Multikilogram-scale synthesis of a chiral cyclopropanol and an investigation of the safe use of lithium acetylide-ethylene diamine complex

Article abstract of DOI:10.1021/op2002497

A six-step route starting from a readily available vinyl boronate was identified to produce an enantioenriched cyclopropanol in an overall 16% yield. Key steps involve the use of lithium acetylide-ethylene diamine complex 5 and an enzymatic resolution of a racemic cyclopropanol acetate. Process safety considerations surrounding the use of 5 were examined, and an improved procedure is described which was safely demonstrated at multikilogram scale.

Full text of DOI:10.1021/op2002497

ARTICLE
pubs.acs.org/OPRD
Multikilogram-Scale Synthesis of a Chiral Cyclopropanol and an
Investigation of the Safe Use of Lithium AcetylideꢀEthylene
Diamine Complex
Ephraim M. Bassan,† Carl A. Baxter,*,‡ Gregory L. Beutner,*,§ Khateeta M. Emerson,*,† Fred J. Fleitz,§
Simon Johnson,‡ Stephen Keen,‡ Mary M. Kim,§ Jeffrey T. Kuethe,§ William R. Leonard,§ Peter R. Mullens,‡
Daniel J. Muzzio,† Christopher Roberge,§ and Nobuyoshi Yasuda§
†Department of Chemical Process Development and Commercialization, Merck and Co., Inc., Rahway, New Jersey 07065, United States
‡Global Process Chemistry, Merck, Sharp and Dohme Ltd., Hertford Road, Hoddesdon, EN11 9BU, U.K.
§Department of Process Research, Merck and Co., Inc., PO Box 2000, Rahway, New Jersey 07065, United States
S Supporting Information
b
ABSTRACT: A six-step route starting from a readily available vinyl boronate was identified to produce an enantioenriched
cyclopropanol in an overall 16% yield. Key steps involve the use of lithium acetylide-ethylene diamine complex 5 and an enzymatic
resolution of a racemic cyclopropanol acetate. Process safety considerations surrounding the use of 5 were examined, and an
improved procedure is described which was safely demonstrated at multikilogram scale.
Scheme 1. Cyclopropanol synthetic methods
’ INTRODUCTION
Despite recent advances in asymmetric SimmonsꢀSmith1 and
transition metal-catalyzed cyclopropanations,2 the preparation of
chiral, nonracemic cyclopropanols remains a formidable challenge.3
The two most common routes to cyclopropanols are the Simmonsꢀ
Smith cyclopropanation of vinyl ethers (Scheme 1, eq 1) and the
Kulinkovich cyclopropanation4 (Scheme 1, eq 2). These reac-
tions have both been investigated with chiral catalysts and/or
auxiliaries, although the scope and selectivity of these reactions is
limited. Shi and co-workers have shown that a dipeptide-derived
catalyst gives excellent yields and enantioselectivities in the
SimmonsꢀSmith cyclopropanation of ketone-derived silyl enol
ethers.5 Corey and co-workers have demonstrated that a titaniumꢀ
TADDOL complex gives moderate levels of enantioselectivity in
the Kulinkovich cyclopropanation of an acetate-derived ester.6
Several auxiliary-based methods have also been developed for
the SimmonsꢀSmith cyclopropanations of chiral vinyl ethers7
and chiral boronate esters,8 but these methods typically suffer
from low yields and difficulties in the removal of the chiral
auxiliary. Additionally, the asymmetric synthesis of cyclopropyl
boronates has been realized starting from allylic carbonates9 or
cyclopropenes,10 but both procedures possess significant limitations
in terms of scope.
Considering the state of the art for the asymmetric synthesis of
cyclopropanols, the development of a scalable synthesis of ent-1
to support an ongoing drug discovery program presented a
significant challenge (Scheme 2). Since the asymmetric Simmonsꢀ
Smith cyclopropantion of silyl enol ethers has only been demon-
strated with ketone-derived substrates and there is little pre-
cedent for the Kulinkovich cyclopropanation of formate esters,
the literature provided few options in terms of developing a
catalytic asymmetric synthesis for ent-1. Therefore, to access the
desired ent-1, an alternative six-step route starting from vinyl
boronate 4 was identified which would rely on a final, enzymatic
Scheme 2. Retrosynthetic analysis of ent-1
resolution to generate the desired, enantioenriched cyclopro-
panol. The racemic alkynyl cyclopropanol rac-1 could be generated
from the corresponding cyclopropanol chloride 2. The cyclo-
propanol would be unmasked via cleavage of boronate 3 which
would be prepared from the E-vinyl boronate 4, a commercially
available compound.
Even after successful demonstration of this new route at
laboratory scale, significant issues remained, particularly in the
context of the safe use of lithium acetylideꢀethylene diamine
Received: September 7, 2011
Published: December 07, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/op2002497 Org. Process Res. Dev. 2012, 16, 87–95
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Scheme 3. Alkynylation of 2 with lithium acetylideꢀethylene
conditions represented a significant improvement when com-
pared to results using Zn(CH2I)2.
diamine complex 5
With 3 in hand, investigation of the oxidation of the
boronꢀcarbon bond was undertaken. Initial attempts to employ
sodium perborate8h,14 led to significant decomposition. How-
ever, it was found that treatment of 3 with 1 equiv of 10 M
sodium hydroxide in methanol at 0 °C followed by 2.0 equiv of
30 wt % hydrogen peroxide gave clean conversion to 2 after an
aqueous workup. Initial attempts showed that extractive removal
of pinacol was challenging and would require further develop-
ment for large scale (vide infra); thus, the removal of pinacol
from crude 2 was accomplished at this stage of development by
column chromatography to give a 69% yield of the desired chloro
cyclopropanol 2.
