Continuous-Flow Sequential Schotten-Baumann Carbamoylation and Acetate Hydrolysis in the Synthesis of Capecitabine

Article abstract of DOI:10.1021/acs.oprd.9b00206

Capecitabine is an important anticancer drug whose synthesis comprises late-stage carbamoylation and ester hydrolysis. Herein we report the use of the Schotten-Baumann reaction in order to perform these transformation in one pot both in batch and under continuous flow. In batch, capecitabine was obtained in 82% yield in 5 h, while under continuous flow it was obtained in 81% yield in 30 min. This one-pot reaction reduces the chemical waste produced, labor, time, and cost and additionally comprises the use of environmentally friendly solvents and reagents as well as energy-efficient and safe methods, all of which fulfill the requirements of a green process.

Full text of DOI:10.1021/acs.oprd.9b00206

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Communication
Continuous-flow Sequential Schotten-Baumann Carbamoylation
and Acetate Hydrolysis in the Synthesis of Capecitabine
Leandro S. de M. Miranda, Rodrigo Octavio Mendonça Alves de Souza, Raquel A. C. Leão, Paula F.
Carneiro, Sérgio Falomir Pedraza, Otávio Vianna Carvalho, Stefânia P de Souza, and Rebeca V Neves
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00206 • Publication Date (Web): 07 Oct 2019
Downloaded from pubs.acs.org on October 8, 2019
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Continuous-flow Sequential Schotten-Baumann
Carbamoylation and Acetate Hydrolysis in the
Synthesis of Capecitabine
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Leandro S. de M. Miranda,* [a] Rodrigo O. M. A. de Souza, [a,b] Raquel A. C. Leão,[a,b]
Paula F. Carneiro,[a] Sergio F. Pedraza, Otavio V. de Carvalho,[c ] Stefânia P. de
Souza,[a] Rebeca V. Neves[a]
[a] Biocatalysis and Organic Synthesis Group, Chemistry Institute, Universidade Federal
[b]
do Rio de Janeiro, Bloco A 622, Rio de Janeiro, RJ- Brazil, 21941-909.
School, Universidade Federal do Rio de Janeiro, RJ-Brazil, 21941-909.
Pharmacy
[c]
Nortec
Química AS, Distrito Industrial Duque de Caxias, Rio de Janeiro, RJ-Brazil, 25250-612
leandrosoter@iq.ufrj.com.br
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Table of Contents graphic.
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Abstract: Capecitabine is an important anti-cancer drug which synthesis comprises late
stage carbamoylation and ester hydrolysis. Here in we report the use of Schotten-
Baumann reaction in order to perform these transformation in one single pot, both in
batch and continuous flow. Under batch Capecitabine was obtained in 82% yield in 5h
while under continuos flow it was obtained in 81% in 30 minutes. This one pot reaction
reduces the chemical waste produced, labor, time and cost and additionally comprises
the use of environmentally friendly solvents and reagents as well as energy efficient and
safe methods, all of which fulfill the requirements of a green process.
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Key-Words: Capecitabine, Continuous-Flow, Carbamoylation, Schotten-Baumann
Reaction
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1-Introduction
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Capecitabine 1 is a broad spectrum anti-cancer pro-drug of 5-fluorouracyl 2 used
clinically as the first line treatment for metastatic colorectal cancer, as adjuvant in large
bowel colon cancer and metastatic and advanced breast cancer1,2. 5-fluorouracil is an
analogue of pyrimidine that acts as an antimetabolite, inhibiting the growth of tumor
cells. In the body, capecitabine is transformed in the active 5-fluorouracyl through a
sequence of enzymatic reactions. First, liver carboxyesterases hydrolase the carbamate
functionality yielding 5’-deoxy-5-fluorocitidine 3, which under the action of a cytidine
deaminase, leads to the respective 5’-deoxy-5-fluoruridine 4. Compound 4 then
releases the toxic 5-fluorouracil in the tumor cells by the action of thymidine
phosphorilase.2 The release of the active anti-metabolite within the neoplasic cells
greatly increases the safety of the drug.3,4
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O
O
H
O
O
O
Carboxylesterase 2
N
Citidine Deaminase
N
N
NH2
NH
O
O
O
O
N
N
N
Liver and Tumor
F
F
F
OH
HO
OH
HO
OH
HO
4
3
1
5'-deoxy-5-fluorcytidine
Capecitabine
5'-deoxy-5-fluoruridine
Thymidine Phosphorilase
in tumor Cells
H
O
N
O
N
H
F
2
5-fluoruracil
Figure 1: The release of the cytotoxic 5-fluorouracil from Capecitabine 1.
