Green synthesis improvement of tenofovir disoproxil

Article abstract of DOI:10.14233/ajchem.2014.19058

Polyethylene glycol, known as 'Green Chemical', is a catalyst for the synthesis of tenofovir disoproxil. Some technological parameters were discussed by adoptting via single-factor experiments. Through the catalytic reaction, not only tenofovir disoproxil yield was improved but also by-products was reduced obviously. The results showed that the optimal conditions were as follows: 0.6 equiv PEG-600, 4.0 equiv triethylamine, 6.0 equiv N-methyl-2-pyrrolidone and temperature at 50°C for 16 h with a yield of 65.12 %.

Full text of DOI:10.14233/ajchem.2014.19058

Asian Journal of Chemistry; Vol. 26, Supplementary Issue (2014), S255-S258
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.19058
Green Synthesis Improvement of Tenofovir Disoproxil
1
,*
2
1
GANG WANG , YONG MEI XIE and XING HUA WANG
1
2
Zunyi Medical College, Zunyi 563003, Guizhou Province, P.R. China
Sichuan University, Chengdu 610000, Sichuan Province, P.R. China
*
Corresponding author: E-mail: wg8855350@163.com
Published online: 24 December 2014;
AJC-16484
Polyethylene glycol, known as ‘Green Chemical’, is a catalyst for the synthesis of tenofovir disoproxil. Some technological parameters
were discussed by adoptting via single-factor experiments. Through the catalytic reaction, not only tenofovir disoproxil yield was improved
but also by-products was reduced obviously. The results showed that the optimal conditions were as follows: 0.6 equiv PEG-600, 4.0
equiv triethylamine, 6.0 equiv N-methyl-2-pyrrolidone and temperature at 50 °C for 16 h with a yield of 65.12 %.
Keywords: Polyethylene glycol, Tenofovir Disoproxil, Tenofovir, Alkylation.
Now polyethylene glycol is widely used in organic synthesis
6
reaction as a green solvent and phase transfer catalys .
INTRODUCTION
Tenofovir disoproxil (TD) is a key intermediate in the
preparation of tenofovir disoproxil fumarate (TDF) which is
1
a prodrug of tenofovir (known as PMPA) and a nucleoside
In the light of the advantages and disadvantages of various
phase transfer catalyst, polyethylene glycol was adopted as
phase transfer catalyst in the experiment. Via singl-factor
experiments and some technological parameters were discu-
ssed and the best reaction conditions were established.
analogue reverse transcriptase inhibitor (nRTI) that is used to
2
treat HIV/AIDS and hepatitis B.1 . PMPA was converted into
tenofovir disoproxil based on promotting alkylation and
chloromethyl isopropyl carbonate (CIC) was used to adopte
as alkylation reagents.
EXPERIMENTAL
Polyethylene glycol was heated at 80 °C under vacuum
1
for 0.5 h before use to remove traces of moisture. H NMR
However, the conversion of PMPA into tenofovir disoproxil
with excess chloromethyl isopropyl carbonate is accompanied
3
by the generation of some by-products . Due to the hydrolysis
3
spectra in CDCl on a Bruker Avance DPX instrument (400
MHz). Tenofovir was purchased from Xian ShuaiDi biotech-
nology co., LTD. Polyethylene glycol , N-methyl-2-pyrroli-
done, cyclohexane, triethylamine and ethyl acetate were
purchased from Chengdu kelon chemical reagent co., Ltd All
organic reagents and solvents were of reagent grade purity.
Products were characterized by comparison of their physical
of PMPA and its salts, the reaction must be run in a polar and
4
aprotic solvent . But chloromethyl isopropyl carbonate has
poor solubility in the solvent. In order to increase the solubility
of chloromethyl isopropyl carbonate and improve yield, we
considered to add phase transfer catalyst in chemical reaction.
Polyethylene glycol (PEG) has high thermal stability, low
1
data, High performance liquid chromatography and H NMR
spectra with known samples.
5
toxicity, difficult to volatile, non-flammable, low cost, etc. .
NH2
NH
2
O
N
N
N
O
N
N
O
O
P
OH
Cl
O
O
P
O
O
N
O
O
N
N
OH
O
H2O
(PMPA)
(Tenofovir disoproxil)
O
O

