Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint-Driven Innovation

Article abstract of DOI:10.1021/acs.oprd.0c00145

A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low-cost, widely available starting materials - we refer to this as supply-centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precursors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate, and water to produce the oxathiolane.

Full text of DOI:10.1021/acs.oprd.0c00145

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Communication
Synthesis of an Oxathiolane Drug Substance
Intermediate Guided by Constraint Driven Innovation
K. Kashinath, David Snead, Justina M. Burns, Rodger W. Stringham, B. Frank Gupton, and D. Tyler McQuade
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00145 • Publication Date (Web): 13 May 2020
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Organic Process Research & Development
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Synthesis of an Oxathiolane Drug Substance Intermediate Guided by
Constraint Driven Innovation
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K. Kashinath,‡ David R. Snead,‡* Justina M. Burns, Rodger W. Stringham, B. Frank Gupton, D. Tyler
McQuade*
Supporting Information Placeholder
which is driven to completion via selective crystallization of a
single isomer from solution.
ABSTRACT: A new route was developed for construction of the
oxathiolane intermediate used in the synthesis of lamivudine (3TC)
and emtricitabine (FTC). We developed the presented route by
constraining ourselves to low cost, widely available starting
materials – we refer to this as supply centered synthesis. Sulfenyl
chloride chemistry was used to construct the framework for the
oxathiolane from acyclic precursors. This bond construction choice
enabled the use of chloroacetic acid, vinyl acetate, sodium
thiosulfate and water to produce the oxathiolane.
Perhaps a different way to approach the problem would be to work
within the current manufacturing route. One such strategy would
be to improve the route to oxathiolanes themselves thus
complementing the existing knowledge, supply chain, and
regulatory framework. The majority of syntheses make use of
condensation of 1,4-dithiane-2,5-diol with l-menthol glyoxylate 5,
with an exception presented in the step-wise ring closing of a
protected hemi-thioacetal by Rayner and coworkers also at GSK.2f
We hypothesized that a new approach that replaced the use of the
glyoxylate ester and the dithiane-diol could accomplish three
outcomes: (1) decrease the raw material costs; (2) increase the
supply-chain security for making 3TC and FTC; and (3) increase
the number of producers because an entirely new approach might
fit well in to the skill set of new market entrants.
Keywords: antiviral, nucleoside, oxathiolane, supply chain, HIV
Lamivudine 1, and emtricitabine 2, are essential components of
widely prescribed multi-drug regimens.1 Both nucleosides analogs
are high dosage/high demand drugs and manufactured in large
volumes (>1000 MT/yr). Though the price of 3TC (~$140/kg) is
low by comparison to other APIs of similar structural complexity,
procurers (GOs and NGOs) spend >$200MM/year and the number
of patients that receive these life-saving medicines is fixed by
procurer budgets. For this reason, decreasing production costs
constitutes an impactful yet difficult challenge.
Building Blocks for Oxathiolane Ring
Carboxy Fragment
Sulfur
Anomeric Fragment
Mining, Water
Treatment
Adhesives
Cl
Cl
X = OH
O
OEt
Cl
SCl2
Na2S2O3
$0.35/kg
S8
OAc
Cl
X
Cl
$0.90/kg
$0.28-0.80/kg
$0.74/kg
$0.23/kg
$0.70/kg
$0.80/kg
Oxygen
Cellulose
Derivatives
O
Water
H2O
R
O
O
S2Cl2
Na2S
NaSH
Cl
O
NH2
NH2
HO
HO
O
O
N
N
N
N
$0.66/kg
$2.4/kg
$0.66/kg
$0.66/kg
$0.94/kg
$0.00/kg
O
HO
S
S
O
O
3
How Can Chemical Reactivity be Manipulated to Achieve the Desired Result?
1
R = H (Lamivudine)
2
F (Emtricitabine)
O
O
O
+
Na2S2O3 +
Cl
O
O
OAc
OH
OH
HO
O
O
OH
O
S
O
OH
S
OH
4
?
