Article pubs.acs.org/OPRD
Synthesis of Donepezil Hydrochloride via Chemoselective Hydrogenation Ajay Singh Rawat,*,‡ Sachin Pande,‡ Nilay Bhatt,‡ Raju Kharatkar,‡ Chandrakant Belwal,‡ and Anand Vardhan‡ ‡
Sterling Biotech Limited, Jambusar State Highway, Village Masar 391421, Taluka, Padra, Distt: Vadodara Gujarat India S Supporting Information *
ABSTRACT: A simple and highly chemoselective and cost-effective process for the synthesis of Donepezil 1 has been developed for commercial production. In the process, the exocyclic double bond is mainly targeted for catalytic hydrogenation in the presence of an N-benzyl group using sulfur, nitrogen, and phosphorous catalyst modifiers. In some cases, catalytic hydrogenation with Pd on charcoal also produced an undesired side product along with the main product due to over reduction. Removal of these impurities by crystallization, column chromatography, or other means of purification makes the process tedious and lengthy, and sometimes it is difficult to achieve the impurity limit as per International Conference on Harmonisation (ICH) guidelines for active pharmaceutical ingredients. In the present investigation we report the synthesis of Donepezil 1 in pure form wherein the debenzyl impurity is within the acceptable limits.
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INTRODUCTION Donepezil 1,1 chemically known as l-benzyl-4-[(5,6-dimethoxyl-indanon)-2-yl] methyl piperidine, as its hydrochloride 1a is used for the treatment of all kinds of senile dementia, in particular being useful for prevention, treatment, and amelioration of Alzheimer’s disease by virtue of its acetyl cholinesterase inhibitory action. The unique chemical structure of Donepezil makes it more specifically effective for Alzheimer’s disease.2 The general procedure for making Donepezil (Scheme 1) is by an aldol condensation of 5,6- dimethoxyindan-1-one with N-
wherein additional purification steps are required to achieve the desired quality. This not only reduces the efficiency but also does not necessarily provide a scalable process. A process for the preparation of Donepezil using metal borohydride in the presence of catalytic amounts of cobalt salts is also described in the literature.8 However, use of inorganic catalysts on commercial scale gives an additional burden of ensuring the product to be free from inorganics. Niphade et al.9 reported the major debenzyl impurity 5 in the range of 10−20% when performing hydrogenation using 10% Pd/C in a 2:1 ratio of methanol and dichloromethane. There are a few reports in the literature which mention the high activity of Pd/C to be the culprit favoring impurity formation,10 which in most of the cases is the over-reduction product. It is well-known that moderation of Pd/C activity can reduce the catalyst activity toward hydrogenation. Maegawa et al.11 have reported addition of a catalyst modifier (catalytic poison) such as a sulfur or nitrogen containing molecule to suppress the catalyst activity of Pd/C.
Scheme 1. General Scheme for Donepezila
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RESULTS AND DISCUSSION Aiming to reduce major impurity 5 formation during Donepezil synthesis, the present paper describes the selective reduction of the exocyclic ethylene bond using catalyst deactivators. In addition, solvent media can also affect the chemoselectivity during hydrogenation.10 It has also been shown that a nonprotic solvent12 helps in lowering the catalyst activity. So, some nonprotic solvents as listed in Table 1 were selected for conducting experiments, and all the reactions were carried out with 20% loading of 10% palladium on charcoal with respect to substrate at room temperature under hydrogen atmosphere. The results of the performed experiments are summarized in Table 1.
a Reaction and conditions: (a) KOH, dichloromethane, reflux; (b) H2Pd on charcoal; (c) IPA·HCl, THF.
benzylpiperidine-4-carboxyaldehyde1 or by using a Wittig reaction of a substituted 5,6-dimethoxy indan-1-one,3,4 followed by dehydration and catalytic reduction of the exocyclic double bond to yield 1. Further synthetic methods for 1 are also reported in the literature.5 Various catalytic hydrogenation processes for producing Donepezil are disclosed in patents;6,7 most of these procedures suffer from impurity formation, © XXXX American Chemical Society
Received: January 10, 2013
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Table 1. Effect of Solvent on Hydrogenation with Pd/C without Using Catalytic Modifier at Room Temperature % HPLC purity S. No.
