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Synthesis of tegafur by alkylation of 5-fluorouracil under the Lewis acid- and metal salt-free conditions Aleksandra Zasada, Ewa Mironiuk-Puchalska, and Mariola Koszytkowska-Stawi#ska Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 10 May 2017 Downloaded from http://pubs.acs.org on May 11, 2017

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Organic Process Research & Development

Synthesis of tegafur by alkylation of 5-fluorouracil under the Lewis acid- and metal salt-free conditions Aleksandra Zasada, Ewa Mironiuk-Puchalska, Mariola Koszytkowska-Stawińska* Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warszawa, Poland

ACS Paragon Plus Environment

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For Table of Contents Only


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ABSTRACT. A novel protocol for preparation of tegafur (a prodrug of 5-fluorouracil) is reported. The process involves the DBU-mediated alkylation of 5-fluorouracil with 2acetoxytetrahydrofuran at 90 °C, followed by treatment of the pre-purified mixture of the alkylation products with aqueous ethanol at 70 °C. Yield of the two-step process is 72% yield.

Keywords: tegafur, 5-fluorouracil, green chemistry, prodrug


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INTRODUCTION Tegafur1 (Figure 1), a prodrug of 5-fluorouracil (5-FUra), was discovered in 1967.2 The compound features high lipophilicity3 and water solubility4 compared to 5-FUra. Tegafur is used as a racemate since no significant difference in antitumor activity of enantiomers was observed.5 The prodrug is gradually converted to 5-FUra by metabolism in the liver. Hence, rapid breakdown of the released 5-FUra the in the gastrointestinal tract is avoided.6 In injectable form, tegafur provoked serious side effects, such as nausea, vomiting or central nervous system disturbances.7 The first generation of oral formulation of tegafur (Figure 1, UFT®) is a combination of tegafur and uracil in a fixed molar ratio of 1:4, respectively. The uracil slows the metabolism of 5-FUra and reduces production of 2-fluoro-α-alanine as the toxic metabolite. UFT was approved in 50 countries worldwide excluding USA.8 S-1 is the next generation of oral formulation of tegafur (Figure 1).7 It is a combination of tegafur, gimeracil and oteracil in a fixed molar ratio of 1:0.4:1, respectively.9 Gimeracil inhibits enzyme responsible for the degradation of 5-FUra. Oteracil prevents activation of 5-FUra in the gastrointestinal tract, thus minimizing the gastrointestinal toxicity of 5-FUra. S-1 is well tolerated but its safety can be influenced by schedule and dose, similar to any other cytotoxic agent.10 Since common side effects of S-1 can be managed with antidiarrheal and antiemetic medications, the drug can be administered in outpatient settings. S-1 was approved in Japan, China, Taiwan, Korea and Singapore for the treatment of patients with gastric cancer.10 In 2010, the Committee for Medicinal Products for Human Use (CHMP), a division of the European Medicines Agency (EMA), recommended the use of S-1 for the treatment of adults with advanced gastric cancer when given in a combination with cisplatin.11 Currently, S-1 has not been approved by the FDA in the United States.9 There is a great interest in further examination of S-1 as anticancer chemotherapeutic. Currently, twenty


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three clinical trials with S-1 has been registered in National Institutes of Health (NIH).12 Combinations of S-1 and other anticancer agents has been employed in a majority of these trials.

Figure 1. Components of tegafur oral formulations.

O F

HN

O N

O

HN

O

O

tegafur

O

OH Cl

N H

HO

uracil

Combination drug UFT S-1

HN O

N gimeracil

N N H

CO2 K

oteracil

Components tegafur, uracil tegafur, gimeracil, oteracil

Several methods for preparation of tegafur were developed.13 The industrial methods, depicted in Scheme 1, involve alkylation of 5-FUra14,15,16 or its persilylated derivative 117,18,19,20 with furan derivatives, such as 2,3-dihydrofuran 2, 2-acetoxytetrahydrofuran 3a (R = Ac), 2chlorotetrahydrofuran 3b (R = Cl), or 2-methoxytetrahydrofuran 3c (R = OMe). Unfortunately, these methods suffer from some disadvantages: (i) high reaction temperature (usually above 120 °C),

