pubs.acs.

org/OPRD Article

Development of a Kilogram-Scale Route for Clinical Sample

Production of the Intravenous Anesthetic Cipepofol
Xiaowei Zhang,* Shuowen Yu, Zhaojun Liu, Yuanqiang Long, Jinwei Zhao, Wei Xu, Haifeng Zhang,
and Haijun Zhang
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ABSTRACT: Propofol has been widely used as a clinical anesthetic for a few decades. Its derivative with a three-membered ring,
Cipepofol, was found to be equally effective and with less side effects. Here, we report a process for the scale-up total synthesis of
Cipepofol. It could be obtained in five steps from the commercially available 2-isopropylphenol. The key reactions involved Claisen
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rearrangement, Simmons−Smith cyclopropanation, and chiral resolution through carbamate formation/crystallization, followed by
hydrolysis and wiped-film distillation. The reaction conditions were mild, and the involved reagents were easily accessible. With this
process, the final product was synthesized in a 14% overall yield, without column chromatographic purification. The synthetic route
offered a shorter, robust, and economical production of Cipepofol (chemical purity > 99.5%, 99.5% ee) in kg scale.
KEYWORDS: anesthetic, Claisen rearrangement, Simmons−Smith reaction, wiped-film, distillation

■ INTRODUCTION
GABAA receptors are ion channels responsible for mediating
inhibitory neurotransmission in the CNS. GABAA receptors are
involved in the pathogenesis, diagnosis, and treatment of many
diseases, such as anesthesia, depression, anxiety, epilepsy,
memory disorders, drug dependence, and so on.1 Propofol is a
GABAA receptors agonist, which is a mature intravenous
anesthetics in clinical.2−6 Compared with propofol, Cipepofol
can obviously improve the side effects (e.g., injection pain,
respiratory depression, and decrease in blood pressure); phase
III clinical trials are ongoing.7 We explored a variety of
methods for the synthesis of Cipepofol in preclinical studies.
After optimization and evaluation, we identified the kilogram-
scale production process. Earlier, we developed two synthetic
routes to obtain the intermediate 5. A Weinreb amide was
applied as an acylation reagent for coupling the aryl and the
cyclopropyl moieties in both routes. The following methylation
and the chiral resolution gave the final product, Cipepofol.
Although this scheme finally afforded the target product, it
shows some limitations, especially when a kilogram scale is
required. For instance, organometallics such as n-butyl lithium
or Grignard reagents are not preferable for large scales; the
toxicity of pyridinium p-toluenesulfonate (PPTS) introduces
extra risk to quality control. On the other hand, multistep
reactions result in a complicated impurity profile, while column
chromatography should be least used in purification. Addi-
tionally, the yield of each step and the overall yield were
disappointing. Therefore, this scheme was restricted to be
applied only during the drug discovery stage. For clinical study
and future market need, a new synthetic process with higher
applicability and efficiency is demanded. Here, we report a
highly practical process for manufacturing Cipepofol. Starting
from commercially available 2-isopropylphenol, after five steps,
kilogram-scale product can be obtained.
■ RESULTS AND DISCUSSION
First-Generation Synthetic Route for Cipepofol. The
first-generation synthetic route used to provide the initial
material of Cipepofol (Scheme 1) for pharmaceutical research
centered on the key cyclopropyl ketone 5, which was
synthesized using two different routes from different starting
materials. In route A, phenol 8 was protected as its
tetrahydropyran (THP)-ether 7; the reaction with n-BuLi
and subsequent nucleophilic addition to Weinreb amide 9
followed by acid hydrolysis afforded intermediate 5.8−10 In
route B, the Weinreb amide of commercially available
carboxylic acid 10 was reacted with cyclopropyl magnesium
bromide to afford intermediate 5.11
With the key intermediate 5 in hand, Cipepofol was
synthesized in four steps. Grignard addition to 5 afforded the
desired tertiary alcohol 4, which was isolated after column
chromatographic purification in 42% yield. Reduction of the
hydroxyl group was effected using a two-step sequence of
triethylsilyl hydride in CF3CO2H at −30 °C, followed by the
addition TBAF to afford the racemic target 3 in 70% yield.
Cipepofol (1) samples were obtained by column chromatog-
raphy, but this was difficult to achieve kilogram-scale
production. The chiral resolution of 1 was eventually afforded
by the recrystallization of the carbamate intermediate 2, which
was derived from the reaction between (R)-(+)-1-phenylethyl
isocyanate and 3. Recrystallization afforded the optically pure
Received: August 3, 2021
Published: February 22, 2022

© 2022 American Chemical Society https://doi.org/10.1021/acs.oprd.1c00306

1054 Org. Process Res. Dev. 2022, 26, 1054−1062
Organic Process Research & Development pubs.acs.org/OPRD Article

Scheme 1. Discovery Research Synthetic Route for Cipepofola

a
Reagents and conditions: (a) dihydropyran (DHP), pyridinium p-toluenesulfonate (PPTS), CH2Cl2, 20 °C, overnight; (b) n-BuLi,
tetrahydrofuran (THF), 20 °C, 2 h; (c) HCl, MeOH, 20 °C, overnight; (d) CDI, THF, 20 °C, overnight, 75%; (e) cyclopropyl magnesium
bromide 1.0 M in THF, THF, 20 °C, overnight, 45%; (f) MeMgBr 3.0 M in THF, THF, 20 °C, 3 h, 42%; (g) (1) Triethylsilyl hydride, TFA,
CH2Cl2, −30 °C, 2 h; (2) TBAF, 25 °C, overnight, 70%; (h) triethylamine (TEA), THF, 65 °C, 10 h, 10%; (i) NaOH, 1,4-dioxane, 80−85 °C, 2 h,
78%.