solvent
volume (mL)
1 2 3 4
acetonitrile ethyl acetate THF pyridine
50.0 50.0 50.0 30.0
4
100.00 100.00 25.50 0.30
reaction time
1
h
74.00 99.67
1.0 1.0 1.0 2.0
5
Table 3. Assessment of Sulfur Containing Organic and Inorganic Modifier for Selective Hydrogenation in THFa
S. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
It was observed from the results that pyridine (S. No. 4, Table 1) acted as both a solvent and catalyst modifie,r which not only depressed the activity of Pd/C but also suppressed the formation of debenzyl impurity 5 to a very low extent and produced the desired product in excellent purity. However, pyridine could not be taken as the solvent of choice for optimizing the process due to its associated practicality and environmental and safety disadvantages. Thus, tetrahydrofuran (S. No. 3, Table 1) was the next most favored solvent and was taken as the solvent of choice for our further investigation. The next step of the investigation was to fix the optimum amount of catalyst (Pd/C) loading with respect to substrate; therefore, trials to check the effect of catalyst loading in this regard were performed. The results so obtained are summarized in Table 2. From the result it was observed that, with catalyst Table 2. Effect of Pd/C Loading with Respect to Substrate on Hydrogenation in THFa at Room Temperature % HPLC purity S. No.
% catalyst loading
1 2 3 4
20.0 10.0 5.0 2.0
4
reaction time
5
1
h
25.45 5.00 4.40 2.80
73.98 94.80 95.60 97.00
1.0 2.5 5.0 22.0
reaction time
% HPLC purity
29
modifier CYTAc
thioanisole
thiophenol
thiourea phenyl sulfide
sodium sulfide
barium sulfate calcium sulfate magnesium sulfate sodium sulfate
qty (mg) 10.0 5.0 4.0 3.0 2.0 0.5 0.1 0.01 0.02 0.03 0.04 0.05 0.01 0.02 0.03 0.04 0.5 0.01 7.0 5.8 3.0 2.0 3.0 5.0 7.0 10.0 10.0 10.0 20.0
4
0.58 0.2 1.66 1.23 32.41 81.42
15.6 0.29 57.25 3.33 1.53 0.07 0.06
5
1
h
no reaction 0.26 0.8 0.22 5.35 10.73 0.18 1.91 0.48 0.06 0.65 0 5.48 0.43 0.14 0 no reaction 0.17 0.29 0.02 0.05 3.72 0.78 0.13 no reaction 5.12 5.42 7.17
92.57 93.64 90.9
6.0 22.0 3.0 2.0 3.0 2.0 18.0 3.0 6.0 8.0 9 23 6 11 15 12 6 3.5 16 6 16 2 4 7 2 3 2 4
8.83
90.07
2
98.63 98.04 99.36 93.56 88.37 98.92 97.91 97.92 99.27 98.73 98.34 93.75 98.19 66.51 18.58 98.83 81.5 97.95 22.75 94.07 94.4 96.51
a
a
All reactions were carried out on a 2 g scale and using 50 mL (25 volumeb) of THF. bSolubility of starting material is a problem; hence, this is the minimum required volume of THF.
All trials were performed on 2 g input of 4 and using 50 mL (25 volumeb) of THF. bSolubility of starting material is a problem; hence, this is the minimum required volume of THF. c1-(Mercaptomethyl)cyclopropane acetic acid.
