Scalable Synthesis of 6,6-Dimethylbicyclo[31.0]hexan-3-one

Article abstract of DOI:10.1055/s-0036-1588484

A simple five-step process for the conversion of technical grade (+)-3-carene into 6,6-dimethylbicyclo[3.1.0]hexan-3-one was developed. A robust process was required that delivered the 6,6-dimethylbicyclo[3.1.0]hexan-3-one, minimized chromatography, reduced the excess of silver salts, and avoided toxic chromium oxidants. A simple and scalable process that relies on crystallization and distillation was developed and demonstrated to produce hundreds of grams of 6,6-dimethylbicyclo[3.1.0]hexan-3-one.

Full text of DOI:10.1055/s-0036-1588484

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
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S. M. Mennen et al.
Letter
Synlett
Scalable Synthesis of 6,6-Dimethylbicyclo[3.1.0]hexan-3-one
Steven M. Mennen*a
Athimoolam Arunachalampillaib
Deborah M. Choquettea
Harikrishna Muppallab
Krishna Sheenab
O
N
O
Br
OH
Me
1) H2O
Me
Br
Me
Me
Me
Me
Me
Me
O
2) crystallization
94–97% purity
54–55% yield
1 kg scale
6,6-dimethylbicyclo[3.1.0]hexan-3-one
≥90% (+)-3-carene
a Process Development, Amgen, Inc., 360 Binney Street,
Cambridge, Massachusetts 02142, USA
smennen@amgen.com
b Chemical Development, Syngene Intl. Ltd., Biocon Park,
Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road,
Bangalore 560099, India
Received: 26.04.2017
Accepted after revision: 02.06.2017
Published online: 18.07.2017
(1, Scheme 1).6 The synthetic sequence begins with the
conversion of 1 into bromohydrin 2 which is isolated as a
solid after silica gel chromatography. The bromohydrin 2 is
then treated with excess Ag2O and undergoes a semi-Pina-
col rearrangement to give the ring-contracted product 3.
Baeyer–Villiger oxidation transforms ketone 3 to acetate 4,
and hydrolysis of acetate 4 with aqueous LiOH affords alco-
hol 5 which is subsequently oxidized with pyridine/CrO3 to
give the target compound 6.
DOI: 10.1055/s-0036-1588484; Art ID: st-2017-r0291-l
Abstract A simple five-step process for the conversion of technical
grade (+)-3-carene into 6,6-dimethylbicyclo[3.1.0]hexan-3-one was de-
veloped. A robust process was required that delivered the 6,6-dimethyl-
bicyclo[3.1.0]hexan-3-one, minimized chromatography, reduced the
excess of silver salts, and avoided toxic chromium oxidants. A simple
and scalable process that relies on crystallization and distillation was de-
veloped and demonstrated to produce hundreds of grams of 6,6-di-
methylbicyclo[3.1.0]hexan-3-one.
Step 1
Step 2
OH
NBS (1.3 equiv)
CaCO3 (1.3 equiv)
Me
Me
Br
Key words semipinacol, Dess–Martin, carene, bromohydrin, silver ni-
trate, Baeyer–Villiger
Ag2O (2.7 equiv)
Me
Me
Me
Me
1,4-dioxane/water
r.t. 20 h
1,4-dioxane/water
r.t., 1 h
1
2
6,6-Dimethylbicyclo[3.1.0]hexan-3-one (6) is a compact
bicyclic ketone whose ridged structure and meso stereo-
chemistry make 6 an excellent component for the introduc-
tion of a nonflexible lipophilic tert-butyl isostere.1 Several
literature preparations of 6 have been published, however,
6 is not readily available beyond the gram quantities need-
ed in medicinal chemistry. Installing the gem-dimethylcy-
clopropane is limited to only a handful of synthetic strate-
gies which include conjugate addition of a sulfonium ylide,2
cyclopropanation of allylic alcohols,3 palladium-catalyzed
cycloisomerization,4 and conversion of a gem-dibromocy-
clopropane into the gem-dimethycyclopropane.5 All of
these synthetic strategies either do not allow access to the
desired 6,6-dimethylbicyclo[3.1.0]hexan-3-one and/or
could not be readily applied to multikilogram scale. Alter-
natively, (+)-3-carene and chrysanthemic acid are readily
available natural products which contain gem-dimethylcy-
clopropane and could be converted into the desired 6,6-di-
methylbicyclo[3.1.0]hexan-3-one.6,7
(+)-3-carene
Step 3
Step 4
O
m-CPBA
(1.3 equiv)
Me
Me
Me
Me
4N LiOH (6 equiv)
Me
Me
O
CH2Cl2
r.t, 14 h
EtOH/H2O
r.t., 1.5 h
O
3
4
Step 5
CrO3 (6.25 equiv)
Me
Me
Me
Me
O
OH
pyridine/CH2Cl2
r.t., 3 h
5
6
Scheme 1 Synthesis of 6 from (+)-3-carene
During route evaluation, several areas were identified
that required development in order to allow for a practical
route capable of a multikilogram delivery. Silica gel chro-
matography was required after step 1 to ensure that bromo-
hydrin 2 was sufficiently pure for downstream processing
and step 2 required a large excess of Ag2O to perform the
semi-Pinacol rearrangement. Chromatography significantly
