Efficient synthesis and resolution of tenofovir alafenamide

Article abstract of DOI:10.2174/1570178614666170907115708

Background: Tenofovir alafenamide (TAF) is an oral antiviral prodrug of tenofovir (TFV), we have developed a facial and efficient method for the synthesis and chiral resolution of TAF. Method: The practical synthetic route of a mixed two diastereomers at phosphorous could start from (R)-9-[2-(Phosphonomethoxy)propyl]adenine (PMPA), the esterification reaction between PMPA and phenol occurred under the catalysis of dicyclohexylcarbodiimide (DCC) in 1-methyl-2-pyrrolidinone (NMP) at the temperature of 100^o C to afforded 1. Phosphonochloridate was synthesized from 1 by chloride acetylation with thionyl chloride, and then react with an excess of L-Alanine isopropyl ester hydrochloride to give the diastereomer mixture of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)ethyl] amino]-phenoxyphosphinyl]methoxy]propyl]adenine (2). The antipodes of 2 were separated in a satis-factory yield and diastereomeric excess (99% de) by resolution via formation diastereoisomer salt or inclusion complex to afford the more potent diastereomer (3). Tenofovir Alafenamide hemifumarate could be afforded by 3 and fumaric acid in a 1:0.5 ratio. Results: The diastereomeric excess of 3 could reach to 99% de. Conclusion: In a word, we have developed an efficient and chromatography-free route for the prepara-tion of TAF. In consideration of the expensive equipment and higher operation cost of SMBC, we chose a traditional resolution route to obtain chiral phosphorus.

Full text of DOI:10.2174/1570178614666170907115708

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Letters in Organic Chemistry, 2018, 15, 10-14
RESEARCH ARTICLE
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Efficient Synthesis and Resolution of Tenofovir Alafenamide
BENTHAM
S
CIENCE
Bin Yang1, Hongmeng Xie1, Kerui Ran1 and Yongjun Gan2,*
1Department of Pharmacy, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Labora-
tory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child De-
velopment and Critical Disorders, Chongqing Key Laboratory of Pediatrics, 400014 Chongqing, P.R. China;
2Experimental Teaching Center, Chongqing Medical University, 400016 Chongqing, P.R. China
Abstract: Background: Tenofovir alafenamide (TAF) is an oral antiviral prodrug of tenofovir (TFV),
we have developed a facial and efficient method for the synthesis and chiral resolution of TAF.
Method: The practical synthetic route of a mixed two diastereomers at phosphorous could start from
(R)-9-[2-(Phosphonomethoxy)propyl]adenine (PMPA), the esterification reaction between PMPA and
phenol occurred under the catalysis of dicyclohexylcarbodiimide (DCC) in 1-methyl-2-pyrrolidinone
(NMP) at the temperature of 100oC to afforded 1. Phosphonochloridate was synthesized from 1 by
A R T I C L E H I S T O R Y
chloride acetylation with thionyl chloride, and then react with an excess of L-Alanine isopropyl ester
hydrochloride to give the diastereomer mixture of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)ethyl]
Received: January 12, 2017
Revised: June 20, 2017
amino]-phenoxyphosphinyl]methoxy]propyl]adenine (2). The antipodes of 2 were separated in a satis-
Accepted: August 23, 2017
factory yield and diastereomeric excess (99% de) by resolution via formation diastereoisomer salt or
DOI:
inclusion complex to afford the more potent diastereomer (3). Tenofovir Alafenamide hemifumarate
10.2174/1570178614666170907113121
could be afforded by 3 and fumaric acid in a 1:0.5 ratio.
Results: The diastereomeric excess of 3 could reach to 99% de.
Conclusion: In a word, we have developed an efficient and chromatography-free route for the prepara-
tion of TAF. In consideration of the expensive equipment and higher operation cost of SMBC, we
chose a traditional resolution route to obtain chiral phosphorus.
Keywords: Chiral phosphorus, inclusion complex, resolution, D-(-)-Tartaric acid, TADDOL, tenofovir alafenamide.
1. INTRODUCTION
non-stereoselective led to the chiral center at phosphorous
was racemic [6], so GS-7171 was a 1:1 mixture of two di-
astereomers be composed with GS-7339 and GS-7340,
(Scheme 1) GS-7340 was about ten-fold more active than
GS-7339 in vitro anti-HIV-1 activity [7], the process for
separation of the diastereomers of GS-7171 involves the use
of simulated moving bed chromatography(SMBC) [8], which
needs expensive equipment and has a higher operation cost.