loading of 2%, debenzylation impurity was under control but the conversion needed a longer reaction time. Maximum debenzyl 5 impurity formation was observed when the conversion was performed with 20% catalyst loading. The reactions performed with 5 and 10% catalyst loading showed almost similar results in terms of impurity formation, though differing in reaction time. For our trial purpose, we selected 20% catalyst loading purely on the basis of less conversion time, and also as it showed appreciable amount of debenzyl 5 impurities, it could help us in screening and choosing the best additive catalyst modifier more realistically. Finally, after choosing the solvent and the optimum catalyst loading, trials for suitable catalyst activity modifiers were performed. Initially, we examined some of the organic and inorganic sulfur containing compounds as catalyst activity modifiers. The results so obtained are summarized in Table 3. Amongst the organic modifiers taken for investigation, it was observed that the optimized amount of thiophenol (S. No. 14, Table 3) required longer reaction time, which showed >1% starting material and ∼0.45% debenzyl impurity 5, while the reaction with an optimized quantity of thioanisole (S. No. 11, Table 3) and phenyl disulfide (S. No. 20, Table 3) showed
completion of reaction within 8 h, and both the reactions showed ∼0.06% of debenzyl impurity 5 formation. Furthermore, it was found that addition of 3 mg of CYTA [1(mercaptomethyl)cyclopropane acetic acid] (S. No. 4, Table 3) to the reaction mixture helped the reaction to be completed within 2 h, which also restricted impurity 5 formation to ∼0.22%. Also, it was observed that an increase in CYTA quantity was detrimental to the reaction in terms of conversion and impurity reduction. Amongst the sulfur containing inorganic catalyst modifiers investigated, sodium sulfide showed some moderation of catalyst activity in terms of impurity formation along with the completion of reaction. Other inorganic catalyst modifiers investigated, namely barium, calcium, and magnesium sulfate, inhibited debenzyl impurity 5 formation, but not to the extent as shown by other catalytic moderators or modifiers. Further to our investigations, a few nitrogen containing molecules were also evaluated (Table 4). From the experiments, it was found that pyridine provided a quite selective hydrogenation, thus being the most suitable modifier. However, keeping in view safety and hazards in scale up, the idea with pyridine was not used for optimization. B
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Table 4. Effect of Amines on Debenzyl Impurity 5 Formationa % HPLC purity S. No.
modifier
volume (mL)
4
1
5
reaction time (h)
1 2 3
diisopropylethyl amine pyridinec 0.5% tetrabutylammonium hydroxide in tetrahydrofuran
5.0 5.0 0.4
0.45
95.63 98.8 77.85
3.92 1.2 21.55
1.0 1.5 3.0
a Note: All trials were performed on 2 g input of 4 and using 50 mL (25 volume) of THF. bSolubility of starting material is a problem; hence, this is the minimum required volume of THF. cSee author note.
Table 5. Summary of Scale up Batchesa % HPLC purity RM
a
1
1a
S. No.
batch no.
input 4 kg
output 1 kg
1
4
5
1
4
5
1a
4
5
1 2 3 4 5 6
DNP/170/034 DNP/170/036 DNP/170/050 2013DNP0502 2013DNP0503 2013DNP0504
0.4 0.4 0.4 20.0 20.0 20.0
0.361 0.355 0.359 18.25 18.18 18.20
98.38 98.96 98.69 98.48 98.69 98.34
0.2 0.32 0.68 0.06 0.09 0.07
0.05 0.07 0.03 0.22 0.11 0.18
99.73 99.58 99.51 99.13 99.26 99.28
0.14 0.13 0.21 0.05 0.09 0.07
0.05 0.08 0.05 0.08 0.03 0.05
99.95 99.83 99.91 99.90 99.88 99.93
ND ND ND ND ND ND
ND ND ND ND ND ND
RM, reaction mass; ND, not detected.
Table 6. Summary of Scale up Batches (Pd, Solvent and Thioanisole Content)a S. No.
batch no.
1 2 3 4 5 6
DNP/170/034 DNP/170/036 DNP/170/050 2013DNP0502 2013DNP0503 2013DNP0504
Pd % (ppm) NMT NMT NMT NMT NMT NMT
20 20 20 20 20 20
MeOH (ppm)
IPA (ppm)
THF (ppm)
DCM (ppm)
ACN (ppm)
DIPE (ppm)
thioanisole content (%)
281 268 227 181 205 150
BDL BDL BDL BDL BDL BDL
BDL BDL BDL BDL BDL BDL
BDL BDL BDL BDL BDL BDL
170 120 105 110 128 112
50 122 111 88 65 50
BDL BDL BDL BDL BDL BDL
a
MeOH, methanol; ACN, acetonitrile; THF, tetrahydrofuran; DCM, dichloromethane; IPA, isopropanol; DIPE, diisopropyl ether; BDL, below detection limit; NMT, not more than.
