![Page 1: Research Article Microwave-Assisted Synthesis of Isopropyl](https://reader030.vdocuments.site/reader030/viewer/2022012602/6198c0d6f3a2ed2a2a383724/html5/thumbnails/1.jpg)
Hindawi Publishing CorporationJournal of ChemistryVolume 2013, Article ID 505460, 7 pageshttp://dx.doi.org/10.1155/2013/505460
Research ArticleMicrowave-Assisted Synthesis of Isopropyl๐ฝ-(3,4-Dihydroxyphenyl)-๐ผ-hydroxypropanoate
Qun-Zheng Zhang,1,2 Xue-Feng Tian,1 Guan-Le Du,1 Qing Pan,3
Yi Wang,1 and Xun-Li Zhang1,2
1 College of Chemistry and Chemical Engineering, Xiโan Shiyou University, Xiโan 710065, China2 Faculty of Engineering and the Environment, University of Southampton, Southampton SO17 1BJ, UK3Department of Pharmacy, School of Medicine, Xiโan Jiaotong University, Xiโan 710061, China
Correspondence should be addressed to Xun-Li Zhang; [email protected]
Received 14 May 2013; Revised 17 July 2013; Accepted 5 August 2013
Academic Editor: Matthias Dโhooghe
Copyright ยฉ 2013 Qun-Zheng Zhang et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Using microwave irradiation heating, isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate was synthesised from 3,4-dihydroxybenzaldehyde and acetylglycine through the formation of 2-methyl-4-(3,4-acetoxybenzylene)oxazol-5-ones, ๐ผ-acetylamino-๐ฝ-(3,4-diacetoxyphenyl)acrylic acid, and ๐ฝ-(3,4-dihydroxyphenyl)pyruvic acid followed by Clemmensen reductionand esterification. The reaction conditions in terms of operating parameters were optimised by using an orthogonal designof experiment (ODOE) approach, including reaction temperature, reaction time, and microwave power level. Compared withconventional heating, the reaction time was significantly reduced for all reactions and the product yields were increased (exceptfor the third-step reaction) under microwave heating conditions. The most remarkable microwave enhancement was found inthe step of isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate production where the reaction time was reduced from 10 hrs(conventional heating) to 25mins (microwave heating) whilst the yield was increased from 75.6% to 87.1%, respectively.
1. Introduction
Recent studies have demonstrated the pharmaceutical activ-ity of isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypro-panoate against cerebral ischemia and hypobaric hypoxiaof high altitude [1โ4]. As a result, chemical synthesis ofthis compound and its derivatives has been of greatinterest. The most commonly used method for syn-thesising this compound involved the preparation of 2-methyl-4-(3,4-acetoxybenzylene)oxazol-5-ones,๐ผ-acetylam-ino-๐ฝ-(3,4-diacetoxyphenyl)acrylic acid, and ๐ฝ-(3,4-dihy-droxyphenyl)pyruvic acid which was reduced via Clem-mensen reaction that was followed by final esterification[2, 5] under the conventional heating conditions. Othersynthesis routes were also explored, for example, by takingsteps of benzyl protection, Darzens reaction, selective ringopening by Lewis acid, reduction, and, finally, catalytichydrogenation [4]. However, those methods suffered fromlow yield, poor reproducibility, and a long reaction time.
Owing to its advantages over the conventional heatingmethod, microwave heating has been applied to a wide rangeof organic synthesis processes [6โ9], following the pioneeringwork by Gedye et al. [10] and Giguere et al. [11] in the 1980s.The main advantages include the acceleration of reactionrate [12โ14], improved product selectivity [15โ18], and highyield [18โ20]. The application of microwave heating has alsobeen explored in the field of organic synthesis for drugdiscovery [21, 22]. In our previous study, we employed amicrowave heating method for the synthesis of Danshensu,which is an active compound/ingredient in a traditionalChinese herbal medicine Danshen (Salvia miltiorrhiza); weobserved improved yields with shorter reaction time com-pared with conventional heating [23]. For the optimisation ofexperimental conditions, design of experiments (DOE) hasbeen used as a powerful approach to reduce the variation in aprocess and, ultimately, to produce high quality product atlow cost for manufacturing [24, 25]. Among various DOE
![Page 2: Research Article Microwave-Assisted Synthesis of Isopropyl](https://reader030.vdocuments.site/reader030/viewer/2022012602/6198c0d6f3a2ed2a2a383724/html5/thumbnails/2.jpg)
2 Journal of Chemistry
approaches, the Taguchi method [26] has been frequentlyemployed to investigate the effect of different parameters onthe mean and variance of a process performance character-istics which defines how well the process is functioning; itgenerally involves using orthogonal arrays to organise theparameters affecting the process and the levels at which theyshould be varied [25, 27].
