Synthesis of Tegafur by the Alkylation of 5-Fluorouracil under the Lewis Acid and Metal Salt-Free Conditions

Article abstract of DOI:10.1021/acs.oprd.7b00103

A novel protocol for preparation of tegafur (a prodrug of 5-fluorouracil) is reported. The process involves the 1,8-diazabicycloundec-7-ene-mediated alkylation of 5-fluorouracil with 2-acetoxytetrahydrofuran at 90 °C, followed by treatment of the prepurified mixture of the alkylation products with aqueous ethanol at 70 °C. The yield of the two-step process is 72%.

Full text of DOI:10.1021/acs.oprd.7b00103

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Communication
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
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Synthesis of tegafur by alkylation of 5ꢀfluorouracil
under the Lewis acidꢀ and metal saltꢀfree conditions
Aleksandra Zasada, Ewa MironiukꢀPuchalska, Mariola KoszytkowskaꢀStawińska*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00ꢀ664
Warszawa, Poland
1
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
For Table of Contents Only
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
ACS Paragon Plus Environment

Page 3 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ABSTRACT. A novel protocol for preparation of tegafur (a prodrug of 5ꢀfluorouracil) is
reported. The process involves the DBUꢀmediated alkylation of 5ꢀfluorouracil with 2ꢀ
acetoxytetrahydrofuran at 90 °C, followed by treatment of the preꢀpurified mixture of the
alkylation products with aqueous ethanol at 70 °C. Yield of the twoꢀstep process is 72% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Keywords: tegafur, 5ꢀfluorouracil, green chemistry, prodrug
3
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
INTRODUCTION
1
2
Tegafur (Figure 1), a prodrug of 5ꢀfluorouracil (5-FUra), was discovered in 1967. The
3
4
compound features high lipophilicity and water solubility compared to 5-FUra. Tegafur is used
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
as a racemate since no significant difference in antitumor activity of enantiomers was observed.
The prodrug is gradually converted to 5-FUra by metabolism in the liver. Hence, rapid
6
breakdown of the released 5-FUra the in the gastrointestinal tract is avoided. In injectable form,
tegafur provoked serious side effects, such as nausea, vomiting or central nervous system
7
disturbances. 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 2ꢀfluoroꢀαꢀalanine as the toxic metabolite.
8
UFT was approved in 50 countries worldwide excluding USA. Sꢀ1 is the next generation of oral
7
formulation of tegafur (Figure 1). It is a combination of tegafur, gimeracil and oteracil in a fixed
9
molar ratio of 1:0.4:1, respectively. 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. Sꢀ1 is well tolerated but its safety can be influenced by
1
0
schedule and dose, similar to any other cytotoxic agent. Since common side effects of Sꢀ1 can
be managed with antidiarrheal and antiemetic medications, the drug can be administered in
outpatient settings. Sꢀ1 was approved in Japan, China, Taiwan, Korea and Singapore for the
1
0
treatment of patients with gastric cancer. In 2010, the Committee for Medicinal Products for
Human Use (CHMP), a division of the European Medicines Agency (EMA), recommended the
use of Sꢀ1 for the treatment of adults with advanced gastric cancer when given in a combination
1
1
9
with cisplatin. Currently, Sꢀ1 has not been approved by the FDA in the United States. There is
a great interest in further examination of Sꢀ1 as anticancer chemotherapeutic. Currently, twenty
4
ACS Paragon Plus Environment