Scheme 2. Second-Generation Synthetic Route for Racemic Cyclopropyl Phenol 3

2, with de value over 99%. The hydrolysis of the carbamate
using NaOH solution in THF or 1,4-dioxane and column
chromatography afforded pure Cipepofol in a 78% yield with
over 99% ee and 99% purity, but the overall yield was only 1−
2%. Problems with this route involve the formation of complex
impurities that required column chromatographic purification
and a low yield (10%) of late-stage chiral resolution.
Process Evaluation of the First-Generation Route.
Discovery research initially tried to develop a chiral synthetic
route, but none of the chemistries were successful, so a late-
stage chiral resolution of the racemic Cipepofol with
1055
isocyanate chiral auxiliary was necessary. Our evaluation of
this resolution deemed it to be feasible for production as it
afforded a crystalline product with an ee over 99%. With this in
mind, our evaluation focused on the key intermediate 3
(Scheme 1). In our initial assessment, there were concerns
with route A and the use of a large amount of n-BuLi in the
nucleophilic alkylation step, as well as the toxicity of the PPTS
used to synthesize the THP ether. While route B had one less
synthetic step, it involved a complex column chromatographic
purification to get to the key intermediate 5, which could be
problematic at scale.
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Organic Process Research & Development
Scheme 3. Synthesis and Crystallization of Carbamate 2
With these concerns in mind, we developed a second-
generation route (Scheme 2) for the preparation of all clinical
material, which centered on the racemic cyclopropyl phenol 3
as the key intermediate. Our process development work
focused first upon the optimization of each step of this new
route, followed by the optimization of resolution via carbamate
2.
Process Development of Racemic Phenol 3. Commer-
cially available (E)-1-chlorobut-2-ene typically, which contains
5−10% of 3-chlorobut-1-ene, reacted with phenol 8 (Scheme
2) under the strongly basic conditions (NaOH) at 25−30 °C
afforded complete consumption of the chloride along with the
maximum amount (5−10%) of the undesired the isomer 14.
We analyzed that this was due to the difference in reactivity of
(E)-1-chlorobut-2-ene and its isomer, 3-chlorobut-1-ene. The
presence of this contaminant required column chromatography
for purification, resulting in a low yield (60−70%) of the
desired 12. To our delight, we found that when this reaction
was performed at 10−15 °C, less than 0.5% 3-chlorobut-1-ene
appeared to participate in the reaction, and the desired ether
12 was isolated in 95% yield (96% pure, 14 less than 0.5%).
This material so obtained was able to be used directly in the
next step without purification. By controlling the side reaction,
the purification operation was simplified and product loss was
reduced.
Next, the phenolic ether 12 underwent σ [3,3] Claisen
rearrangement reaction to furnish olefin 13, with 30−40% of
the undesired para-isomer 15 and other nonpolar impurities.
In 1998, the Isobe group reported that the presence of a small
amount of potassium carbonate in the Claisen rearrangement
reaction mixture generally enhanced the product yield and
purity.12 We found that the addition of 1 mol % K2CO3 to the
reaction mixture minimized the formation of 15 to only 3%.
The total impurity content of the reaction solution decreased
to 20%. The nonpolar impurities were easily removed by an
extractive workup from a mixed solution of 1,2-ethanediol and
methanol (v/v = 1:1) with n-hexane and gave the oily crude 13
with an 89% purity. About 40% of the product was lost due to
extraction. The resulting oil was purified by vacuum distillation
to give compound 13 in 30% overall yield (98% pure, less than
1.0% of 15). Furthermore, the overall yield of 13 was improved
to 53% at the kilogram scale when we generously reduced the
volume of the 1,2-ethanediol and methanol mixture and n-
hexane. The product loss by extraction was reduced to about
20%.
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The Simmons−Smith reaction is a classic method for
cyclopropanation.13,14 An organozinc carbenoid is often used
to react with an alkene.15 The Simmons−Smith cyclo-
propanation of olefin 13 provided racemic 3. The use of the
highly reactive Zn(Et)2/CH2I2/CF3CO2H reagent proved to
be very exothermic and afforded a low conversion of only 70−
80%, possibly due to the presence of the phenolic hydrogen.
With the Zn−Cu/CH2I2 (large excess) method, the conversion
was very slow, affording only 45% after 24 h. We next looked at
the milder Al(Et)3/CH2I2 cyclization reagent. At 4 kg scale
with Al(Et)3(3 equiv)/CH2I2(4 equiv), the conversion was
50% after 24 h but went up to greater than 99%, after 48 h with
no byproducts observed. However, care had to be taken when
the reaction was quenched as the cyclopropyl ring was prone
to ring opening, and the formation of contaminant 16 was
closely related to the quench temperature. When it was
quenched at 10 °C with 10% NaOH, 10−15% of 16 was
observed, but at −10 °C, the amount of 16 was reduced to 1−
2%. Unfortunately, this lower temperature requirement
prolongs the quench time to 10 h at the 4 kg scale. Crude
racemic 3 was purified by high vacuum distillation (100−150
°C and >3 mbar, Claisen distillation) to afford 3.5 kg in an
80% yield (96% pure, less than 1.0% of 16).
Process Development of Carbamate 2 and Reso-
lution of Diastereoisomers. Having racemic phenol 3 in
hand, we looked at the synthesis of carbamate 2 (Scheme 3).
When phenol 3 reacted with (R)-(+)-1-phenylethyl isocyanate
under basic conditions in THF, CH2Cl2, or 1,4-dioxane, these
reactions involved a standard workup involving extraction,
washing, and concentration operations. We found that when
this reaction was performed in heptane, which proceeded
readily at room temperature, carbamate 2 readily crystallized
out of the reaction mixture. When the reaction was deemed
complete, the crude carbamate 2 was isolated with 70−80% de
by simple filtration. Two more recrystallizations from heptane
afforded carbamate 2 in 25% yield (97% pure, >99.5% de)
along with 1−3% of urea 20, which was produced by the side
reaction of isocyanate with water, even strictly controlling the
water content in the reaction solution below 1.0%.
Evolution of Cipepofol Endgame Synthesis. A critical
evaluation of the second-generation synthesis showed that
although the cyclopropanation reaction using Al(Et)3/CH2I2
had few impurities, the reaction was slow and the quenching
conditions were severe and time-consuming. Also, it appeared
that the presence of phenolic hydrogen was the problem, so we
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Organic Process Research & Development pubs.acs.org/OPRD Article