Scheme 4. Diastereoselective cyclopropanation of 6
At this point, the direct displacement of the primary chloride
in 2 to generate the terminal alkyne in 1 was investigated. This
would avoid the installation of an oxygen-protecting group and
the addition of two steps to the synthesis for protection and
deprotection of this early-stage intermediate. The lithium
acetylideꢀethylene diamine complex 5 seemed an attractive
choice for an alkynylating agent since it is a relatively air-stable,
commercially available solid. A survey of the literature on
alkynylations with 5 revealed that this reaction was known to
proceed even in the presence of protic functionality such as a
carboxylic acid.15 However, a more pressing issue was the fact
that alkyl chlorides showed poor reactivity with 5. Extensive
literature examples exist on the displacement of bromides,16
iodides,17 and oxygen-centered leaving groups such as tosylates,
triflates, and epoxides18 with 5, but only a single publication
could be found on the reaction of alkyl chlorides.19 A highly polar
solvent such as dimethyl sulfoxide (DMSO) was required for the
displacement reaction. Investigations on the reaction of 2 with
5 revealed that the only viable solvents for this transformation
were N,N0-dimethylacetamide (DMAc), N-methylpyrrolidinone
(NMP), and DMSO. DMAc gave good conversion, but the
impurity profile was not as favorable as the reaction performed in
either DMSO or NMP. Although the impurities formed during
reactions in DMAc were not identified, the possibility of acetyla-
tion of either 5 or 1 by DMAc could not be ruled out.
The initially developed conditions called for the use of 2.1
equiv of 5 in DMSO (Scheme 6). Due to the low reactivity of the
chloride, long reaction times were required at room temperature
to obtain >90% conversion. However at 50 °C, after only 1 h,
>98% conversion and a 76% yield of rac-1 could be obtained. The
crude solution was directly acetylated to give cyclopropyl acetate,
rac-7, which could be used directly in the subsequent enzymatic
resolution.
Although the alkynylation of the unprotected cyclopropanol 2
did avoid the need for a protecting group strategy, the use of
excess lithium acetylideꢀethylene diamine complex 5 to perform
both the deprotonation of the cyclopropanol and the alkynyla-
tion led to the generation of a full equivalent of acetylene. The
uncontrolled release of acetylene gas would pose a significant risk
upon scale-up. Furthermore, the known incompatibility of
DMSO and strongly basic reagents raised additional safety
concerns which would require careful investigation prior to
implementing this procedure on larger scale.20
complex 5 for installation of the terminal alkyne on larger scale
(Scheme 3). In this report, we describe the development and
successful implementation of a synthesis of ent-1 on a multi-
kilogram scale. Detailed studies focusing on the hazards of the
key alkynylation step with 5 are described which shed light on the
hazards of this commercially available reagent and defined a clear
path forward for its safe use.
’ RESULTS AND DISCUSSION
Development of a Synthesis of the Alkynyl Cyclopropanol
rac-1. The cyclopropanation of vinyl boronates has been re-
ported in the literature, predominantly in the context of
diastereoselective SimmonsꢀSmith cyclopropanations.8 Initial
attempts to perform a diastereoselective cyclopropanation of a
tartaramide-modified vinyl boronate 68i gave a 24% yield of
2 after oxidative cleavage, with significant process impurities
which could only be removed after a difficult chromatography
(Scheme 4).
Therefore, the racemic cyclopropanation of the commercially
available pinacol vinyl boronate 411 was investigated. Literature
precedent existed for this transformation, but only moderate
yield was obtained after running the reaction for 10 h at 50 °C.8h
In our hands, treatment of 4 with bis-iodomethylzinc
(Zn(CH2I)2) prepared from diethylzinc and diiodomethane
gave poor conversion (<5%), even after prolonged reaction
times at room temperature. The electron-deficient nature of this
alkene combined with the lack of a coordinating group was
suspected as the cause of this poor reactivity.12 Therefore, the use
of the trifluoroacetic acid-modified reagent developed by Shi and
co-workers13 was attempted, and it showed a dramatic increase in
reactivity at room temperature. After formation of the iodo-
methylzinctrifluoroacetate (ICH2ZnO2CCF3) from diethylzinc,
trifluoroacetic acid, and diiodomethane in a dichloromethane
(DCM)/hexane mixture at 0 °C, addition of vinyl boronate 4
followed by stirring at room temperature for 16 h gave >98%
conversion to the cyclopropyl boronate 3 in 79% isolated yield
after only an acidic aqueous workup (Scheme 5). The high
conversion and clean impurity profile obtained under the Shi
An examination of the stability of lithium acetylideꢀethylene
diamine complex 5 in DMSO immediately confirmed the con-
cerns about processing the reaction on large scale. Testing was
carried out using a closed system accelerating rate calorimeter
(ARC) corrected for thermal inertia such that the test results
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Scheme 5. Preparation of chloro cyclopropanol 2
Scheme 6. Alkynylation of the chloro cyclopropanol 2 with 5
Figure 2. Rates of self-heating and pressure generation vs temperature
for 5 in DMPU.
Figure 1. Rates of self-heating and pressure generation vs temperature
for 5 in DMSO.
mimic what can be expected in the factory (500-L vessel or
larger). The test results demonstrated that 5 in DMSO was
unstable at temperatures greater than 50 °C, which could
potentially lead to thermal runaway (Figure 1). The ARC results
showed that around 50 °C a very slow adiabatic runaway reac-
tion started which accelerated to a rapid but controllable rate.
