An efficient one-pot microwave-assisted hydrogenation of codeine was achieved in aqueous solution. This technique is simple, fast, environmentally friendly, and highly efficient. Structure of produced dihydrocodeine was approved by using FT-IR, 1H NMR, 13C NMR, EIMS, and elemental analysis technique. Its purity analysis was performed by using HPLC and assay analysis was performed by using potentiometric titration methods.
Dihydrocodeine is a semisynthetic alkaloid that has preventive effects of shortness of breath and cough, as well as used extensively in killing postoperative pain [
A number of methods have been reported to prepare dihydrocodeine. Grew and coworkers have prepared dihydrocodeine by hydrogenation of hydrocodone [
Here, we describe the microwave-assisted synthesis of dihydrocodeine, which achieved reductions in reaction times, higher yields, and cleaner reactions than for the previously reported synthetic processes. Dihydrocodeine was obtained in purity suitable for use in pharmacopy (99.80%) in high efficiency (98%) without using any deactivating agent and using metal catalyst in lower rate.
Synthesis of the dihydrocodeine which is a semi-synthetic opioid was achieved under microwave irradiation out of codeine as outlined in Scheme
Hydrogenation of codeine to dihydrocodeine.
In order to determine optimized conditions for the hydrogenation under microwave irradiation, codeine was exposed to different reaction variables. The effect of temperature, reaction time, and microwave power on hydrogenation yield was studied and the initial hydrogen pressure and catalyst ratio fixed as 5 psi and 1% (Pt/C), respectively, in the following experiments. Fixing reaction temperature and time to 20°C and 5 min, respectively, the effect of microwave power on yield of dihydrocodeine was studied. Dihydrocodeine conversion increased from 60 to 98% as microwave power increased from 250 to 450 W, as exhibited in Table
Optimization of microwave-assisted hydroganation conditions.
Experiment | Temperature | Power (W) | Time (min) | Yield (%) |
---|---|---|---|---|
1 | 20 | 250 | 5 | 60 |
2 | 20 | 350 | 5 | 78 |
3 | 20 | 350 | 10 | 84 |
4 | 20 | 450 | 5 | 98 |
5 | 40 | 450 | 5 | 79 |
6 | 20 | 450 | 10 | 93 |
Consequently, 20°C, 450 W, and 5 min reaction time are determined as the best conditions in this process. When the temperature and reaction time increased, product yield decreased due to more induced side-reactions. Nevertheless, the reaction efficiency was highly microwave oven power dependent.
The mV titration curve of this agent is shown in Figure
Potentiometric titration curve of dihydrocodeine.
The well-exhibited HPLC chromatogram of dihydrocodeine was shown in Figure
HPLC trace of dihydrocodeine.
Finally, it was potentiometrically and chromatographically determined that dihydrocodeine product obtained in the study is in pharmacopy standards. This value complies with the values given in official documents [
Microwave-assisted preparation procedure stated in this study for dihydrocodeine synthesis offers reduction in the reaction time, operation simplicity, cleaner reaction, easy work-up, and improved yields. All spectroscopic analysis confirmed the proposed structure of this compound.
All chemicals and platin catalyst (on activated charcoal 1%) used in the present study are of analytical grade purchased from Merck. Codeine in pharmacopy standards was obtained from Turkish Grain Board.
The infrared spectra were recorded as potassium bromide disks using a PerkinElmer Spectrum One FT-IR spectrometer. The 1H and 13C-NMR spectra of the dihydrocodeine were recorded using the Bruker 500 NMR spectrometer. Mass spectra by EI (electron impact) techniques of dihydrocodeine were determined by an Agilent 6890 model GC-MS. The percentage compositions of the elements (CHNO) for the compound were determined using a ThermoFinnigan FLASH 1112 SERIES EA instrument.
HPLC analysis. HPLC analysis is conducted using Agilent 1200 which is equipped with UV/VIS Detector. Separation was accomplished on a 25 cm Eurospher-100 (WATERS) C18 column (4.6 mm i.d., 5
The assay for dihydrocodeine product was determined by potentiometric titration. The potentiometric measurements were made at 25 ± 1°C, using a Mettler Toledo DL53 titrator. 0.35 g dihydrocodeine product was dissolved in 60 mL of glacial acetic acid. This solution was titrated against 0.1 M perchloric acid. The end-point was determined potentiometrically. These measurements were repeated five times.
2.5 g codeine was suspended in water (30 mL) and acetic acid was added until codeine dissolved (1 mL). pH of codeine solution was recorded at 4.75. 0.20 g Pt on activated charcoal catalyst (1% Pt/C) was added to solution. This solution was put into a CEM discover microwave reactor (CEM Corporation, Matthews, NC). The upper part of the reactor was filled with inert nitrogen gas by passing nitrogen gas and the addition of H2 to the system is started. The initial hydrogen pressure was set as 5 psi in all experiments. H2gas was deflated giving the reactor nitrogen gas. The reaction mixture was filtered (0.45