Scheme 4. Evolution of Cipepofol Endgame Synthesis

postulated using the carbamate as a protection for the phenol. Table 2. Effect of the Ratio of CF3CO2H on
This new route now entailed the reaction of olefin 13 with the Cyclopropanation
isocyanate to produce olefin carbamate 17, followed by the
conversation HPLC
Simmons−Smith reaction to afford carbamate 2 (Scheme 4). equivalents (%)
Using the carbamate reaction conditions from above, olefin
Zn(Et)2 CF3CO2H CH2I2 time (h) 17 2
13 reacted with (R)-(+)-1-phenylethyl isocyanate in heptane,
and carbamate 17 crystallized out of the reaction mixture. 1.5 1.1 1.6 2 0.76 96.50
During the pilot plant synthesis, we found that the temperature 1.5 1.4 1.6 2 0.56 95.82
of the n-heptane addition greatly affected the quality of the 1.5 1.6 1.6 2 8.22 86.56
particulate slurry. When the temperature of heptane addition 1.5 2.0 1.6 2 48.79 43.87
was over 0 °C, it formed a pasty solution that was hard to filter.
However, when we inverse added the hot reaction solution Table 3. Effect of Reaction Temperature on
directly into n-heptane at −15 to 0 °C, the slurry was easily Cyclopropanation
filtered to afford carbamate 17 in 91% yield. conversation HPLC (%)
With the complications of the phenol alleviated, we temperature (°C) time (h) 17 2
reexamined the use of the more active Zn(Et)2/CH2I2/
0−10 2 53.14 41.19
CF3CO2H reagent for the cyclopropanation of carbamate 17.16
20−30 2 0.15 98.94
When an initial ratio of 3.0:4.0:3.0 (Zn(Et)2/CH2I2/
30−35 2 not detected 94.27
CF3CO2H) was used, at 99% conversion, we found that
more than 40% (quantity of 1% HCl solution for quenching)
of the active reagent still existed in solution. When the ratio of carbamate was easily hydrolyzed affording recovery of the
Zn(Et)2/CH2I2/CF3CO2H was reduced to 1.5:1.6:1.4, re- starting phenol 13. When the reaction was determined to be
spectively, complete conversion was still achieved in 4 h at complete by high-performance liquid chromatography
room temperature at 11 kg scale. Further attempts to reduce (HPLC), the mixture could be quenched using either 0.9−
the excess of the reagent resulted in incomplete reaction 1.0% HCl or 10% NH4Cl solution. However, we found that the
(Tables 1−3 show the effects of different ratios and 10% NH4Cl solution caused emulsification in the pilot-scale
temperatures on cyclopropanation.) We also determined that synthesis complicating separation. It is usually necessary to add
the ratio of CF3CO2H should not exceed Zn(Et)2, as the 1% sodium chloride solution for demulsification.
The crude carbamate 2 was submitted to crystallization by
Table 1. Effect of Different Ratios of Zn(Et)2/CF3CO2H/ temperature cycling (3 cycles) in n-heptane to afford the
CH2I2 on Cyclopropanation desired product 2 in 30−35% yield (99.4% de, and 99% HPLC
purity). This modified sequence improved the reaction rate
equivalents conversation HPLC (%) and overall yield with fewer byproducts. This repeated
purification was indispensable for quality control despite
Zn(Et)2 CF3CO2H CH2I2 time (h) 17 2
some product loss. Considering that the removal of enantiomer
1.1 1.1 1.1 4 6.25 86.89 gives a dramatic 50% yield loss, this yield is relatively
>48 4.56 90.42 satisfactory (Table 4 shows the relationship between
1.3 1.3 1.3 3 1.39 97.46 recrystallization times and isomer residues).
1.5 1.5 1.5 3 0.04 97.21 Hydrolysis of Carbamate 2. The target Cipepofol was
1.6 1.6 1.6 3 not detected 97.33 obtained after a final hydrolysis to afford the desired phenol
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Table 4. Relationship between Recrystallization Times and
S-Isomer of 2 (S-2)
chiral purity HPLC (%)
times S-isomer of 2 (S-2)
0 50.00
1 13.53
2 1.71
3 0.16
(de >99%). The carbamate group could be effectively removed
using either acidic or alkaline conditions, but we found that the
cyclopropyl group was not stable in acid, generating the ring-
opened impurity in the presence of acid and under heat. Yet,
the cyclopropyl group was relatively stable under basic
conditions, even when heated. Impurities from this reaction
include dimer 19, urea 20, and minute quantities of quinone
18 (Scheme 5). The hydrolysis reaction and the formation
mechanism of oxidized impurities 18 and 19 were speculatively
analyzed (Scheme 6).
Initially, hydrolysis of carbamate 2 was affected by heating in
a solution of 6% sodium hydroxide and 1,4-dioxane. However,
these conditions afforded 10−15% of dimer 19 in the reaction
mixture. But when the hydroxide/dioxane solution was
sufficiently sparged to remove oxygen, only 1−5% of dimer
19 was generated. Also, benzoquinone 18 is usually known to