In the present study, we extended the microwave-assisted method to the synthesis of isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate (Scheme 1). Adesign of experiments via Taguchi method was used todetermine the influencing factors and levels in order tooptimise the product yield; the factors included reactiontemperature, reaction time, and microwave power level.
2. Results and Discussion
2.1. Selection of Operating Reaction Parameters. The mainfocus of this study was to investigate the effect of microwaveradiation heating on the four-step synthesis process incomparison to conventional heating method. The reactionconditions were initially examined by varying reaction tem-perature, reaction time, andmicrowave radiation input powerlevel in order to determine the variable range. Based on theinitial results, an orthogonal experimental design was carriedout, and the three experimental factors at three levels for eachsynthesis step are shown in Table 1.
2.2. Synthesis of 2-Methyl-4-(3,4-acetoxybenzylene)oxazol-5-ones. With the determination of experimental factors andlevels shown in Table 1 experiments were carried out follow-ing the orthogonal test programs, L
9(33). The experimental
results are summarised in Table 2. All yields shown in thetables are the mean value of three experiment runs. Theexperimental data was analysed with statistical softwareMinitab 16, and the ANOVA results are shown in Table 3.
The variance analysis showed that all three factorshad insignificant impact on reaction yields at the selectedlevel ranges as all three P values were greater than 0.05.However, the order of influencing factors was C > B >A, indicating that the microwave radiant power was thedominant influence among the three. The highest yieldof 89.7% was obtained under the conditions of A
2B2C3
among the nine experiment runs. The design of experimentsuggested the optimised conditions of A
2B2C2, and using that
optimisation a yield of 90.8% was obtained in the exper-iment. That confirmed the optimised reaction conditionsof A2B2C2for the microwave synthesis of 2-methyl-4-(3,4-
acetoxybenzylene)oxazol-5-ones.
2.3. Synthesis of ๐ผ-Acetylamino-๐ฝ-(3,4-diacetoxyphen-yl)acrylic Acid. Table 4 shows the orthogonal test programs,L9(33), and test results for the synthesis of ๐ผ-acetylamino-๐ฝ-
(3,4-diacetoxyphenyl)acrylic acid under microwave heatingconditions. The ANOVA results are shown in Table 5.
The variance analysis also showed that all three factorshad no significant impact on reaction yields at the selectedlevel ranges where all three P values were greater than
0.05. However, the order of influencing factors was foundto be C > B > A, suggesting that the microwave radiantpower was the dominant influence among the three.The bestexperiment result (i.e., yield 87.5%) from the nine experi-mental runs was obtained under the reaction of A
1B3C3. The
optimum conditions found from the design of experimentwere A
2B1C3, based on which the experiment was carried
out reaching a yield of 88.6%, which was higher than thatunder all nine experiment conditions. This confirmed thatthe reaction conditions of A
2B1C3to be the optimised
conditions for the microwave synthesis of ๐ผ-acetylamino-๐ฝ-(3,4-diacetoxyphenyl)acrylic acid.
2.4. Synthesis of ๐ฝ-(3,4-Dihydroxyphenyl)pyruvic Acid. It wasinteresting to note that this step of synthesis required arelatively higher microwave power level.The product was notobtained until a power level of 900Wwas applied.Therefore,the power level of 900Wwas set throughout the experiment.Table 6 summarises the results at different temperatures for agiven reaction time of 30mins.
Further experiments for different reaction time periodswere carried out to explore the highest possible yields. Theresults are shown in Table 7. It was observed that withincreasing reaction time the yield increased. However, whenthe reaction time exceeded 30mins, the yield remainedapproximately constant. This indicated that the highest yieldwas reached under the reaction conditions of 90โC for30mins at a microwave power level of 900W.
2.5. Synthesis of Isopropyl ๐ฝ-(3,4-Dihydroxyphenyl)-๐ผ-hy-droxypropanoate. The orthogonal test programs, L
9(33),
and test results for the synthesis of isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate are summarised inTable 8, and the ANOVA results are shown in Table 9.