From the structural point of view, capecitabine is a pentyl carbamate derived
from 5’-deoxy-5-fluorocitidine 3. Over the literature, the large scale synthesis described
for 1 5-9, the carbamate group is introduced at a late stage, specifically on the
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commercially available 2’,3’-diacetoxy-5’-deoxy-5-fluorcitidine 5. The carbamoylated
nucleoside is then deprotected with the removal of acetyl groups from 2’ and 3’
positions, Scheme 1. These reported methods for carbamoylation/deprotection are
laborious at large scale, once it demands the use of two different reactions to achieve the
synthesis of the desired active pharmaceutical ingredient. Additionally, it also suffers
from some drawbacks as the use of low temperatures and hazardous solvents such as
pyridine, dichloromethane, dimethylformamide or toluene for carbamoylation and
methanol for deprotection; all of which are inherently toxic class 2 solvents.
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O
O
O
O
O
O
O
N
N
N
NH2
NH
2-NaOH, MeOH
NH
O
O
O
O
N
N
N
+
1-Py, DCM
-10oC
F
O
Cl
F
F
OAc
AcO
OAc
AcO
OH
Capecitabine
HO
5
Scheme 1: Late stage carbamoylation of 2’,3’-diacetoxy-5’-deoxy-5-fluorcitidine 5 in the course
of capecitabine synthesis.
The Schotten-Baumann reaction is a method for the preparation of esters and amides
with high potential to fulfill the principles for a green transformation which includes the
use of environmentally friendly solvents and reagents as well as energy efficient
methods.10,11 12 13. It is performed in water as solvent and in the presence of a base,
usually an alkaline metal hydroxide or carbonate.14 This transformation has also been
used for the introduction of carbamate groups from chloroformates or anhydrides
although to a much less extent then for the synthesis of amides or esters. The great
advantage of such procedure is the use of safe green solvents and bases and, depending
on the case, the drop in water solubility after the introduction of acyl group leads to a
simple work up, a very important issue when dealing with the production of hazardous
waste at large scale synthesis. Additionally, this reaction has already been studied under
continuous-flow as exemplified by the synthesis of acyl-sulphonamide by White and co-
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workers 15. These advantages make the Schotten-Baumann reaction an interesting green
method for the introduction of the pentyl-carbamate in the synthesis of capecitabine
from the commercially available acetate 5. In the present case, the Schotten-Baumann
reaction can afford additional advantages once the use of aqueous base can lead to the
carbamoylation-deprotection of the acetate groups in a one-pot reaction. Such “pot-
economy”16 is known to reduce the amount of chemical waste produced, labor, time and
cost; increasing the efficiency and greenness of the process. However, such
methodology does not come without any difficulties, where the presence of aqueous
base may lead to over carbamoylation as well as to the competing hydrolysis of the
pentyl chloroformate. Such issues can be addressed with the use of continuous flow
conditions, once reactions conducted under continuous flow can present advantages
over those conducted under batch conditions. The high surface-to-volume ratio enhance
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heat transfer and temperature control while the more efficient mixing in micro and
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mesoflow reactors (micromixing) allow better mass transfer.17
Additionally, it
improves the process in terms of accident prevention, which is also desirable in order to
increase the greenness of any process.20 21 22 23
The synthesis of capecitabine has already been reported under continuous-flow
by Jamison and co-workers, where the glycosylation, carbamoylation and deprotection
all occur in sequence, in three different compartments24. In their study, the
carbamoylation is conducted in a mixture of acetonitrile/pyridine and the final ester
deprotection with the introduction, in a different compartment, of a mixture of
water/methanol, rendering a complex final reaction media. In our view, the development
of a continuous-flow Schotten-Baumann reaction may allow carbamoylation and
deprotection in water in one single reactor improving greenness and cost. In order to
take advantage of these characteristics and our continuous efforts on enabling API
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synthesis under continuous-flow conditions, here in we present our approach towards
the continuous-flow carbamoylation-deprotection cascade under Schotten-Baumann
conditions, bringing green chemistry in the context of capecitabine synthesis.