be toxic and its level needs to be strictly controlled. To our
delight, we found that hydrolysis of the carbamate in the
sparged solution generally afforded less than 0.05% of the
benzoquinone. And Ames test showed that the genotoxicity of
compound 18 was negative. Upon completion of the reaction,
the solid urea 20 was removed by filtration. Distillation of the
crude phenol 1 (bp over 200 °C) was effective in removing the
higher boiling impurity 19 at reduced pressure (phenol
distillation ∼150 °C) (Table 5 shows the thermal stability
data) to give the desired product with 99.8% purity and over
80% yield. Under this protocol, 18 and 19 were determined to
be less than 0.05%; however, traces of 1,4-dioxane persisted
(ICH Q3C Impurities: Residual Solvents, the PDE of 1,4-
dioxane was 380 ppm) at a residual level of 350−380 ppm.17
To avoid the problems associated with 1,4-dioxane, we
replaced it with heptane (the PDE was 5000 ppm) using a 30%
sodium hydroxide solution to effect hydrolysis. Following
distillation, the residual level of heptane was generally lower
than 1500 ppm, but the rate of two-phase reaction was very
slow, even at high temperatures (95−100 °C). We found that
using solid sodium hydroxide in n-heptane greatly improved
the rate of the reaction. Under these conditions, the hydrolysis
of carbamate 2 was complete within 1 h (99.5% conversion),
with only 1−3% dimer 19 being generated. Under these
reaction conditions, large amounts of sodium carbonate
Scheme 5. Hydrolysis of Carbamate 2
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byproduct formed a slurry in the reaction, so we quenched
the reaction with water at low temperatures to avoid any
degradation. Distillation, as before, effected the purification of
Cipepofol. However, larger production quantities resulted in
prolonged distillation times, resulting in degradation and
oxidation impurities. We found that wiped-film distillation
(WFE) was optimal for the distillation and continuous
purification of this heat-sensitive material. Heating temper-
ature, vacuum pressure, and wiper speeds were critical for
distillation (100−110 °C, vacuum lower than 3 Torr, and
250−350 rpm wiper speed) yield of 1 at kilogram scale (Table
6). With the optimized conditions, 500−800 g of crude 1
could be distilled every hour, with 90% yield and over 99.5%
HPLC purity with impurities 18 and 19 less than 0.05% and an
ee over 99.5%.
■
CONCLUSIONS
We have developed a second-generation synthetic route for
Cipepofol for the production of the clinical material. This
route entailed Claisen rearrangement to produce the key
intermediate 13, avoiding previous use of large amounts of n-
BuLi and methyl Grignard reagents; it also improved upon the
original low overall yield of only 1−2% and a complex impurity
profile. Subsequent Simmons−Smith cyclopropanation using
Zn(Et)2/CH2I2/CF3CO2H followed by recrystallization in n-
heptane provided chiral pure compound 2. Carbamate 2 was
hydrolyzed using solid sodium hydroxide in heptane, and
wiped-film distillation finally afforded high purity and higher
yield of Cipepofol. Starting from 2-isopropylphenol 8, the
overall yield of the optimized second-generation route was
12−14%. This route offered a shorter, robust, and economical
production of Cipepofol (chemical purity > 99.5%, 99.5% ee)
in kg scale.
■ EXPERIMENTAL SECTION
All reactions were carried out under a nitrogen atmosphere. All
solvents and reagents were purchased from commercial sources
and were used without further purification. 1H and 13C NMR
spectra were obtained using a Bruker 400 MHz spectrometer
in the solvents indicated. HPLC was used to monitor the
reaction progress.
Cyclopropyl(2-hydroxy-3-isopropylphenyl)-
methanone (5). Route A. To a glass reactor were charged 2-
isopropylphenol 8 (1500 g, 11.01 mol), PPTS (276.78 g, 1.10
mol), and CH2Cl2 (6.0 L). The mixture was cooled to 0 °C,
and dihydropyran (1390 g, 16.52 mol) was added slowly in
portions keeping the reaction below 0 °C. After complete
addition, the mixture was warmed to 20−25 °C and agitated
overnight (16−24 h). The resulting solution was washed with
water (2 L × 3), 1 N NaOH solution (2 L × 4), and NaCl
solution (2 L × 2). The organic layer was dried with Na2SO4
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Scheme 6. Speculated Mechanism of Hydrolysis

Table 5. Thermal Stability of Crude Cipepofol

temperature before heating 90 °C 100 °C 120 °C 150 °C
heating time (h) 0 2 2 2 2
HPLC (%) 18 0.05 not detected not detected not detected 0.01
19 0.12 0.16 0.17 0.20 0.23
other maximum single impurities 0.02 0.02 0.03 0.02 0.02
Cipepofol 99.44 99.52 99.49 99.43 99.48
chiral HPLC (%) S-isomer 0.14 0.12 0.12