(ii)

limited

availability

of

substrates

(2-chlorotetrahydrofuran21

3b

or

2-

methoxytetrahydrofuran22 3c), or (iii) use of additives, such as a Lewis acid or an inorganic salt, in order to obtain the alkylation product(s) in acceptable yields and/or to decrease the reaction temperature.13,23 Protocols involving a Lewis acid additive have to be performed under anhydrous conditions. On the other hand, addition of an inorganic salt can lead to difficult-torecycle wastes. And more importantly, application of 2,3-dihydrofuran 2 as a substrate (boiling point of 52-55 °C) requires a pressure apparatus.24


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Scheme 1. Industrial preparations of tegafur.13-20

Herein we report the preparation of tegafur via alkylation of 5-FUra with 2acetoxytetrahydrofuran 3a under basic conditions (Table 1 and 2) with no addition of a Lewis acid or a metal salt. RESULTS AND DISCUSSION Our experience with alkylation of pyrimidines with 2,3-dihydrofuran 2 by the literature methods25 (i.e. in pyridine at temperature exceeding 178 °C) were not encouraging.26 For that reason, our attention was turned to methods employing 2-acetoxytetrahydrofuran (3a). According to the literature data, compound 3a can be considered as the easiest to obtain 2substituted derivative of tetrahydrofuran among derivatives applied in the preparations of tegafur.27 A survey of synthetic protocols involving compound 3a revealed methods employing NaH28 or K2CO329 as the only additive. We excluded the method employing NaH28 because its application required anhydrous reaction conditions and a very high reaction temperature (150 °C). On the other hands, the reaction employing K2CO329 did not work in our hands. Although


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the reaction was reported to be high-yielding, the 93% recovery of 5-FUra was obtained from our experiment (Table 1, entry 1). An attempt to increase the yield of the alkylation products by an addition of Bu4NBr as a phase-transfer catalyst was not successful (Table 1, entry 2).30 For that reason, our attention was turned to amine bases. Selecting potentially useful bases among common non-nucleophilic amines, we excluded both triethylamine and pyridine. Although efficient in the alkylation of 5-FUra with 2-chlorotetrahydrofuran 3b,31,32 triethylamine required a Lewis acid additive (Me2SiCl2) to give the product of reaction between 5-FUra and 2acetoxytetrahydrofuran 3a in an acceptable yield.33 Our preliminary experiments showed that triethylamine did not promote the reaction between 5-FUra and compound 3a in the absence of a Lewis acid. On the other hand, the literature data showed that the use of pyridine in the alkylation of 5-FUra with 2,3-dihydrofuran 2 in the presence of acetic acid was not satisfactory regardless of the molar ratio of the reagents.13 In view of these facts, we chose to examine an effect of TMG (tetramethylguanidine) or DBU (1,8-diazabicycloundec-7-ene) on the studied reaction (Table 1, entries 3-7). The use of TMG or DBU resulted in a significant increase of the yields of the alkylation products (Table 1, entry 3 or 4 vs. entry 2). Under these conditions, both amine-mediated reactions resulted in: (i) a comparable total yield of the alkylation products, (ii) formation of tegafur as the main product, and (iii) formation of a comparable amount of the 3substituted derivative 5. The tegafur : 4 molar ratio obtained from the TMG-mediated reaction was more favorable than the ratio obtained from the DBU-mediated reaction (TMG, entry 4, tegafur : 4 molar ratio = 2 : 1 vs. DBU, entry 3, tegafur : 4 molar ratio = 1.2 : 1). When conducted for 24 hours, the DBU-mediated reaction gave tegafur in 51% yield and the 1,3disubstituted derivative 4 in 29% yield (Table 1, entry 5). Interestingly, the extension of the reaction time from 5 hours to 24 hours did not affect the yield of the 3-substituted derivative 5


