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Article

Depolymerization of P4HB and PBS Waste and Synthesis of the Anticancer Drug Busulfan from Plastic Waste

by
Daniel L. Lourenço
and
Ana C. Fernandes
*
Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
*
Author to whom correspondence should be addressed.
Catalysts 2022, 12(4), 381; https://doi.org/10.3390/catal12040381
Submission received: 25 February 2022 / Revised: 24 March 2022 / Accepted: 25 March 2022 / Published: 29 March 2022
(This article belongs to the Special Issue New Frontiers in Organometallic Catalysis)
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Abstract

:
Sustainable synthesis of pharmaceuticals is one of the main challenges for the pharmaceutical industry. Production of these compounds from plastic waste can provide an innovative and ecological approach to their sustainable synthesis. In this context, plastic waste can be regarded as a potential cheap resource for the production of compounds of interest to the pharmaceutical industry. In this work, the first methodologies for the reductive depolymerization of poly(4-hydroxybutyrate) (P4HB) and polybutylene succinate (PBS) plastic waste are reported using the catalyst systems MoO2Cl2(H2O)2/silane, MoO2Cl2(H2O)2/borane and KOH/PhSiH3 with moderate to excellent yields. We also developed the first synthetic strategy for the synthesis of a drug, the anticancer busulfan, from P4HB and PBS plastic waste with moderate overall yields.

Graphical Abstract

1. Introduction

Plastics have become ubiquitous materials in our daily life, and the world without plastics seems unimaginable today. Consequently, plastic pollution has increased drastically over the last century and is currently one of the biggest problems facing the planet. It is urgent to mitigate the environmental impact of plastics. To address this challenge, it is crucial to continue the development of new, cost-efficient and sustainable processes for the valorization of plastic waste. In the last years, great efforts have been made to develop new methodologies for the depolymerization of plastic waste into a value-added chemical to be used as raw materials in the chemical industry [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. Among these methodologies, the reductive depolymerization [16] of polyester waste has attracted the attention of the scientific community using different catalysts and H2, silanes and alcohols as the reducing agents [17,18,19,20,21,22,23,24,25].
Sustainable synthesis of biologically active and pharmaceutical compounds is one of the main challenges for the pharmaceutical industry and has been investigated mainly from biomass resources [26,27,28,29,30,31,32]. Plastic waste can also be regarded as a potential cheap resource for the production of biologically active compounds and pharmaceuticals. To the best of our knowledge, there is no example of the synthesis of a drug from plastic waste described in the literature. Most of the research on the valorization of plastic waste has been directed towards the synthesis of monomers and fuels [16,17,18,19,20,21,22,23,24,25].
Busulfan, 4-methylsulfonyloxybutyl methanesulfonate (Figure 1), is an antineoplastic in the class of alkylating agents, used to treat various forms of cancer since 1959. Busulfan has been used to treat chronic myelogenous leukemia and certain blood disorders, such as polycythemia vera and myeloid metaplasia, and it has also been applied in some conditioning regimens prior to bone marrow transplant [33,34,35,36].
The search for new synthetic strategies for the production of anticancer drugs, which usually involves several reaction steps [37,38], in a sustainable way, continues to be a challenging topic for the pharmaceutical industry. In continuation of our research using oxo-complexes as efficient catalysts for the synthesis of organic compounds [39,40,41,42,43], in this work, we investigated the reductive depolymerization of P4HB and PBS plastic waste into 1,4-butanediol. We also developed the first synthesis of a pharmaceutical, the anticancer drug busulfan, from these plastic wastes.