S256 Wang et al.
Asian J. Chem.
Preparation of tenofovir disoproxil: PMPA (25 g), dry
Selection of base: Bases included both inorganic bases and
organic bases. Inorganic bases produced insoluble phosphonic
N-methyl-2-pyrrolidone (NMP, 6.0 equiv, 50 mL) and cyclo-
hexane (120 mL) were charged to a reactor vessel and agitated
with a magnetic stirrer (500 rpm) at 50 °C. PMPA was dried
in advance at about 80 °C under vacuum for 24 h. Cyclohexane
was removed in advance by distillation twice under reduced
pressure at 50 °C. When the reaction was cooled to 45 °C,
triethylamine (35.2 g, 4.0 equiv) and PEG-600 (31.3 g, 0.6
equiv, water content < 1 %) were added. Precipitation of
triethylamine salts of PMPA was caused. The reaction mixture
was heated to 50 °C and chloromethyl isopropyl carbonate
7
acid salts, which affect the tenofovir disoproxil yield . Therefore,
several organic bases were selected and compared about the
affection of the yield, such as triethylamine (TEA), N,N-diisopro-
pylethylamine (N,N- DEM), tetramethylguanidine (TMG) and
2,6-lutidine. As shown in Fig. 1, triethylamine provided the best
performance among organic bases in the reaction.
70
60
50
40
30
20
(
66.4 g, 5.0 equiv) was added at this temperature. The reaction
was monitored for completion at 16 h and the initially thick
suspension was almost clear. The reaction samples were
analyzed by HPLC (purity 88.7 %) which was performed on a
liquid chromatograph (Shimadzu, Japan, 10 Atvp) with
Shimadzu DAD detectoran and ACQUITY BEH C18 column
(
2.1 mm × 150 mm, 1.7 um). The binary mobile phase was
10
0
composed of water and methanol in proportion 40/60 (v/v).
The flow rate was 0.6 mL/min.
Product isolation: The reaction mixture was cooled to
TEA
N,N-DEM
TMG
2,6-lutidine
Base
Fig. 1. Selection of base. PMPA, 25 g; PEG-600, 0.6 equiv; N-methyl-2-
pyrrolidone, 6.0 equiv; temperature, 50 °C reaction time, 16 h
25-30 °C and ethyl acetate (250 mL) and water (120 mL) were
added. The mixture was stirred for 10 min and phases were
clearly separated from each other. The aqueous phase was
successively separated twice with ethyl acetate (70 mL each).
The organic phases were combined and washed three times
with water (150 mL each) and aqueous solution of 10 % NaCl.
The organic phase was dried with solid sodium sulfate and
evaporated in vacuum. The residue was cooled at 5 °C and
Selection of triethylamine concentration: As depicted
in Fig. 2, with the increase of triethylamine concentration, the
yield was improved continuously. When the base exceeded
4.0 equiv, the yield was almost no obvious change. By consi-
dering the experiment economic, 4.0 equiv triethylamine was
adopted.
1
provided solid mass of 29.4 g (65.12 % yield). H NMR
(
CDCl
CHN), 5.54 (m, 4H, 2 × OCH
CH(CH ], 4.35 (dd, J = 3.0,13.8 Hz,1H, NCH
J = 7.1, 14.0 H, 1H, NCH ), 3.86-3.90 (m, 2H, OCH
.79 (dd, J = 9.2, 13.2 Hz, 1H, CH CHO), 1.31 [d, J = 14.3
Hz, 12H, 2 × CH (CH ], 1.26 (d, J = 7. 1 Hz, 3H, CH ).
3
, 400 MHz), δ: 8.38 (s, 1H, N = CHN), 7.94 (s, 1H, N
O), 4.86-4.91 [m, 2H, 2 ×
), 4.23 (dd,
P), 3.76-
70
=
2
65
60
55
50
45
40
3
)
2
2
2
2
3
2
3
)
2
3
RESULTS AND DISCUSSION
Several key impurities included reaction intermediate (1)
and N-hydroxymethylated impurities (2), which leads to
7
reduction of product . It might be that N-methyl-2-pyrrolidone
0
1
2
3
Amount of TEA (equiv)
4
5
6
7
brought water into the reaction and the presence of triethyl-
amine produced a basic water layer (pH 10) to promote reaction
hydrolysis. In addition, chloromethyl isopropyl carbonate is
sparingly soluble in the polar and aprotic solvent.
Fig. 2. Selection of triethylamine parameter. PMPA, 25 g; PEG-600, 0.6
equiv; N-methyl-2-pyrrolidone, 6.0 equiv; temperature, 50 °C;
reaction time, 16 h
Therefore, improving conversion fully and product stabil-
ity must be intensive to investigate.Addition of phase-transfer
reagents were identified to affect mainly tenofovir disoproxil
yield. Other critical processing parameters include base
concentration, reaction concentration, reaction mixture and
reaction temperature.
Selection of polyethylene glycol type: The triethylamine
salt of PMPA originally formed was sparingly soluble in
N-methyl-2-pyrrolidone and leaded to heterogeneous in the
reaction. Thus, a phase-transfer catalyst was adopted to
enhance the dissolution rate and conversion in the reaction. In
order to identify this, a number of polyethylene glycol additives
were tested in the reaction. PEG600 was best among the
catalyst in the experiment (Fig. 3).
NH2
NHC OH
2
N
N
O
P
N
N
Selection of PEG 600 concentration: As illustrated by
the results in Fig. 4, when PEG600 exceeded 0.6 equiv, with
the increase of PEG 600 concentration, the tenofovir disoproxil
yield has little change. According to the experimental econo-
mics and security, 0.6 equiv PEG 600 was adopted.
N
O
P
OH
OR
OR
OR
N
O
O
N
N
1
2