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(entry 5 vs. entry 3). When the DBU-mediated reaction was conducted for 48 hours instead of 24 hours, tegafur and the 1,3-disubstituted derivative 4 were produced in the unchanged yields (Table 1, entry 6 vs. entry 5). However, the 3-substituted derivative 5 was obtained in significantly higher yield from the 48-hour reaction (Table 1, entry 6 vs. entry 5). When conducted for 48 hours, the TMG-mediated reaction gave tegafur in a lower yield than that observed in the DBU-mediated reaction after 24-hours (Table 1, entry 7 vs. entry 5). However, derivatives 4 and 5 were produced in the yields comparable to that observed in the DBUmediated reaction after 24-hours. These findings allowed us to further optimize the reaction shown in Table 1- entry 5. Hence, the two-step process was performed (Scheme 2). The first step was the DBU-mediated alkylation of 5-FUra for 24 hours. After the heating period and removal of volatiles under reduced pressure, an extraction of the reaction mixture with AcOEt at 60 °C was performed. The extraction was sufficient to separate the alkylation products from an unreacted 5-FUra and the amine salt. The second step was carried out in accordance with the literature protocol.34 In order to transform the 1,3-disubstituted derivative 4 into tegafur without separation of the alkylation products, the pre-purified mixture of the alkylation products was treated with aqueous ethanol at 70 °C for 1.5 hour. The workup of the reaction mixture was limited to removal of the volatiles under reduced pressure. Tegafur was isolated from the residue by crystallization from EtOH (first crop), followed by chromatographic purification of the postcrystallization residue (second crop). The combined yield of the two-step process was 72%. Identity of tegafur obtained from this process was confirmed by the NMR spectra, thermal analysis and elemental analysis. Although ethanol is one the most often used solvents for crystallization of tegafur, there are significant differences between the reported melting points.2,14-17,35 For that reason, both crops of tegafur obtained from our process were collected


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and crystallized from methanol, according to Yamamoto et al.36 DSC analysis of the obtained solid revealed one endothermic peak corresponding to its melting at 164 °C (see Supporting Information). The estimated melting point is in a good agreement with the value reported by Yamamoto et al. (δ crystalline form, 165 °C).36 TGA/MS analysis showed 3.1% weight loss of the sample between 60-150 °C (see Supporting Information). The observed weight loss was attributed to the loss of water, as evidenced by the fact that the m/z 18 ion was detected in TG effluent at this temperature. The TGA results were confirmed by elemental analysis.

Table

1.

Optimization

of

the

amine-mediated

reaction

between

5-FUra

and

2-

acetoxytetrahydrofuran 3a.a

Entry

Additive

1 2 3 4 5 6 7

K2CO3 K2CO3, Bu4NBr DBU TMG DBU DBU TMG

a

Molar ratio of 3a: 5-FUra : Additive 2:1:1 2 : 1 : 1 : 0.2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2

Reaction time/h 5 5 5 5 24 48 48

Yield/%b tegafur 4 trace trace 3 12 23 18 30 14 51 29 50 29 41 31

5 trace 2 13 13 11 17 12

Reactions conducted in a scale of 300 mg of 5-FUra. bThe isolated yield.


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Scheme 2. New process for the synthesis of tegafur.

CONCLUSIONS The presented process features the following advantages over the published processes: (i) high atom economy when compared with silyl methods (Table 2, entry 1 vs. entries 2-4);37 (ii) high yield of tegafur with no addition of a Lewis acid or a metal salt; (iii) the reaction temperature below 100 °C; (iv) easy separation of by-products, (v) small number of manual operations. A relatively low Reaction Mass Efficiency of our method (Table 2, entry 1) is a consequence of the molecular weight of DBU. The fact that the current method employs 2-acetoxy-tetrahydrofuran 3a, that is a derivative of 2,3-dihydrofuran 2, cannot be regarded as a weakness of the method. Following literature,25 in-house preparation of 2-acetoxy-tetrahydrofuran 3a was very straightforward. It was limited to mixing of 2,3-dihydrofuran 2 with the stoichiometric amount of glacial acetic acid, followed by keeping of the mixture overnight at room temperature. 2Acetoxy-tetrahydrofuran 3a thus obtained did not require purification prior the use in the alkylation reaction. Implementation of our method in industry would incur extra costs over the cost of 2,3-dihydrofuran 2, such as a price of glacial acetic acid and a one-time cost of a plant for the production of 2-acetoxy-tetrahydrofuran 3a. These costs might not to be significant when compared with the total cost incurred by the silyl method employing 2,3-dihydrofuran 2 under


