A Continuous Flow Sulfuryl Chloride-Based Reaction - Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine

Article abstract of DOI:10.1021/acs.oprd.0c00146

We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines emtricitabine and lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm and evolution of hydrogen chloride and sulfur dioxide. Keeping gaseous byproducts in solution and controlling the temperature led to better outcomes. These reactions are ideal candidates for implementation in a continuous mesoscale system for the sake of superior control. In addition, we found that fast reagent additions at controlled temperatures decreased byproduct formation. Herein we discuss the flow implementation and the final reactor design that led to a system with a 141 g/h throughput.

Full text of DOI:10.1021/acs.oprd.0c00146

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A CONTINUOUS FLOW SULFURYL CHLORIDE BASED
REACTION – SYNTHESIS OF A KEY INTERMEDIATE IN A
NEW ROUTE TOWARD EMTRICITABINE AND LAMIVUDINE
Juliana M. de Souza, Mateo Berton, David Snead, and D. Tyler McQuade
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00146 • Publication Date (Web): 13 May 2020
Downloaded from pubs.acs.org on May 14, 2020
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A Continuous Flow Sulfuryl Chloride Based Reaction – Synthesis of a Key Intermediate in
a New Route Toward Emtricitabine and Lamivudine
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Juliana M. de Souza, Mateo Berton, David R. Snead* and D. Tyler McQuade*
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*e-mail: drsnead@vcu.edu, tmcquade@vcu.edu
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Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond,
VA, 23284–3068, USA.
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ABSTRACT
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We demonstrate a continuous two-step sequence where sulfenyl chloride is formed, trapped by vinyl acetate
and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our
new approach to the oxathiolane core used to prepare the anti-retroviral medicines Emtricitabine and
Lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm
and evolution of hydrogen chloride and sulfur dioxide. Keeping gaseous byproducts in solution and
controlling the temperature led to better outcomes. These reactions are ideal candidates for implementation
in a continuous, mesoscale system for the sake of superior control. In addition, we found that fast reagent
additions at controlled temperatures decreased byproduct formation. Herein, we discuss the flow
implementation and the final reactor design that led to a 141g/h throughput system.
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Keywords: Lamivudine, Emtricitabine, API, Flow Chemistry, Continuous Processing, Scale-up
INTRODUCTION
Lamivudine and Emtricitabine (3TC and FTC, respectively), both nucleosides analogs, are high
dosage/high demand drugs and manufactured in large volumes (>106 kg/yr).1 Considering global health
applications, the active pharmaceutical ingredient (API) price (~$100/kg) is the major cost contributor
towards delivering these medicines to the patients. The Medicines for All Institute (M4ALL) seeks to
facilitate positive market conditions by creating low cost API routes to help balance the needs of procurers
and producers. M4ALL recently developed a new batch route to the oxathiolane core that serves as a key
intermediate for the synthesis of both 3TC and FTC (Scheme 1).
Our route relies on a sulfuryl chloride (SO2Cl2) mediated chloro-thioene reaction (Scheme 1). The process
begins with a Fischer esterification between L-menthol (1) and thioglycolic acid (2).2 The menthyl
thioglycolate (3) is then treated with SO2Cl2 to produce a sulfenyl chloride intermediate 4.3 The reaction
between the thioglycolate 3 and SO2Cl2 is exothermic along with the reaction of 4 with vinyl acetate (5).
The processing conditions were shown to have significant influence over the reaction outcome –
yield, product distribution and byproduct formation. In addition to the desired dichloro acetate 7, trichloride
byproduct 8 is produced in greater amounts when the reaction is not well-controlled (temperature, mixing
and residence time). Intermediate 7 cyclization was also studied by our group2 and the steps following
oxathiolane 9 are well described in the literature.4 We hypothesized that a continuous approach would
enable greater control over mixing rate and temperature.5 These features would offer potential adopters an
alternative approach to safely scale-up with improved selectivity. Herein, we present the reaction
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thermodynamic properties, reactor configurations and their influence on yields and selectivity for
transforming 3 into 7 (Scheme 1).
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7
8
9
O
SH
OAc
HO
O
Cl
O
O
2
5
SO2Cl2, toluene
-20 °C, 6h
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S
SCl
SH
PTSA H2O
toluene, reflux
O
OAc
O
OH
O
-20 °C
98%
6
3
4
1
O
Cl
O
O
Cl
SO2Cl2
-20 °C, 95%
O
1) H2O, MeCN, 70 °C
+
S
S
O
O
OAc
OAc
2) 1% TEA in hexanes
0 to -15 °C
O
OH
Cl Cl
Cl
AY: 88%
S
62% overall
9
byproduct
7
8
O
N
O
NH2
HO
Coupling / Reduction
Ref. 4
N
S
X
10:
11
X = H Lamivudine (3TC)
: X = F Emtricitabine (FTC)
Scheme 1. M4ALL’s new route to lower cost 3TC ⁄ FTC production – reaction steps from 3 to 7 are excellent candidates for the
presented continuous approach.
RESULTS AND DISCUSSION
BATCH EXPERIMENTS
Heat Flow Calorimetry. Reaction between SO2Cl2 and thiols are well-known to produce strong
exotherms.6 This is true for our case shown in Scheme 1; when SO2Cl2 and 3 are combined, the reaction
occurs immediately and the initially colorless solution becomes yellow with evolution of heat and gas
(HCl and SO2). As shown in our prior publication, the reaction is sensitive to both temperature and pressure
control.2 In scaling our route from milligram to gram scale (batch), the temperature rise was large and fast
enough to prompt a safety assessment using heat flow calorimetry. Using a batch-based heat flow
calorimeter, we measured the heat released during these transformations (Step 1 and 2, Figure 1).