2. Discussion and Results

In the first part of this work, we studied the reductive depolymerization of the two aliphatic polyesters poly(4-hydroxybutyrate) (P4HB) and polybutylene succinate (PBS), obtained from a non-infected commercial surgical suture (Figure 2a) and a Delta Q eQo coffee capsule, a Portuguese coffee (Figure 2b), respectively. To the best of our knowledge, there are no methodologies reported in the literature for the reductive depolymerization of these polyesters. The reductive depolymerization of P4HB was investigated using the catalytic system silane and MoO2Cl2(H2O)2, which employs different silanes as the reducing agents, including PhSiH3, (EtO)2MeSiH, PMHS (poly(methylhydrosiloxane)) and TMDS (1,1,3,3-tetramethyldisiloxane).
The reductive depolymerization of P4HB was initially carried out in the presence of 2 mol% of MoO2Cl2(H2O)2 using 1 or 3 equivalents of PMHS in toluene at reflux temperature for 24 h. These reactions led to the formation of 1,4-butanediol with 39% and 59% yields, respectively (Table 1, entries 1 and 2). When the reaction was carried out in the presence of 5 mol% of catalyst and 3 equiv. of PMHS, the yield of 1,4-butanediol increased slightly to 63% (Table 1, entry 3). The depolymerization of P4HB was also studied using (EtO)2MeSiH (3 equiv.) as the reducing agent and MoO2Cl2(H2O)2 (2 mol%) as the catalyst, producing 1,4-butanediol with 50% yield after 24 h at reflux temperature (Table 1, entry 4). This diol was also obtained in the 55% yield from the reaction of P4HB with PhSiH3 (3 equiv.) in the presence of 5 mol% of MoO2Cl2(H2O)2 (Table 1, entry 5).
To evaluate the efficiency of the catalytic system MoO2Cl2(H2O)2/TMDS in the depolymerization of P4HB, this reaction was explored using different amounts of MoO2Cl2(H2O)2 and TMDS in toluene at reflux and ambient temperatures. The best yield of 1,4-butanediol (72%, Figures S1 and S2) was observed in the presence of 5 mol% of MoO2Cl2(H2O)2 and 3 equivalents of TMDS after 24 h at reflux (Table 1, entry 6). When the depolymerization was carried out with smaller amounts of catalyst and TMDS, the diol was formed with yields of approximately 50% (Table 1, entries 7–9). At room temperature, the depolymerization of P4HB with the MoO2Cl2(H2O)2/TMDS system did not occur, demonstrating the effect of temperature on the depolymerization of P4HB (Table 1, entry 10).
To study the possible scale-up of this methodology, the depolymerization of P4HB was performed from 2 mmol (0.172 g) of this polyester with the catalytic system MoO2Cl2(H2O)2/TMDS, which also leads to the formation of 1,4-butanediol with good yield (65%) (Table 1, entry 11). This result is very interesting because it suggests the possible application of this cheap and environmentally friendly catalytic system to the large-scale production of 1,4-butanediol, which would contribute to reducing the use of fossil resources.
In this work, the possible use of the catalyst MoO2Cl2(H2O)2 (5 mol%) in several consecutive reductive depolymerizations of P4HB was also explored. This study was carried out in toluene at 110 °C by successive additions of P4HB and TMDS to the reaction mixture, without separating the catalyst at the end of each reaction. We concluded that the catalyst remained active during the eight reactions, by observing the complete reduction of P4HB and the formation of 1,4-butanediol in yields between 67% and 72% (Figure 3).
The reductive depolymerization of polyester PBS, obtained from Delta Q eQo coffee capsules cut into small pieces was also studied with the catalytic system MoO2Cl2(H2O)2/silane (Table 2). The depolymerization of PBS was initially investigated using PMHS as the reducing agent and MoO2Cl2(H2O)2 as the catalyst. The reaction performed with 5 mol% of catalyst and 2 equivalents of PMHS produced 1,4-butanediol with only 48% yield after 48 h (Table 2, entry 1). When this reaction was carried out using 6 equivalents of PMHS, this diol was obtained with 72% yield (Table 2, entry 2). Then, the depolymerization of PBS was studied using PhSiH3 (6 equiv.) in the presence of 5 mol% of MoO2Cl2(H2O)2, producing 1,4-butanediol with 67% yield after 48 h at reflux temperature (Table 2, entry 3). The reductive depolymerization of PBS carried out with TMDS (6 equiv.) and 5 mol% of MoO2Cl2(H2O)2 led to the formation of 1,4-butanediol with the best yield (75%) after 48 h at reflux temperature (Table 2, entry 4), while using 4 equivalents of TMDS, 1,4-butanediol was obtained with only 48% yield (Table 2, entry 5). In contrast, at room temperature, this reaction did not occur (Table 2, entry 6). Finally, we also successfully applied the catalytic system MoO2Cl2(H2O)2/TMDS to the depolymerization of 2.0 mmol (0.344 g) of PBS, obtaining 1,4-butanediol with 69% yield (Table 2, entry 7).