Thus, a more simple and efficient method is necessary to
develop in order to separate and get GS-7340.
Tenofovir alafenamide (TAF) is an oral antiviral prodrug
of tenofovir (TFV), which is a HIV-1 nucleotide reverse
transcriptase inhibitor. Tenofovir disoproxil fumarate (TDF)
is another TFV prodrug developed by Gilead Sciences, was
first approved for the prophylaxis or treatment of HIV and
HBV in 2001 [1-3]. TAF is mostly converted to TFV af-
ter absorbed by human body, compared with the TDF, TAF
has a higher tenofovir diphosphate (TFV-DP) levels in pe-
ripheral blood mononuclear cells. As a result, TAF has dem-
onstrated potent anti-HIV-1 activity at lower doses than TDF
in monotherapy studies [4]. Besides, the high oral bioavail-
ability and favorable tissue-selective distribution of TAF
made it a promising candidate for HBV therapy [5].
2. EXPERIMENTAL
2.1. General Experimental Procedures
Reactions were monitored by thin layer chromatography
with silica gel plates under the UV light. NMR spectra were
determined on a Bruck 300 NMR spectrometer with the sol-
vent of D2O, CDCl3 or DMSO-d6. HPLC purity was deter-
mined on Agilent Proshell 120 Bonus-RP column with Ag-
ilent 1120. All solvents, reagents, and the starting materials
were used as received from commercial vendors.
TAF also known as GS-7340, it has the formula
C21H29N6O5P (Fig. 1). The existing synthetic route has
*Address correspondence to this author at the Experimental Teaching Cen-
ter, Chongqing Medical University, 400016 Chongqing, P.R. China;
Tel: +86 18623627351; E-mail: cqjy0708@126.com
1875-6255/18 $58.00+.00
© 2018 Bentham Science Publishers

Efficient Synthesis and Resolution of Tenofovir Alafenamide
Letters in Organic Chemistry, 2018, Vol. 15, No. 1 11
H2N
O
N
O
P
N
NH
N
O
N
O
H2N
N
O
O
O
N
3
P
NH
GS-7340(TAF)
N
O
N
O
O
H2N
N
2
O
O
N
P
GS-7171
NH
N
O
N
O
O
GS-7339
Scheme (1). The diastereomers of 2.
2.1.1. [(R)-2-(Phenylphosphonomethoxy)propyl]adenine(1)
solid. The yellow semi solid was diluted with dichloro-
methane (400 mL) and the mixture was cooled to −30oC by
ice-salt bath. A solution of L-alanine isopropyl ester hydro-
chloride (83.2g, 497 mmol) in dichloromethane (200 mL)
was added dropwise over a period of 1h and control the in-
side temperature not more than -20oC by ice-salt bath, fol-
lowed to it was added triethylamine (100.3 g, 993 mmol)
over 30 minutes at the same temperature. The reaction liquid
was warmed to room temperature after stirred at -20oC for
2h, and then 10% NaH2PO4 solution(600 mL) added and
separated after the reaction became clarification. The organic
solution was dried with Na2SO4 after washed with another
600mL 10% NaH2PO4 solution, and concentrated to brown
oil under reduced pressure. Acetonitrile (600 mL) and fu-
maric acid (38.4 g, 331 mmol) was added to the reside, the
mixture was heated under reflux for an hour, filter while hot
and the filtrate cooled to 0oC for 2h. The solid was isolated
by filtration, rinsed with 100 mL acetonitrile, and dried to
122 g light brown solid. The solid was dissolved in a mixture
of 100 mL ethyl acetate and 100 mL saturated sodium bicar-
bonate solution, the organic layer was collected and concen-
trated to pale yellow oil (98 g, 62% yield) under reduced
Phenol (131g, 1392 mmol) and triethylamine (115 mL,
831 mmol) were added to a stirred solution of anhydrous
PMPA (200 g, 696 mmol) in NMP (520 mL) at room tem-