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the anhydrous conditions. Tegafur was obtained in the final yield of 72% in our method. The yield was slightly lower than the yields of the silyl methods (Table 2). On the other hand, our method generates savings resulting from a significant limitation of auxiliary substances, in comparison with the silyl methods. The fact that our method does not require strictly anhydrous reaction conditions and features small number of manual operations can be considered as its most important advantages over the protocols based on alkylation of the silylated 5-FUra. Taking abovementioned key features of the presented method into account, it can be concluded that this method meets principles of the Green Chemistry concept. Table 2. The reaction metrics of the presented method and the published silyl methods Entry

Metrics

Yield of Atom Reaction Mass tegafur/% Economya/% Efficiencya/% 72 28.6 20.4

1

Current method

2

Silyl method employing 2-acetoxytetrahydrofuran 3a19

82b

20.5

18.6

3

Silyl method employing 2-chlorotetrahydrofuran 3b17

80c

27.4

32.5

4

Silyl method employing 2,3-dihydrofuran 220

78d

21.8

24.9

a

Calculated according to Green Chemistry in the Pharmaceutical Industry. Edited by Peter J. Dunn, Andrew S. Wells and Michael T. Williams; © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, pp. 50-51. bSnCl4 as a catalyst. cReaction temperature of −78 ÷ −65 °C. dSnCl4 as a catalyst. Reaction temperature of 40 °C.

EXPERIMENTAL SECTION Materials and methods Pre-coated Merck silica gel 60 F-254 plates were used for thin-layer chromatography (TLC, 0.2 mm); spots were detected under UV light (254 nm). Column chromatography was performed using silica gel (200–400 mesh, Merck). High Resolution Mass Spectra (Electrospray Ionisation, ESI) were performed on a Mariner spectrometer. The NMR spectra were measured on a Varian


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VNMRS spectrometer (1H NMR at 500 MHz, 13C NMR at 125 MHz). 1H and 13C chemical shifts (δ) are reported in parts per million (ppm) relative to the solvent signals: CDCl3, δH (residual CHCl3) 7.26 ppm, δC 77.00 ppm; signals are quoted as “d” (doublet),”t” (triplet), “q” (quartet), “m” (multiplet), “br s” (broad singlet), and “dd” (doublet of doublets). Coupling constants J are reported in Hertz. Volatiles were distilled off under reduced pressure on a rotating evaporator. DSC measurements were performed on a DSC Q200 V24.2 Build 107 instrument: heating rate, 5.0 K/min; open Al pan; flow rate of nitrogen, 25.0 mL/min; flow rate of helium, 25.0 mL/min. TGA-MS analysis was performed on a NETZSCH STA 449 C instrument: Al2O3 pan; mass of sample, 5.8 mg; heating rate, 5.0 K/min, flow rate of argon, 50 mL/min. N,N-Dimethylformamide was purchased from Avantor Performance Materials Poland S.A. (formerly POCH S.A.) ul. Sowińskiego 11, 44-101 Gliwice. Specification; Catalogue Number 355120429, Grade/Description: pure. Assay min. 99 %, Density (20 °C) 0.946÷0.95 g/ml, Water max.

0.1

%,

Non-volatile

residue

max.

0.02

%.

Specification

available

at

http://www.english.poch.com.pl/1/katalog-produktow,1,2,N (last accessed on April 20 2017). The commercial solvent was distilled under reduced pressure (55-59 °C, 20 Torr). Alkylation of 5-FUra for the process optimization purposes. Reactions were preformed in glass screw-cap tubes. According to a molar ratio of the reagents shown in Table 1, the additive (K2CO3, K2CO3/Bu4NBr, TMG or BDU) was added to a suspension of 5-FUra (300 mg, 2.3 mmol) in dry DMF (4 mL). After stirring for 30 min at room temperature, compound 3a (600 mg, 4.6 mmol) was added in one portion. The mixture was stirred at 90 °C for the time given in Table 1 and cooled to room temperature. The volatiles were distilled off under reduced pressure (8 mbar, 50 °C). AcOEt (15 mL) was added to the oily residue. The mixture was stirred at 60 °C for 15 min and then cooled to room temperature without stirring. The AcOEt phase was