A large amount of heat was generated. The approximate adiabatic
temperature rise observed was +170 K. This activity self-heated
the sample to 210 °C where a second decomposition reaction
involving the DMSO solvent occurred, resulting in an extremely
violent and uncontrollable runaway reaction. Test results showed
that the temperature rose at a rate exceeding 1000 K/min, and an
associated pressure generation rate exceeded 100,000 psi/min.
Over 4000 psi was generated, causing the test equipment to fail.
At this point it was obvious that the process was not safe to
scale up.
alternative (Table 1, Route A). Using 2.1 equiv of lithium
acetylideꢀethylene diamine complex 5, 1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)pyrimidone (DMPU), DMAc and NMP were
identified as potential candidates on the basis of the high
conversions observed at room temperature. Examination of the
stability of 5 in DMPU using the ARC revealed that 5 in DMPU
started to slowly decompose at 70 °C. However, the resulting
adiabatic temperature rise was about half of that observed in
DMSO, and the maximum rate of temperature increase was
reduced by at least an order of magnitude (Figure 2). More
importantly, the violent higher-temperature secondary de-
composition was not encountered. ARC testing using 5 in
NMP gave results comparable to those observed with DMSO
for the controllable first exotherm. However, even at tem-
peratures above 215 °C, no secondary decomposition was
observed. From this initial data, the thermal stability of 5 in
both DMPU and NMP suggested that either would be a safe
solvent for scale-up of the reaction of 2 with 5 at 50 °C.
However, from a safety perspective, DMPU was clearly the
better choice.
Since initial studies indicated that a polar aprotic solvent
would be required for high conversions to rac-1 and DMSO
was clearly not suitable for further development, a brief screen
of other polar aprotic solvents was undertaken to identify an
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Table 1. Survey of solvents for reactions of 2 with 5
route A: 2.2 equiv 5
route B: 1.1 equiv 5, 1 equiv n-HexLi
conv, time (%, h) yield (%)
1 h, RT (% conv)
20 h, RT (% conv)
DMSO
DMAc
NMP
90
10
>98
>98
>98
ND
ꢀ
58, 4
ꢀ
24
56
81
23
98, 2.5
96, 4
DMPU
>98
ethylene oxide and butadiene. Due to the special safety controls
required for the use of acetylene gas, few if any US pharmaceutical
pilot plants are rated for Class 1, Group A. In the EU, however,
acetylene has an electrical classification of group IIC, which also
includes hydrogen, and some European pharmaceutical pilot plants
are rated for group IIC. Although monitoring of the release of
acetylene gas during this reaction is required in all cases, the
quantification of acetylene in the headspace would have implications
regarding where this chemistry could be performed on kilogram scale.
In order to understand and quantify the timing and the
amount of acetylene produced during this reaction, a ReactIR
4000 was used to measure the evolution of acetylene gas
(absorption at 3300 cmꢀ1) in the headspace. The ReactIR 4000
was equipped with an online gas cell connected to a 250-mL
jacketed flask (see Experimental Section for details). The gas
phase in the reactor was examined over the entire course of the
reaction by purging dry nitrogen gas through the headspace at a
rate of 20 mL/min. A condenser at 5 °C was used to minimize the
loss of THF. To quantify the exact amount of acetylene present,
calibration with a known mixture of acetylene in nitrogen was
used to create a calibration curve.
When the optimized procedure using a sacrificial base and
1.1 equiv of 5 (Scheme 7) was performed in the apparatus equipped
with the ReactIR, it was observed that acetylene was still evolved
during the reaction (Figure 3), with the majority of the acetylene
evolving during the early stages of the reaction. It was found that
suspending 5 in dry DMPU led to some acetylene release (<1%
acetylene in the headspace). During the reaction, the bulk of the
acetylene was released upon addition of the solution of the
lithium alkoxide of 2 in THF to the suspension of 5 in DMPU
and the subsequent heating to 50 °C. At its highest point, the
level of acetylene measured in the headspace during the reaction
was 7.2% (Figure 3). The acetylene level reached this point at
t = 50 min and then slowly dropped over the remainder of the
reaction. Monitoring was continued during the quench of the
reaction with 1 M HCl, but no acetylene release was evident at
this point. On the basis of these results, it was clear that even with
a sacrificial base present, some acetylene was being produced.
Therefore, safely performing this chemistry on kilogram scale in
countries that use the American electrical classification system
would require a pilot plant rated for Class 1 Group A gases, and in
countries that use the European system would require a pilot plant
capable of handling classIIC gases. Ifthe reactor and/or its venting
pathways are not rated for acetylene, the amount of acetylene in
the headspace should be limited to e1% for single batch and
Scheme 7. Optimized conditions for formation of rac-1
Having addressed the issue of reaction solvent, our attention
turned to the issue of acetylene generation during the reaction. In
the original procedure, 2.1 equiv of 5 were employed to both
deprotonate the cyclopropanol and perform the displacement of
the chloride to give rac-1. We hoped to identify a sacrificial base
to replace the extra equivalent of 5 used in the original procedure
and thus avoid the generation of a full equivalent of acetylene
during the reaction. Treatment of a solution of 2 in tetrahydro-
furan (THF) at 0 °C with 1 equiv of n-hexyllithium to form the
corresponding alkoxide, followed by transfer of that solution into a
suspension of 5 in DMPU before heating to 50 °C, proved
successful (Table 1, Route B). On the basis of yield, the use of
DMPU was clearly superior to NMP or DMAc. Using DMPU as
the solvent, an 81% isolated yield could be obtained after acidic
workup as described above (Scheme 7). The final solvent
composition of the reaction was approximately 1:1 THF/
DMPU, and it was hoped that the amount of DMPU could be
reduced to increase volume efficiency and decrease the use of this
costly solvent. However, increasing the ratio of THF to DMPU
led to low conversions, even after prolonged reaction times.