Vol. 26, Suppl. Issue (2014)
Green Synthesis Improvement of Tenofovir Disoproxil S257
70
60
50
40
30
20
10
0
aprotic solvent selection was studied. As Fig. 6 shown N-
methyl-2-pyrrolidone was confirmed as the optimal solvent
for the reaction.
70
60
50
40
30
PEG200
PEG400
PEG600
PEG800 PEG2000
PEG model
20
Fig. 3. Selection of polyethylene glycol model. PMPA, 25g; triethylamine,
.0 equiv; N-methyl-2-pyrrolidone, 6.0 equiv; temperature, 50 °C;
reaction time, 16 h
10
4
0
EA
Acetonitrile DMSO
Solvent
DMF
NMP
70
65
60
55
50
45
40
35
30
Fig. 6. Selection of solvent. PMPA, 25 g; PEG-600, 0.6 equiv; triethyl-
amine, 4.0 equiv; temperature, 50 °C; reaction time, 16 h
N-Methyl-2-pyrrolidone concentration:As depicted in
Fig. 7, when N-methyl-2-pyrrolidone exceeded 6.0 equiv, with
the increase of N-methyl-2-pyrrolidone concentration, the
tenofovir disoproxil yield has almost little change. According
to the experimental economics and security, 6.0 equiv N-
methyl-2-pyrrolidone was adopted as the optimum.
66
0
0.2
0.4
0.6
Amount of PEG600 (equiv)
0.8
1.0
1.2
6
4
2
Fig. 4. Selection of the PEG600 parameter. PMPA, 25 g; triethylamine,
.0 equiv; N-methyl-2-pyrrolidone, 6.0 equiv; temperature, 50 °C;
6
4
reaction time, 16 h
60
5
8
Temperature: The tenofovir disoproxil yield was impro-
ved continuously with the increase of reaction temperature.
When reaction temperature reached 50 °C, the tenofovir
disoproxil yield was maximum (63.08 %). But with the reaction
temperature rise, the tenofovir disoproxil yield began to
reduced slowly. It might be the increase of reaction by-
products. Thus, temperature 50 °C was adopted (Fig. 5).
56
5
4
2
5
2
4
Amount of NMP (equiv)
6
8
Fig. 7. Investigate of solvent consumption. PMPA, 25 g; PEG-600, 0.6
equiv; triethylamine, 4.0 equiv; temperature, 50 °C; reaction time, 16 h
7
6
6
5
5
4
4
3
3
2
2
0
5
0
5
0
5
0
5
0
5
0
Reaction time:As illustrated by the results in Fig. 8, with
the increase of reaction time, the tenofovir disoproxil yield
70
60
50
40
30
20
20
30
40
50
Temperature (°C)
60
70
80
10
0
Fig. 5. Selection of temperature. PMPA, 25 g; PEG-600, 0.6 equiv; N-methyl-
-pyrrolidone, 6.0 equiv; triethylamine, 4.0 equiv; reaction time, 16 h
2
0
6
12
18
24
30
36
Time (h)
Solvent: A polar aprotic solvent is necessary for the alky-
4
lation reaction, as a solvent of the starting material . In order
Fig. 8. Selection of reaction time. PMPA, 25 g; PEG-600, 0.6 equiv;
triethylamine, 4.0 equiv; temperature, 50 °C; N-methyl-2-pyrro-
lidone, 6.0 equiv
to improve the yield, A cursory examination of several polar

S258 Wang et al.
Asian J. Chem.
rise initially soon. When the reaction time was 16 h, the
tenofovir disoproxil yield was maximum (64.72 %). But with
the increase of reaction time, the tenofovir disoproxil yield
was reduced slowly. It maight be the increase of reaction
by-products. The reaction time 16 h was adopted as the
optimum.
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2
In the presence of PEG600 as phase-transfer catalyst, the
results of study show that Tenofovir disoproxil could be
obtained in high yields. In addition, polyethylene glycols are
welcome phase-transfer catalyst, particularly in base condi-
tions. The optimal reaction conditions were: 0.6 equiv PEG-
5
.
(
3
7
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6
00, 4.0 equiv triethylamine, 6.0 equiv N-methyl-2-pyrro-
lidone, reaction temperature of 50 °C and reaction time of
6 h. The yield of tenofovir disoproxil was 65.12 %.
1
(
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