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Step 1
Step 2
4
5
6
7
O
OAc
O
Cl
O
SO2Cl2
SO2Cl2
5
SH
S
S
O
DCM, -20°C
OAc
DCM, -20°C
2h
O
O
Cl
DCM, -20°C
4h
3
4
6
1.09 mol/L
8
9
O
Cl
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O
Cl
100% Mass Balance
S
2 SO2 (g)
+ 2 HCl (g)
S
+
OAc
+
O
AY:
7
8
88% (dichloro, ); 12% (trichloro, )
O
OAc
Cl Cl
Cl
7
8
byproducts
(B)
(A)
Figure 1. EasyMax HFCal runs (17.4 mmol of 3). (A) Addition of 38.3 mmol (2.2 equiv.) SO2Cl2 over 30 minutes – Step 1: 242
kJ/mol. (B) Addition of 34.8 mmol (2.0 equiv.) vinyl acetate (5) over 10 minutes – Step 2: 438 kJ/mol.
Batch optimization experiments revealed that 2.2 equiv. of SO2Cl2 produced the best yields and
selectivity. Two equivalents are necessary to support the multiple chlorinations (Step 1 and 2, Figure 1) and
we presume the 10% excess is due to reagent decomposition.2 The heat released during the formation of
sulfenyl chloride 4 (Step 1) is 242 kJ/mol. The vinyl acetate (5) addition (Step 2) is also exothermic
involving both the sulfenyl chloride 4 addition to vinyl acetate (5) and the chlorination of the alpha position
to the ester (6) to yield the desired dichloride 7. For this sequence of reactions, the generated heat is 438
⁰
kJ/mol. We predict this translates to an adiabatic temperature rise of 102–133 C for Step 1 and 138–207
⁰
C for Step 2, if the reaction is carried out in toluene. These highly energetic exotherms require either
changing the reactor modality, slowing the reagent’s addition or active cooling strategies.7 We demonstrate
below that a continuous approach is a viable strategy to perform this two-step sequence of reactions.
Batch Observations Germane to Creating a Continuous Process. Optimization experiments revealed
⁰
that Step 1 provides 6 in high yields (94–100%) over a wide operating temperature window, −20 C to 25
⁰
C. On the other hand, Step 2 provides the highest yields and selectivity for 7 when the reaction is carried
⁰
out at −20 C. Higher temperatures increase the ratio of trichloro 8 to dichloro 7 products and reduces the
overall yield due to material decomposition to a range of unidentified products.
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During reaction optimization, we observed that reactions carried out under autogenous pressure
provided better outcomes. Small perturbations to the system headspace such as sampling the reaction by
opening the reactor decreased yields at least 10%. The reaction produces a number of gaseous byproducts
including HCl and SO2. We observed that 7 is more stable under acidic solutions, which may indicate HCl
loss in the headspace can affect the yield. It appears lower reaction temperatures for Step 2 increases
reaction tolerance to pressure changes. This is likely due to higher amounts of HCl gas dissolving in the
reaction mixture. The combination of exotherm and pressure sensitivity suggest a continuous flow approach
might be an ideal modality to run this reaction sequence.
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The order of addition was expected to be important. We confirmed this suspicion by evaluating if
the first step could tolerate premixing the thiol 3 and vinyl acetate (5). This is an important consideration
for our potential flow system because the holding time of reagent/substrate solutions within reservoirs is an
opportunity for unanticipated chemistry. Unfortunately, when the thiol 3 and the vinyl acetate (5) were
combined, a thio-ene reaction took place with byproduct 14 formation (Scheme 2B). After SO2Cl2 addition,
the overall reaction provided 7 in lower assay yields (AY = 57%).8 Vinyl acetate (5) also reacts with SO2Cl2
to form 1,2-dichloroethyl acetate (12) (only traces were observed; Scheme 2A) and with hydrogen chloride
to produce 1-chloroethyl acetate (13).
(A)
k1 > k2
O
O
Cl
O
Cl
k1
SO2Cl2
S
S
+
S
OAc
O
Cl
O
OAc
Pathway A
O
OAc
5
Cl
4
6
7
Pathway B
SO2Cl2
Pathway C
HCl
k2
Cl
Cl
byproduct
Cl
OAc
OAc
12
13
(B)
O
O
O
Thio-ene reaction
OAc
byproduct
SH
+
S
O
O
O
h
3
5
14
Scheme 2. Possible pathways involving vinyl acetate (5) – (A) Desired reaction with sulfenyl chloride 4 to form 6 and reaction
with SO2Cl2 leading to 1,2-dichloroethyl acetate (12). (B) Thiol-ene reaction (alkene hydrothiolation) leading to byproduct 14 –
radical click mechanism initiated in the presence of light.