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Hydrogenation using phosphorous containing organic molecule catalyst modifiers was not found in the literature search. In order to evaluate phosphorous containing organic molecules, an investigation was carried out with triphenylphosphine wherein a positive effect of the same in reducing debenzyl impurity 5 formation during the reaction was observed. In our investigations, use of 1% w/w of triphenylphosphine with respect to the input quantity of starting material to modify 0.4 g of 10% Pd/C (65% moist) was found to be the optimum quantity to give the desired results. The trial using this optimum quantity provided Donepezil of 98% purity contaminated with ∼0.07% of debenzyl impurity 5.
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EXPERIMENTAL SECTION
Generally, all solvents and reagents were obtained of L.R. grade from commercial suppliers and used without further purification. 10% Palladium on charcoal (Batch No. M8300151 and Type 10T374 paste, 65% moist) was bought from Johnson Matthey Chemicals. All reactions were monitored by thin-layer chromatography (TLC) using Merck TLC silica gel 60 F254 (aluminum sheet), and HPLC analyses were performed with a Waters Alliance 2996 using a C18, 150 mm × 4.6 mm reversed phase column with a 5 μm particle size with detection at 230 nm in water/acetonitrile/perchloric acid (75:25:0.1 v/v) and the flow rate of 1 mL/min. General Experimental Procedure for Synthesis of 4. 5,6-Dimethoxy indanone (2; 25 kg) and N-benzyl piperidine-4carbaldehyde (3; 29 kg) were dissolved in dichloromethane (1000 L), after which potassium hydroxide (8.75 kg) was added at room temperature. The reaction mass was then refluxed until reaction completion, after which the reaction mixture was cooled to room temperature and passed through a hyflow bed. The obtained dichloromethane filtrate was then concentrated under vacuum at 30−35 °C. The obtained residue was washed with process water until the pH of the filtrate was found to be neutral. The solid was then filtered and dried under vacuum at 45 °C. The dried solid was then suspended in acetonitrile (250 L) and refluxed for 60 min and cooled to 0 °C. The precipitated solid was then filtered, washed with acetonitrile (25
CONCLUSION
From the investigations carried out for the use of catalyst modifier with Pd/C in THF to reduce undesired Debenzyl impurity in the Donepezil APIs, thioanisole, triphenylphosphine, and CYTA were found to be the best. CYTA was dropped due to its high cost and unknown toxicity data, while thioanisole was preferred over TPP, as it was cheaper and reportedly13,14 had a lower toxicity than TPP. Thus, thioanisole was preferred amongst them in terms of commercial use. Experimental results of scale up batches using thioanisole as a catalyst modifier are summarized in Tables 5 and 6. C