Page 5 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
12
three clinical trials with Sꢀ1 has been registered in National Institutes of Health (NIH).
Combinations of Sꢀ1 and other anticancer agents has been employed in a majority of these trials.
Figure 1. Components of tegafur oral formulations.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
F
HN
O
O
OH
O
N
HN
Cl
HN
N
O
O
N
H
O
N
H
CO K
2
HO
N
tegafur
uracil
gimeracil
oteracil
Combination drug Components
UFT
S-1
tegafur, uracil
tegafur, gimeracil, oteracil
1
3
Several methods for preparation of tegafur were developed. The industrial methods, depicted
14,15,16
17,18,19,20
in Scheme 1, involve alkylation of 5-FUra
or its persilylated derivative 1
with
furan derivatives, such as 2,3ꢀdihydrofuran 2, 2ꢀacetoxytetrahydrofuran 3a (R = Ac), 2ꢀ
chlorotetrahydrofuran 3b (R = Cl), or 2ꢀmethoxytetrahydrofuran 3c (R = OMe). Unfortunately,
these methods suffer from some disadvantages: (i) high reaction temperature (usually above 120
2
1
°
C), (ii) limited availability of substrates (2ꢀchlorotetrahydrofuran
3b or 2ꢀ
2
2
methoxytetrahydrofuran 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
1
3,23
temperature.
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 difficultꢀtoꢀ
recycle wastes. And more importantly, application of 2,3ꢀdihydrofuran 2 as a substrate (boiling
2
4
point of 52ꢀ55 °C) requires a pressure apparatus.
5
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13ꢀ20
Scheme 1. Industrial preparations of tegafur.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Herein we report the preparation of tegafur via alkylation of 5-FUra with 2ꢀ
acetoxytetrahydrofuran 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 2,3ꢀdihydrofuran 2 by the literature
2
5
26
methods (i.e. in pyridine at temperature exceeding 178 °C) were not encouraging. For that
reason, our attention was turned to methods employing 2ꢀacetoxytetrahydrofuran (3a).
According to the literature data, compound 3a can be considered as the easiest to obtain 2ꢀ
substituted derivative of tetrahydrofuran among derivatives applied in the preparations of
2
7
tegafur. A survey of synthetic protocols involving compound 3a revealed methods employing
2
8
29
3
28
NaH or K CO as the only additive. We excluded the method employing NaH because its
2
application required anhydrous reaction conditions and a very high reaction temperature (150
29
°
C). On the other hands, the reaction employing K CO3 did not work in our hands. Although
2
6
ACS Paragon Plus Environment

Page 7 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
the reaction was reported to be highꢀyielding, 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
3
0
an addition of Bu NBr as a phaseꢀtransfer catalyst was not successful (Table 1, entry 2). For
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
that reason, our attention was turned to amine bases. Selecting potentially useful bases among
common nonꢀnucleophilic amines, we excluded both triethylamine and pyridine. Although
3
1,32
efficient in the alkylation of 5-FUra with 2ꢀchlorotetrahydrofuran 3b,
triethylamine required
a Lewis acid additive (Me SiCl ) to give the product of reaction between 5-FUra and 2ꢀ
2
2
3
3
acetoxytetrahydrofuran 3a in an acceptable yield. 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 2,3ꢀdihydrofuran 2 in the presence of acetic acid was not satisfactory
13
regardless of the molar ratio of the reagents. In view of these facts, we chose to examine an
effect of TMG (tetramethylguanidine) or DBU (1,8ꢀdiazabicycloundecꢀ7ꢀene) on the studied
reaction (Table 1, entries 3ꢀ7). 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
amineꢀmediated 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 3ꢀ
substituted derivative 5. The tegafur : 4 molar ratio obtained from the TMGꢀmediated reaction
was more favorable than the ratio obtained from the DBUꢀmediated 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 DBUꢀmediated reaction gave tegafur in 51% yield and the 1,3ꢀ
disubstituted 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 3ꢀsubstituted derivative 5
7
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
entry 5 vs. entry 3). When the DBUꢀmediated reaction was conducted for 48 hours instead of 24
hours, tegafur and the 1,3ꢀdisubstituted derivative 4 were produced in the unchanged yields
Table 1, entry 6 vs. entry 5). However, the 3ꢀsubstituted derivative 5 was obtained in
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
significantly higher yield from the 48ꢀhour reaction (Table 1, entry 6 vs. entry 5). When
conducted for 48 hours, the TMGꢀmediated reaction gave tegafur in a lower yield than that
observed in the DBUꢀmediated reaction after 24ꢀhours (Table 1, entry 7 vs. entry 5). However,
derivatives 4 and 5 were produced in the yields comparable to that observed in the DBUꢀ
mediated reaction after 24ꢀhours. These findings allowed us to further optimize the reaction
shown in Table 1ꢀ entry 5. Hence, the twoꢀstep process was performed (Scheme 2). The first step
was the DBUꢀmediated 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
3
4
literature protocol. In order to transform the 1,3ꢀdisubstituted derivative 4 into tegafur without
separation of the alkylation products, the preꢀpurified 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 postꢀ
crystallization residue (second crop). The combined yield of the twoꢀstep 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
2,14ꢀ17,35
points.
For that reason, both crops of tegafur obtained from our process were collected
8
ACS Paragon Plus Environment