perature. The mixture was heated to 100oC. A solution of 1,
3-dicyclohexylcarbodiimide (287g, 1.391 mmol) in NMP (20
mL) was then added over 6 hours at 100oC. The mixture was
stirred at this temperature for 10 hours more. Water (400
mL) was added after the reaction was cooled to 45oC, then
the reaction was cooled to room temperature and stirred for
30 min, the mixture was filtered and solids were rinsed with
water (200 mL) to give the filtrate. The filtrate and rinse
were combined and evaporated under reduced pressure, after
removing the solvent by reduced pressure distillation, the tan
slurry obtained finally. Water (300 mL) was added, and ad-
justed to pH=11 with 25% sodium hydroxide solution. The
suspension was removed by filtration through a funnel
charged with celite. The filtrate was extracted with ethyl
acetate (500 mL*3). Concentrated hydrochloric acid was
added into the aqueous solution until the mixture was ad-
justed to pH=3.1, and then cooled to 0oC and stirred for 2h,
the precipitation was isolated by filtration under reduced
pressure and washed with methanol (500 mL), and dried to
1
pressure. H NMR (300 MHz, CDCl3, δ): 1.64-1.22 (m,
12H), 3.65 (dd, J=9.8, 8.1Hz, 1H), 3.96-3.84 (m, 5H), 4.2-
4.09 (m, 1H), 4.9-4.83 (m, 1H), 6.2 (s, 2H), 7.15-7.07 (m,
5H), 8.0 (s, 1H), 8.27(s, 1H); 13CNMR (100 MHz, DMSO-
d6): δ171.9 (C-26), 155.8(C-6), 152.7(C-2), 149.6(C-18),
149.2 (C-4), 140.8(C-8), 129.5(C-20), 129.5(C-22), 125.1(C-
21), 121.3(C-19), 121.3(C-23), 119.8(C-5), 72.1(C-12), 68.8
(C-29), 62.0(C-14), 52.9(C-11), 49.5(C-24), 21.7(C-30) 21.7
(C-31), 18.9(C-33), 18.3(C-25);31P NMR (72 MHz, CDCl3,
δ): 21.0, 22.5(decoupled).
1
give 1 as a white powder (120 g. 47.6% yield). H NMR
(300 MHz, D2O, δ): 1.16 (d, J = 3.7 Hz, 3H), 3.54 (m, 2H),
3.71 (dd, J = 10.5 Hz, 2H), 4.03 – 3.99 (m, 2H), 4.22-4.10
(m, 2H), 4.45 (dd, J=11.3, 8.3Hz, 2H), 6.59 (d, J =5.2 Hz,
2H), 7.05 (t, J =5.3 Hz, 1H), 7.21 (t, J =5.1 Hz, 2H), 8.05 (s,
1H), 8.16 (s, 1H); 13CNMR (100 MHz, DMSO-d6): δ155.8
(C-6), 152.7(C-2), 151.3(C-19), 149.2(C-4), 140.7(C-8),
130.0 (C-21), 130.0(C-23), 124.9(C-22), 120.6(C-20), 120.6
(C-24), 119.8(C-5), 72.4(C-12), 56.3(C-14), 55.6(C-11),
19.0 (C-25); 31P NMR (72 MHz, D2O, δ):15.0 (decoupled).
2.1.3. 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]
amino]-phenoxyphosphinyl]methoxy]propyl]adenine (3)
2.1.2. 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)ethyl]
amino]-phenoxyphosphinyl]methoxy]propyl]adenine (2)
To a stirred solution of 2 (20 g, 42 mmol) in isopropanol
(200 mL) D-(-)-Tartaric acid (3.2 g, 21 mmol) and D-DBTA
(7.5 g, 21 mmol) were added at room temperature. The reac-
tion liquid was heated under reflux until solids dissolved,
and then cooled to 0oC over a period of 5 h, the mixture
was filtered under reduced pressure and the solid rinsed with
isopropanol. The solid was dissolved in a mixture of ethyl
To a stirred solution of 1 (120g, 331 mmol) in anhydrous
acetonitrile (600 mL) thionyl chloride (78.7g, 661 mmol)
was added at room temperature in 10 min. The mixture was
heated under reflux until solids dissolved, then the solvent
was evaporated under reduced pressure to give yellow semi

12 Letters in Organic Chemistry, 2018, Vol. 15, No. 1
Yang et al.
acetate (50 mL) and saturated sodium bicarbonate solution
(50 mL), the organic layer was separated and concentrated to
off-white powder (9.6 g, 48% yield, 99% de).