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Results and Discussion
To the best of our knowledge, the Schotten-Baumann carbamoylation of
capecitabine has never been reported on the literature. So, in order to gain information
on the viability of such transformation, the reaction of 2’,3’-diacetoxy-5’-deoxy-5-
fluorcitidine (5) under batch conditions was carried out for the capecitabine synthesis.
The reaction between pentyl chloroformate and 5 in a 10% NaOH aqueous solution
afforded capecitabine in 42% isolated yield after 12h, with the concomitant persistent
presence of the starting material. This result demonstrated the one-pot process
feasibility for carbamoylation and acetate hydrolysis in the synthesis of capecitabine.
We hypothesized that this slow capecitabine formation was probably due to the
immiscibility of the pentyl-chloroformate in the aqueous reaction media. In order to
increase the rate of capecitabine formation, acetone was added as a co-solvent to the
reaction mixture. In the presence of 20% of acetone, an increase in the rate of
capecitabine formation was observed. After 5h of reaction at room temperature,
capecitabine was isolated in 82% yield.
Interestingly, when this reaction was monitored by HPLC, it was observed the
consumption of starting material 2’,3’-diacetoxy-5’-deoxy-5-fluorcitidine (5), with the
concomitant formation of a substance with a retention time distinct from capecitabine.
The reaction profile concerning the consumption of the staring material, this unknown
intermediate and capectabine production is depicted in the graph present in Figure 2.
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Fluorocytidine
Intermediate
Capecitabine
0
10
20
30
60
300
Time (min)
Figure 2: The reaction profile concerning the production and consumption of the staring material,
intermediate and Capecitabine.
As can be seen in the graph, under the conditions of the Schotten-Baumann
reaction in the presence of 20% acetone there is a fast consumption of the starting
material with the concomitant formation of capecitabine and unknown intermediate,
which slowly leads to the desired product.
This intermediate was isolated and analyzed by one and two dimensional 1H,13C
NMR and by HRMS. The HRMS afforded a m/z ratio for its sodium adduct [M+Na]+ of
610.2746Da, corresponding to a molecular formula of C27H42FN3O10, which is
consistent with a compound resulting from the reaction of 5´-Deoxy-5-Fluorocytidine 5
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with 3 equivalents of pentyl chloroformate (theoretical mass 610.2746 Da) . Two
dimensional NMR analysis (HMBC) show correlation between the carbonyl carbons
with the 2’ and 3’ carbohydrate hydrogens suggesting that the unknown substance to be
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compound 6, instead of possible isobaric imide (see Supporting Information). The
5
6
7
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presence of this product early in the reaction demonstrates a rapid hydrolysis of the
acetates present at positions 2’ and 3’ and their subsequent reaction with the pentyl
chloroformate. A separate reaction where 6 is submitted to the same condition of the
carbamoylation demonstrate that it affords capecitabine in high yields.