Table 6. Effect of Distillation Conditions on the Distillation
Yield of Cipepofol
heating temperature (2.0 Torr, 310 rpm)
80 °C 85 °C 95 °C 100 °C 105 °C 115 °C 120 °C
yield (%) 82 90 94 96 95
vacuum pressure (100 °C, 310 rpm)
5.0 Torr 4.0 Torr 3.0 Torr 2.0 Torr
yield (%) 84 89 93 96
wiper speeds (100 °C, 2.0 Torr)
260 rpm 310 rpm
yield (%) 92 95
and concentrated to afford 2500 g of crude 7. To a solution of
crude 7 (1000 g) in THF (5 L) at −20 °C was added n-BuLi
solution (2.5 M in hexane, 2.18 L, 5.45 mol). The reaction
mixture was then agitated for 2 h maintaining a temperature
between 20 and 25 °C. The reaction mixture was then cooled
to −20 °C, and a solution of Weinreb amide 9 (821 g, 6.36
mol) in THF (821 mL) was added over about 30 min while
the internal temperature was maintained between −20 and
−15 °C. The reaction mixture was then warmed to 20 °C and
agitated overnight (16−24 h). The reaction was quenched with
saturated NH4Cl solution (5 L) and extracted with ethyl
acetate (5 L × 2). The combined organic phases were washed
with saturated NaCl solution (5 L × 2), dried with Na2SO4,
and then concentrated to afford 1400 g of crude 6. To the
concentrated crude 6 was added a solution of HCl (12 M, 180
mL) in MeOH (2 L) at −20 °C, then warmed to 20 °C, and
agitated for 2 h. Water (1 L) was added, followed by ethyl
acetate (1.5 L). The organic phase was separated, and the
aqueous layers were back-extracted with ethyl acetate (1.5 L ×
2). The combined organic phases were washed with saturated
NaCl solution (2 L × 2), dried with Na2SO4, and then
concentrated to afford 1150 g of crude 5 as a yellow oil, which
was used without further purification.
96 94 Route B. To a cooled (0 °C) solution of 2-hydroxy-3-
isopropylbenzoic acid 10 (100 g, 0.55 mol) in THF (1.2 L)
1.0 Torr was added CDI (178 g, 1.11 mol). The reaction mixture was
98
agitated for 3 h maintaining a temperature between 0 and 5 °C.
Next, N,O-dimethylhydroxylamine hydrochloride (108.3 g,1.11
mol) and diisopropylamine (157.8 g, 1.22 mol) were added.
360 rpm The reaction mixture was then warmed to 20 °C and agitated
95 overnight (16−24 h). The reaction mixture was quenched with
saturated NH4Cl solution (1 L) and extracted with ethyl
acetate (1 L). The organic phase was washed with saturated
NaCl solution (1 L × 2), dried with Na2SO4, and then
concentrated under vacuum. The crude product was then
purified by silica gel chromatography (100−200 mesh, 15/1
petroleum ether/ethyl acetate) to afford Weinreb amide 11
(92.7 g, 75% yield, light yellow oil). To a cooled (0 °C)
solution of 11 (54 g, 0.24 mol) in THF (540 mL) was added
cyclopropyl magnesium bromide solution (1.0 M in THF, 847
mL, 0.85 mol) over 30 min. The reaction mixture was then
warmed to 20 °C and agitated overnight (16−24 h). The
reaction mixture was quenched by adding saturated NH4Cl
solution (1 L) at 10−15 °C over 30 min and extracted with
ethyl acetate (1 L). The organic phase was washed with HCl
solution (1 N, 1 L) followed by saturated NaCl solution (1 L ×
2). The organic layer was dried over Na2SO4 and concentrated
under vacuum. The crude was then purified by silica gel
chromatography (100−200 mesh, petroleum ether) to give the
desired ketone 5 (22 g, 45% yield, light yellow oil). 1H NMR
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Organic Process Research & Development
(400 MHz, CDCl3) δ 12.90 (s, 1H), 7.83 (dd, J = 8.1, 1.5 Hz,
1H), 7.42 (dd, J = 7.5, 1.4 Hz, 1H), 6.89 (t, J = 7.8 Hz, 1H),
3.39 (dt, J = 13.8, 6.9 Hz, 1H), 2.86−2.53 (m, 1H), 1.32−1.26
(m, 2H), 1.24 (d, J = 6.9 Hz, 6H), 1.08 (dq, J = 7.3, 3.6 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 205.9, 159.9, 137.7,
132.4, 127.4, 119.5, 118.4, 76.7, 26.4, 22.3, 16.6, 12.0. HRMS
(ESI), m/z: [M − H]− calcd for C13H15O2, 203.1150, found
203.1068.
2-(1-Cyclopropyl-1-hydroxyethyl)-6-isopropylphenol
(4). To a cooled (−20 °C) solution of 5 (1100 g,5.39 mol) in
THF (5 L) was added methylmagnesium bromide solution
(3.0 M in THF, 4.5 L, 13.5 mol) over 40 min. The reaction
mixture was then warmed to 20 °C and agitated for 3 h. The
reaction mixture was quenched with saturated NH4Cl solution