The variance analysis showed that the three factors hadinsignificant impact on reaction yields in the chosen levelranges; however, the order of influence was B > C > A;indicating the reaction time to be the dominant factor.The best experiment result (i.e., a yield of 86.1%) from thenine reaction runs was observed under the conditions ofA2B3C1. However, the design of experiment suggested the
optimised experimental conditions of A3B3C2. To address the
seemly contradictory results in terms of reaction conditions,further three experimental runs were conducted under theODOE-suggested optimal conditions, and the highest yieldof 87.1% was obtained.With that yield (i.e., 87.1%) ODOEwaschecked which confirmed the optimised microwave reactionconditions of A
3B3C2for the synthesis of isopropyl ๐ฝ-(3,4-
dihydroxyphenyl)-๐ผ-hydroxypropanoate.It should be noted that the initial design of the reaction
time was 10, 20, and 30mins at microwave power levels of100, 300, and 500W, respectively. However, it was found thatwith 500W for 30mins, the reaction product became blackdue to overheat which was likely attributed to the presenceof metallic catalyst zinc amalgam used in this experiment.Therefore, the final reaction time at high power level (i.e.,500W) was reduced to 25mins.
![Page 3: Research Article Microwave-Assisted Synthesis of Isopropyl](https://reader030.vdocuments.site/reader030/viewer/2022012602/6198c0d6f3a2ed2a2a383724/html5/thumbnails/3.jpg)
Journal of Chemistry 3
HO
HOO
O
C
Zn(Hg), MWHO
HO
HO OH
O
OH
HO
CHOCH3CONHCH2COOH
Ac2O, NaAc, MW
AcO
AcO COOHHCl
MWAcO
B
D
AcON
A
O
O
CH3
H2O, MW(CH3)2CO
NHCOCH3CH3CH(OH)CH3
OCH(CH3)2
Scheme 1: Synthesis route for isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate.
Table 1: Experimental factors and levels.
Reaction Level Factor Atemperature (โC)
Factor Btime (min)
Factor CMW power (W)
Azolactone synthesis1 128 12 5002 138 15 6003 148 18 700
Acrylic acid synthesis1 65 8 3002 70 10 4003 75 12 500
๐ฝ-(3,4-Dihydroxyphenyl) pyruvic acid synthesis1 90 15 9002 95 20 9003 100 30 900
Isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate synthesis1 80 10 1002 85 20 3003 90 25 500
2.6. Comparison of Microwave and Conventional HeatingMethods. It is generally understood that the process ofmicrowave radiation heating is different from conventionalheating in terms of heat generation and energy transfer[6, 28]. Firstly, microwave heating is a volumetric processand sometimes referred to as โinterior heatingโ where heatcan be generated throughout the sample, whilst most ofconventional heating relies on conduction and/or convection[29]. This can result in a shorter microwave reaction timedue to the quicker heatingup. Secondly, microwave heating isโselectiveโ depending on the materials dielectric properties,suggesting that some microwave strong absorbers can reachhigher temperatures than others [29, 30]. This allows togenerate possible spatial โhot-spots,โ for example, on catalyst
active sites, leading to an apparent reaction rate accelerationwith reference to that at the measured overall temperature.On the other hand, the โselectiveโ heating may also lead to anapparent reaction slowdown where the reaction active siteshave lower temperature than the overall temperature.
Table 10 compares the reaction time and yield forthe four-step reactions. As can be seen from the Table,it took 5 hrs to carry out the synthesis of azolactone inconventional heating with a yield of 80.0%, while 15minswith microwave heating gave a yield of 90.8%. Similarresults were observed for the synthesis of ๐ผ-acetylamino-๐ฝ-(3,4-diacetoxyphenyl)acrylic acid. More remarkably wasthe synthesis of isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate under microwave heating conditions
![Page 4: Research Article Microwave-Assisted Synthesis of Isopropyl](https://reader030.vdocuments.site/reader030/viewer/2022012602/6198c0d6f3a2ed2a2a383724/html5/thumbnails/4.jpg)
4 Journal of Chemistry
Table 2: Orthogonal experiments on synthesis of 2-methyl-4-(3,4-acetoxybenzylene)oxazol-5-ones.
Trialno.