The occurrence of different side reactions involving vinyl acetate (5) prompted us to consider its
rate of addition before designing our continuous reactor arrangement. In particular, we sought to define a
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set of starting conditions. We elected to run each stage at −20 °C and add the SO2Cl2 over 15 minutes (213
µL/min) based on our earlier observations. Using these standard batch conditions, we varied the vinyl
acetate (5) (2 equiv.) addition rate (640, 213 and 53 µL/min) and analyzed the outcome by measuring
product distribution of the crude reaction after 4 h from the beginning of vinyl acetate (5) addition. The
results are shown in Table 1 and indicate that the addition rate of vinyl acetate (5) is inversely proportional
to the selectivity. As the rate of addition decreases, the proportion of byproduct 8 increases; however, since
the reaction is temperature sensitive yet also highly exothermic, slow addition is required. As the reaction
is progressively scaled, required addition time may escalate to maintain low temperatures. This indicates
that precise temperature control is required for the Step 2.
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Table 1. Variation of the vinyl acetate (5) addition rate – 4.0 g scale reaction.
Addition
time (min)
Mass
Balance (%)
Add. rate of 5
(µL/min)
∆T (°C)
Monochloro
Dichloro
7 (%)
Trichloro
8 (%)
Entry
6 (%)
1
2
3
640
213
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5
24
13
0
0
1
88
73
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99
99
15
60
1.5
100
CONTINUOUS FLOW EXPERIMENTS
Continuous flow experiments, system design and considerations. Formation of HCl and SO2 during the
reaction sequence limits the use of certain materials for the system construction due to the chemical
resistance incompatibility, which can generate safety issues. The rapid heat rise observed for both steps
suggested the use of better heat conductors such as stainless-steel reaction loops. However, this option was
discarded due to its poor compatibility with strong acid.9 Glass systems were also considered, but the
possible risk of polymerization/clogging encouraged us to take a different approach. Finally, we selected
perfluoroalkoxy (PFA) tubing as material for our coil reactor due to its high chemical resistance against
strong acid and solvent. We also leveraged a variety of pumping options – syringe, peristaltic and HPLC
pumps – to facilitate multiple reactor configurations. We avoided pumping SO2Cl2 with piston-based pumps
to avoid corrosion. We used spring-type back-pressure regulators (BPR) to be able to easily clean the solid
deposited on the BPR spring after each reaction.
Reactor Configurations. We began surveying reactor configurations by focusing on Step 1, the formation
of sulfenyl chloride 4. Thiol 3 (1.74 mol/L in DCM, Solution A) and SO2Cl2 (3.82 mol/L in DCM, 2.2
equiv., Solution B) were delivered using syringe pumps at 0.168 mL/min flow rate through a T-union
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(Internal volume = 0.5 mL) and then, through a 10 mL coil reactor (1/16’’ O.D., 0.030 I.D., PFA tubing,
Figure 2). We initially used 1/16’’ O.D. tubing for a high surface-to-volume ratio and therefore short
diffusion paths (no need for extra mixing elements) and efficient heat transfer (no need for extra cooling).
Due to the HCl and SO2 formation, a BPR (75 psi) was added at the end of the coil reactor to maintain the
gases dissolved into the reaction mixture and achieve a stable flow rate (Figure 2).
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SOLUTION A
Syringe
pump
O
SH
O
0.168
mL/min
3
BPR
O
T-union
0.5 mL
1.74 M DCM
S
O
Cl
75 psi
10 mL, 25°C
Syringe
pump
4
SOLUTION B
SO2Cl2
3.82 M DCM
0.168
mL/min
Figure 2. Initial flow setup for sulfenyl chloride 4 synthesis.
When a total flow rate of 0.336 mL/min was applied at 25 °C, compound 4 was obtained in 92% AY and
no remaning starting material 3 was detected (Table 2, Entry 1). Lowering the temperature to 0 °C, sulfenyl
chloride 4 yield obtained was 80% AY and 15% of thiol 3 remained unreacted (Table 2, Entry 2). By
decreasing residence time to 15 min at 25 °C, comparable results were obtained (Table 2, Entry 3). Although
mesitylene was used as the ¹H NMR internal standard during the first experiments (Table 2), we decided to
replace it for 1,2,3-trichloropropane (see Supporting Information). This non-standard trichloride is inert to
SO2Cl2, while mesitylene can present reactivity toward ring chlorination.10 This may be the cause of the
variable mass balance observed when Entry 1 (Table 2) was repeated in triplicate (95 ± 3 %).
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Table 2. Initial results for sulfenyl chloride 4 formation in continuous conditions – 400 mg scale.a
5
6
7
8
Reactor Residence
Mass Balance
Total flow rate
(mL/min)
Compound 4
AY (%)
92
Thiol 3
AY (%)
Entry
vol.
time
(%)
T (°C)
(mL)
(min)
9
1
2
3
0.336
0.336
0.336
10
10
5
30
30
15
25
0
0
92b
95
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15
12
80
82
25
94
a The whole volume of reagent solutions injected in the reactor was collected at 25 ⁰C and then 1 equiv. of mesitylene was added
relative to starting material 3.
b When the crude mixture was diluted with DCM and held at -78 °C during collection, the reaction between the remaining SO2Cl2
and mesitylene is suppressed and product 4 is obtained in 99 ± 1% AY and no loss in mass is observed (triplicate experiment) –
the same result is observed if 1,2,3-trichloropropane is used as the ¹H NMR internal standard.