12

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decanted and the residue was treated with new portions of AcOEt (15 mL) under the same conditions. Progress of the extraction process was monitored by TLC (CHCl3/MeOH, 95/5, v/v). The extracts were collected and volatiles were distilled off under reduced pressure. Column chromatography of the residue (CHCl3/MeOH, 99/1, v/v) afforded the alkylation products in the yields given in Table 1. 5-Fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (tegafur). δH 1.89-2.10 (m, 3H), 2.38-2.45 (m, 1H), 3.97-4.01 (q-like m, 1H), 4.20-4.24 (dq-like m), 5.97-5.98 (m, 1H), 7.41 (d, 3JHF 6.1), 9.21 (bs, 1H, NH). δC 23.82, 32.90, 70.26, 87.58, 123.63 (d, 2JCF 33.89), 140.33 (d, 1

JCF 237.20) 148.66, 156.9 (d, 2JCF 26.81). HRMS m/z calcd for C8H10N2O3F [M-H]+ 201.0670,

found 201.0669. Elemental Analysis. Found C%, 46.42; H%, 4.45; N%, 13.35. Calcd for 3(C8H9N2O3F)*H2O: C%, 46.61; H%, 4.73; N%, 13.59. 5-Fluoro-1,3-bis(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (4), δH (a mixture of two rotamers) 1.81-2.48 (m, 8H), 3.90-3.98 (m, 2H), 4.18-4.29 (m, 2H), 5.93-5.95 (m, 1H), 6.576.61 (q-like m, 1H), 7.33 (d, 3JHF 5.8), 7.33 (d, 3JHF 5.7). δC (a mixture of two rotamers) 23.61, 23.67, 26.41, 26.44, 28.63, 28.68, 32.83, 32.95, 70.16, 70.22, 70.65, 70.67, 84.87, 85.07, 87.79, 87.89, 121.55 (d, 2JCF 34.1), 121.66 (d, 2JCF 34.1), 139.78 (d, 1JCF 233.2), 139.81 (d, 1JCF 234.0), 148.543, 148.694, 157.08 (d,

2

JCF 25.3), 157.20 (d,

2

JCF 25.4). HRMS m/z calcd for

C12H16N2O4F [M-H]+ 271.1089, found 271.1086. 5-Fluoro-3-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (5), δH 1.95-2.04 (m, 1H), 2.21-2.37 (m, 2H), 2.45-2.52 (m, 1H), 3.92-3.96 (dt-like m, 1H), 4.25-4.29 (q-like m, 1H), 6.536.56 (dd-like m, 1H), 7.20 (d, 3JHF 4.2), 9.92 (bs, 1H, NH). δC 157.561 (d, 2JCF 25.37), 151.29, 140.475 (d, 1JCF 234.65), 122.753 (d, 2JCF 32.10), 85.05, 77.25, 70.74, 28.73, 26.39. HRMS m/z calcd for C8H10N2O3F [M-H]+ 201.0670, found 201.0673.


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Preparation of tegafur in the two-step process. According to the protocol given above, 5-FUra (2.1 g, 16 mmol) was treated with DBU (5 g, 32 mmol) and 3a (4.2 g, 32 mmol) in DMF (25 ml). The resulting mixture was stirred at 90 °C for 24 hours. After distillation off of volatiles under reduced pressure (8 mbar, 50 °C), the alkylation products were extracted with AcOEt (6 x 50 ml) under conditions given above. Extracts were collected and volatiles were distilled off under reduced pressure. The residue was dissolved in a water-95% ethanol mixture (120 ml, 1:1, v/v). The mixture was heated in oil bath (70 °C) for 1.5 hour. Volatiles were distilled off under reduced pressure. The residue was dissolved in hot ethanol (98%, 15 ml) and refrigerated for 1 day. The white solid (1.3 g of tegafur) was filtered off, washed with cold ethanol (2 x 1 ml) and dried in air. Volatiles were distilled off from the filtrate under reduced pressure. The residue was subjected to column chromatography (CHCl3/MeOH, 99/1, v/v) to obtain additional 1.0 g of tegafur (72% yield calculated on 5-FUra). The 1H and