Next, we tested the reductive depolymerization of P4HB and PBS using pinacolborane (HBpin) as the reducing agent catalyzed by MoO2Cl2(H2O)2 (5 mol%). The reaction of P4HB produced pinBO(CH2)4OBpin with 71% yield after 24 h in toluene at reflux (Scheme 1). Similarly, the reductive depolymerization of PBS produced pinBO(CH2)4OBpin with 73% yield (Scheme 1). During the execution of this work, Cantat and coworkers [44] reported the first methodology for the depolymerization of polyesters using boranes as the reducing agent catalyzed by La[N(SiMe3)2]3, but the depolymerization of P4HB and PBS was not investigated in this work. Our methodology has the advantage of using a molybdenum catalyst, which is cheaper and more environmentally friendly than the lanthanum complex.
The development of efficient methodologies for the depolymerization of plastic waste in the absence of a metallic catalyst is also an extremely important issue that needs to be addressed. Nolan and coworkers [45] reported a new procedure for the reduction of esters using the system KOH/PhSiH3, which provides the corresponding alcohols with good yields; however, this catalyst system has never been used in the reductive depolymerization of plastic waste. Based on these results, we decided to apply this methodology to the depolymerization of P4HB and PBS (Table 3).
The reductive depolymerization of P4HB was performed with KOH (0.4 equiv.) and PhSiH3 (3 equiv.) in toluene at reflux temperature during 24 h, producing 1,4-butanediol with 95% yield (Table 3, entry 1). A similar reaction using only 2 equivalents of PhSiH3 also led to the formation of 1,4-butanediol but with a lower yield of 38% (Table 3, entry 2). In contrast, at room temperature, no product was formed (Table 3, entry 3). When, this reaction was performed with TMDS and PMHS at reflux temperature, 1,4-butanediol was produced with 65% and 47% yields, respectively (Table 3, entries 4 and 5).
The reductive depolymerization of PBS, obtained from a coffee capsule, was investigated with the catalytic system KOH/ PhSiH3 using 0.8 equivalents of KOH and 6 equivalents of PhSiH3 in toluene at 110 °C for 48 h, leading to the formation of 1,4-butanediol with 61% yield (Table 3, entry 6).
This result demonstrates, for the first time, the applicability of the system KOH/PhSiH3 in the reductive depolymerization of plastic waste. Beyond the excellent yield obtained from the reductive depolymerization of P4HB, this system also has the advantages of using a cheap base and a non-metallic catalyst.
Our next goal was the valorization of 1,4-butanediol, obtained from the depolymerization of P4HB and PBS plastic waste, in the synthesis of compounds of interest to the pharmaceutical industry. Then, we decided to investigate the synthesis of the anticancer drug busulfan from P4HB and PBS plastic waste.
A sample of P4HB, obtained from a non-infected commercial surgical suture, was initially converted to 1,4-butanediol by reductive depolymerization with the catalytic system MoO2Cl2(H2O)2/TMDS, followed by hydrolysis. We decided to use TMDS because this reducing agent has the advantages of being less toxic and expensive. Next, the 1,4-butanediol obtained was mesylated by reaction with methanesulfonyl chloride and triethylamine in dry dichloromethane at room temperature under nitrogen atmosphere, producing busulfan in a moderate overall yield (54%, Figures S3–S5; Scheme 2). This result is very encouraging, suggesting that this method can contribute to a more sustainable production of this drug.
A similar procedure was also developed for the synthesis of busulfan from PBS plastic waste, obtained from a Delta Q eQo coffee capsule, also leading to the formation of 1,4-butanediol, which was then mesylated, giving the anticancer drug busulfan with an overall yield of 51% (Scheme 3).