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PentylO
O
O
N
NH
O
O
NaOH 10%, rt
Acetone 20%
NaOH 10%, rt
Acetone 20%
O
N
O
O
NH2
N
H
H3C
H
O
O
O
F
N
N
NH
Pentylchloroformate
F
O
O
N
PentylO
O
F
O
O
O
O
OH
HO
OPentyl
2',3'-diacetoxy-5'-deoxy-5-fluorcitidine
Capecitabine
6
Scheme 2: The sequence producing the intermediate and capecitabine.
Importantly to note that intermediate 6 has already been reported previously by
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researches from Hoffmann-La Roche. In this report, the reaction of the 5’-deoxy-5-
fluorcytidine with penthyl-chloroformate was carried out in pyridine and
dichloromethane at -10oC. In this patent, capectabine is delivered in a subsequent
reaction with sodium hydroxide in methanol also at -10oC. The results presented in
Figures 1 and 2 demonstrates that the sequential acetate hydrolysis, carbamoylation and
hydrolysis of the carbonates at 2’ and 3’ positions can be carried out as an one-pot
reaction using only water:acetone as solvent and sodium hydroxide as base at room
temperature in high yield.
With the feasibility of the Schotten-Baumann reaction demonstrated in the
synthesis of capecitabine, we moved to its optimization under continuous-flow. In order
to evaluate the effect of temperature and base concentration on the reaction, an
optimization was run in a dedicated microwave reactor, and then translated and refined
to the continuous-flow processes, as depicted in table 1.26 The translation of the
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optimized reaction conditions to the continuous flow was conducted with two different
feeds using two Asia flow chemistry syringe pump and a 10mL Teflon tubing with
0.125‘’ OD and 0.00625’’ I.D.
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Table 1: Continuos-Flow reaction between 2’,3’-diacetoxy-5’-deoxy-5-
fluorcitidine 5 and Pentyl Chloroformate
O
O
OH
O
O
O
O
O
OH
O
N
N
N
N
F
F
NH2
NH2
OH
OH
5
1 mL, rt
PFA
10 mL
PFA
O
Feed A
Feed B
(0,38M in NaOH solution)
N
O
O
N
F
30°C
Cl
O
FeedC
726L/min
HN
O
Pentyl Chloroformate
(2,35M in acetone)
O
Capicetabine
HCl 10%
Entry
Residence
time (min)
Feed A
(µL/min)
Feed B
(µL/min)
182
NaOH %
(m/v)
40
Capecitabine (%)
1
2
3
4
5
6
7
15
30
30
30
30
60
60
484
242
242
242
242
121
242
72
81
41
29
0
90.8
40
90.8
30
90.8
20
90.8
10
45.5
40
48
8
90.8
30
Different base concentrations and residence times were evaluated. Both variables had a
profound impact on the reaction conversion. The highest yield of capecitabine was
observed with 30 minutes of residence time with the use of a NaOH 40% solution
(entry 2) at 30oC, where higher temperature lead to lower yields due to decomposition
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of the starting material (See Supporting Information). Lower yields were observed with
shorter residence time due to incomplete reaction (entry 1 vs entry 2) as well as lower
base concentration. Interestingly, longer residence times produced, with the same base
concentrations (entries 2 and 6 as well as 3 and 7), lower the yields of capecitabine due
to decomposition.
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In order to verify the robustness of the methodology developed, a steady state
experiment was performed and was observed that the system was stable at constant
conversion for a period higher then 4 hours as shown in figure 3.
Figure 3: The Robustness of the developed synthesis of Capecitabine under continuous-
flow.
An important observation was made during the continuous-flow reaction. It was
observed that the dissolution of 5 in the 40% NaOH solution, which leads to the higher
yields of Capecitabine (entry 2), rapidly hydrolyze the 2’, 3’acetate groups, leading, in
fact, to the pumping of 5´-Deoxy-5-Fluorocytidine. This is an interesting observation
since no intermediate could be observed under continuous flow. The immiscibility of
the NaOH 40% and acetone solutions and the increased nucleophilicity of the nitrogen
atom may prevent over acylation to the production of 6.