Despite the use of a sacrificial base to minimize acetylene gas
evolution, the potential to form acetylene gas in the headspace
from the decomposition of 5 was a major concern and needed to
be investigated. Acetylene is very sensitive to excess pressure,
excess temperature, static electricity, and/or mechanical shock.
Acetylene is incompatible with certain materials and metals, such
as copper.21 It is extremely flammable and readily forms explosive
mixtures with air over an unusually broad range of concen-
tration.22 The explosive limits can range from 2.5 to 81% in air.23
Acetylene will violently self-react at >15 psi.24 The high bond
energy of the carbonꢀcarbon triple bond makes acetylene explo-
sionsmore violent than those of most other fuels. For these reasons,
the electrical classification of acetylene in the United States is
Class 1, Group A.25 Acetylene is categorized by itself in Group A
due to the unique hazards of this compound. As a point of
reference, Group B includes hydrogen and, in some situations,
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Figure 3. ReactIR analysis of reactor headspace for acetylene.
Scheme 8. Enzymatic resolution of rac-7
e0.6% for regular production, placing significant restrictions on
the broad utility of this chemistry at plant scale. Despite the low
levels of acetylene which can potentially be produced by this
reaction, care should be taken when using 5 on any scale to avoid
potentially dangerous explosions from the buildup of acetylene.
Having examined the safety concerns surrounding lithium
acetylideꢀethylene diamine complex 5 and gained a better
understanding of the alkynylation of 2, we had some confidence
about continuing the development of this route at larger scale.
Therefore, with a route to the racemic cyclopropyl acetate rac-7
in hand, investigations of the crucial enzymatic resolution step
were undertaken (Scheme 8). Hydrolysis of the cyclopropyl
acetate rac-7 was screened against our library of commercially
available lipases and amidases, consisting of a number of lyophi-
lized powders, liquid enzyme preparations, and immobilized
enzyme preparations. For the lyophilized powders and liquid
enzyme preparations the screening was conducted using a 0.1 M,
pH = 8.0, aqueous phosphate buffer in a 96-well plate format.
The cyclopropyl acetate was dispensed to each reaction tube as a
solution in DMSO to give a substrate concentration of 5 mg/mL
and a DMSO concentration of 10 vol %. For the immobilized
enzyme screen, MTBE was shaken in a separatory funnel with a
solution of 0.1 M, pH = 8.0, aqueous phosphate buffer, and then
the layers were allowed to separate. The cyclopropyl acetate was
then added to a portion of the buffer-saturated MTBE to give a
substrate concentration of 5 mg/mL. The substrate/MTBE
solution was then mixed with a previously dispensed quantity
of the immobilized enzymes in a 96-well plate format at 30 °C.
The reactions were then monitored for conversion and enantio-
meric excess (see Experimental Section for GC conditions).
From the initial screening results, Novozym 435 with MTBE
as solvent was selected for further reaction optimization. It was
identified that the desired enantiomer ent-1 was the hydrolyzed
product of the reaction with rac-7. Screening of additional
organic solvents (ethyl acetate, heptane, toluene, THF, acetoni-
trile, etc.) for an increase in hydrolysis selectivity did not offer any
advantages over the initial MTBE conditions. With the MTBE
solvent system, no significant background hydrolysis of rac-7 to
rac-1 occurred when the MTBE solution was shaken with a 0.1 M
aqueous solution of potassium phosphate dibasic (approximate
pH of 8.6), indicating that there would be no unselective,
uncatalyzed background hydrolysis of this species under these
conditions. Using these more basic conditions removed a pH
adjustment from the original procedure and modestly simplified
the reaction setup. Finally, the charges of cyclopropyl acetate
rac-7 and Novozym 435 were optimized to give a reaction rate
that was sufficient to complete the reaction in one day but was
still slow enough that overhydrolysis (and a corresponding loss
in product enantiomeric excess) could be avoided. When the desired
end point of the reaction was obtained (product ee of 96%, approx
40% conversion) the reaction mixture was filtered to remove the
enzymatic catalyst and halt any further hydrolysis. The crude
reaction mixture was concentrated and then solvent switched to
heptane for the subsequent chromatographic purification. Since all
of the reactions thus far were to be conducted as a through-process
with no isolations or purification, separation of the mixture of ent-1
and rac-7 would serve not only to give the enantioenriched product
but also to remove process impurities generated thus far. Purification
by column chromatography was successful at removing a variety of
impurities which had been formed during this five-step through-
process and gave material of sufficient quality for the final delivery.
’ LARGE-SCALE DEMONSTRATION OF THE SYNTHE-
SIS OF CYCLOPROPYL ALCOHOL RAC-1
Having established proof of concept for the synthesis of ent-1
as well as identified the relevant issues for the safe handling and use
of lithium acetylideꢀethylene diamine complex 5, the procedure
was ready for scale-up to multikilogram scale. Although vinyl
boronate 4 is commercially available, due to cost and lead-time it
was decided to implement a quick synthesis from the chloroalkyne
8 (Scheme 9). The hydroboration of 8 was carried out using
pinacol borane in the presence of a catalytic amount of BH3ꢀTHF
(0.05 equiv) and cyclohexene (0.1 equiv).26
The key concerns with this step were the highly exothermic
charges of the reagents to an essentially neat reaction mixture.