Factor Atemperature
(โC)
Factor Btime (min)
Factor CMW power
(W)Yield (%)
1 1 1 1 80.72 1 2 2 86.43 1 3 3 82.04 2 1 2 84.75 2 2 3 89.76 2 3 1 82.07 3 1 3 85.58 3 2 1 82.29 3 3 2 87.4๐พ1
249.1 250.9 244.9 ๐พ = 760.6
๐พ2
256.4 258.3 258.5 ๐ = 64279.2
๐พ3
255.1 251.4 257.2๐ 64289.3 64290.6 64316.7Q 10.1 11.4 13.3(๐พ = ๐1+๐2+ โ โ โ ๐9; ๐ = ๐พ
2/9; ๐พ1
๐ด= ๐1+๐2+๐3; ๐พ2
๐ด= ๐4+๐5+
๐6; ๐พ3๐ด= ๐7+๐8+๐9; ๐พ1
๐ต= ๐1+๐4+๐7; ๐พ2
๐ต= ๐2+๐5+๐8, ๐พ3
๐ต=
๐3 + ๐6 + ๐9; ๐พ1๐ถ= ๐1 + ๐6 + ๐8; ๐พ2
๐ถ= ๐2 + ๐4 + ๐9; ๐พ3
๐ถ=
๐3 + ๐5 + ๐7; ๐๐ด = ๐พ1๐ด+ ๐พ2๐ด+ ๐พ3๐ด; ๐๐ต = ๐พ1
๐ต+ ๐พ2๐ต+ ๐พ3๐ต; ๐๐ถ =
๐พ1๐ถ+ ๐พ2๐ถ+ ๐พ3๐ถ; ๐๐ด = ๐๐ด โ ๐; ๐๐ต = ๐๐ต โ ๐; ๐๐ถ = ๐๐ถ โ ๐; ๐๐ =
๐โ ๐; ๐๐ธ = ๐๐ โ ๐๐ด โ ๐๐ต โ ๐๐ถ; ๐๐ด2= ๐๐ด/๐๐ด; ๐๐ต
2= ๐๐ต/๐๐ต; ๐๐ถ
2=
๐๐ถ/๐๐ถ; ๐๐ธ2= ๐๐ธ/๐๐ธ; ๐น๐ด = ๐๐ด
2/๐๐ธ2; ๐น๐ต = ๐๐ต
2/๐๐ธ2; ๐น๐ถ = ๐๐ถ
2/๐๐ธ2).
Table 3: Variance analysis of orthogonal experiments on synthesisof 2-methyl-4-(3,4-acetoxybenzylene)oxazol-5-ones.
Source Sum ofsquares
Degree offreedom
Meansquare ๐น value ๐ value
Factor Atemperature(โC)
10.11 2 5.05 0.27 0.788
Factor Btime (min) 11.40 2 5.70 0.30 0.767
Factor CMW power(W)
13.27 2 6.63 0.35 0.739
Error 37.55 2 18.77
to take 25mins reaching a yield of 87.1% compared to theconventional heating of 10 hrs for a yield of 75.6%. This waslikely due to the addition of zinc-mercury amalgam catalystwhich is a strong microwave absorber.
For the synthesis of ๐ฝ-(3,4-dihydroxyphenyl) pyruvicacid a shorter reactionwas observed withmicrowave heating.However, the yield under microwave heating conditions waslower than that with conventional heating which may beattributed to the different dielectric properties of the reagents.However, to get a deeper insight into the mechanism of thisprocess further investigation is required.
Table 4: Orthogonal experiment on synthesis of ๐ผ-acetylamino-๐ฝ-(3,4-diacetoxyphenyl)acrylic acid.
Trial no.Factor A
temperature(โC)
Factor Btime (min)
Factor CMW power
(W)Yield (%)
1 1 1 1 86.32 1 2 2 76.23 1 3 3 87.54 2 1 2 83.05 2 2 3 86.86 2 3 1 81.37 3 1 3 85.48 3 2 1 76.29 3 3 2 81.1๐พ1
250.0 254.7 243.8 ๐พ = 743.8
๐พ2
251.1 239.2 240.3 ๐ = 61470.9
๐พ3
242.7 249.9 259.7U 61484.8 61512.9 61542.2Q 13.9 42.0 71.3
Table 5: Variance analysis of orthogonal experiment on synthesis of๐ผ-acetylamino-๐ฝ-(3,4-diacetoxyphenyl)acrylic acid.
Source Sum ofsquares
Degree offreedom
Meansquare F value P value
Factor Atemperature(โC)
13.9 2 6.95 0.63 0.613
Factor Btime (min) 41.98 2 20.99 1.90 0.344
Factor CMW power(W)
71.27 2 35.63 3.23 0.236
Error 22.04 2 11.02
Table 6: Experimental results for synthesis of ๐ฝ-(3,4-dihydrox-yphenyl)pyruvic acid at different temperatures.