3. Conclusions

In this work, we reported the first study on the reductive depolymerization of P4HB and PBS plastic waste in moderate to excellent yields. These methodologies involved the use of the catalytic systems MoO2Cl2(H2O)2/TMDS, MoO2Cl2(H2O)2/HBpin and KOH/PhSiH3, which have the advantages of using a cheap and environmentally friendly catalyst or using a non-metallic catalyst. The catalytic systems MoO2Cl2(H2O)2/borane and KOH/PhSiH3 were applied for the first time in the depolymerization of plastic waste and the results obtained suggest the future application of these systems to the depolymerization of other plastic waste.
We also described the first example of the production of a drug, the anticancer drug busulfan, from plastic waste, namely, P4HB and PBS, with moderate overall yields. This synthetic approach enabled the production of busulfan in a very simple and sustainable way.
The synthesis of busulfan from plastic waste showed a completely new application of plastic waste, adding new options for the circular economy of plastics. New applications could include the use of plastic waste in the total synthesis of other drugs and in the production of pharmaceutical ingredients, allowing the integration of plastic waste into the drug supply chain. However, contaminations or impurities in the raw materials used are a concern and may affect the safety and effectiveness of the drug. Nonetheless, nowadays, the sensitivity of analytical methods to control the quality of the raw materials used in medication, especially in stages near the end, is very high and well regulated.
This work also has other benefits, including the development of new methodologies to recycle and extract value from plastic waste, to reduce the use of fossil resources and to preserve natural sources of carbon. This investigation can also contribute to solving two concerning issues that the planet is currently facing: the impact of plastic pollution and the sustainability of the pharmaceutical industry. Finally, we hope that this work can stimulate both academics and the industry to use plastic waste as a cheap and versatile carbon source.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/catal12040381/s1, Figure S1: 1H NMR spectrum of 1,4-butanediol in CDCl3, Figure S2: 13C NMR spectrum of 1,4-butanediol in CDCl3, Figure S3: 1H NMR spectrum of busulfan in CDCl3, Figure S4: 13C NMR spectrum of busulfan in CDCl3, Figure S5: HPLC-HRMS analysis of a sample of Busulfan. (Ref. [46] cited in the supplementary materials).

Author Contributions

Conceptualization, A.C.F.; methodology, A.C.F.; investigation, D.L.L.; writing—original draft preparation, A.C.F.; writing—review and editing, A.C.F. and D.L.L.; supervision, A.C.F.; All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by Fundação para a Ciência e Tecnologia (FCT) through projects PTDC/QUI-QOR/0490/2020, (UIDB/00100/2020), UIDP/00100/2020 and LA/P/0056/2020.