Page 9 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
36
and crystallized from methanol, according to Yamamoto et al. 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
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
6
Yamamoto et al. (δ crystalline form, 165 °C). TGA/MS analysis showed 3.1% weight loss of
the sample between 60ꢀ150 °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 amineꢀmediated reaction between 5-FUra and 2ꢀ
a
acetoxytetrahydrofuran 3a.
b
Molar ratio of
3a: 5-FUra : Additive
2 : 1 : 1
Reaction
time/h
Yield/%
4
Entry
Additive
tegafur
trace
3
5
trace
2
13
13
11
17
12
1
2
3
4
5
6
K CO
3
5
5
5
trace
12
18
14
29
2
3
K CO , Bu NBr
2 : 1 : 1 : 0.2
2 : 1 : 2
2
4
DBU
23
30
51
50
TMG
DBU
DBU
TMG
2 : 1 : 2
2 : 1 : 2
2 : 1 : 2
2 : 1 : 2
5
24
48
48
29
31
7
41
a
b
Reactions conducted in a scale of 300 mg of 5-FUra. The isolated yield.
9
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 2. New process for the synthesis of tegafur.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CONCLUSIONS
The presented process features the following advantages over the published processes: (i) high
3
7
atom economy when compared with silyl methods (Table 2, entry 1 vs. entries 2ꢀ4); (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 byꢀproducts, (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 2ꢀacetoxyꢀtetrahydrofuran
3a, that is a derivative of 2,3ꢀdihydrofuran 2, cannot be regarded as a weakness of the method.
2
5
Following literature,
inꢀhouse preparation of 2ꢀacetoxyꢀtetrahydrofuran 3a was very
straightforward. It was limited to mixing of 2,3ꢀdihydrofuran 2 with the stoichiometric amount of
glacial acetic acid, followed by keeping of the mixture overnight at room temperature. 2ꢀ
Acetoxyꢀtetrahydrofuran 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 2,3ꢀdihydrofuran 2, such as a price of glacial acetic acid and a oneꢀtime cost of a plant for
the production of 2ꢀacetoxyꢀtetrahydrofuran 3a. These costs might not to be significant when
compared with the total cost incurred by the silyl method employing 2,3ꢀdihydrofuran 2 under
10
ACS Paragon Plus Environment

Page 11 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
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.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. The reaction metrics of the presented method and the published silyl methods
Entry
Yield of
Atom a
Reaction Mass
Metrics
Current method
Silyl method employing
-acetoxytetrahydrofuran 3a
Silyl method employing
-chlorotetrahydrofuran 3b
a
tegafur/% Economy /% Efficiency /%
1
2
72
28.6
20.5
20.4
b
19
82
80
78
18.6
2
c
3
4
17
27.4
21.8
32.5
24.9
2
Silyl method employing
d
20
2,3-dihydrofuran 2
a
Calculated according to Green Chemistry in the Pharmaceutical Industry. Edited by Peter J. Dunn, Andrew S. Wells
b
and Michael T. Williams; © 2010 WILEYꢀVCH Verlag GmbH & Co. KGaA, Weinheim, pp. 50ꢀ51. SnCl as a
catalyst. Reaction temperature of −78 ÷ −65 °C. SnCl as a catalyst. Reaction temperature of 40 °C.
4
c
d
4
EXPERIMENTAL SECTION
Materials and methods
Preꢀcoated Merck silica gel 60 Fꢀ254 plates were used for thinꢀlayer 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
11
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13
1
13
VNMRS spectrometer ( H NMR at 500 MHz, C NMR at 125 MHz). H and C chemical shifts
(δ) are reported in parts per million (ppm) relative to the solvent signals: CDCl , δ (residual
3
H
CHCl ) 7.26 ppm, δ 77.00 ppm; signals are quoted as “d” (doublet),”t” (triplet), “q” (quartet),
3
C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
“
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.
TGAꢀMS analysis was performed on a NETZSCH STA 449 C instrument: Al O pan; mass of
2
3
sample, 5.8 mg; heating rate, 5.0 K/min, flow rate of argon, 50 mL/min.
N,NꢀDimethylformamide was purchased from Avantor Performance Materials Poland S.A.
formerly POCH S.A.) ul. Sowińskiego 11, 44ꢀ101 Gliwice. Specification; Catalogue Number
55120429, Grade/Description: pure. Assay min. 99 %, Density (20 °C) 0.946÷0.95 g/ml, Water
(
3
max. 0.1 %, Nonꢀvolatile residue max. 0.02 %. Specification available at
http://www.english.poch.com.pl/1/katalogꢀproduktow,1,2,N (last accessed on April 20 2017).
The commercial solvent was distilled under reduced pressure (55ꢀ59 °C, 20 Torr).
Alkylation of 5-FUra for the process optimization purposes. Reactions were
preformed in glass screwꢀcap tubes. According to a molar ratio of the reagents shown in Table 1,
the additive (K CO , K CO /Bu NBr, TMG or BDU) was added to a suspension of 5-FUra (300
2
3
2
3
4
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
ACS Paragon Plus Environment