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Scheme 9. Large-scale demonstration of the synthesis of rac-7
The addition of cyclohexene to borane and the subsequent
addition of the alkyne 8 to this mixture were highly exothermic,
but these could be controlled by adjusting addition rate. A RC-1
(reaction calorimeter) run on the final pinacol borane addition at
30 °C over 2 h showed a 40% accumulation of reagents with a
reaction exotherm of 154 kJ/mol and an adiabatic temperature rise
of >300 K. Thus, it was decided to do an extended addition over at
least 2 h, with careful monitoring of the exotherm throughout
the charge. On a 20-kg scale the pinacol borane addition took 4 h
40 min, and after a further 50-min age, the batch temperature
stabilized, and 1H NMR showed 85% conversion. After an over-
night age, 94% conversion27 was achieved, and the batch was then
quenched and worked up to afford 38 kg of 4 in 84% yield.
The SimmonsꢀSmith reaction of 4 (80 wt % solution in
heptane) was efficient on 20-g runs, achieving >98% conversion
after an overnight age. The reactions were very clean, giving 3,
after workup and concentration, as a solution in heptane in >90%
yield (>95% purity by 1H NMR and GC). Large exotherms were
observed upon sequential addition of the reagents; therefore, the
reaction was examined further using DSC (differential scanning
calorimeter) and RC-1 calorimetry. DSC showed no exotherms
in the slurries after additions, quench, and concentration. RC-1
was used for the reagent additions to examine the heat transfer of
the reaction in order to calculate a safe addition rate and vessel
jacket temperature in the plant. For the specific vessel used in the
pilot plant, these data showed the following:
For the oxidation of the boronate to the cyclopropyl alcohol, this
was achieved by treating boronate 3 with 10 M sodium hydroxide
(1.0 equiv) and aqueous hydrogen peroxide (30%, 1.2 equiv). Once
the oxidation was complete, the reaction was quenched with
hydrochloric acid followed by aqueous sodium sulfite and stirring
overnight to ensure complete hydrolysis of any intermediate
boronate species. Although all four of the additions are exothermic,
running this chemistry in the RC-1 confirmed that there was very
little heat accumulation at the end of each of these additions,
indicating that the exotherms observed could be controlled by
adjusting the addition rate, and that reasonable addition times would
be achievable on scale. Furthermore, GC analysis both part way
through and at the completion of the peroxide addition indicated
that the reaction was almost instantaneous at ꢀ5 to 5 °C.
In previous lab runs the alcohol 2 was isolated by extraction
into MTBE and purification by column chromatography to
remove pinacol. It was found, however, that the chromatographic
removal of pinacol could be avoided by washing the MTBE
extracts with water several times. DCM or toluene could be used
in place of MTBE, but its relative ease of removal and disposal
made it a better choice for scale-up. Therefore, the quenched
reaction mixture was extracted twice with MTBE, and the combined
extracts were then washed once with 0.5 M sodium hydroxide and
then washed three times with water. The resulting MTBE solution
was azeotropically dried by distillation and then concentrated to
minimum volume to afford a 75% corrected yield of alcohol 2. The
final material typically contained less than 2% pinacol relative to
2 (based on GC) and, excluding solvents, contained only one
impurity larger than this (3% LC area percent (LCAP)). A total of
8% of desired product 2 was lost to the initial aqueous layer and the
four washes. It was decided to use crude 2 directly in the next step.
This process was successfully run on 35 kg scale, without incident, to
afford a 27 wt % MTBE solution of alcohol 2, containing 16.1 kg of
desired product (83% yield). Pinacol level, aqueous losses, and
purity profile all matched typical lab runs.
(1) Addition rates and vessel jacket temperatures needed to
maintain a reaction at 3 °C were:
TFA addition to Et2Zn: 32.6 KJ/mol exotherm with
adiabatic temperature rise of ∼57 K. TFA addition could
be done over 80 min with jacket at ꢀ11 °C.
CH2I2 addition to TFA/Et2Zn/DCM slurry: 9.3 KJ/mol
exotherm with adiabatic temperature rise of ∼12 K. CH2I2
addition could be done over 20 min with jacket at ꢀ10 °C.
Substrate addition: 23.6 KJ/mol exotherm with adiabatic
temperature rise of ∼28 K. Substrate addition could be
done over 45 min with jacket at ꢀ12 °C.
The Li-acetylide/DMPU chemistry developed to avoid the
generation of acetylene was scaled. In order to achieve optimum
conversion and purity during the course of the reaction when
using the bulk stream of 2, the conditions were altered slightly.
Upon changing the reaction parameters, we found the most
successful and consistent procedure was deprotonation of the
alcohol in MTBE and THF at <ꢀ10 °C with 1.2 equiv HexLi,
followed by addition of this alkoxide to the lithium acetylideꢀ
ethylene diamine complex 5 in DPMU at <25 °C and heating to
50 °C. This slightly modified procedure resulted in good conver-
sions, while keeping the impurities at less than 5 GC area percent
(2) Addition rate and vessel jacket temperature to maintain
the quench at 25 °C were:
Quench with aqueous HCl: 7.4 kJ/mol exotherm with
adiabatic temperature rise of ∼8 K. On scale addition
could be done over 10 min with jacket at +6 °C.
On scale the SimmonsꢀSmith reaction was run in two batches
using 34.3 kg of 4. Both proceeded identically (>98% conversion)
and gave 3 as a solution in heptane (44.8 kg at 78 wt %, 96% yield).
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(GCAP) each. Using 16.1 kg of 2, the alkynyl alcohol rac-1 was
isolated as a 31 wt % solution, which was used directly in the
acylation. The impurities were kept to below 3% each, with six
impurities at 1ꢀ3% GCAP, and the total impurities were 13 GCAP.