We turned our attention to the vinyl acetate (5) addition (Step 2). Sulfenyl chloride 4 is not stable
and has to be generated in-situ to optimize the second sequence step. The flow setup is essentially made of
two combined modules (reactors 1 and 2) – the first module produces 4 and the second combines 4 with
vinyl acetate (5) to generate 7. The second module consists of a syringe pump delivering neat vinyl acetate
(5) to a T-union where mixing of 4 is commenced. The combined streams were reacted within another PFA
coil (Reactor 2) and a single BPR (75 psi) was placed after this loop (Figure 3).
Syringe
pump A
O
REACTOR 1
SH
O
0.504
mL/min
3
T-union
1.74 M DCM
0.5 mL
30 mL, 25 ºC
Syringe
pump B
REACTOR 2
SO2Cl2
BPR
Cl
3.82 M DCM
O
T-union
0.5 mL
0.504
S
mL/min
O
OAc
75 psi
30 mL, 25 ºC
Cl
Syringe
pump C
7
OAc
5
Neat (10.7 M)
0.162
mL/min
Figure 3. The initial flow setup with two modules - Module 1: Production of the sulfenyl chloride 4 in the Reactor 1; Module 2:
Combination of 4 with the vinyl acetate (5) stream at the Reactor 2 to produce 7.
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Using our initial reactor configuration (Figure 3), we explored different system properties. The
residence time in Reactor 1 was held constant at 30 min. Lengthening the reactor was necessary to achieve
this. The temperature of both modules was kept at 25 °C for all experiments shown in Table 3. The first run
using this two-module configuration (Figure 3) yielded 85% AY of dichloro acetate 7 and 13% AY of
byproduct 8, with a 98% mass balance (Table 3, Entry 1), which is similar to the results obtained in the
batch approach (data not shown). Decreasing Step 2 residence from 40 to 20 minutes produced compound
7 in 92% AY and trichloro 8 in 6% AY (Entry 2). The highest flow rate 1.17 mL/min does not provide
enough residence time to fully consume the monochlorinated intermediate 6 (Table 3, Entry 3). Doubling
the reactor loop volume from 15 to 30 mL resulted in the highest yield for the desired product 7 (Table 3,
Entry 4) – presumably due to improved mixing at higher flow rates. We ran these conditions in triplicate
and obtained the same results each time.
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Table 3. Continuous synthesis of compound 7 using the two-module configuration.a, b
Reactor 2 Residence
Mass
Balance
(%)
Total flow rate
(mL/min)
Trichloro 8
Dichloro
7 (%)
Entry
vol. (mL)
time
(min)
40
T (°C)
(%)
1
2
3
4
0.390
0.780
1.170
1.170
15
15
15
30
25
25
25
25
85
92
84
99
13
8
98
20
13
26
100
99c
3
1
100
a Residence time in the Reactor 1 was held constant at 30 min for all experiments (25 °C). This table presents the parameters
only for the Reactor 2. All experiments were ran in a 1.0 g scale.
b 1,2,3-trichloropropane was used as the internal standard (¹H NMR).
c 10% intermediate 6 and 2% sulfenyl chloride 4 left.
Reactor Refinement, Steady-State Evaluation and Scale-up. Positive results were obtained using 1/16”
O.D. tubing and increasing total flow rate to 1.17 mL/min. However, we wanted to further simplify the
setup, assess steady state stability and scale-up by increasing reactor diameter. An early observation
indicated that Reactor 1 (Step 1) residence time could be drastically reduced. At residence time of 15 min
at 0 °C (Step 1), a new unstable intermediate that leads to the formation of sulfenyl chloride 4 was detected
by ¹H NMR (see Supporting Information). Although this intermediate is not well-described, a few accounts
suggest that 14 is formed as a precursor of the sulfenyl chloride 4 (Scheme 3).11,12 We speculated that 14
might form so quickly that we could combine the output from module 1 with the vinyl acetate (5) stream
directly without need for a residence time loop (Reactor 1). Our hypothesis is that intermediate 14 would
not react directly with 5, thereby acting as a temporary protecting group against unwanted thio-ene reaction.
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"Protecting Group"
HCl
O
O
SO2Cl2
O
O
S
SH
S
O
O
S
O
Cl
O
Cl
4
3
SO2
7
15
8
9
OAc
OAc
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BYPRODUCT
O
S
O
O
14
BYPRODUCT
Scheme 3. First stage reaction of 3 with SO2Cl2 working as a thiol “protecting group”.
We tested this hypothesis by building two new reactor configurations. The same reagent concentrations and
reaction conditions were kept to perform these experiments. The first configuration fed a reactor with a
SO2Cl2, a vinyl acetate (5) and a thiol 3 containing stream into a single T-union at the same time – this
served as a control experiment where no thiol 3/SO2Cl2 premixing occurred before vinyl acetate (5) addition
(see Supporting Information). As expected, due to the different rates of the thiol 3 reaction with SO2Cl2 and
vinyl acetate (5) and SO2Cl2 reaction with 5, a complex mixture of products was obtained. For the second
reactor configuration, we premixed the thiol 3 and the SO2Cl2 using a small loop (1 mL) right after the first
T-union and immediately combined the resulting solution with the vinyl acetate (5) stream (see Supporting
Information). For this configuration, syringe pumps A and B operated at 0.504 mL/min and syringe pump
C at 0.162 mL/min (1.17 mL/min total flow rate), yielding product 7 in 95% AY and byproduct 8 in 5%
during a 26 minutes residence time. This result supports the model presented in Scheme 3 and enabled us
to refine our initial reactor setup to decrease the residence time between the two modules.