Page 13 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
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 (CHCl /MeOH, 95/5, v/v).
3
The extracts were collected and volatiles were distilled off under reduced pressure. Column
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
chromatography of the residue (CHCl /MeOH, 99/1, v/v) afforded the alkylation products in the
3
yields given in Table 1.
5
-Fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (tegafur). δ 1.89ꢀ2.10 (m,
H
3H), 2.38ꢀ2.45 (m, 1H), 3.97ꢀ4.01 (qꢀlike m, 1H), 4.20ꢀ4.24 (dqꢀlike m), 5.97ꢀ5.98 (m, 1H), 7.41
3
2
(
d, J 6.1), 9.21 (bs, 1H, NH). δ 23.82, 32.90, 70.26, 87.58, 123.63 (d, J 33.89), 140.33 (d,
HF
C
CF
1
2
+
J 237.20) 148.66, 156.9 (d, J 26.81). HRMS m/z calcd for C H N O F [MꢀH] 201.0670,
CF
CF
8
10
2
3
found 201.0669. Elemental Analysis. Found C%, 46.42; H%, 4.45; N%, 13.35. Calcd for
3
(C H N O F)*H O: C%, 46.61; H%, 4.73; N%, 13.59.
8 9 2 3 2
5
-Fluoro-1,3-bis(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (4), δ (a mixture of
H
two rotamers) 1.81ꢀ2.48 (m, 8H), 3.90ꢀ3.98 (m, 2H), 4.18ꢀ4.29 (m, 2H), 5.93ꢀ5.95 (m, 1H), 6.57ꢀ
3
3
6
2
8
.61 (qꢀlike m, 1H), 7.33 (d, J 5.8), 7.33 (d, J 5.7). δ (a mixture of two rotamers) 23.61,
HF
HF
C
3.67, 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,
2
2
1
1
7.89, 121.55 (d, J 34.1), 121.66 (d, J 34.1), 139.78 (d, J 233.2), 139.81 (d, J 234.0),
CF
CF
CF
CF
2
2
148.543, 148.694, 157.08 (d, J 25.3), 157.20 (d, J 25.4). HRMS m/z calcd for
CF
CF
+
C H N O F [MꢀH] 271.1089, found 271.1086.
12
16
2
4
5
2
6
-Fluoro-3-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (5), δ 1.95ꢀ2.04 (m, 1H),
H
.21ꢀ2.37 (m, 2H), 2.45ꢀ2.52 (m, 1H), 3.92ꢀ3.96 (dtꢀlike m, 1H), 4.25ꢀ4.29 (qꢀlike m, 1H), 6.53ꢀ
3
2
.56 (ddꢀlike m, 1H), 7.20 (d, J 4.2), 9.92 (bs, 1H, NH). δ 157.561 (d, J 25.37), 151.29,
HF
C
CF
1
2
140.475 (d, J 234.65), 122.753 (d, J 32.10), 85.05, 77.25, 70.74, 28.73, 26.39. HRMS m/z
CF
CF
+
calcd for C H N O F [MꢀH] 201.0670, found 201.0673.
8
10
2
3
13
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Preparation of tegafur in the two-step process. According to the protocol given above,
-FUra (2.1 g, 16 mmol) was treated with DBU (5 g, 32 mmol) and 3a (4.2 g, 32 mmol) in DMF
5
(
25 ml). The resulting mixture was stirred at 90 °C for 24 hours. After distillation off of volatiles
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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 waterꢀ95% 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 (CHCl /MeOH, 99/1, v/v) to obtain additional 1.0 g of
3
1
13
tegafur (72% yield calculated on 5-FUra). The H and C NMR spectra of both crystallization
crops were consistent with those described above. The crops were homogenized by
3
6
crystallization from methanol, according to Yamamoto et al.
ASSOCIATED CONTENT
1
13
Supporting Information contains H and C NMR spectra of the discussed compounds and
DSC and TGꢀMS thermograms of tegafur. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: mkoszyt@ch.pw.edu.pl.
Author Contributions
14
ACS Paragon Plus Environment