The acylation of cyclopropanol rac-1 to give cyclopropyl acetate
rac-7 proceeded without incident using Et3N (1.3 equiv) and AcCl
(1.2 equiv). The resulting MTBE solution of cyclopropyl acetate
rac-7 contained 12.5 kg by assay (46 wt %; 79% yield over two steps
from alcohol 2) and was ready for use in the enzymatic hydrolysis.
Completion of the preparation of ent-1 was performed
through enzymatic hydrolysis of rac-7 followed by silica gel
chromatography. The crude MTBE stream of rac-7 was used
directly under conditions identical to those employed at smaller
scales. When the reaction reached 41% conversion to ent-1 with
96% ee, the reaction mixture was filtered and purified by silica gel
chromatography using a EtOAc/heptanes solvent system to
remove unhydrolyzed acetate rac-7 and other impurities gener-
ated in the five-step through-process. Unfortunately, heating of
the sample occurred upon loading onto the column, leading to
some hydrolysis of the undesired acetate rac-7. Therefore, the
96% ee of ent-1 obtained in the enzymatic hydrolysis of rac-7 was
lowered to 92% ee in the final, isolated ent-1. The undesired
hydrolysis in the presence of silica was not observed on smaller scales.
Despite this drawback, productivity was high and significant quan-
tities of ent-1 of acceptable quality for the downstream chemistry
were produced, allowing completion of the delivery. In total, 3.48 kg
of an 81 wt % solution ent-1 in MTBE (2.81 kg, 30% yield from
rac-7) with 92% ee was isolated. This represents an overall 15.8%
yield for the six-step synthesis starting from the chloroalkyne 8.
solution in heptane (0.8 mol, 1.07 equiv). The solution was
cooled with an ice bath to an internal temperature of 3 °C. To the
flask was then added from the dropping funnel a solution of
57.6 mL trifluoroacetic acid (0.748 mol, 1.0 equiv) in 200 mL of
dichloromethane over 1 h, keeping the internal temperature below
10 °C. The resulting suspension was stirred for 30 min at 3 °C. To
the flask was then added 72.4 mL of diiodomethane (0.897 mol, 1.2
equiv) in a single portion. After stirring at 3 °C for 30 min, 172 mL of
4(0.748 mol, 1.0 equiv) was added to the solution in a single portion.
The flask was then allowed to warm to room temperature, and a
white precipitate began to form. After 3 h, GC analysis indicated the
reaction was at 90% conversion. The suspension was aged for an
additional 17 h or until complete consumption of 4 is observed. At
that point, 800 mL of 1 M HCl (0.8 mol, 1.07 equiv) was added, and
a +5 °C exotherm was observed. The biphasic mixture was stirred for
30 min to dissolve the precipitated solids, and the organic layer was
separated. Extraction of the aqueous layer with 200 mL of dichloro-
methane, washing of the combined organic layers with 500 mL
brine, and concentration in vacuo to give 194 g of 3 as a yellow oil
(74 wt % in DCM, 79% yield). 1H NMR (400 MHz, CDCl3) δ 3.59
(t, 2H, J= 6.7 Hz), 1.90 (pent, 2H, J= 7.1 Hz), 1.49 (sext, 1H, J = 7.0
Hz), 1.36 (sext, 1H, J = 7.0 Hz), 1.23 (s, 12H), 0.93 (m, 1H), 0.71
(m, 1H), 0.44 (m, 1H), ꢀ0.35 (dt, 1H, J = 9.4, 5.7 Hz); 13C NMR
(100 MHz, CDCl3) δ 82.82, 44.74, 32.67, 32.22, 24.64, 17.22, 11.24,
0.5 (bs); GC: HP1 (30 m ꢁ 0.32 mm ꢁ 0.25 μm), 25 psi, 200 °C
front inlet. Five minutes @ 50 °C, ramp 25 °C/min to 250 °C, then
hold for 4 min, tr(4) = 9.78 min, tr(3) = 10.08 min.
Preparation of 2-(3-Chloro-propyl)-cyclopropanol (2). To
a 3-L RBF equipped with a nitrogen inlet, mechanical stirrer,
dropping funnel, and thermocouple was added 143 g of 3 (0.585
mol, 1.0 equiv) in 1 L of methanol. The solution was cooled
with an acetone/water/dry ice bath to an internal temperature
of ꢀ8 °C. To the flask was then added from the dropping funnel
58.5 mL of 10 M sodium hydroxide (0.585 mol, 1.0 equiv) over
30 min, keeping the internal temperature below 10 °C. After
stirring for 30 min, 120 mL of 30 wt % hydrogen peroxide
solution (1.17 mol, 2 equiv) was slowly added from the dropping
funnel over 1 h, keeping the internal temperature below 10 °C.
Upon completion of the addition, the cooling bath was removed,
and the resulting colorless slurry was stirred at RT for 30 min or
until complete consumption of 3 is observed by GC. The
suspension was then cooled in an ice bath to an internal
temperature 2 °C, and 375 mL 2 M HCl was added from the
dropping funnel over 30 min, keeping the internal temperature
below 10 °C. To this clear, yellow solution at 4 °C was then
slowly added 500 mL of a 1 M solution of Na2SO3 from the
dropping funnel, keeping the internal temperature below 10 °C.