As we refined the system and moved our efforts toward confirming steady-state stability and
increasing throughput, we ran the system for longer periods of time. Increasing the reaction scale and the
volume of highly corrosive SO2Cl2 forced us to change the form of solution delivery from syringe to
peristaltic pump. Since a concentrated solution of SO2Cl2 (3.82 mol/L) is pumped through the system, we
were unsure how the pulsing of the peristaltic pump would affect the reaction. As such we selected
chemically resistant peristaltic pumps from Vapourtec (E-series). Initial testing was challenging because
the rubber hose swelled overtime when contacting the SO2Cl2 solution. This caused the system performance
to decrease or fluctuate overtime. To avoid swelling, we replaced the tubing before long reaction runs and
no tubing deformation was observed for the following ~100 h of pumping SO2Cl2. It is worth mentioning
that the E-series pumps must be properly calibrated from time to time. For some experiments we observed
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irregular pumping. Different volumes of thiol 3 and SO2Cl2 solutions were injected into the system despite
equal flow rates being applied to both solutions. This issue can be easily overcome after the calibration.
6
7
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9
During these longer runs (reagent solutions with total volume Vtotal ≥ 100 mL, ca. 5 reactor
volumes), yield decrease was detected. This appeared to be correlated with a temperature increase in the T-
union 2 (Figure 4, without the second 1 mL loop). In this case, compound 7 assay yield was about 90% and
10% trichloro acetate 8 was formed. Temperature control was achieved by submerging both T-unions into
a 2 L water bath at 20 °C. A thermocouple was placed in-line immediately after the T-piece 2 (ca. 20 mm)
and a second one inside the water bath. A temperature rise of 2 °C was observed right after T-union 2,
which remained constant through the entire experiment. The 1 mL PFA loop positioned after T-union 2
provides enough residence time for the reaction mixture to reestablish its original temperature. The high
yields of compound 7 were recovered (98 ± 2% AY) most likely due to the better temperature control,
which limited byproduct 8 rate formation. During these long runs, the pressurized system was ca. 2 bar
higher than the applied back pressure (5 bar) due to pressure drop across the system at larger scale. This
observation prompted us to lower system pressure using a 40 psi BPR and work the peristaltic pumps closer
to their optimum operation pressure as indicated by Vapourtec (3 bar).
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Peristaltic
pump A
O
Water Bath 20 ºC
REACTOR 1
SH
O
0.504
mL/min
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T-union
0.5 mL
1.74 M DCM
Quench
Waste
NaOH
(2 M)
1 mL
Peristaltic
pump B
REACTOR 2
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BPR
3.82 M DCM
T-union
0.5 mL
0.504
mL/min
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40 psi
20 mL, 25 ºC
Peristaltic
pump C
Gas
S
OAc
= In-line
Thermocouple
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0.162
mL/min
Neat (10.7 M)
Cl
O
O
OAc
Cl
7
Figure 4. The improved configuration where the residence time feature for the sulfenyl chloride 4 module is reduced in volume (1
mL); the temperature after T-union 2 is monitored via an in-line thermocouple and part of the two-module system is cooled via two
units of a 1 mL residence time loop submerged in a water bath at 20 °C (highlighted by the red dotted line). The 75 psi BPR was
replaced for a 40 psi and the final product is collected in a holding tank fitted with a base scrubber.
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A study of the steady state stability over time was performed (approximately 70 min or 3.5 times
the reactor volume) using the flow setup shown in Figure 4. Nearly 50 samples were collected over the total
experiment time and analyzed by ¹H NMR to assay yield determination. The steady state is reached after 5
minutes and the assay yield average of compound 7 is 98 ± 1%. The switch between starting material
solutions and solvent (Figure 5) causes small variations at the end of the steady state.
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Volumetric Turnover #2
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Volumetric Turnover #4
Volumetric Turnover #1
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Time (min)
Figure 5. Variation of dichloro acetate 7 yield over time – total flow rate 1.17 mL/min with a 17 minutes residence time – In the
steady state product 7 assay yield is 98 ± 1% and 0% of 6 was observed using 1H-NMR with 1,2,3-trichloropropane as the internal
standard. Volumetric turnover ≈ 20 mL.
During solvent screening we found that DCM and toluene provide the best yields of compound 7.
Sulfuryl chloride reacts with many solvents so the range of options is smaller than usual.13 During batch
experiments DCM provided higher assay yields than toluene (88% versus 78%, respectively). However, no
difference was observed under continuous conditions (steady state). Thus, we decided to proceed with
toluene for both economic and environmental considerations. Having defined a configuration that
functioned at steady state for long runs, we continued defining best operating conditions for scaling-up.
Increasing the flow rates of this refined system (Figure 4) from 1.17 up to 2.11 mL/min does not alter the
yield of 7, but does increase the system productivity (Table 4). We decided to use the middle residence time
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of 14 minutes (Table 4, Entry 2) – a condition where no unreacted intermediate 6 is observed – to test
scaling-up the system by doubling the tubing diameter from 0.03 in I.D. (1/16” O.D.) to 0.06 in I.D. (1/8”
O.D.).
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9
Table 4. Optimization of reaction in toluene and steady state conditions.a, b
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Total flow Residence
Mass
Balance
(%)
Monochloro
Dichloro Trichloro
Entry Solvent
rate
(mL/min)
1.17
time
(min)
17
6 (%)
7 (%)
8 (%)
1
toluene
toluene
toluene
toluene
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100
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4
a All samples were collected in vials containing a saturated NaHCO3 aqueous solution to quench the remaining SO2Cl2 and
the HCl, avoiding over-reactions.
b 1,2,3-trichloropropane was used as the internal standard (¹H NMR).