4
6
5
Key Intermediate
Figure 2. Supply centered synthesis molecular construction from
commodity chemical materials.
Figure 1. Commercial retro-synthetic route for lamivudine and
emtricitabine.
Our team at M4All starts designing new routes from the perspective
that APIs can be built from simple, high-volume, low-cost raw
materials using modern synthetic methods/knowledge. We call this
approach “Supply Centered-Synthesis”. To envision new
economical routes to oxathiolanes, we developed a subset of
building blocks with the right oxidation state, functionality, and
carbon count for each fragment of the ring (Figure 2). Viability of
each building block was assessed by examining volume and price
of each chemical as found through import/export records of India,
a major player in the global manufacture of API. Instead of
considering the most straightforward retrosynthetic assembly of
The vast majority of innovation related to 3TC and FTC has
focused on improved methods to establish stereochemistry about
the oxathiolane ring2 and install the cytosine and 5-fluorocytosine
nucleobases.2a,h,k,3 Despite these efforts, the original synthesis
developed at GSK by Whitehead and coworkers remains in place
today as the manufacturing bond forming sequence of choice
(Figure 1).2i,k The GSK approach features a dynamic kinetic
resolution to afford optically pure hydroxyoxathiolane 4, a key
intermediate in the synthesis.
L-Menthol 6 controls the
stereochemical outcome of the dynamic kinetic resolution (DKR)
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Page 2 of 6
mixture of vinyl acetate and SO2Cl2. f) Reaction run in CDCl3. g) Reaction
run in toluene.
fragments, we prioritized reagent availability and cost and then
sought reactions to render a viable process.
1
2
3
4
5
6
7
The key transformation was validated by combining methyl
thioglycolate (MTG, 7) and vinyl acetate (VA) (Table 1).
Optimization increased the yield of the dichlorinated intermediate
10 to >95%. The model system was quickly extended to the l-
menthyl ester with performance matching that of the methyl ester,
and the reaction was conducted in toluene for increased
sustainability.
Chloroacetic acid, sodium thiosulfate and vinyl acetate quickly
emerged as lead candidates, presuming they could be transformed
into the oxathiolane core in a modest number of steps. All of these
O
O
SO2Cl2
OAc
O
Cl
SH
S
S
RO
RO
Cl
RO
OAc
7
R = Me,
8
9
R = Me,
R = Me,
12
R = Menthyl,
13
14
R = Menthyl,
R = Menthyl,
8
9
We observed an unanticipated feature of the reaction early on
where reactions run in sealed vessels provided much higher yields
compared to reactions run in open vessels (Entries 1 and 2). When
sealed reactions were opened, gas release was evident. Further, in
a pressurized NMR tube, HCl reacted with vinyl acetate to make 1-
chloroethyl acetate. The reaction appears to be sensitive to the HCl
gas concentration in solution and we suspect that this is the origin
of the pressure dependence.
O
Cl
O
SO2Cl2
H2O
O
S
OH
10
11
12
13
14
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RO
OAc
RO
S
Cl
11
R = Me,
R = Menthyl,
10
R = Me,
R = Menthyl,
4
15
Figure 3. Proposed route to oxathiolane from vinyl acetate and
glycolate ester.
raw materials are fundamental feedstocks for the chemical industry
and are <$1/kg. Their end uses point toward their high volume
consumption: chloroacetic acid is used to make cellulose
derivatives for the food and cosmetics industry, sodium thiosulfate
is used in mining, water treatment and fertilizer industries, and
vinyl acetate is used as the precursor to polyvinyl acetate, a major
adhesive class. Since these are produced in the 100’s of MM kg/yr,
the supply chain and availability is secure. While starting from low
cost, high-volume raw materials is somewhat obvious, the key to
their use is development of an efficient route. Five bonds must be
constructed, three oxidations are needed, and one functional group
must be hydrolyzed. Although many routes were considered by our
team, we found the route in Figure 3 to be the most promising.
The reaction also showed a strong temperature dependence.