The resulting suspension was then filtered and extracted 3 ꢁ
200 mL MTBE. Concentration followed by silica gel column
chromatography (6:4 hexane/ethyl acetate), to remove pinacol,
gave 60.6 g of product 2 as a clear oil (90 wt %, 69% yield). 1H
NMR (400 MHz, CDCl3) δ 3.62 (t, 2H, J = 6.6 Hz), 3.27 (dt, 1H,
J = 6.3, 2.6 Hz), 1.89 (pent, 2H, J = 6.8 Hz), 1.85 (bs, OH), 1.43
(sext, 1H, J = 7.0 Hz), 1.28 (sext, 1H, J = 7.0 Hz), 0.94 (m, 1H),
0.75 (m, 1H), 0.38 (q, 1H, J = 6.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 52.21, 44.69, 31.91, 28.69, 19.69, 14.15; GC: HP1
(30 m ꢁ 0.32 mm ꢁ 0.25 μm), 25 psi, 200 °C front inlet. Five
minutes @ 50 °C, ramp 25 °C/min to 250 °C, then hold for
4 min, tr(3) = 10.08 min, tr(2) = 7.15 min.
’ CONCLUSIONS
Over the course of studies towards a multikilogram synthesis
of ent-1, we had the opportunity to carefully evaluate the use of
lithium acetylideꢀethylene diamine complex 5. While acceptable
for small-scale development, careful evaluation of the commonly
employed literature conditions in DMSO revealed serious safety
concerns with uncontrolled exothermic activity of mixtures of
lithium acetylideꢀethylene diamine complex 5 in DMSO. An
interplay between chemical and thermochemical analysis of the
reaction in a variety of solvents quickly led to identification of
safer alternatives to DMSO. Use of either NMP or DMPU can
provide a safe and practical method for the alkynylation of even
unreactive chloroalkanes. Safety issues surrounding the evolution
of acetylene gas during the reactions of 5 were carefully studied,
and an improved process employing a sacrificial base and a stable
solvent was identified and used for scaling this process. Finally, an
efficient enzymatic resolution of the trans-cyclopropanol rac-1
was developed, providing access to this deceptively complex
chiral motif which could not be readily accessed through existing
asymmetric methodologies. All these studies combined to allow
for successful completion of the synthesis of ent-1 on multi-
kilogram scale in a safe and timely fashion to support ongoing
drug discovery efforts.
’ EXPERIMENTAL SECTION
Preparation of 2-[2-(3-Chloro-propyl)-cyclopropyl]-4,4,5,
5-tetramethyl- [1,3,2]dioxaborolane (3). To a 5-L round-
bottom flask (RBF) equipped with a nitrogen inlet, mechanical
stirrer, dropping funnel, and thermocouple under N2 was added
800 mL of dichloromethane and 800 mL of a 1 M diethylzinc
Preparation of 2-Pent-4-ynyl-cyclopropanol (rac-1). To a
two-necked 500-mL round-bottom flask equipped with a tempera-
ture probe, N2 inlet, and septum was added 27.0 g of 2 (0.201 mol,
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Organic Process Research & Development
ARTICLE
1.0 equiv, 100 g as a 27 wt % solution in MTBE) and 54 mL of THF.
The solution was cooled to an internal temperature of ꢀ15 °C. To
this solution was added 67.2 g of 33 wt % n-hexyllithium (0.241 mol,
1.2 equiv) slowly via syringe pump over 1 h, keeping the internal
temperature below 0 °C. In a separate three-necked 1-L RBF
equipped with a temperature probe, N2 inlet, and septum was
slurried 20.7 g of lithium acetylideꢀethylenediamine complex 5
(0.221 mol, 1.1 equiv) in 136 mL of DMPU at room temperature.
To this room temperature slurry was transferred via cannula over
15 min the cold solution of the deprotonated cyclopropanol. After
the addition, the brown mixture was heated to an internal tempera-
ture of 52 °C for 11 h (97% conversion was observed by GC). The
brown mixture was cooled with an ice bath to 3 °C, then 221 mL of
1.0 N HCl (0.221 mol, 1.1 equiv) was added slowly, keeping the
internal temperature below 10 °C. The mixture was then diluted with
108 mL of MTBE and 108 mL of water before transfer to a
separatory funnel and removal of the aqueous layer. The aqueous
layer was extracted twice with 108 mL of MTBE, and then the
combined organic layers were washed with 50 mL of water followed
by 50 mL of 5% brine. The organic layer was then concentrated in
vacuo to afford 31.5 g of rac-1 as a yellow oil (63 wt %, 80% yield).
1H NMR (400 MHz, CDCl3) δ 3.24 (dt, 1H, J = 2.6, 5.3 Hz), 2.25
(dt, 2H, J = 2.6, 7.6 Hz), 1.96 (t, 1H, J = 2.6 Hz), 1.92 (s, 1H, OH),
1.64 (pent, 2H, J = 7.3 Hz), 1.38 (sext, 1H, J = 6.9 Hz), 1.24 (sext,
1H, J = 6.9 Hz), 0.93 (m, 1H), 0.72 (m, 1H), 0.35 (q, 1H, J =
6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 84.49, 68.37, 52.45, 30.50,
27.74, 20.17, 18.01, 14.25; GC: HP1 (30 m ꢁ 0.32 mm ꢁ 0.25 μm),
25 psi, 200 °C front inlet. Five minutes @ 50 °C, ramp 25 °C/min to
250 °C, then hold for 4 min, tr(2) = 7.15 min, tr(rac-1) = 6.72 min.
ReactIR Monitoring of Acetylene Gas Formation in the
Preparation of 2-Pent-4-ynyl-cyclopropanol (rac-1). To a
four-necked 250-mL RBF fitted with a ReactIR probe, N2 inlet
with flow meter, condenser, and outlet to a FTIR gas cell was
charged 5.0 mL of DMPU followed by 5 (0.82 g, 8 mmol). In a
second two-necked 15-mL RBF equipped with a temperature
probe, N2 inlet, and septum was added 1 g of 2 (7.28 mmol,
1.0 equiv) and 3.0 mL of THF. The solution was cooled to an
internal temperature of 0 °C with an ice bath. To this solution
was added 2.95 mL of 33 wt % n-hexyllithium (7.28 mmol, 1.0 equiv)
slowly via syringe pump over 1 h. Upon completion of the addi-
tion, the solution of the lithium alkoxide of 2 was transferred via
cannula to the flask containing the slurry of 5 in DMPU. Upon
completion of the addition, the reaction was heated to an internal
temperature of 52.1 °C for 4 h to effect complete conversion.