13

C NMR spectra of both crystallization

crops were consistent with those described above. The crops were homogenized by crystallization from methanol, according to Yamamoto et al.36 ASSOCIATED CONTENT Supporting Information contains 1H and 13C NMR spectra of the discussed compounds and DSC and TG-MS thermograms of tegafur. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Author Contributions


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All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT This work was financially supported by Warsaw University of Technology. The authors thank Aldona Zalewska, PhD, Warsaw University of Technology, for recording and interpretation the of the DSC thermogram, Wioletta Raróg-Pilecka, PhD, and Magdalena Zybert, PhD, Warsaw University of Technology, for recording and interpretation of the TGA-MS thermogram. ABBREVIATIONS AcOEt, ethyl acetate; 2-AcO-THF, 2-acetoxytetrahydrofuran; Bu4NBr, tetrabutylammonium bromide; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DMF, dimethylformamide; DSC, differential scanning microcalorimetry; EtOH, ethanol; 5-FUra, 5-fluorouracil; INN, International Nonproprietary Name; MS, mass spectroscopy; TG, thermogravimetry; TMG, tetramethylguanidine; TLC, thin layer chromatography. REFERENCES

(1) Formerly ftorafur. (2) Giller, S. A.; Zhuk, R. A.; M. Yu. Lidak Dokl. Akad Nauk SSSR 1967, 176, 332-335. (3)

According

to

U.S.

Environmental

Protection

Agency

(EPA),

https://comptox.epa.gov/dashboard. Last accessed, April 24 2017. (4) According to Material Safety Data Sheet (MSDS) of tegafur or 5-FUra published at the Selleckchem.com website, www.selleckchem.com. Last accessed, April 24 2017.


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(5) Yaumoto, M.; Ueda, S.; Yamashita, J.; Hashimoto S. J. Carbohydr. Nucleos. Nucleot. 1979, 6, 309-331. (6) Takiuchi H.; Ajani J. A. J. Clin. Oncol. 1998, 16, 2877-2885. (7) Shirasaka, T. Jpn. J. Clin. Oncol. 2009, 39, 2-15. (8) Hammond, W. A.; Swaika, A.; Mody, K. Ther. Adv. Med. Oncol. 2016, 8, 57-84. (9) Wald, O.; Smaglo, B. Mok, H.; Groth, S. S. Ann. Cardiothorac. Surg. 2017, 6, 159-166. (10) Blum, M.; Suzuki, A.; Ajani, J. A. Future Oncol. 2011, 7, 715-726. (11)

Lawler,

M.;

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e1-e4;

doi:

10.1634/theoncologist.2011-0333. (12) See, https://clinicaltrials.gov, “Basic search. Search for studies: tegafur”. Last accessed April 26 2017. Trials with a status of “Active, not recruiting”, “Recruiting” or “Not yet recruiting” were considered. (13) Lukevits, É.; Zablotskaya A. Chem. Heterocycl. Comp. 1991, 27, 1271-1299. (14) Nakamura, T.; Hoshide, Y.; Hashimoto, Y.; Suzuki, K.; Yoshida Y. U.S. Patent Number US 4121037 (1978). Chem. Abs. 88, 152656 (1978). (15) Minami, I.; Yoshioka, Y.; Nomura H. U.S. Patent Number US 4249006 (1981). Chem. Abs. 87, 135384 (1977). (16) Kojima, A.; Kohno, Y.; Ike, Y.; Yokoyama, T.; Odate M. U.S. Patent Number US 4256885 (1981). Chem. Abs. 88, 136653 (1978).