2.1.4. Tenofovir Alafenamide Hemifumarate (4)
To a stirred solution of 3 (8 g, 16.8 mmol) in acetonitrile
fumaric acid (0.97 g, 8.4 mmol) was added. The mixture was
heated under reflux until solids were dissolved, filtered while
hot to remove any undissolved particulates. The filtered solu-
tion was cooled to 55oC and stirred for 2h at this tempera-
ture. The mixture was cooled to 0-5oC over 2 hours, filtered
under reduced pressure and the solid dried under vacuum at
50oC to provide the TAF (4) (8.3 g, 92% yield). δ1.18-1.10
(m, 12H), 3.58 (dd, J =9.8, 8.0Hz, 1H), 3.90-3.84 (m, 2H),
3.94 (m, 1H), 4.14 (dd, J = 5.2, 11.1 Hz, 1H), 4.27(m, 1H),
4.83 (heptet, J= 4.5 Hz, 1H), 5.67 (t, J= 8.4 Hz, 1H), 6.62 (s,
1H), 7.08 (d. J =5.7 Hz, 2H), 7.13 (t, J =5.3 Hz, 1H), 7.22 (s,
2H), 7.28 (t, J = 5.7 Hz, 2H), 8.13 (t, J = 10.4Hz, 2H).
13CNMR (100 MHz, DMSO-d6): δ171.9 (C-26), 167.1(C-
36), 155.8(C-6), 152.7(C-2), 149.6(C-18), 149.2(C-4), 140.8
(C-8), 133.8(C-34), 129.5(C-20), 129.5(C-22), 125.1(C-21),
121.3 (C-19), 121.3(C-23), 119.8(C-5), 72.1(C-12), 68.8(C-
29), 62.0(C-14), 52.9(C-11), 49.5(C-24), 21.7(C-30) 21.7
(C-31), 18.9(C-33), 18.3(C-25).
To a stirred solution of 2 (20 g, 42 mmol) in acetone (100
mL) (R,R)-TADDOL (9.8 g, 84 mmol) was added at room
temperature. The mixture was heated under reflux until sol-
ids dissolved, and then cooled to 20oC over a period of 2 h,
the mixture was filtered under reduced pressure and the solid
further purified by one recrystallizations from acetone (50
mL). The dissociation of the complex was using column
chromatography (silica gel, 200-300 mesh), the column was
eluted with ethyl acetate to get 3 (7.8 g, 39% yield, 99% de,
the HPLC column was Agilent Proshell 120 Bonus-RP col-
umn 150 mm × 4.6 mm, 2.7 μm, Mobile phase solution A
was 0.02% phosphoric acid aqueous, and mobile phase solu-
tion B was Methanol, Gradient elution was performed as
shown in Table 1 with a run time of 50 min. The flow rate
was 0.5 mL/min and the column temperature was 40 °C. The
UV detection was performed at 260 nm. The retention time
1
was 25.69 min). H NMR (300 MHz, CDCl3, δ): 1.18 -1.10
(m, 12H), 3.57 (dd, J=9.8, 8.0Hz, 1H), 3.86-3.77 (m, 5H),
4.2(dd, J=10.8, 2.3Hz, 1H), 4.7-5.62 (m, 1H), 6.1 (s, 2H),
7.1-7.03 (m, 5H), 8.0 (s, 1H), 8.27 (s, 1H) 13CNMR (100
MHz, DMSO-d6): δ171.9(C-26), 155.8(C-6), 152.7(C-2),
149.6(C-18), 149.2(C-4), 140.8(C-8), 129.5(C-20), 129.5 (C-
22), 125.1(C-21), 121.3(C-19), 121.3(C-23), 119.8(C-5), 72.1
(C-12), 68.8(C-29), 62.0(C-14), 52.9(C-11), 49.5 (C-24),
21.7 (C-30)21.7(C-31), 18.9(C-33), 18.3(C-25); 31P NMR
(72 MHz, CDCl3, δ): 21.0 (decoupled).
3. RESULTS AND DISCUSSION
In our work Scheme (2), the commercially available (R)-
PMPA side-chain and L-alanine isopropyl ester hydrochloride
were homochiral starting materials, the esterification reaction
between PMPA and phenol occurred under the catalysis of
dicyclohexylcarbodiimide (DCC) in 1-methyl-2-pyrrolidinone
(NMP) at the temperature of 100oC to afforded 1. Phos-
Table 1. The gradient elution of HPLC.
Time (min):
0
25
40
40.1
50
B%:
20
60
60
20
20
H2N
H2N
N
HO
SOCl2
OH
O
N
N
O
HO
P
P
N
OH
O
DCC,DMAP,NMP
N
O
N
O
N
N
PMPA
1
O
H2N
H2N
N
O
H2N
N
O
Resolution
O
O
N
N
O
P
N
P
NH
N
O
Cl
O
N
O
N
O
2
H2N
N
H2N
O
O
COOH
N
N
COOH
O
O
HOOC
P
P
N
NH
NH
N
O
N
O
N
N
O
O
COOH
0.5
O
O
4(TAF)
3
Scheme (2). The synthesis of TAF.