(5 L) and extracted with ethyl acetate (5 L × 2). The
combined organic phases were washed with saturated NaCl
solution (5 L × 2). The organic layer was dried over Na2SO4
and concentrated under vacuum. The crude was then purified
by silica gel chromatography (100−200 mesh, 30/1 petroleum
ether/ethyl acetate) to give alcohol 4 (500 g, 42% yield, light
red oil). 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 7.11
(dd, J = 7.6, 1.3 Hz, 1H), 7.04 (dd, J = 7.8, 1.5 Hz, 1H), 6.77
(t, J = 7.7 Hz, 1H), 3.35 (dt, J = 13.8, 6.9 Hz, 1H), 2.76 (s,
1H), 1.47 (s, 3H), 1.37 (ddd, J = 8.0, 5.3, 2.3 Hz, 1H), 1.22 (d,
J = 7.0 Hz, 7H), 0.67−0.56 (m, 1H), 0.51−0.41 (m, 2H),
0.38−0.29 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 152.3,
135.4, 127.9, 124.5, 123.0, 117.9, 77.4, 25.6, 25.6, 21.8, 21.7,
21.1, 2.17. HRMS (ESI), m/z: [M − H]− calcd for C14H19O2,
219.1463, found 219.1381.
1-[(E)-But-2-enoxy]-2-isopropyl-benzene (12). To a
glass reactor were charged 2-isopropylphenol 8 (3000 g, 22.0
mol) and DMF (15 L). The solution was cooled to 10 °C
before NaOH (969 g, 24.2 mol) was added in portions. Next, a
solution of (E)-1-chloro-2-butene (2595 g, 28.7 mol) in DMF
(6 L) was added maintaining an internal temperature between
10 and 15 °C. The reaction mixture was then agitated for an
additional 5 h, and the reaction conversion was monitored by
thin-layer chromatography (TLC). When the reaction was
deemed complete, the reaction mixture was poured into ice
water (27 L) and extracted with hexane (15 L × 2). The
combined organic phases were washed with saturated NaCl
solution (12 L × 2) and then dried over Na2SO4, filtered, and
concentrated to afford phenol ether 12 (3995 g, 95% yield,
light yellow oil, 97% purity, and 0.3% impurity 14). 1H NMR
(400 MHz, CDCl3) δ 7.26−7.18 (m, 1H), 7.17−7.07 (m, 1H),
6.91 (tt, J = 7.5, 1.7 Hz, 1H), 6.84 (td, J = 7.8, 0.9 Hz, 1H),
5.93−5.61 (m, 2H), 4.67−4.37 (m, 2H), 3.44−3.22 (m, 1H),
1.85−1.65 (m, 3H), 1.21 (dd, J = 6.9, 1.7 Hz, 6H). 13C NMR
(101 MHz, CDCl3) δ 156.0, 137.4, 129.2, 127.9, 126.6, 126.4,
126.3, 126.1, 126.0, 120.7, 120.6, 111.8, 111.7, 68.8, 64.0, 26.8,
26.8, 22.7, 17.8, 13.4. HRMS (ESI), m/z: [M + H]+ calcd for
C13H19O, 191.1358, found 191.1427.
2-Isopropyl-6-(1-methylallyl)phenol (13). Claisen Re-
arrangement. A glass reactor was charged with 23 (5000 g,
26.28 mol) and K2CO3 (363 g, 2.63 mol) and then heated to
200 °C. After agitation for 10 h, the reaction solution was
cooled to 20−25 °C and diluted with the mixture of ethylene
glycol (25 L) and MeOH (25 L). The mixture was extracted
with hexane (14 L) to remove less polar impurities and
discarded. To the ethylene glycol and MeOH phase was added
saturated NaCl solution (25 L) and extracted with hexane (19
L × 2). The combined organic phases were washed with
saturated NaCl solution (25 L), dried over Na2SO4, filtered,
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and concentrated to afford an oil. The oil was purified by
vacuum distillation at 130−150 °C and 1−2 mbar to yield
olefin 13 (2660 g, 98% purity, 53% yield). 1H NMR (400
MHz, CDCl3) δ 7.09 (dd, J = 7.6, 1.6 Hz, 1H), 6.97 (dd, J =
7.6, 1.6 Hz, 1H), 6.90−6.81 (m, 1H), 6.19−5.96 (m, 1H), 5.18
(tt, J = 10.2, 1.4 Hz, 3H), 3.62 (p, J = 7.0 Hz, 1H), 3.23 (dt, J =
13.8, 6.9 Hz, 1H), 1.39 (d, J = 7.1 Hz, 3H), 1.28−1.12 (m,
6H). 13C NMR (101 MHz, CDCl3) δ 151.4, 142.7, 135.4,
129.6, 125.3, 124.6, 120.8, 114.7, 38.6, 27.1, 22.9, 22.8, 18.8.
HRMS (ESI), m/z: [M − H]− calcd for C13H17O, 189.1358,
found 189.1275.
2-(1-Cyclopropylethyl)-6-isopropylphenol (3) Meth-
od A. A glass reactor was charged with 4 (900 g, 4.09 mol),
TFA (2.4 L, 32.68 mol), and CH2Cl2 (8 L). The mixture was
cooled to −30 °C before adding triethylsilyl hydride (1.3 L,
8.17 mol) over 40 min. The reaction mixture was agitated for 1
h, warmed to 0 °C, and washed with water (2 L × 2), saturated
NaHCO3 solution (3 L), and saturated NaCl solution (2 L).
TBAF·3H2O (644 g, 2.04 mol) was then added to the organic
phase, and the mixture was stirred at 20−25 °C for at least 2 h.
The reaction mixture was washed with water (2 L × 2) and
saturated NaCl solution (2 L). The organic layer was dried