The 0.5 N HCl (17.5 mL) was added slowly, and an ice bath
was applied to maintain an internal temperature below 21 °C.
ReactIR monitoring of the headspace gas was continuous
throughout the reaction. Acetylene gas concentrations were
quantified using known mixtures of H2 in N2.
Preparation of Acetic Acid Racemic trans-2-Pent-4-ynyl-
cyclopropyl Ester (rac-7). To a 5-L RBF equipped with a
nitrogen inlet, mechanical stirrer, dropping funnel, and thermo-
couple under N2 was added 31.2 g of rac-1 (251 mmol,
1.0 equiv), 350 mL of MTBE, and 45.5 mL of triethylamine
(327 mmol, 1.3 equiv) prior to cooling the solution in an
acetone/ice bath to an internal temp of <5 °C. To the solution
was added from the dropping funnel 23.7 mL of acetyl chloride
(301 mmol, 1.1 equiv) over a 30-min period while maintaining
the internal temp <10 °C. The resulting slurry was then warmed
to room temperature and aged for 2 h. At this point, the reaction
mixture was diluted with 200 mL of water. The biphasic mixture
was transferred to a separatory funnel and the aqueous layer
removed. The organic layer was washed with 200 mL of 2 N HCl
and then with 300 mL of sat. NaHCO3 prior to drying over
MgSO4. The solvent was removed in vacuo to give 41.8 g of rac-7
(>99% yield). 1H NMR (400 MHz, CDCl3) δ 3.84 (dt, 1H, J =
6.7, 2.9 Hz), 2.25 (dt, 2H, J = 2.7, 7.0 Hz), 2.03 (s, 3H), 1.95
(t, 1H, J = 2.6 Hz), 1.67 (m, 2H), 1.39 (m, 2H), 1.01 (m, 1H),
0.89 (m, 1H), 0.57 (q, 1H, J = 6.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 171.60, 84.15, 68.47, 54.20, 30.12, 27.40, 20.85, 17.92,
17.83, 11.81; GC: Restek RT-Bdex SA (30 m ꢁ 0.25 mm ꢁ
0.25 μm), 60 cm/s linear velocity, 20:1 split, 120 °C isothermal,
tr(1) = 25.0, 29.6 min, tr(7) = 17.1, 17.5 min.
Preparation of (1R, 2R)-2-Pent-4-ynyl-cyclopropanol (ent-1).
To a 2-L round-bottom flask equipped with an overhead stirrer
and temperature probe was added a 60 wt % solution of rac-9 in
MTBE (44.8 g, 0.27 mol) and an additional 650 mL of MTBE
that had been saturated with aqueous 0.1 M pH 7 phosphate
buffer, giving a final solution concentration of rac-7 of 60 g/L.
The flask was placed in an ice bath to maintain an internal
temperature of approximately 10 °C throughout the hydrolysis
reaction, which was initiated by the addition of 730 mg of
Novozym 435. The reaction was aged at 10 °C for approximately
4 h until conversion had reached 41%, at which point the ee of
ent-1 was 96%. The reaction mixture was then filtered through a
150-mL medium-pore glass filter funnel, and the solid immobi-
lized enzyme was washed three times with 80 mL of MTBE. The
resulting MTBE solution was then solvent switched to heptane.
The mixture in heptane was applied to a 120-g silica column and
eluted with a 2.5 to 25.0% EtOAc in heptane gradient (v/v). The
alcohol ent-1 was located by TLC (silica, 20% EtOAc/heptane)
and then the fractions were analyzed by GC (HP-1, 30 m ꢁ 320
μm ꢁ 0.25 μm film, 9.14 psi constant He pressure, 15:1 split,
50 °C for 5 min then 25 °C/min to 275 °C and hold 5 min, RT
of alcohol 8.8 min). Clean fractions were concentrated to give
10.1 g (80 wt %, 95%ee, 30% yield from rac-7) of the desired ent-1.
GC: Restek RT-Bdex SA (30 m ꢁ 0.25 mm ꢁ 0.25 μm), 60 cm/s
linear velocity, 20:1 split, 120 °C isothermal, tr(1) = 25.0,
29.6 min, tr(7) = 17.1, 17.5 min.
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of the NMR spectra for
b
rac-1, 2, 3, and rac-7. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mails: carl_baxter2@merck.com; gbeutner@gmail.com; khateeta_
emerson@merck.com.
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Organic Process Research & Development
ARTICLE
(19) Smith, N. W.; Beumel, O. F., Jr. Synthesis 1974, 441–442.
’ ACKNOWLEDGMENT
(20) Lam, T. T.; Virckery, T.; Tuma, L. J. Therm. Anal. Calorim.
2006, 85, 25–30.
(21) http://encyclopedia.airliquide.com/Encyclopedia.asp?GasID =1,
We thank Dr. Robert Reamer for his valuable assistance with
NMR spectroscopy.
downloaded 20-Oct-2011.
(22) P€assler, P., Hefner, W., Buckl, K., Meinass, H., Meiswinkel, A.,
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(26) Shirakawa, K.; Arase, A.; Hoshi, M. Synthesis 2004, 1814–1820.
(27) The starting chloroalkyne 8 could be removed by distillation of
the heptane stream after workup.
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