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INTENSIFICATION OF CHEMICAL-PHARMACEUTICAL PROCESSES WITH

APPLICATIONS OF GREEN CHEMISTRY

C O N T I N U O U S S Y N T H E S I S O F G I N KG O L I D E B D E R I VAT I V ES I N A M I C R O - F LOW
SYSTEM
Yinlin Qin, Wei He, Mei Su, Zheng Fang, Jiajia Gu, Pingkai Ouyang, Kai Guo – 2015

Edson Nascimento dos Santos Junior


Ginkgolide B
Ginkgolides are biologically active terpenic lactones present in 1
Ginkgo biloba. 2 3 3’ 2’
5 4 5’
7 6 6’
Is an effective platelet activating factor antagonist, shows the 9 7’
8 8’ 9’
highest physiological activity among various ginkgolides. Thus,
ginkgolide B has attracted considerable interest since ginkgolide B 11 11’ 12’
10 10’
plays an important role in protective intestine and intestinal 15
mucosa, anti-inflammatory and immune regulation, migraine, 13 15’
14’
treatment of Alzheimer’s disease, antioxidant, especially in the
treatment of ischemic cerebrovascular disease.
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Ginkgolide B
1
2 3 3’ 2’
Tebonin aiming at expansion of the cerebral arteries and prevention 5 4 5’
of cerebral infarction has come to market since 1965. 7 6 6’
Another ginkgo biloba extract, named as Tanakan, has been 9 7’
developed by Beaufour Ipsen to treat brain dysfunction and 8 8’ 9’
peripheral vascular disease. 11 11’ 12’
10 10’
15
In order to obtain more effective platelet activating factor receptor 13 15’
14’
antagonists, a series of ginkgolide B derivatives were synthesized.

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Ginkgolide B
• Bulky aromatic substituents in the 10-OH position of ginkgolide B increased activity at the platelet activating factor receptor;
1
• A series of alkyl and alkoxycarbonyl derivatives of ginkgolide B were prepared in one step from ginkgolide2B through alkylation
2’ and acylation
reaction; 3 3’
5 4 5’
• 7 6 6’
These derivatives showed equivalent or superior activities toward ginkgolide B. 9 7’
8 8’ 9’
• IC50 value of dimethylaminoethyl ginkgolide B was 4,8.10-6 M, whose pesticide effect was 1,8 times higher than that of ginkgolide B;
11 11’ 12’
10 10’ containing a
• 15
Typically, O-alkylation of ginkgolide B was carried out by adding appropriate halogenated reagent into ginkgolide B solution
catalytic amount of potassium carbonate and potassium iodide; 13 15’
14’
• However, only a yield of 46,2% was obtained using conventional methods. Thus, higher yields were necessary considering the high raw
material price; MR4
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• Strong acids were selected to react with dimethylaminoethyl ginkgolide B, resulting in water-soluble components, because lower hydrophily
led to limited clinical application.

IC50 - Concentration of a compound necessary to reduce population growth of organisms, including eukaryotic cells, by 50 percent in vitro.
Process Intensification
1
• Process intensification has received considerable attention as a promising method for reducing investment and energy costs in the past
several years; 2 3 3’ 2’
5 4 5’
• Was used micro-flow system (MFS) that integrates micro-structured reactors and separation units into7custom 6’ process design;
6 continuous
9 7’
8 8’ 9’
• MFS provides better mixing and more efficient heat and mass transfer, that are two primary advantages compared with conventional
instruments, hence better yields and fewer side reactions were observed in MFS; 11 11’ 12’
10 10’
15
• 15’
Significant progress has been made in the development of micro fluidic systems during the past several years.13Because this the group was
motivated to conduct the combined process consisting of etherification and salification in MFS.
14’

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Setup
• Are a number of issues associated with
numbering-up;

• Uniformity of the flow for parallelized


reactors;

• Multiple pumps to enable the control of


the flow rate of each parallelized reactor
leads to a complicate system which may
cause various troubles during operation.

• Manifold-type or bifurcation-type flow


distributors are often used to distribute a In this study, the volume of empty microreactor used was 24.5 ml.

reactant flow among the parallelized


microreactors.
SRFD
Optimization of etherification conditions
• Inorganic bases, such as carbonates were chosen as acid-binding agents in the etherification reaction of ginkgolide B and dimethylamino ethyl
chloride hydrochloride (DECH), mainly due to operability and fewer side reactions.

Organic bases gave no target products, while other five inorganic


bases resulted in target products in a yield of 10,2–42,8% when 1.5
equiv of acid-binding agents were used. Increased alkalinity in the
fluid promoted the side reactions when the microreactor was filled
with inorganic bases. Thus, the highest yield was obtained when
calcium carbonate was used as an acid-binding agent in this study.
SRFD
Optimization of etherification conditions
• As the next step in the optimization process, the effect of acidbindin agent dosage on the yield was investigated.
SRFD
Optimization of etherification conditions
• The optimal calcium carbonate-to-ginkgolide B molar ratio was set to 2.5:1, aiming at obtaining higher yields;

• Residence time in the microreactor was altered from 1 to 8 min by adjusting the flow rate;

• The maximum yield was obtained when residence time was adjusted to 3 min. With longer reaction times, the yield decreased. This was a
common phenomenon in the MFS, because a longer reaction time corresponded to a smaller average velocity for fixed-volume microreactor.
(Generally, etherification is an endothermic reaction, which requires sufficient energy supply to facilitate the reaction. Due to worse heat and
mass transfer, more than 1.5 h was necessary for the etherification in the flask.);

• Generally, etherification is an endothermic reaction, which requires sufficient energy supply to facilitate the reaction. Due to worse heat and
mass transfer, more than 1.5 h was necessary for the etherification in the flask;

• The optimal temperature was obtained as 85 °C in MFS. Although more target compounds were generated with temperature increasing from
65 °C to 85°C, the yield was found to be reduced from 92,7% to 79,4% when the temperature rose from 85 °C to 105 °C. This was mainly
because that heating promoted the hydrolysis of ster groups in ginkgolide B;

• The effect of molar ratio of ginkgolide B to DECH was also studied in the molar ratio range 1:1.5–3.5 (the yield was found to be decreased to
87.4% with 3.5 - fold DECH, which is probably due to the side reactions between other two hydroxyl groups and DECH);

• Which demonstrated that MFS had good potential for common etherification process.
SRFD
Scope of the etherification reaction in MFS
• Next, with the optimized conditions in hand, the scope of the substrate was also explored. The etherification between ginkgolide B
and other halides was also evaluated.
SRFD
Conclusion

In conclusion, four ginkgolide B derivatives were successfully synthesized in MFS in


terms of process intensification and product quality. Compared with batch reaction,
MFS could cut the reaction time from several hours to 3 min, which brought significant
benefits for energy consumption. The best yield of dimethylaminoethyl ginkgolide B
obtained in MFS was 94.3% in this study, which was twice higher than that of batch
experiments.