Lowering reaction temperature increased yield significantly
(Entries 6-8 vs. 9-11). A large exotherm was observed both on
addition of sulfuryl chloride and vinyl acetate. Presumably cooling
helps to mitigate the detrimental effects of the exotherm. Reactions
run at room temperature rather than -20 °C contained primarily
monochlorinated sulfide 9 as a major impurity, a surprising result
of incomplete reaction. One would expect a system to be overly
reactive at elevated temperatures. Perhaps the reason for this
phenomenon is similar to that of the observed pressure sensitivity.
There is a need to maintain headspace control and keep gases in
solution; however, gases become less soluble as temperature
increases. Sulfuryl chloride is stated to behave as a source of
chlorine gas, a compound which is known to promote α-
chlorination.8 Possibly HCl or Cl2 is the required for the
transformation to take place, and temperature rise might drive these
out of the system. This is consistent with decrease in yield as
reaction concentration increases tight temperature control is more
difficult to maintain.
The route we envisioned starts with chlorination of thioglycolic
acid using the method of Smit (Figure 3). 4 If we wanted to take the
process to very high volume starting materials, thioglycolic acid
can be accessed from chloroacetic acid and sodium thiosulfate.5 We
imagined that the sulfur-carbon bond could result via regioselective
1,2-insertion of a sulfenyl chloride into the olefin of vinyl acetate
to directly couple the two carbon containing fragments.6 In this
way, the required oxidation state at the anomeric center, a masked
aldehyde, could be established. Futhermore, we hypothesized that
excess sulfuryl chloride could α-chlorinate the ester thereby
establishing all of the necessary oxidations states.7 Reaction with
water to close the ring would complete the oxathiolane synthesis.
O
O
O
Cl
O
MeCN/H2O
OH
S
O
O
OAc
S
Cl
15
4
O
Cl
Table 2. Optimization of Ring Closing in Water
1) SO2Cl2, DCM, rt, 30 min
+
SH
OAc
S
RO
RO
OAc
Cl
MeCN: Temp
Time Yield
Table 1: Oxidative coupling of thioglycolic acid and vinyl acetate
Entry
1c
2b
H2Oa
1.5
2
(°C)
Additive
-
(hr)
(%)
Order of Volumes
Addition Solvent
65
15
42
Temp. ( ﾟC)
Entry
1a,c
2b,c
R
Yield (%)
55
NaOAc
TEA
15
48
Me
VA Last
"
10x
"
20
"
76
91
3b,d
2
55
22
69
Me
Me
1M TEA in
ACN
3b,d
SO2Cl2 Last
"
"
90
4b,d
5b,d
6c
7c
8c
1
1
1
1
1
1
80
80
2
2
64
68
63
66
69
66
5b,e
6b,c
7b,c
8b,c
9b,c
10b,c
11b,c
12b,f
13g
MTG Last
"
2x
6x
10x
2x
6x
10x
6x
"
"
"
89
83
91
91
90
97
95
99
95
1M NaHCO3
α-pinene
Me
Me
60
8
VA Last
80
α-pinene
3
Me
"
"
"
"
"
"
"
"
Me
100
90
α-pinene
2
"
9c
Styrene oxide
2.5
Me
-20
"
Me
2,2-Dimethyl
oxirane
10c
1
90
2.5
62
Me
"
a) 20 volumes of acetonitrile b) Reaction run at 100 mg scale c) Reaction
run at 1g scale. d) Additive was added portion wise.
Menthyl
Menthyl
"
"
a) Reaction run in 4 mL vial open to atmosphere. b) Reaction run in sealed
NMR tube. c) Vinyl acetate added to mixture of MTG and SO2Cl2. d)
SO2Cl2 added to a mixture of MTG and vinyl acetate. e) MTG added to a
Proof of concept for the process was completed by demonstrating
viability of ring closing to form the oxathiolane from 15 (Table 2).