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3.5 (d, 2H, −CH2), 3.29−3.24 (m, 1H, >CH−), 2.93−2.89 (t, 2H, −NH−CH2), 2.67−2.64 (m, 2H, −NH−CH2), 2.39 (s, 1H, −NH−), 2.01−1.98 (m, 1H, >CH−), 1.94−1.9 (m, 2H, >CH2), 1.76−1.7 (m, 2H, −CH2−CH2−), 1.46−1.41 (m, 2H, −CH2−). 13 C NMR Recorded at 125.75 MHz in CDCl3 (δ/ppm). 206.9 (>CO), 155.7 (>CC−OCH3), 148.5 (>C− OCH3), 128.9 (>CCH−), 104.3 (>CH−), 56.3− 56.1 (−OCH3), 44.5, 44.0 (s, >CH−), 38.1 (CH2−), 33.5 (−NH−CH2−), 32.5 (−NH−CH2−), 30.9 (−CH2), 28.9− 28.6 (−CH2−CH2−). General Experimental Procedure for Synthesis of 1a (Donepezil Hydrochloride). Donepezil free base (20.0 kg, 52.77 mol) was charged, and 10% IPA·HCl (19.0 L) was added under stirring at room temperature. After the reaction mixture was stirred for 1 h at room temperature, the precipitated solid was filtered, washed with THF (2.5 L), and dried in a vacuum tray dryer. The dried solid was then suspended in acetonitrile (200 L) and refluxed for 60 min and cooled to RT. The precipitated solid was then filtered, washed with acetonitrile (50 L), and dried in a vacuum tray dryer. Finally, this solid was dissolved in methanol (80.0 L) at reflux temperature, and then the reaction mixture was brought to the temperature at which diisopropyl ether (480 L) was added. The precipitated solid was filtered, washed with diisopropyl ether, and dried in a vacuum tray dryer at 50 °C under vacuum for 16 h to afford a white solid of Donepezil hydrochloride as per USP. Yield, 80%; HPLC purity, ≥99.8%; appearance, white solid; mp, 229−231 °C; molecular weight, 415.9; molecular formula, C24H29NO3·HCl. 1 H NMR Recorded at 500 MHz in DMSO-d6 (δ/ppm). 10.35 (s, 1H, HCl), 7.6−7.58 (m, 2H, Ar), 7.47−7.46 (m, 3H, Ar), 7.11−7.05 (m, 2H, Ar), 4.26 (s, 2H, −CH2−Ph), 3.86 (s, 3H, −OCH3), 3.79 (s, 3H, −OCH3), 3.3 (m, 2H, >N−CH2−), 3.25−3.2 (m, 1H, >CH−), 2.9 (m, 2H, −CH2−), 2.67 (m, 2H, −CH2−), 1.95 (d, 1H, −CH−), 1.83 (d, 1H, >CH), 1.69−1.66 (m, 2H, −CH2−), 1.52−1.49 (m, 2H, −CH2), 1.29 (m, 1H, >CH−). 13 C NMR Recorded at 125.75 MHz in DMSO-d6 (δ/ppm). 206.7 (>CO,), 155.7 (>CCCCH−), 59.4 (−CH2−), 56.4−56.1 (−OCH3), 51.8−51.7 (>N−CH2−), 45.3 (>CH−), 37.9 (−CH 2 −), 33.1 (>CH−), 32.1 (−CH2−), 29.5−28.6 (>N−CH2−CH2−).
L), and finally dried at 50 °C in vacuum for 14 h to afford an off-white solid. Yield, 67 kg; yield, 67%; HPLC purity, ≥95%; mp, 176−178 °C; molecular weight, 377.48; molecular formula, C24H27NO3. General Experimental Procedure for Synthesis of 1. lBenzyl-4-[ (5, 6-dimethoxy-l-indan on)-2-ylidenyl]methylpiperidine) (4; 20.0 kg, 53.05 mol) was dissolved in THF (500 L), after which thioanisole (0.3 g) was added and the contents were stirred at room temperature for 10 min. To the stirred contents was added 10% Pd/C (2.0 kg), and the reaction mixture was stirred under hydrogen atmosphere (no pressure) for 8 h. The progress of the reaction was monitored by HPLC. After completion of the reaction, the catalyst was filtered through a Celite bed and the filtrate was concentrated under reduced pressure to give ∼18 kg of the title compound as an off white solid. Yield, 91%; appearance, off white solid; mp, 207−209 °C; molecular weight, 379.49; molecular formula, C24H29NO3. Analytical Data of Donepezil Free Base. Infrared Spectrum Recorded as KBr Pellet (λ in cm−1). 3435 (O−H stretching), 2923 (aromatic C−H stretching), 1697 (CO stretching), 1589 (aromatic CC stretching), 1499, 1454 (aliphatic C−H bending), 1312 (C−N stretching), 1265, 1033 (C−O stretching), 748,702 (aromatic C−H bending). 1 H NMR Recorded at 500 MHz in DMSO-d6 (δ/ppm). 7.32− 7.27 (m, 4H, Ar), 7.24−7.23 (m, 1H, Ar), 7.07 (s, 2H, Ar), 3.89 (s, 3H, −OCH3), 3.77 (s, 3H, −OCH3), 3.42 (s, 2H, −CH2− Ph), 3.23−3.17 (m, 1H, >CH−), 3.8−2.76 (m, 2H, −CH2−), 2.65−2.62 (m, 2H, −CH2), 1.91−1.86 (t, 2H, −CH2−CH2−), 1.72−1.67 (m, 2H, −CH2−), 1.6−1.57 (m, 1H, >CH), 1.41 (br, 1H, >CH−), 1.25−1.11 (m, 2H, −CH2), 1.03−1.02 (m, 1H, >CH−). 