Level Temperature (โC) Yield (%)1 80 02 90 51.33 95 33.54 100 17.2
3. Experimental
3.1. Materials and Apparatus. 3,4-Dihydroxybenzaldehyde(CP) was purchased from Guangxi Chemicals Import andExport Ltd. N-acylglycine (AR) and acetic anhydride (AR)were purchased from Xiโan Chemical Reagent Factory. Mer-cury chloride (AR) was supplied by Shanghai Shanpu Chem-ical Reagent Co., Ltd, and Zinc granular (AR) by Xiโan Sanpu
![Page 5: Research Article Microwave-Assisted Synthesis of Isopropyl](https://reader030.vdocuments.site/reader030/viewer/2022012602/6198c0d6f3a2ed2a2a383724/html5/thumbnails/5.jpg)
Journal of Chemistry 5
Table 7: Experimental results for synthesis of ๐ฝ-(3,4-dihydrox-yphenyl) pyruvic acid at different reaction time periods.
Level Time (min) Yield (%)1 15 9.72 20 34.13 30 51.34 40 51.3
Table 8: Orthogonal experiment on synthesis of isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate.
Trial no.Factor A
temperature(โC)
Factor Btime (min)
Factor CMW power
(W)Yield (%)
1 1 1 1 48.52 1 2 2 83.23 1 3 3 57.44 2 1 2 49.55 2 2 3 59.16 2 3 1 86.17 3 1 3 69.38 3 2 1 57.79 3 3 2 80.2๐พ1
189.1 167.3 192.3 ๐พ = 591
๐พ2
194.7 200.0 212.9 ๐ = 38809
๐พ3
207.2 223.7 185.8U 38866.2 39343.7 38942.4Q 57.2 534.7 133.4
Table 9: Variance analysis of orthogonal experiment on synthesis ofisopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate.
Source Sum ofsquares
Degree offreedom
Meansquare F value P value
Factor Atemperature(โC)
57.2 2 28.6 0.06 0.943
Factor Btime (min) 534.7 2 267.3 0.56 0.641
Factor CMW power(W)
133.4 2 66.7 0.14 0.877
Error 955.0 2 477.5
Chemical Reagent Co., Ltd. Isopropanol (AR) was obtainedfrom Tianjin Chemical Reagent Factory 6.
All microwave-assisted reactions were carried out usinga WF-400 Microwave Reaction System (Shanhai Yiyao Ana-lytical Instruments Ltd.) operated at atmospheric pressure.A WRS-1A digital melting point instrument (Shanghai Pre-cision and Scientific Instrument Co., Ltd.) was used formelting point measurements. An RE-52AA rotatory evapo-rator (Shanghai Rong Biochemical Instrument Factory) anda DZ1-BC vacuum oven (Tianjin Tester Instrument Co., Ltd.)were also used for the experiment. Chemical analysis was
performed by both NMR (INOVA-400MHz, Varian) andinfrared spectroscopy (FT-IR360, Nicolet Instrument Co.,USA).
3.2. Preparation of 2-Methyl-4-(3,4-acetoxybenzylene)oxazol-5-ones. A mixture of 3,4-dihydroxybenzaldehyde (13.8 g,0.1mol), N-acylglycine (14.2 g, 0.13mol), and anhydrousNaOAc (10.7 g, 0.13mol), Ac
2O (51.2 g, 0.5mol) was made in
a 150mL double-neck flask. The flask was connected to themicrowave reactor system equipped with magnetic stirrers,a reflux condenser and high precision platinum resistancetemperature sensors, which was linked with the temperaturecontrol system. In a typical process of microwave-irradiatedreactions, when the microwave was switched on, the temper-ature started to rise until it reached the preset level whilstthe reaction timing started to count.The temperature controlsystem would switch on and/or cut off microwave irradiationin an intermittent way to keep the temperature in the rage ofยฑ0.1โC at the preset level.
The reaction was carried out in the microwave reactorsystem under preset conditions. Once the mixture turnedinto a dark yellow solution with temperature rising, therefluxing started and remained until solution turned darkbrown. When cooling to room temperature 60mL ice waterwas added, and the mixture was stirred until yellow crystalsprecipitated. It was then filtered, washed with cold water, anddried under vacuum to produce yellow crystals product A,2-methyl-4-(3,4-acetoxybenzylene)oxazol-5-ones (mp 161.2โ161.5โC, lit. [31] mp 161.0โ161.4โC).