2
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Organic Process Research & Development
Combining 15 with water and acetonitrile provided the desired
toluene and crystallizing with hexanes as antisolvent in 56%
overall yield and >99% purity. Compound 4 was converted to
lamivudine 1 with 99% chiral purity by following known
procedure.2i
1
2
3
4
5
6
7
8
material in a modest 42% yield and with optimization the yield was
improved to 69%. During optimization, we discovered that highest
yields were obtained when the ring closure was run between pH
3-4 using base additions to maintain the pH within those
constraints. While selective transesterification is necessary to
initiate the reaction, an overly reactive system leads to cleavage of
the menthyl ester as observed by presence of free menthol.
Controlling pH to neutralize HCl generated in the course of
reaction led to slight improvement in yield, but it was important not
to reach alkaline pH as base rapidly decomposes starting material
and product.
Thioglycolic acid
SO2Cl2
0 °C
O
SH
OH
PTSA•H2O, toluene
reflux
O
12
6
10g
9
10
11
12
13
14
15
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O
Cl
Vinylacetate
-20 °C
O
We propose that the reaction proceeds first through hydrolysis of
the acetate 15, to generate aldehyde 17. The α-chloride is then
hydrolyzed and the ring closes. This hypothesis is supported by
generation of the dimethoxyacetal in 90% yield along with
methylacetate when 15is exposed to methanolic HCl. The α-
S
S
O
OAc
NH2
O
Cl
Cl
15
13
O
O
OH
H2O, MeCN, 70 °C
ref 2i
O
N
O
N
chloro-functionality is retained.
Conversion of 10 slows
HO
S
1% TEA in hexanes
0 to -15 °C
S
O
significantly in the absence of HCl as the transesterification
requires acid catalyst. Indeed, when run in water, trace aldehyde
peak (<5%) is detected by NMR. The α-chlorosulfide can then be
functionalized with a variety of oxygenated nucleophiles including
alcohols and carboxylates. Many unsuccessful attempts were made
to isolate by-products and side-products including preparative
HPLC and liquid nitrogen trap of any gaseous compounds. Both
NMR and LC traces showed little besides oxathiolane 4 leading to
frustratingly little evidence to aid optimization.
4
1
56% Overall
Figure 6: Synthesis of 4 directly from l-menthol.
We investigated a wide range of conditions to improve the yield of
the cyclization from 15 to 4. The modest yield of product is
accompanied by off-products that appeared as broad signals by
NMR and were not observed using HPLC or other characterization
technique. We speculate that either 15 decomposes to materials that
evaporate readily or oligomerize. Because our attempts at
byproduct analysis did not provide actionable insights, we explored
the effect of replacing vinyl acetate with ethyl vinyl ether (Figure
7). Ethyl vinyl ether is widely available via vinylation of ethanol
with acetylene and is used in a variety of adhesive applications.10
The more electron rich olefin was highly reactive with sulfenyl
chloride, and unexpectedly, the aldehyde 17 was obtained upon
working up the addition of sulfenyl chloride to olefin rather than
the chloroether 19. Perhaps accelerated C—Cl cleavage is also an
effect of the ether’s greater electron density. The overall yield
increased moderately after cyclization, but more importantly, the
solvent quantity required for cyclization is reduced by half as
compared to the vinyl acetate approach.11 Alkyl chlorides are quite
hydrophobic, and presumably the reduced need for solvent is an
effect of cleaving one of the alkyl chlorides.
O
Cl
O
O
Cl
OH
OH
S
S
O
O
O
O
Cl
15
Cl
O
16
H
H
H
H
O
O
H
- HOAc, - HCl
- HCl
S
O
O
Cl
17
O
O
H
O
OH
S
O
O
O
S
OH
4
18
Figure 4: Proposed mechanism of oxathiolane 4 from 15
commencing with hydrolysis of acetate.
This route depends on access to l-menthyl ester 12. Fortunately,
esterification of thioglycolic acid provided entry to this compound
in high yield (98%).9 Only trace solvent (0.5 volumes of toluene)
was needed for the sake of temperature control and removal of
water to drive the esterification. (Figure 5).
Thioglycolic acid
PTSA•H2O, reflux, 2h
O
1. SO2Cl2, 0°C, 2h
SH
OH
O
Ethyl vinyl ether
2.