Acknowledgments

This research was supported by Fundação para a Ciência e Tecnologia (FCT) through projects PTDC/QUI-QOR/0490/2020, (UIDB/00100/2020), UIDP/00100/2020 and LA/P/0056/2020.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 12 00381 g001 550
Figure 1. Structure of busulfan.
Figure 1. Structure of busulfan.
Catalysts 12 00381 g001
Catalysts 12 00381 g002 550
Figure 2. (a) Non-infected commercial surgical suture; (b) Delta Q eQo coffee capsules.
Figure 2. (a) Non-infected commercial surgical suture; (b) Delta Q eQo coffee capsules.
Catalysts 12 00381 g002
Catalysts 12 00381 g003 550
Figure 3. Use of MoO2Cl2(H2O)2 in consecutive reductive depolymerizations of P4HB. The reactions were carried out using MoO2Cl2(H2O)2 (5 mol%) by successive additions of P4HB (0.5 mmol) and TMDS (1.5 mmol) to the reaction mixture, without separating the catalyst at the end of each reaction. Yields were determined by 1H NMR spectroscopy, using mesitylene as an internal standard.
Figure 3. Use of MoO2Cl2(H2O)2 in consecutive reductive depolymerizations of P4HB. The reactions were carried out using MoO2Cl2(H2O)2 (5 mol%) by successive additions of P4HB (0.5 mmol) and TMDS (1.5 mmol) to the reaction mixture, without separating the catalyst at the end of each reaction. Yields were determined by 1H NMR spectroscopy, using mesitylene as an internal standard.
Catalysts 12 00381 g003
Catalysts 12 00381 sch001 550
Scheme 1. Reductive depolymerization of P4HB and PBS waste with the system MoO2Cl2(H2O)2/HBpin.
Scheme 1. Reductive depolymerization of P4HB and PBS waste with the system MoO2Cl2(H2O)2/HBpin.
Catalysts 12 00381 sch001
Catalysts 12 00381 sch002 550
Scheme 2. Synthesis of busulfan from a P4HB surgical suture.
Scheme 2. Synthesis of busulfan from a P4HB surgical suture.
Catalysts 12 00381 sch002
Catalysts 12 00381 sch003 550
Scheme 3. Synthesis of busulfan from PBS waste, obtained from a Delta Q eQo coffee capsule.
Scheme 3. Synthesis of busulfan from PBS waste, obtained from a Delta Q eQo coffee capsule.
Catalysts 12 00381 sch003
Table
Table 1. Reductive depolymerization of P4HB with the catalytic system MoO2Cl2(H2O)2/Silane a.
Table 1. Reductive depolymerization of P4HB with the catalytic system MoO2Cl2(H2O)2/Silane a.
Catalysts 12 00381 i001
EntryCatalyst
(mol%)		SilaneSilane
(Equiv.)		Temp.
(°C)		Time
(h)		Yield
(%) b
12PMHS11102439
22PMHS31102459
35PMHS31102463
42(EtO)2MeSiH31102450
55PhSiH331102455
65TMDS31102472
72TMDS21102452
82TMDS31102459
95TMDS21102452
105TMDS3r. t.48No reaction
115TMDS31102465 c
a The reactions were carried out with 0.5 mmol of P4HB, obtained from a non-infected surgical suture. b Yields were determined by 1H NMR using mesitylene as the internal standard. c The reaction was carried out using 2.0 mmol of P4HB.
Table
Table 2. Reductive depolymerization of PBS with the catalytic system MoO2Cl2(H2O)2/Silane a.
Table 2. Reductive depolymerization of PBS with the catalytic system MoO2Cl2(H2O)2/Silane a.
Catalysts 12 00381 i002
EntrySilaneSilane
(Equiv.)		Temp.
(°C)		Yield
(%) b
1PMHS211048
2PMHS611072
3PhSiH3611067
4TMDS611075
5TMDS411048
6TMDS6r. t.No reaction
7TMDS611069 c
a The reactions were carried out with 0.25 mmol of PBS, obtained from a Delta Q eQo coffee capsule. b Yields were determined by 1H NMR using mesitylene as the internal standard. c The reaction was carried out using 2.0 mmol of PBS.
Table
Table 3. Reductive depolymerization of P4HB and PBS with the system KOH/PhSiH3 a.
Table 3. Reductive depolymerization of P4HB and PBS with the system KOH/PhSiH3 a.
Catalysts 12 00381 i003
EntryPolyesterKOH
(Equiv.)		SilaneSilane
(Equiv.)		Temperature (°C)Time (h)Yield (%) b
1P4HB0.4PhSiH331102495
2P4HB0.4PhSiH3 21102438
3P4HB0.4PhSiH33r. t.24No reaction
4P4HB0.4TMDS31102465
5P4HB0.4PMHS31104847
6PBS0.8PhSiH361104861c
a The reactions were carried out with 0.5 mmol of P4HB, obtained from non-infected surgical suture. b Yields were determined by 1H NMR using mesitylene as the internal standard. c The reaction was carried out with 0.25 mmol of PBS, obtained from a Delta Q eQo coffee capsule.
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Lourenço, D.L.; Fernandes, A.C. Depolymerization of P4HB and PBS Waste and Synthesis of the Anticancer Drug Busulfan from Plastic Waste. Catalysts 2022, 12, 381. https://doi.org/10.3390/catal12040381

AMA Style

Lourenço DL, Fernandes AC. Depolymerization of P4HB and PBS Waste and Synthesis of the Anticancer Drug Busulfan from Plastic Waste. Catalysts. 2022; 12(4):381. https://doi.org/10.3390/catal12040381

Chicago/Turabian Style

Lourenço, Daniel L., and Ana C. Fernandes. 2022. "Depolymerization of P4HB and PBS Waste and Synthesis of the Anticancer Drug Busulfan from Plastic Waste" Catalysts 12, no. 4: 381. https://doi.org/10.3390/catal12040381

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