3.3. Preparation of ๐ผ-Acetylamino-๐ฝ-(3,4-diacetoxyphen-yl)acrylic Acid. The above produced 2-methyl-4-(3,4-acetoxybenzylene)oxazol-5-ones (12.54 g, 0.04mol) wasmixed with acetone (46mL) and water (46mL) in a 150mLdouble-neck flask, which was then attached to the microwavereaction system. With stirring and refluxing, the reactionsolution turned dark brown, which was then decolorizedusing active carbon with microwave heating and refluxing.A vacuumed filtration step followed and resulted in a redsolution. When cooling to room temperature needle-shapedyellow crystals formed from the solution, which were thenwashed with ice water and vacuum filtered resulting incompound B. The filtrate was further concentrated byevaporation, cooled and vacuum filtered to recover yellowproduct B, ๐ผ-acetylamino-๐ฝ-(3,4-diacetoxyphenyl)acrylicacid (mp 188.8โ189.4โC, lit. [31] mp 188.9โ189.1โC).
3.4. Preparation of ๐ฝ-(3,4-Dihydroxyphenyl)pyruvic Acid. Amixture of compound B (12.85 g, 0.04mol) with 125mL HCl(1M) was made in a 250mL double-neck flask, which wasconnected to the microwave reactor system. When the reac-tion finished, the light yellow solution was decolorized usingactive carbonwithmicrowave heating and refluxing, followedby vacuumed filtration.The filtrate was concentrated throughevaporation to form light yellow crystals which were furtherpurified by filtration, washing, and drying for product C,๐ฝ-(3,4-dihydroxyphenyl)pyruvic acid (mp 191.2โ191.6โC, lit.[31] mp 191.4โ191.6โC).
![Page 6: Research Article Microwave-Assisted Synthesis of Isopropyl](https://reader030.vdocuments.site/reader030/viewer/2022012602/6198c0d6f3a2ed2a2a383724/html5/thumbnails/6.jpg)
6 Journal of Chemistry
Table 10: Comparison of reaction results using microwave and conventional heating methods.
Product Conventional heating Microwave heatingTime (h) Yield (%) Time (min) Yield (%)
Azolactone 5 80 15 90.8Acrylic acid 4 72.9 8 88.6๐ฝ-(3,4-Dihydroxyphenyl) pyruvic acid 8 74.5 30 51.3Isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate 10 75.6 25 87.1
3.5. Preparation of Isopropyl ๐ฝ-(3,4-Dihydroxyphenyl)-๐ผ-hydroxypropanoate. The above synthesised ๐ฝ-(3,4-dihydroxyphenyl)pyruvic acid (1 g) was mixed with 5.5mLconcentrated HCl, 36mL isopropanol, and 2 g zinc-mercury amalgam in a 100mL double-neck flask whichwas connected to the microwave reactor system. Upon thecompletion of reaction, the reaction mixture was filtratedand distilled to remove catalyst and solvent. After adding30mL ethyl acetate, the solution pH was adjusted withsaturated sodium bicarbonate to pH < 7 for phase separation.The brown oily phase was then dehydrated with NaS
2O4
followed by filtration and vacuumed distillation for solventremoval. The product was further purified by hydrothermalrecrystallisation to obtain light yellow powder product D,isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate(mp 79.2โ80.0โC, lit. [4] mp 79.4โ80.2โC).
4. Conclusions
Microwave radiation was employed as an effective heat-ing method in the synthesis of a pharmaceutically activecompound isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxy-propanoate.The reaction conditions were optimised by usingan orthogonal design of experiment (ODOE) approach, andthe operating parameters including reaction temperature,reaction time, and microwave power level were examined.Microwave heating was applied to all four reaction stepsand compared to conventional heating method. It was foundthat the reaction time was significantly reduced for allreactions and the product yields were increased (exceptthe third-step reaction) under microwave heating condi-tions. The most remarkable microwave enhancement wasobserved in the step of isopropyl ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxypropanoate production where the reaction timewas reduced from 10 hrs (conventional heating) to 25mins(microwave heating) whilst the yield was increased from75.6% to 87.1%, respectively.
Acknowledgments
This work was financially supported by grants from Impor-tant Science & Technology Specific Projects of InnovativeProgram of Shaanxi Province (2010ZDKG-46), ScientificResearch Plan Projects of Shaanxi Education Department(12JK0582; 12JK1012), Scientific Research Foundation forPh.D. of Xiโan Shiyou University (2011BS010), and 2012National Innovation and Entrepreneurship Training Projectfor College Students (201210705047).
