dihydrocodeine is a semisynthetic alkaloid that has preventive effects of shortness of breath and cough , as well as used extensively in killing postoperative pain . importance of dihydrocodeine is increasing day by day as second step of the  analgesic ladder proposed for the treatment of cancer pain [ 24 ] . by extending the duration of action of the drug , since dihydrocodeine became available as a slow - release preparation , in this regard , it has begun to replace codeine . dihydrocodeine is also an important intermediate used in synthesis of other alkaloids such as hydrocodone . a number of methods have been reported to prepare dihydrocodeine . grew and coworkers have prepared dihydrocodeine by hydrogenation of hydrocodone [ 7 , 8 ] . however , when compared with the hydrogenation process from codeine , additional steps are incorporated into the process and this ultimately increases the cost for obtaining dihydrocodeine . for hydrogenation of codeine palladium supported on carbon , catalysts are generally studied [ 6 , 9 ] . in these methods , generally there is a need for excessive amounts of organic solvent for hydrogenation these processes bear risks in terms of health as well as causing environmental pollution . therefore , rapoport and lithotworik used water as a solvent in the hydrogenation process of codeine [ 10 , 11 ] . disadvantages of some of these methods are a number of side reactions difficult to control , undesirable side products , long reaction times , and necessity of using a deactivating agent which is connected to the surface of catalytic metal that can minimize isomerisation side reactions of codeine . microwave - assisted organic synthesis is an invaluable technology for drug synthesis because it often reduces reaction times , typically from days or hours to minutes or even seconds [ 1214 ] . on the other hand , the use of microwave irradiation to accelerate catalytic reactions can be used to obtain good results from low - yielding reactions [ 15 , 16 ] . with the employment of microwaves in metal , 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 1 . in this study , an extremely simple , inexpensive , and highly efficient and noncomplex method has been reported . in addition , white crystalline dihydrocodeine in pharmacopical purity is easily obtained alkalinizing the solution environment . catalyst ratio used is very low when compared with values reported so far ; any deactivating agent required to minimize side reactions in reaction environment was not used in these study . catalyst amount used in selected reaction conditions was determined optimally , the highest efficiency ( 98% ) reported so far in this reaction conditions was obtained , as well as formation of side reactions was significantly eliminated and product in pharmacopy standards was obtained .   in order to determine optimized conditions for the hydrogenation under microwave irradiation , 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 20c 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 1 . keeping reaction temperature and microwave power to 20c and 450  w , respectively , the effect of reaction time on the yield of dihydrocodeine was determined . table 1 indicated that the yield of dihydrocodeine slightly decreased as the irridation time was increased from 5 to 10  min . on the other hand , when the microwave power was set as 350  w , the yield of dihydrocodeine increased as the reaction time the microwave power and reaction time were set as 450  w and 5  min , respectively . when the temperature was increased from 20 to 40c , this result was attributed to the fact that side reactions were such as isomerisation of codeine to hydrocodone and cleavage of 4 , 5-epoxymorphinane ring of codeine to form dihydrothebainone overly induced at high temperature . consequently , 20c , 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 . potentiometric assay showed that dihydrocodeine product conforms to the stated limit as required by the bp . measurements were repeated five times and the percent purity of dihydrocodeine was calculated as 100.3 on average . hplc of the product revealed the presence of a single peak with a rt of 13.666  min . finally , it was potentiometrically and chromatographically determined that dihydrocodeine product obtained in the study is in pharmacopy standards . 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 . the infrared spectra were recorded as potassium bromide disks using a perkinelmer spectrum one ft - ir spectrometer . the h and c - 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 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 . the uv detector was set at 284  nm and the flow rate was 1.0  ml / min . the potentiometric measurements were made at 25  1c , using a mettler toledo dl53 titrator . 0.35  g dihydrocodeine product was dissolved in 60  ml of glacial acetic acid . 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 ) . 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 reaction mixture was filtered ( 0.45  m of pore size ) . active pt catalyst ( on carbon ) dihydrocodeine was precipitated between 9.80 and 9.90  ph by adding the 30% naoh solution . the resulting white solid corresponded to a yield of 98% and purity ( by hplc ) of 99.80% . h nmr ( 500  mhz , d6-dmso ) :  = 0.90 ( q , j = 12.2  hz , 1h ) , 1.17 ( q , j = 13.5  hz , 1h ) , 1.35 ( m , 1h ) , 1.37 ( m , 1h ) , 1.44 ( d , j = 11.8  hz , 1h ) , 1.821.76 ( m , 1h ) , 2.05 ( d , j = 12.0  hz , 1h ) , 2.11 ( m , 1h ) , 2.25 ( s , 3h ) , 2.29 ( d , j = 5.5  hz , 1h ) , 2.34 ( d , j = 7.6  hz , 1h ) , 2.86 ( bd , j = 18.3  hz , 1h ) , 2.93 ( bs , 1h ) , 3.42 ( s , 1h ) , 3.76 ( s , 3h ) , 4.47 ( dd , j = 18.84.4  hz , 1h ) 6.53 ( d , j = 8.0  hz , 1h , 6.68 ( d , j = 8.0  hz , 1h ) ; c nmr ( 500  mhz , d6-dmso ) :  = 19.32 ( ch2 ) , 19.58 ( ch2 ) , 25.75 ( ch2 ) , 37.12 ( ch2 ) , 38.29 ( ch ) , 41.80 ( q ) , 42.68 ( ch3 ) , 45.96 ( ch2 ) , 56.16 ( och3 ) , 58.81 ( ch ) , 65.89 ( ch ) , 90.31 ( ch ) , 113.87 ( ch ) , 117.95 ( ch ) , 127.11 ( q ) , 130.31 ( q ) , 140.78 ( q ) , 146.96 ( q ) . anal calcd . for c18h23no3 : c , 71.64 ; h , 7.62 ; n , 4.64 ; found : c , 71.62 ; h , 7.64 ; n , 4.40 .
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 .