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Conclusion:
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The use of the Schotten-Baumann reaction for the introduction of the pentyl-carbamate
in the synthesis of Capecitabine from 2’,3’-diacetoxy-5’-deoxy-5-fluorcitidine resulted
in a high yield (82%) green one-pot reaction where the carbamoylation and deprotection
reactions occurred in a one-pot process. This “pot-economy” enabled the development
of a transformation without the use of the hazardous solvents reported in batch as well
as in flow, and with the avoidance of low-temperature, intermediate work-up and
isolation, thus decreasing cost, time and labor. When this reaction was translated to
continuous-flow synthesis of capecitabine the reaction time could be drastically
decreased leading to a clean one-pot reaction in only 30 minutes in 81% isolated yield.
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Experimental Section:
Schotten-Baumann Carbamoylation and Deprotection of 5: In a 20 mL reactor
warmed at 30 ºC, was added a solution of 2',3'-diacetoxy-5'-deoxy-5-fluorcitidine (3.04
mmols) in 8 mL of 10% NaOH. To this mixture was added dropwise a solution of n-
pentyl chloroformate (7.06 mmols; 2.41 equiv.) in acetone (2 mL). After 5h, the
reaction medium was acidified with 10% HCl (10 mL) to pH 4 and extracted with ethyl
acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate,
filtered and the solvent removed under reduced pressure. The crude thick yellow oil was
crystallized from hexane to give a white crystalline solid with the same
chromatographic and spectroscopic data of capecitabine in 82% yield.1H NMR (300
MHz, CDCl3) δ 7.70 (s, 1H), 5.65 – 5.64 (m, 1H), 4.21 – 4.20 (m, 2H), 4.14 – 4.09 (m,
2H), 3.82 – 3.79 (m, 1H), 1.65 – 1.60 (m, 2H), 1.35 (d, J = 6.4 Hz, 3H), 1.31 – 1.27 (m,
13
4H), 0.84 (t, J = 6.8 Hz, 3H). δ C NMR (126 MHz, CDCl3) δ 153.40, 153.29, 92.17,
80.83, 75.06, 66.89, 28.30, 27.93, 22.36, 18.67, 13.99.
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Synthesis of intermediate 6: The same experimental protocol described for
Carbamoylation/deprotection of 5 was employed. However, in this case the reaction was
interrupted after 1h. After the usual workup a crude solid was obtained, which was
purified by chromatography in sílica gel (20% AcOEt in hexane) to furnish a white
solid (35% yield).1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 7.34 (s, 1H), 5.79 (d, J =
3.6 Hz, 1H), 5.23 (s, 1H), 4.85 (s, 1H), 4.69 (s, 1H), 4.28 – 4.19 (m, 1H), 4.07 (dd, J =
12.7, 6.1 Hz, 6H), 3.98 (t, J = 6.7 Hz, 1H), 1.69 – 1.52 (m, 7H), 1.41 (d, J = 6.2 Hz,
3H), 1.34 – 1.21 (m, 14H), 0.83 (s, 10H).13C NMR (101 MHz, CDCl3) δ 153.07,
153.03, 152.40, 152.22, 68.26, 68.07, 65.67, 64.26, 27.58, 27.22, 27.17, 27.12, 26.93,
26.91, 26.68, 26.64, 21.32, 21.30, 21.22, 17.31, 16.12, 12.96, 12.93, 12.88. HRMS
[M+Na]+ of 610.2746 Da
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Acknowledgement
We thank Nortec Química for the donation of 2’,3’-diacetoxy-5’-deoxy-5-fluorcitidine
and a capecitabine standard. The authors acknowledge financial support and fellowships
from FAPERJ, FINEP, CAPES, and CNPq.
Supporting Information: All experimental details, Chromatographic and
Spectroscopic data are presented in the Supporting Information File
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