References
[1] X. L. Deng, X. M. Chen, F. S. Jiang, and X. C. Yiao, โSynthesisof Sodium ๐ฝ-(3, 4-Dihydroxyphenyl)lactate,โ Chinese Pharma-ceutical Journal, vol. 36, no. 9, pp. 523โ524, 2005.
[2] X. H. Zheng, Y. C. Zhang, S. X. Wang, and X. F. Zhao, โPrep-aration of isopropyl ๐ฝ-(3, 4-dihydroxyphenyl)-๐ผ-hydroxypro-pionate for treatment of cardiovascular and cerebrovasculardiseases,โ CN1583710, 2005.
[3] X. H. Zheng, Q. Z. Zhang, S. X. Wang, and X. F. Zhao, โBeta-(3, 4) dihydroxy phenyl-alpha hydroxy borneol propionate, itssynthesis method and use,โ CN1868998, 2006.
[4] Q. Zhang, Y. Dong, Y. Nan, X. Cai, and X. Zheng, โSynthesisof ๐ฝ-(3,4-dihydroxyphenyl)-๐ผ-hydroxy propionic acid esters,โChinese Journal of Organic Chemistry, vol. 29, no. 9, pp. 1466โ1469, 2009.
[5] X. H. Zheng, Q. Z. Zhang, S. X. Wang, and X. F. Zhao,โSubstituted ๐ฝ-phenyl-๐ผ-hydroxy-propanoic acid, synthesismethod and use thereof PCT/CN2007/0011550,โ US8017786,2011; EP2019090, 2012; RU2421443, 2011; CAC07C69/732,2011; AU2007250364, 2011; SG147841WO2007/131446, 2011;NZ572958, 2011; KR10-1059639, 2011., 2006.
[6] C. O. Kappe, โThe use of microwave irradiation in organicsynthesis. From laboratory curiosity to standard practice intwenty years,โ Chimia, vol. 60, no. 6, pp. 308โ312, 2006.
[7] M. Gupta, S. Paul, and R. Gupta, โGeneral characteristics andapplications of microwaves in organic synthesis,โ Acta ChimicaSlovenica, vol. 56, no. 4, pp. 749โ764, 2009.
[8] A. M. Rodriguez, P. Prieto, A. de la Hoz, and A. Dฤฑaz-Ortiz,โโIn silicoโ mechanistic studies as predictive tools in microwave-assisted organic synthesis,โ Organic & Biomolecular Chemistry,vol. 9, no. 7, pp. 2371โ2377, 2011.
[9] R. O. M. A. de Souza, L. S. de M., and M. Miranda, โMicrowaveassisted organic synthesis: a history of success in Brazil,โQuim-ica Nova, vol. 34, no. 3, pp. 497โ506, 2011.
[10] R. Gedye, F. Smith, K. Westaway et al., โThe use of microwaveovens for rapid organic synthesis,โ Tetrahedron Letters, vol. 27,no. 3, pp. 279โ282, 1986.
[11] R. J. Giguere, T. L. Bray, S. M. Duncan, and G. Majetich, โAppli-cation of commercial microwave ovens to organic synthesis,โTetrahedron Letters, vol. 27, no. 41, pp. 4945โ4948, 1986.
[12] A. M. Sajith and A. Muralidharan, โMicrowave enhancedSuzuki coupling: a diversity-oriented approach to the syn-thesis of highly functionalised 3-substituted-2-aryl/heteroarylimidazo[4,5-b]pyridines,โ Tetrahedron Letters, vol. 53, no. 9, pp.1036โ1041, 2012.
[13] N. Gruber, M. C. Mollo, M. Zani, and L. R. Orelli, โMicrowave-enhanced synthesis of phosphonoacetamides,โ Synthetic Com-munications, vol. 42, no. 5, pp. 738โ746, 2012.
![Page 7: Research Article Microwave-Assisted Synthesis of Isopropyl](https://reader030.vdocuments.site/reader030/viewer/2022012602/6198c0d6f3a2ed2a2a383724/html5/thumbnails/7.jpg)
Journal of Chemistry 7
[14] A. M. G. Silva, B. Castro, M. Rangel et al., โMicrowave-enhanced synthesis of novel pyridinone-fused porphyrins,โSynlett, no. 6, pp. 1009โ1013, 2009.
[15] M. A. H. Zahran, H. F. Salama, Y. G. Abdin, and A. M. Gamal-Eldeen, โEfficient microwave irradiation enhanced stereoselec-tive synthesis and antitumor activity of indolylchalcones andtheir pyrazoline analogs,โ Journal of Chemical Sciences, vol. 122,no. 4, pp. 587โ595, 2010.