13 C NMR Recorded at 125.75 MHz in CDCl3 (δ/ppm). 207.1 (>CO), 155.7 (>CCCCCH−), 62.9 (−CH 2−), 56.3−56.0 (−OCH 3), 53.7 (−CH2 −), 45.2 (>CH−), 38.7 (−CH2−), 34.3 (−CH−), 33.2 (−CH2−), 33.1 (−CH2−), 31.9 (−CH2-). General Experimental Procedure for Synthesis of Debenzyl Impurity 5 as Its Hydrochloride. l-Benzyl-4[(5,6-dimethoxy-l-indanon)-2-ylidenyl]methylpiperidine (4, 2.0 g, 5.207 mmol) was dissolved in ethyl acetate (50 mL), 10% Pd/C (0.4 g) was added, and stirring was continued under hydrogen atmosphere. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was filtered through a Celite bed and the filtrate was stirred with a 5% methanolic HCl solution for 60 min, as a result of which an off white solid was precipitated. The solid was then filtered and dried under reduced pressure at 45 °C to obtain debenzyl impurity 5 as its hydrochloride salt . Yield, 85%; HPLC purity, ≥ 98%; appearance, off white solid; mp, 257−259 °C; molecular weight, 289.36; molecular formula, C17H23NO3. Analytical Data of Debenzyl Impurity 5-(5,6-Dimethoxy-2-(piperidin-4-yl)methyleneindan-1-one) as Its Hydrochloride. Infrared Spectrum Recorded as KBr Pellet (λ in cm−1). 2939.0 (aliphatic C−H stretching), 2799.0 (aliphatic C−H stretching), 1679.0 (CO stretching), 1602.0 (CC stretching), 1474 (aliphatic C−H bending), 1216, 1105 (C−O stretching). 1 H NMR Recorded at 500 MHz in CDCl3 (δ/ppm). 9.54 (brs, 1H, NH2+Cl−), 9.30 (brs, 1H, NH2+Cl−), 7.12 (s, 1H, Ar), 6.84 (s, 1H, Ar), 3.99 (s, 3H, −OCH3), 3.9 (s, 3H, −OCH3), 3.52−
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ASSOCIATED CONTENT
S Supporting Information *
1
H NMR spectrum of Donepezil free base 1; 13C NMR of Donepezil free base 1; 1H NMR spectrum of Donepezil hydrochloride 1a; 13C NMR of Donepezil hydrochloride 1a; 1H NMR spectrum of Donepezil debenzyl impurity 5; and 13C NMR spectrum of Donepezil debenzyl impurity 5. This material is available free of charge via the Internet at http:// pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Telephone no.: +91-2665-237301/2, ext-200. Fax no.: +912665-237304. E-mail address: apoorva6@rediffmail.com. D
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. All authors contributed equally. Notes
The authors declare no competing financial interest. The best effect of pyridine was when it was used as a solvent cum deactivator, as in lower proportions in combination with THF as solvent it did not show the desired effect. The lowest quantity of pyridine having a deactivating effect and control of impurity was 5 mL for 2 g input, as listed in Table 4. Quantities below this hampered the control of impurity 5. Pyridine was also not explored further, as in parallel other better deactivators were being discovered.
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ACKNOWLEDGMENTS We thank our analytical development section for providing their valuable input, especially in the characterization of the prepared product and impurity.
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ABBREVIATIONS Pd/C, palladium on charcoal; THF, tetrahydrofuran; HPLC, high performance liquid chromatography; TLC, thin layer chromatography; NMR, nuclear magnetic resonance
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REFERENCES
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