Using the conditions previously described (Table 4, Entry 2), we confirmed that scaling-up from
1/16 to 1/8” O.D. tubing did not impact product yield or selectivity, and the in-line thermocouple
did not register an increase in temperature (Table 5, Entry 1). Furthermore, we observed that
increasing the flow rate by a factor of five enabled a production campaign of ca. 32 g without
changing the reaction conditions (Table 5, Entry 2). Finally, we increased the run time at the 7
mL/min flow rate and produced around 260 g of dichloro acetate 7 corresponding to a throughput
of 141 g/h (Table 5, Entry 3).
Table 5. Scale-up experiments in steady state conditions.a, b
Total flow
rate
(mL/min)
Mass
Balance
(%)
Scale (g)
Thiol 3
Residence
time (min)
Monochloro 6 Dichloro 7 Trichloro
Entry
(%)
(%)
8 (%)
1
2
3
8
1.40
7.00
7.00
14
14
14
0
98
2
100
100
100
20
1
0
97
98
2
2
158
a Reaction mixture fractions were collected over 1.5 h every six minutes (all them in steady state). All samples were
collected in vials containing a saturated NaHCO3 aqueous solution.
b 1,2,3-trichloropropane was used as the internal standard (¹H NMR).
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CONCLUSION
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8
We recently created a new approach to synthesize the oxathiolane core used in the commercial route to the
high volume anti-retroviral medicines Lamivudine and Emtricitabine. This new route uses SO2Cl2 to
produce the alkyl sulfenyl chloride 4 followed by a chloro-thioene reaction to yield 7. This intermediate
undergoes a cyclization step to produce the oxathiolane 9. This sequence of reactions is sensitive to mixing
and produces strong exotherms (Figure 1). We first conducted a number of experiments in batch to
determine how to implement these two steps in a continuous flow approach. A two-module setup was
developed (Figure 3), where thiol 3 was first premixed with SO2Cl2 (Module 1) and the resulting solution
combined with the vinyl acetate (5) stream (Module 2). While studying this module, we noticed that
intermediate 15 is readily formed when 3 reacts with SO2Cl2, thus acting as a thiol protecting group. This
avoids the reaction of 3 with vinyl acetate (5) and consequently, byproduct 14 formation (Scheme 3). This
enabled a considerable reduction of the residence time in Module 1 (Figure 4). While studying the reaction
in steady-state runs, we observed that the overall yield of 7 and stability of the system can be improved
with better temperature control and heat removal from the mixing zones, where the temperature increase is
more evident (T-unions region, highlighted in red, Figure 4). Finally, we designed a stable flow system that
can be scaled-up and deliver compound 7 in high yields (98 ± 2%). The final run produced around 260 g of
7 with a throughput of 141g/h. The data suggests a continuous production strategy is feasible for producing
the oxathiolane core precursor 7.
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EXPERIMENTAL SECTION
General information. All commercially available reagents and solvents were purchased from
SigmaAldrich, TCI Chemicals, J. T. Baker and MilliporeSigma and used as received. Thin layered
chromatography (TLC) and column chromatography were performed using silica gel 60 F254 plates (0.25
mm) and silica gel (pore size 60 Å, 70–230 mesh, 63–200 μm) respectively (from Sigma-Aldrich). Nuclear
magnetic resonance spectra (1H and 13C NMR) were acquired using a Bruker-600 MHz spectrometer.
Chemical shifts for hydrogens and carbons are reported in parts per million (ppm) downfield from
tetramethylsilane (TMS) or referenced to residual solvent. Data are represented as follows: chemical shift
(δ), multiplicity singlet (s), broad singlet (br. s), doublet (d), broad doublet (br. d), triplet (t), quadruplet (q),
octet (oct), double doublet (dd), double triplet (dt), double double doublet (ddd), triple doublet (td), and
multiplet (m), coupling constants in Hertz (Hz) and integration.
NMR data was processed using the ACD Laboratories software, and the names of compounds were
generated using the PerkinElmer ChemDraw Ultra v.12.0.2 software package. Syringe pumps utilized to
perform flow experiments were purchased from Chemyx (Fusion 4000 and Fusion 6000). For the scale-up,
peristaltic pumps from Vapourtec E-series were used. Perfluoroalkoxy (PFA) tubing (1/16 inch O.D.; 0.030
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inch I.D. and 1/8 inch O.D.; 1/16 inch I.D.), back-pressure regulators (BPR), connections and fittings were
purchased from Swagelok, Cole-Parmer and IDEX Corporation.
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(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-mercaptoacetate (3). L-menthol (1) (100.0 g; 0.64 mol) was
loaded in a 500 mL round-bottom flask and partially dissolved in toluene (100 mL). Thioglycolic acid (46.0
mL; 61.7 g; 0.67 mol) and PTSA (881.7 mg; 5.12 mmol) were added at 25 °C. The reaction mixture was
refluxed (111 °C) for 2.5 h using a Dean-Stark apparatus to remove the water formed during the reaction.