,
Toluene
-20°C, 90min
6
12
O
Thioglycolic acid
SH
O
O
1M NaHCO3
55°C, 1h
O
Cl
OH
+
O
S
PTSA•H2O, toluene
S
O
H
O
OEt
reflux
98%
Cl
Cl
6
12
19
17 major
Figure 5: Esterification of l-menthol.
O
O
O
O
OEt
OEt
OH
ACN, 65°C, 5h
62% over 5 steps
The individual transformations were stitched together to take l-
menthol directly to oxathiolane intermediate 4 needing only a water
rinse prior to isolation by crystallization (Figure 6). 10 g of l-
menthol was reacted with thioglycolic acid in 5 volumes of toluene.
After 2 hours, the reaction was cooled to 0 °C and sulfuryl chloride
was added to ester 12 to afford sulfenyl chloride 13. The reaction
was further cooled to -20 °C before adding vinyl acetate. Reagents
were added over 15 minutes by syringe pump due to the large
exotherms. The reaction mixture was partially quenched with
sodium bicarbonate and the toluene was stripped from chlorinated
residue. Acetonitrile and water were added to after returning the
chlorinated intermediate 15 to a reaction flask. Heating at 70 °C
formed the oxathiolane which was isolated by extraction with
S
S
O
Cl
20 minor
4
Figure 7: One-pot synthesis of 4 from l-menthol and ethyl vinyl
ether.
In this way, the sulfenyl chloride methodology proved to be a
versatile platform for entry into oxathiolane chemistry. Relevant
thiol esters were made from thioglycolic acid. The resultant thiol
was halogenated with sulfuryl chloride, and this sulfenyl chloride
was used to construct a sulfur carbon bond with vinyl acetate and
3
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Resolution of α-acetoxysulfides: A new approach to the synthesis
ethers. Presence of excess sulfuryl chloride halogenated the ester
in the α-position. This dichlorinated intermediate was cyclized in
water to generate the oxathiolane used in synthesis of 3TC and
FTC. By focusing on the chemical industry’s supply chain and base
reagents, a novel route was tailored to fit starting materials.
Combining a target-oriented retrosynthetic perspective with a
supply centered viewpoint served as a useful constraint to generate
creative and novel solutions for longstanding challenges.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information includes experimental details and
compound characterization. It is available free of charge on the
ACS Publications website including experimental details.
AUTHOR INFORMATION
Corresponding Author
* David Snead
Medicines for All Institute
737 N 5th St.
Box 980100
Richmond, Virginia 23298
E-mail: drsnead@vcu.edu
* D. Tyler McQuade
Medicines for All Institute
737 N 5th St.
Box 980100
Richmond, Virginia 23298
E-mail: tmcquade@vcu.edu
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
3) a) Nair, D.S.; Rai, B.P.; Nizar, H.; Meeran, P.N. Tewari, N. Process
and intermediates for the preparation of substituted 1,3-
oxathiolanes, especially lamivudine, US20100311961, 2010. b)
Tewari, N.; Nair, D.S.; Nizar, H.; Meeran, P.N.; Prasad, M. Process
ACKNOWLEDGMENT
We thank the Bill and Melinda Gates Foundation for their
longstanding support of our research.
for
the
preparation
of
substituted
1,3-oxathiolanes,
US20100311970, 2010. c) Shankar, R.; Vennapureddy, R.R.;
Sayyed, A.P.; Ankaraju, M.K.; Madasu, S.B.; Vascuri, J.R.;
Meenakshisunderam, S. Process for preparation of cis-nucleoside
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Graphical Abstract:
5
6
Key Intermediate in
Production of 3TC/FTC
R
7
8
9
O
O
1) SO2Cl2, DCM, rt, 30 min
NH2
O
+
+
SH
OAc
OH
O
HO
OH
N
O
N
2) H2O, MeCN, 50 °C
HO
R = H, Lamivudine
F, Emtricitabine
S
S
O
56% Overall
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