over Na2SO4 and concentrated under vacuum. The crude was
then purified by silica gel chromatography (100−200 mesh,
100/1 petroleum ether/ethyl acetate) to give the racemic 3
(584 g, 70% yield, yellow oil).
2-(1-Cyclopropylethyl)-6-isopropylphenol (3) Meth-
od B. To a solution of triethylaluminum (1.0 M in hexane, 64
L, 64.0 mol) at −5 to 5 °C was slowly added a solution of 13
(4.06 kg, 21.34 mol) in CH2Cl2 (10 L) over 3 h (Note: Ethane
gas was generated). The resulting solution was agitated for
another 30 min, then CH2I2 (20.0 kg, 74.67 mol) was added
over 40 min. The reaction mixture was warmed to 30−35 °C
and agitated for 48 h until >99% consumption of 13 was
achieved, as monitored by HPLC. 10% NaOH solution (140
kg) was cooled to −10 °C before the reaction mixture was
added slowly in portions, while the temperature was
maintained between −15 and −5 °C. The layers were cut,
and the aqueous phase was back-extracted with hexane (35 L).
The combined organic phases were washed with water (60 L)
followed by saturated NaCl solution (60 L). The organic layer
was dried over Na2SO4 and concentrated under vacuum. The
crude oil was distilled under vacuum (100−150 °C and <3
mbar) to afford racemic 3 (3.52 kg, 96.8% purity, 80% yield) as
a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.12 (dd, J =
7.6, 1.6 Hz, 1H), 7.07 (dd, J = 7.7, 1.6 Hz, 1H), 6.89 (t, J = 7.6
Hz, 1H), 4.90 (s, 1H), 3.16 (hept, J = 6.9 Hz, 1H), 2.50 (p, J =
7.1 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.27 (dd, J = 6.9, 0.6 Hz,
6H), 1.05 (qt, J = 8.1, 5.1 Hz, 1H), 0.61−0.51 (m, 1H), 0.51−
0.40 (m, 1H), 0.27−0.11 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 150.4, 133.8, 131.9, 125.0, 123.6, 120.5, 37.3, 27.1,
22.7, 20.0, 17.0, 4.3, 3.8. HRMS (ESI), m/z: [M − H]− calcd
for C14H19O, 203.1514, found 203.1434.
[2-Isopropyl-6-(1-methylallyl)phenyl]-N-[(1R)-1-
phenylethyl]carbamate (17). To a mixture of 13 (8.37
kg,44.05 mol) and TEA (1.78 kg, 17.62 mol) in heptane (12
L) was added (R)-(+)-1-phenylethyl isocyanate (6.80 kg, 46.25
mol) at room temperature. The mixture was then heated to 85
°C and agitated for 2 h until >99% consumption of 13 was
achieved, as monitored by HPLC. The reaction mixture was
directly added to cooled (−15 °C) heptane (120 L) with
agitation while the internal temperature was maintained at <0
°C. The slurry was agitated for an additional 30 min and then
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Org. Process Res. Dev. 2022, 26, 1054−1062
Organic Process Research & Development
filtered, and the cake was washed with heptane (10 L). The
cake was dried in a vacuum oven at 55 °C for 4 h to afford
olefin carbamate 17 (13.47 kg, 91% yield, 98 purity, off-white
solid). 1H NMR (400 MHz, CDCl3) δ 7.41−7.34 (m, 4H),
7.31−7.25 (m, 1H), 7.19−7.09 (m, 2H), 7.04 (d, J = 5.8 Hz,
1H), 6.15−5.80 (m, 1H), 5.31 (s, 1H), 5.08−4.85 (m, 3H),
3.58 (d, J = 5.4 Hz, 1H), 3.00 (dd, J = 13.1, 6.5 Hz, 1H), 1.57
(d, J = 6.8 Hz, 4H), 1.44−1.08 (m, 9H). 13C NMR (101 MHz,
CDCl3) δ 153.8, 145.7, 143.2, 142.5, 142.4, 141.5, 138.2,
128.7, 127.5, 126.2, 126.1, 125.7, 125.2, 124.3, 113.0, 50.9,
36.4, 36.3, 27.4, 23.3, 22.1, 19.8, 19.7. HRMS (ESI), m/z: [M
+ H]+ calcd for C22H28O2N, 338.2114, found 338.2115.
[2-[(1R)-1-Cyclopropylethyl]-6-isopropyl-phenyl]N-
[(1R)-1-phenylethyl]carbamate (2). A glass-lined reactor
was evacuated and filled with N2. A solution of Zn(Et)2 in
hexane (1.0 M, 35.43 kg, 48.90 mol) was added and cooled to
−8 °C. Next, a solution of CH3COOH (5.20 kg, 45.64 mol) in
CH2Cl2 (65.60 kg) was then added dropwise over 3 h keeping
the reaction <0 °C (Note: Ethane gas was generated). After an
additional 30 min of agitation, a solution of CH2I2 (13.97 kg,
52.16 mol) in CH2Cl2 (7.29 kg) was added over 40 min. After
an additional 30 min of agitation, a solution of 17 (11.0 kg,
32.60mol) in CH2Cl2 (72.90 kg) was added over 40 min. After
an additional 30 min of agitation, the reaction mixture was
warmed to 25 °C and agitated for 4 h until >99% consumption
of 17 was achieved, as monitored by HPLC. The reaction
mixture was cooled to 5 °C and quenched with 0.9% HCl
solution (110 kg). The layers were cut, and the aqueous phase