The mixture was allowed to reach room temperature, neutralized with NaOH 1M (100 mL) and extracted
with toluene (3 x 100 mL). The organic phases were combined, dried with anhydrous Na2SO4 and the
solvent was removed in a rotatory evaporator. Remaining toluene was removed under reduced pressure in
a vacuum pump for 6 h. Compound 3 was obtained as a colorless oil in 96% AY and 95% purity (141.5 g;
0.61 mol). Thiol 3 was used in the next step without further purification. Reagents and solvents: L-Menthol,
≥ 99%, FCC, FG (Sigma-Aldrich), Thioglycolic acid, 98% (Sigma-Aldrich), p-Toluenesulfonic acid
monohydrate, ACS reagent, ≥ 98.5% (Sigma-Aldrich), Toluene, 99.5%, Baker Analyzed ACS reagent (J.
T. Baker). 1H NMR (600 MHz, CDCl3): δH 4.64 (dt, J1 = 11.0 Hz, J2 = 4.4 Hz, 1H), 3.15 (d, J = 8.3 Hz,
2H), 1.91–1.99 (m, 2H), 1.80–1.89 (m, 1H), 1.58–1.66 (m, 2H), 1.38–1.48 (m, 1H), 1.30–1.38 (m, 1H),
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0.89–1.05 (m, 2H), 0.76–0.88 (m, 7H), 0.70 (d, J = 7.2 Hz, 3H). C{¹H} NMR (150 MHz, CDCl3): δC
170.1, 75.3, 46.8, 40.4, 34.0, 31.2, 26.6, 26.0, 23.2, 21.8, 20.6, 16.1.
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(chlorothio)acetate (4). Initial experiments to study sulfenyl
chloride 4 formation under continuous flow conditions (syringe pumps): Thiol 3 (4.00 g; 17.4 mmol) was
loaded in a volumetric flask (10 mL) and DCM was added up to the level of the etched line (Solution A).
The same was done to prepare SO2Cl2 (3.2 mL; 38.2 mmol; 2.2 equiv.) solution in DCM (Solution B). The
entire flow system was previously flushed with DCM and pressurized at 75 psi using a BPR. A shut-off
valve was placed between the T-union and the reactor coil to maintain the system pressure and to be able
to switch from solvent to reagent solution and vice versa. Solutions A and B were transferred into 8 mL
Harvard syringes with 2 mL of extra tubing to accommodate the 10 mL solutions. Both solutions were
pumped with Chemyx syringe pumps at 0.168 mL/min flow rate each through a 10 mL PFA coil reactor
(1⁄16" O.D. tubing, Vapourtec). When the two solutions were totally injected, fresh DCM was pumped at
0.336 mL/min (through the shut-off valve) to keep the reaction mixture moving forward at the same flow
rate (see ESI – Fig. S2 and S3). Compound 4 was not isolated. Crude mixture: 1H NMR (600 MHz, CDCl3):
δH 4.77 (dt, J1 = 10.8 Hz, J2 = 4.4 Hz, 1H), 3.88 (s, 2H), 2.00–2.06 (m, 1H), 1.89–1.97 (m, 1H), 1.67–1.73
(m, 2H), 1.34–1.55 (m, 2H), 0.99–1.12 (m, 2H), 0.84–0.94 (m, 7H), 0.77 (d, J = 7.0 Hz, 3H).
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-((2-acetoxy-2-chloroethyl)thio)acetate (6). Intermediate
isolated only to use as a reference to compare with the ¹H NMR of the crude reaction mixture. It was
obtained as a colorless oil. 1H NMR (600 MHz, CDCl3): δH 6.48 (dd, J1 = 8.1 Hz, J2 = 4.0 Hz, 1H), 4.65–
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4.74 (m, 1H), 3.26–3.11 (m, 4H), 2.11 (s, 3H), 1.94–2.01 (m, 1H), 1.81–1.89 (m, 1H), 1.62–1.68 (m, 2H),
1.33–1.51 (m, 2H), 0.93–1.07 (m, 2H), 0.79–0.90 (m, 7H), 0.73 and 0.72 (d, J = 2.8 Hz, 3H). 13C{¹H} NMR
(150 MHz, CDCl3): δC 169.2, 168.1, 81.8, 75.5 and 75.4, 46.9 and 46.8, 40.6 and 40.5, 39.0 and 38.9, 34.2
and 34.1, 34.0, 31.2, 26.1 and 26.0, 23.2, 21.8, 20.6, 16.1 (Duplicate signal – diastereoisomers mixture).
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-((2-acetoxy-2-chloroethyl)thio)-2-chloroacetate (7). Batch
Procedure: Thiol 3 (4.00 g; 17.4 mmol) was loaded in a round-bottom flask and dissolved in anhydrous
DCM (16 mL). The solution was transferred to an EasyMax reactor under nitrogen atmosphere. When the
system stabilized at −20 °C, SO2Cl2 (3.2 mL; 5.16 g; 38.2 mmol) was added at 213 µL/min. The reaction
was kept under these conditions for 2 h. Vinyl acetate (3.2 mL; 3.00 g; 34.8 mmol) was added at 640 µL/min
addition rate. After 4 h, the reaction was neutralized with NaHCO3 saturated solution (50 mL) and extracted
with DCM (3 x 50 mL). The organic phase was separated, dried with anhydrous Na2SO4 and the solvent
was removed under reduced pressure. Compound 7 was obtained in 88% AY (15.3 mmol; 5.90 g) and the
trichloride byproduct 8 in 11% AY (1.91 mmol; 0.80 g). Reagents and solvents: Sulfuryl Chloride, 97%
(Sigma-Aldrich), Vinyl Acetate Monomer (Stabilized with HQ) (TCI Chemicals), Dichloromethane,
anhydrous ≥ 99.8% stabilized, DriSolv® (MilliporeSigma), Toluene, anhydrous ≥ 99.5%, DriSolv®
(MilliporeSigma).