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(17) Townsend, L. B.; Earl, R. A.; Manning S. J. U.S. Patent Number US 3960864 (1976). Chem. Abs. 84, 59575 (1976). (18) Suzuki, N.; Kobayashi, Y.; Hiyoshi, Y.; Takagi, S.; Sone, T.; Wakabayashi, M.; Sowa T. German Patent Number DE 2650918 (1978). Chem. Abs. 87, 135382 (1977). (19) Hiller, S.; Zhuk, R. A.; Berzin, A.; Sherin, L.; Lazdinsh, A. U.S. Patent Number US 3912734 (1975). Chem. Abs. 84, 59538 (1976). (20) Suzuki, N.; Kobayashi, Y.; Hiyoshi, Y.; Takagi, S.; Sone, T.; Wakabayashi, M.; Sowa, T. U.S. Patent Number US 4107162 (1978). Chem. Abs. 84, 59538 (1976). (21) Block, E.; Ahmad, S.; Catalfamo, J. L.; Jain, M. K.; Apitz-Castro R. J. Am. Chem. Soc. 1986, 108, 7045–7055. (22) Frehel, D.; Deslongchamps P. Can. J. Chem. 1972, 50, 1783-1784. (23) Buslov, I.; Xile H. Adv. Synth. Catal. 2014, 356, 3325-3330. (24) Zhiquan Z. Chinese Patent Number CN 103159746 (2015). Chem. Abs. 159, 150343 (2015). (25) Nomura, H.; Yoshika, Y.; Minami I. Chem. Pharm. Bull. 1979, 27, 899-906. (26) In our hands, very long reaction time was required to obtain the alkylation product in an acceptable yield. For instance, the alkylation of uracil gave 1-(tetrahydrofuran-2-yl)pyrimidine2,4(1H,3H)-dione in 73% after heating for 90 hours in a steel autoclave (in contrast to the reported 18 hours heating).


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(27) We quickly established that crude 3a obtained from treatment of 2,3-dihydrofuran with equimolar amount of acetic acid at room temperature was sufficiently pure to be used. For the 1H and

13

C NMR spectra of crude 3a see Supplementary information. The spectra were in a very

good agreement with the spectra reported for the purified 2-acetoxytetrahydrofuran, S. Lee, P. S. J. Kaib, B. List J. Am. Chem. Soc, 2017, 139, 2156–2159. (28) Suzuki, N.; Tagaki, S.; Iizuka, K.; Kobayashi, M.; Kobayashi,

Y.; Sone,

T.;

Wakabayashi, M.; Sowa, T. Japanese Patent Number JP 52083476 (1977). Chem. Abs. 87, 202040 (1977). (29) Yasumoto, M.; Yamashita, J.; Yamawaki, I.; Ueda, S.; Hashimoto, S.; Suzue T. Japanese Patent Number JP 53084981 (1978). Chem. Abs. 90, 54965 (1979). (30) The progress of the discussed reactions was determined from the isolated yields of the reaction products. The use of NMR spectroscopy to determine the molar ratio of the reaction products in a pre-purified reaction mixture was not successful owing to poor separation of diagnostic signals in the range of 5.8-7.5 ppm (see, Supplementary information). The NMR spectra of compound 2 revealed the existence of two rotamers in CDCl3 (see, Supplementary information). The occurrence of the rotamers was confirmed by the 1H and 13C NMR spectra at 50 °C where partial coalescence of the signals was observed (see, Supplementary information). (31) T. Narimoto and Y. Ichikawa, Japanese Patent Number 52131586 (1977). Chem. Abs. 88, 121230 (1978). (32) Narimoto, T.; Ichikawa, Y. Japanese Patent Number 52131587 (1977). Chem. Abs. 88, 105399 (1978).


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(33) Ishibashi, K.; Ishiguro, S.; Komaki, R. Japanese Patent Number 54046789 (1979); Chem. Abs. 91, 140863 (1979). (34) Yasumoto, M.; Yamawaki, I.; Marunaka, T.; Hashimoto, S. J. Med. Chem. 1978, 21, 738– 741. (35) Sakurai, K.; Aoyagi, S.; Toyofuku, H.; Ohki, M.; Yoshizawa, T.; Kuroda, T. Chem. Pharm. Bull. 1978, 26, 3565-3566. (36) Uchida, T.; Yonemochi, E.; Oguchi, T.; Terada, K.; Yamamoto, K.; Nakai, Y. Chem. Pharm. Bull. 1993, 41, 1632-1635. (37) The metrics were calculated according to Green Chemistry in the Pharmaceutical Industry. Edited by Peter J. Dunn, Andrew S. Wells and Michael T. Williams; © 2010 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim, pp. 50-51.


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Synthesis of Tegafur by the Alkylation of 5 ... - ACS Publications

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