Page 15 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
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 RarógꢀPilecka, PhD, and Magdalena Zybert, PhD, Warsaw
University of Technology, for recording and interpretation of the TGAꢀMS thermogram.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ABBREVIATIONS
AcOEt, ethyl acetate; 2ꢀAcOꢀTHF, 2ꢀacetoxytetrahydrofuran; Bu NBr, tetrabutylammonium
4
bromide; DBU, 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene; DMF, dimethylformamide; DSC,
differential scanning microcalorimetry; EtOH, ethanol; 5ꢀFUra, 5ꢀfluorouracil; 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, 332ꢀ335.
(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.
15
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
5) Yaumoto, M.; Ueda, S.; Yamashita, J.; Hashimoto S. J. Carbohydr. Nucleos. Nucleot.
1
979, 6, 309ꢀ331.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(6) Takiuchi H.; Ajani J. A. J. Clin. Oncol. 1998, 16, 2877ꢀ2885.
(
(
(
7) Shirasaka, T. Jpn. J. Clin. Oncol. 2009, 39, 2ꢀ15.
8) Hammond, W. A.; Swaika, A.; Mody, K. Ther. Adv. Med. Oncol. 2016, 8, 57ꢀ84.
9) Wald, O.; Smaglo, B. Mok, H.; Groth, S. S. Ann. Cardiothorac. Surg. 2017, 6, 159ꢀ166.
(10) Blum, M.; Suzuki, A.; Ajani, J. A. Future Oncol. 2011, 7, 715ꢀ726.
(11) Lawler, M.; Johnston, P. G. The Oncologist 2011, 16, e1ꢀe4; doi:
1
0.1634/theoncologist.2011ꢀ0333.
(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, 1271ꢀ1299.
(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
4
256885 (1981). Chem. Abs. 88, 136653 (1978).
16
ACS Paragon Plus Environment

Page 17 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(
17) Townsend, L. B.; Earl, R. A.; Manning S. J. U.S. Patent Number US 3960864 (1976).
Chem. Abs. 84, 59575 (1976).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(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.; ApitzꢀCastro R. J. Am. Chem. Soc.
1
986, 108, 7045–7055.
(
22) Frehel, D.; Deslongchamps P. Can. J. Chem. 1972, 50, 1783ꢀ1784.
23) Buslov, I.; Xile H. Adv. Synth. Catal. 2014, 356, 3325ꢀ3330.
(
(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, 899ꢀ906.
(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 1ꢀ(tetrahydrofuranꢀ2ꢀyl)pyrimidineꢀ
,4(1H,3H)ꢀdione in 73% after heating for 90 hours in a steel autoclave (in contrast to the
reported 18 hours heating).
2
17
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
27) We quickly established that crude 3a obtained from treatment of 2,3ꢀdihydrofuran with
1
equimolar amount of acetic acid at room temperature was sufficiently pure to be used. For the H
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and C NMR spectra of crude 3a see Supplementary information. The spectra were in a very
good agreement with the spectra reported for the purified 2ꢀacetoxytetrahydrofuran, 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 preꢀpurified reaction mixture was not successful owing to poor separation of
diagnostic signals in the range of 5.8ꢀ7.5 ppm (see, Supplementary information). The NMR
spectra of compound 2 revealed the existence of two rotamers in CDCl (see, Supplementary
3
1
13
information). The occurrence of the rotamers was confirmed by the H and C 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,
1
21230 (1978).
(32) Narimoto, T.; Ichikawa, Y. Japanese Patent Number 52131587 (1977). Chem. Abs. 88,
105399 (1978).
18
ACS Paragon Plus Environment

Page 19 of 19
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(
33) Ishibashi, K.; Ishiguro, S.; Komaki, R. Japanese Patent Number 54046789 (1979); Chem.
Abs. 91, 140863 (1979).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(34) Yasumoto, M.; Yamawaki, I.; Marunaka, T.; Hashimoto, S. J. Med. Chem. 1978, 21, 738–
7
41.
(35) Sakurai, K.; Aoyagi, S.; Toyofuku, H.; Ohki, M.; Yoshizawa, T.; Kuroda, T. Chem.
Pharm. Bull. 1978, 26, 3565ꢀ3566.
(36) Uchida, T.; Yonemochi, E.; Oguchi, T.; Terada, K.; Yamamoto, K.; Nakai, Y. Chem.
Pharm. Bull. 1993, 41, 1632ꢀ1635.
(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 WILEYꢀ
VCH Verlag GmbH & Co. KGaA, Weinheim, pp. 50ꢀ51.
19
ACS Paragon Plus Environment