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Optimization of compound 7 synthesis under continuous flow conditions (syringe pumps). The outcome
of the previously described sulfenyl chloride 4 synthesis flow setup was combined with vinyl acetate (5)
through a T-union. Vinyl acetate (5) flow rate was adjusted (syringe pump) to 2 equiv. relative to thiol 3.
After the second T-union, the reaction mixture was pushed through a second PFA coil reactor (15 mL). The
entire setup was pressurized at 75 psi using a BPR (see ESI – Fig. S4 and S5).
Vapourtec peristaltic pumps. Thiol 3 (8.00 g; 34.8 mmol) was loaded in a volumetric flask (20 mL) and
toluene was added up to the level of the etched line (Solution A). The same was done to prepare SO2Cl2
(6.24 mL; 76.4 mmol; 2.2 equiv.) solution in toluene (Solution B). Each solution was transferred to a 20
mL vial under nitrogen atmosphere, and then connected to the V-3 peristaltic pumps (E-Series – Vapourtec
flow system). The whole system was previously flushed with toluene and pressurized to 40 psi using a BPR.
A 50 mL Harvard syringe was filled with vinyl acetate (neat) and pumped using a Chemyx syringe pump.
The two-step reaction was carried out at 25 °C. The crude mixture was neutralized with a NaHCO3 saturated
solution before NMR analysis. The thiol 3 used in these reactions was not purified by chromatographic
column with silica gel. The crude starting material was treated only with a basic wash to remove the PTSA.
The same result was obtained using purified and not purified starting material. However, water traces in
thiol 3 can quench part of SO2Cl2. After basic wash, efficient drying is required to control the addition of
the optimized amount of SO2Cl2 (see ESI – Fig. S6). Compound 7 was obtained as a white goop after
extraction with a saturated solution of NaHCO3(aq). Overall assay yield, starting from thiol 3, is 98% (0.67
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mol; 258.2 g considering 158 g scale-up condition in flow): Crystal (7a, see ESI – Fig. S8) 1H NMR (600
MHz, CDCl3): δH 6.56 (dd, J1 = 8.3 Hz, J2 = 4.03 Hz, 1H), 4.75 (dt, J1 = 11.0 Hz, J2 = 4.4 Hz, 1H), 5.43 (s,
1H), 3.48 (dd, J1 = 14.7 Hz, J2 = 8.3 Hz, 1H), 3.37 (dd, J1 = 14.7 Hz, J2 = 4.0 Hz, 1H), 2.17 (s, 3H), 2.02–
2.07 (m, 1H), 1.87–1.97 (m, 1H), 1.43–1.56 (m, 2H), 1.01–1.12 (m, 2H), 0.92 (dd, J1 = 14.0 Hz, J2 = 6.6
Hz, 6H), 0.84–0.94 (m, 1H), 0.77 (d, J = 7.0 Hz, 3H). 13C{¹H} NMR (150 MHz, CDCl3): δC 168.1, 165.5,
81.6, 77.6, 61.5, 47.0, 40.3, 37.4, 34.0, 31.4, 26.1, 23.3, 22.0, 20,7, 20.6, 16.1.
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(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-((2-acetoxy-2-chloroethyl)thio)-2,2-dichloroacetate (8).
Intermediate isolated only to use as reference to compare with the ¹H NMR of the crude reaction mixture.
It was obtained as a slightly yellow oil. 1H NMR (600 MHz, CDCl3): δH 6.65–6.76 (m, 1H), 4.74–4.81 (m,
1H), 3.55–3.68 (m, 2H), 1.89–2.18 (m, 5H), 1.66–1.74 (m, 2H), 1.44–1.58 (m, 2H), 1.02–1.16 (m, 2H),
0.85–0.95 (m, 7H), 0.76 (d, J = 7.0 Hz, 3H). 13C{¹H} NMR (150 MHz, CDCl3): δC 167.8, 163.0, 87.3 and
87.2, 80.7 and 80.6, 79.8, 46.8, 40.2, 39.8 and 39.7, 33.8, 31.3, 26.0, 23.1, 21.8, 20.6 and 20.5, 16.0
(Duplicate signal – diastereoisomers mixture).
1,2-dichloroethyl acetate (12). Obtained from the reaction of vinyl acetate with SO2Cl2. It was synthesized
1
to use as a reference to compare with the ¹H NMR of the crude reaction mixture. H NMR (600 MHz,
CDCl3): δH 6.45 (dd, J1 = 7.2 Hz, J2 = 4.4 Hz, 1H), 3.77–3.85 (m, 2H), 2.13 (s, 3H).
ASSOCIATED CONTENT
Supporting Information – Adiabatic temperature rise calculation, additional figures (system configuration),
X-ray of compound 7 and ¹H and ¹³C NMR spectra.
ACKNOWLEDGMENTS
The authors thank VCU and the Bill and Melinda Gates Foundation for supporting Medicines for All. We
also thank DARPA (Army W31P4Q–18–1–0001) for supporting MB.
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