Efficient Synthesis and Resolution of Tenofovir Alafenamide
Letters in Organic Chemistry, 2018, Vol. 15, No. 1 13
O
OH
O
OH
O
O
HO
O
OH
O
O
OH
HO
O
D-(-)-Tartaric acid
(+)-Dibenzoyl-D-tartaric Acid(D-DBTA)
H3C
O
OH
O
O
OH
O
O
O
O
O
O
O
O
HO
O
CH3
HO
O
O
(+)-Di-p-toluoyl-D-tartaric Acid(D-DTTA)
(+)-Di-p-anisoyl-D-tartaric Acid(D-DATA)
Fig. (1). D-(-)-Tartaric acid and its derivatives.
Table 2. Dutch resolution of 2.
Resolving Agent
Reagent Ratio
Yield%
de%
D-TA/ D -DBTA/2
D -TA/ D -DTTA/2
0.5:0.5:1
0.5:0.5:1
48
44
33
41
38
35
99
77
85
68
73
87
D -TA/ D -DATA/2
0.5:0.5:1
D -TA/ D -DBTA/D -DTTA/2
D -TA/ D -DBTA/D -DATA/2
D -TA/ D -DTTA/D -DATA/2
0.5:0.25:0.25:1
0.5:0.25:0.25:1
0.5:0.25:0.25:1
O
O
HN
P
O
OH
HO
O
O
H
H
O
O
O
O
O O
N
N
N
(R,R)-TADDOL
H2N
N
Fig. (2). The formation of the inclusion complex with the basic H-bridge interaction between (R,R)-TADDOL and 2.
phonochloridate was synthesized from 1 by chloride acetyla-
tion with thionyl chloride, and then react with an excess of L-
Alanine isopropyl ester hydrochloride to give the diastereomer
mixture of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)
ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine
(2). The antipodes of 2 were separated in a satisfactory yield
and diastereomeric excess (99% de) by resolution via forma-
tion of diastereomeric complexes or inclusion complex, we
choose two resolution methods to afford the more potent
diastereomer (3), the one was the use of mixtures of resolv-
ing agents were composed of D-(-)-Tartaric acid and its de-
rivatives, which also known as ‘Dutch Resolution’ [9], the
other resolution agent was (R,R)-TADDOL, an efficient
chiral resolving agent of chiral phosphine oxides [10, 11].
Tenofovir Alafenamide hemifumarate could been afforded
by 3 and fumaric acid in a 1:0.5 ratio (Fig. 2).
Our work seems to be deadlocked when we had obtained
compounds 2, because the SMBC method is not what we can
afford, so we have to find a more simple and cheaper way to
get 3 fortunately, the purine ring of 2 have alkaline amino
groups, we found that 2 and fumaric acid can form salt and
crystallization from the organic solvent, maybe the tartaric
acid could also form a solid and crystallization from organic
solvent with 2 because of its structural similarity with fu-
maric acid, At the same time the difference solubility of the
diastereomeric complexes in different solvents maybe sig-
nificant because the tartaric acid was a chiral compound,

14 Letters in Organic Chemistry, 2018, Vol. 15, No. 1
Yang et al.
therefore, we have a very good chance to obtain 3 by chiral
resolution. Finally, we found that there is an obvious differ-
ence between the solubility of D-(-)-Tartaric acid and 2 for-
mation of the diastereomeric salt in isopropanol after a lot of
solvent screening experiment, but we can only obtain 3 in a
diastereomeric excess of 21% by crystallization one time of
the diastereomer mixture of D-(-)-Tartaric acid and 2,and the
diastereomeric excess could reach 99% after three times re-
crystallization with the yield of 17% (the theoretical yield of
chiral resolution was 50%). In order to increase the effi-
ciency of resolution, we tried to use the ‘Dutch Resolution’
prepare 3. We studied the effect of resolution between dif-
ferent combinations of D-(-)-Tartaric acid and its deriva-
tives (Fig. 1), to our great surprise, we can almost complete
separation of 3 and GS-7339 when we used to 1:1 propor-
tion of D-(-)-Tartaric acid and D-DBTA as the resolving
agent (Table 2).
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
The authors acknowledge financial support for this
work by the Natural Science Foundation of Chongqing
(cstc2016shmszx130079).
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CONCLUSION
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In a word, we have developed an efficient and chroma-
tography-free route for the preparation of TAF. In considera-
tion of the expensive equipment and higher operation cost of
SMBC, we chose a traditional resolution route to obtain
chiral phosphorus.
DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Edito-
rial Department reserves the right to make minor modifications for further improvement of the manuscript.