[16] N. T. Hoai, A. Sasaki, M. Sasaki, H. Kaga, T. Kakuchi, and T.Satoh, โSelective synthesis of 1,6-anhydro-๐ฝ-D-mannopyranoseand -mannofuranose using microwave-assisted heating,โ Car-bohydrate Research, vol. 346, no. 13, pp. 1747โ1751, 2011.
[17] H. Ichikawa, H. Ohfune, and Y. Usami, โMicrowave-assistedselective synthesis of 2H-indazoles via double Sonogashiracoupling of 3,4-diiodo-pyrazoles and bergman-masamunecycloaroma-tization,โ Heterocycles, vol. 81, no. 7, pp. 1651โ1659,2010.
[18] P. Dao, C. Garbay, and H. Chen, โHigh yielding microwave-assisted synthesis of tri-substituted 1,3,5-triazines using Pd-catalyzed aryl and heteroarylamination,โ Tetrahedron, vol. 68,no. 20, pp. 3856โ3860, 2012.
[19] D. S. Bose and R. K. Kumar, โHigh-yielding microwave assistedsynthesis of quinoline and dihydroquinoline derivatives undersolvent-free conditions,โ Heterocycles, vol. 68, no. 3, pp. 549โ559, 2006.
[20] J. A. F. Joosten, N. T. H. Tholen, F. Ait El Maate et al.,โHigh-yielding microwave-assisted synthesis of triazole-linkedglycodendrimers by copper-catalyzed [3 + 2] cycloaddition,โEuropean Journal of Organic Chemistry, no. 15, pp. 3182โ3185,2005.
[21] M. Pasto, B. Rodrฤฑguez, A. Riera, and M. A. Pericas, โSynthesisof enantiopure amino alcohols by ring-opening of epoxyalco-hols and epoxyethers with ammonia,โ Tetrahedron Letters, vol.44, no. 46, pp. 8369โ8372, 2003.
[22] U. M. Lindstrom, B. Olofsson, and P. Somfai, โMicrowave-assisted aminolysis of vinylepoxides,โ Tetrahedron Letters, vol.40, no. 52, pp. 9273โ9276, 1999.
[23] Q. Z. Zhang, T. He, X. Y. Xiong, G. Chen, and B. Y. Su,โMicrowave assisted synthesis of Danshensu,โChinese ChemicalReagents, vol. 3, no. 3, pp. 259โ262, 2011.
[24] F. Pukelsheim, Optimal Design of Experiments, Society forIndustrial and Applied Mathematics, Philadelphia, Pa, USA,1993.
[25] J. Antony, Design of Experiments for Engineers and Scientists,Elsevier Science, 2003.
[26] G. Taguchi and Y. Yokoyama, Taguchi Methods: Design ofExperiments, ASI Press, 1993.
[27] R. K. Roy,Design of Experiments Using the Taguchi Approach: 16Steps to Product and Process Improvement, John Wiley & Sons,2001.
[28] X. Zhang, D. O. Hayward, and D. M. P. Mingos, โEffectsof microwave dielectric heating on heterogeneous catalysis,โCatalysis Letters, vol. 88, no. 1-2, pp. 33โ38, 2003.
[29] X. Zhang and D. O. Hayward, โApplications of microwavedielectric heating in environment-related heterogeneous gas-phase catalytic systems,โ Inorganica Chimica Acta, vol. 359, no.11, pp. 3421โ3433, 2006.
[30] J. Xu, โMicrowave irradiation and selectivities in organic reac-tions,โ Progress in Chemistry, vol. 19, no. 5, pp. 700โ712, 2007.
[31] X. L. Li, Y. Q. Shan, D. B. Ye, Q. Z. Zhang, and X. H. Zheng,โSynthesis of ๐ฝ-(3, 4-Dihydroxyphenyl)-๐ผ-hydrox-N-[(R)-(3-phenyl-1-ethyloxyformyl) propyl] propanamide,โ Chinese Jour-nal of Synthetic Chemistry, vol. 16, no. 2, pp. 239โ241, 2008.
![Page 8: Research Article Microwave-Assisted Synthesis of Isopropyl](https://reader030.vdocuments.site/reader030/viewer/2022012602/6198c0d6f3a2ed2a2a383724/html5/thumbnails/8.jpg)
Submit your manuscripts athttp://www.hindawi.com
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation http://www.hindawi.com Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttp://www.hindawi.com
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Organic Chemistry International
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation http://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
CatalystsJournal of