pumpIt played a crucial role here. The high-pressure constant current double plunger pump has a wide flow range, from 0.001mL/min to 3000mL/min. The high-pressure constant current explosion-proof PTFE pump also offers various specifications such as 0-20/100/200/500/1000ml to choose from,Regardless of the scale of the experiment or industrial production, it can meet the flow demand.And, their traffic accuracyhighAt a flow rate of 5mL/min (water), the accuracy of a high-pressure constant current explosion-proof PTFE pump can reach 0.5%. During the synthesis of ciprofloxacin hydrochloride, the pump has a one click flushing function, which can reduce the impact of long-term operation on the internal components of the pump; The pump has two functions: constant flow and constant pressure, which can be switched freely. The actual feed flow rate can be adjusted according to process requirements, and it has a timed and quantitative function; There is not only one one-way valve in the pump chamber to ensure stable flow rate and flow stability; The pump can achieve interlocking control of flow rate and material weight by connecting to a balance, thereby ensuring product quality from the source.
Figure 3: Real time photo of high-pressure constant current double plunger pump product
Figure 4 Interface between High Pressure Constant Flow Double Piston Pump and Balance Connection System