was back-extracted with CH2Cl2 (15 kg). The combined
organic phases were washed with 5% Na2SO3 solution (110
kg) followed by water (110 kg × 2). The organic layer was
concentrated under vacuum to afford the crude carbamate 2,
which was dissolved in 65 °C heptane (30 kg); the solution
was then cooled to 10 °C and allowed to crystallize for 5 h.
The slurry was filtered and washed with heptane (7.5 kg). The
filter cake was suspended in heptane (30 kg), heated to 95 °C,
and agitated for 2 h. The solution was then cooled to 10 °C
and allowed to crystallize for 3 h before being filtered, and then
rinsed with heptane (7.5 kg) as needed. The filter cake was
recrystallized again in heptane (30 kg). The solid was dried in a
vacuum oven at 50 °C for 3−5 h to afford carbamate 2 (3.7 kg,
99.5% de, 99.1% purity, 32% yield, off-white solid). 1H NMR
(400 MHz, CDCl3) δ 7.35 (d, J = 5.0 Hz, 4H), 7.29 (dt, J =
8.8, 4.2 Hz, 1H), 7.16 (td, J = 18.3, 9.1 Hz, 3H), 5.19 (d, J =
54.9 Hz, 1H), 5.00−4.77 (m, 1H), 3.20−2.83 (m, 1H), 2.08
(s, 1H), 1.55 (d, J = 6.8 Hz, 4H), 1.29−1.08 (m, 9H), 0.99−
0.88 (m, 1H), 0.48 (s, 1H), 0.31 (s, 1H), 0.03 (d, J = 15.5 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 153.9, 145.6, 143.3,
141.1, 140.3, 128.7, 127.5, 126.2, 126.0, 124.8, 123.9, 50.9,
38.1, 27.4, 23.5, 23.3, 23.2, 22.0, 21.22, 17.5, 4.8, 4.0. HRMS
(ESI), m/z: [M + H]+ calcd for C23H30O2N, 352.2270, found
352.2271.
2-[(1R)-1-Cyclopropylethyl]-6-isopropyl-phenol (1,
Cipepofol). To a glass-lined reactor were charged 2 (2.82
kg, 8.03 mol) and heptane (27 L), and the reactor was
evacuated and filled with N2. To the mixture was added NaOH
solid (642.4 g, 16.06 mol) and heated to 85 °C. The reaction
mixture was agitated for 2 h until >99.5% consumption of 2
was achieved, as monitored by HPLC. The reaction mixture
was cooled to 20−25 °C, then water (14 L) was added slowly.
After agitation for an additional 30 min, the reaction mixture
was filtered through a celite bed and washed with heptane (5.5
L). The filtrate phases were allowed to separate, and the
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aqueous phase was extracted with heptane (5.5 L). The
combined organic phases were washed with water (14 L), 3.6%
HCl solution (wt %, 14 L × 2), and water (14 L × 2) and
concentrated to afford an oil. The oil was purified by wiped-
film distillation (100 °C and 1−3 Torr) to afford Cipepofol
(1) (1.52 kg, 99.6% ee, 99.9% purity, 93% yield, light yellow
oil). 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.08 (dd,
J = 7.6, 1.6 Hz, 1H), 6.96 (dd, J = 7.6, 1.6 Hz, 1H), 6.85−6.71
(m, 1H), 3.38−3.21 (m, 1H), 2.61−2.41 (m, 1H), 1.27−1.09
(m, 9H), 1.06−0.93 (m, 1H), 0.49 (tdd, J = 9.0, 5.4, 3.9 Hz,
1H), 0.35−0.23 (m, 1H), 0.16 (td, J = 9.1, 5.0 Hz, 1H), 0.07
(td, J = 9.1, 5.2 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ
150.7, 135.1, 134.1, 124.1, 122.8, 119.7, 36.4, 26.0, 23.0, 22.9,
20.9, 17.4, 4.5, 3.7. HRMS (ESI), m/z: [M + H]+ calcd for
C14H21O, 205.1587, found 205.1587.
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.1c00306.
1
H and 13C NMR spectra of compounds 4, 5, 12, 13, 3,
17, 2, and Cipepofol; crystal data and structure
refinement for compound 2; HPLC and chiral HPLC
chromatograms for Cipepofol; and safety data (DSC
and ARC) for Cipepofol (PDF)
■ AUTHOR INFORMATION
Corresponding Author
Xiaowei Zhang − Sichuan Haisco Pharmaceutical Co. Ltd.,
Chengdu 611130, China; orcid.org/0000-0001-5916-
0795; Email: zxwxy888@163.com
Authors
Shuowen Yu − Sichuan Haisco Pharmaceutical Co. Ltd.,
Chengdu 611130, China
Zhaojun Liu − Sichuan Haisco Pharmaceutical Co. Ltd.,
Chengdu 611130, China
Yuanqiang Long − Sichuan Haisco Pharmaceutical Co. Ltd.,
Chengdu 611130, China
Jinwei Zhao − Sichuan Haisco Pharmaceutical Co. Ltd.,
Chengdu 611130, China
Wei Xu − Sichuan Haisco Pharmaceutical Co. Ltd., Chengdu
611130, China
Haifeng Zhang − Sichuan Haisco Pharmaceutical Co. Ltd.,
Chengdu 611130, China
Haijun Zhang − Sichuan Haisco Pharmaceutical Co. Ltd.,
Chengdu 611130, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.1c00306
Notes
The authors declare no competing financial interest.
■
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