limited the throughput of the process, and Ag2O resulted in
partial plating the reaction vessel with silver. Besides the
The synthesis of 6 has been previously published em-
ploying a synthetic sequence that was particularly attrac-
tive because it started from readily available (+)-3-carene
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
S. M. Mennen et al.
Letter
Synlett
challenges from a processing standpoint, Ag2O was the larg-
est cost driver of the synthesis. The final oxidation with
chromium was not desired due to the toxicity of chromium
and risk of contamination of 6 and multiproduct reactors
with chromium. Lastly, all of the intermediates of the pro-
cess are low-molecular-weight compounds which were
prone to being removed during concentration or azeotropic
distillation processes.
The challenges to prepare large quantities of 6 became
apparent once our discovery team had identified a candi-
date compound which contained this specific pharmacoph-
ore and was a key bottleneck to further advancement. We
identified several development requirements to ensure 6
could be readily available on multikilogram scale when
necessary: use ≥90% (+)-3-carene due to cost and availabili-
ty compared to 99% (+)-3-carene ($97/kg vs. $5,400/kg),8
identify alternatives to Ag2O and CrO3 due to issues with
cleaning silver and chromium toxicity, and develop process-
es capable of purification by crystallization or distillation.
Additionally, our aim was to develop analytical methods to
monitor the reaction and assess purity of intermediates and
the final product as adequate methods were not available in
the literature.9
Step 1: Conversion of (+)-3-carene into bromohydrin 2
is produced in quantitative yield by the reaction of (+)-3-
carene with N-bromosuccinimide (NBS), CaCO3 in diox-
ane/water. Isolation of 2 by extraction with diethyl ether
followed by silica gel chromatography affords 2 in 47% yield
with 78% GC purity (Table 1, entry 1). The low purity of 2
following silica gel chromatography is attributed to decom-
position during concentration of the chromatography frac-
tions and highlights the reactivity of the bromohydrin. The
extent of decomposition would likely become even greater
with the extended times required to concentrate material
on large scale. To ensure a consistent product purity profile,
our primary focus for improving the process was to develop
the process to allow for isolation by crystallization.
is hypothesized to be the result of residual dioxane and/or
succinimide in the crude reaction stream. Nevertheless,
changing the process from chromatography to crystalliza-
tion not only improve the cycle time, yield, and purity; the
performance of isolated 2 in the downstream process was
significantly improved.
Step 2: With a scalable process to synthesize and isolate
bromohydrin 2 in hand, efforts were focused on improving
the silver oxide mediated semi-Pinacol rearrangement. We
found that less than 2.0 equivalents of Ag2O led to incom-
plete conversion (Table 2). Such excess of Ag2O was not un-
acceptable as a superstoichiometric reagent for scale-up be-
cause of the high cost of a silver salt that contains two at-
oms of silver. In addition to the high cost of excess Ag2O, the
insoluble salts in the reaction were both difficult to stir and
resulted in partial plating of the reactor with silver. We
sought to identify an alternative silver source that reduce
the cost by using less silver and allowed for a simple process
to execute.
Silver(I) nitrate is both readily available and contains
only one molar equivalent of silver compared to the two
equivalents in Ag2O. Since silver is used as a stoichiometric
reagent, reducing the total equivalents of silver has a posi-
tive impact on the viability of the process.12 After an initial
feasibility study we observed that AgNO3could provide a
process advantage of a mobile slurry amendable to scale-
up, no observed silver platting of the reactor, and clean-up
could be executed with HCl.
Harding and coworkers previously demonstrated the
mechanistically related semi-Pinacol rearrangement of an
Table 1 Experimental Conditions for Step 1a
OH
NBS (1.3 equiv)
CaCO3 (1.3 equiv)
Me
Me
Me
Me
Me
Me
dioxane/H2O (2:1)
r.t.
Br
1
2
The extraction solvent was changed to petroleum ether
(PE), which on concentration of the petroleum ether extract
afforded crude 2 that was 89% pure (Table 1, entry 2). Al-
though the crude material was significantly improved, the
purity was not sufficient for the downstream process and
required purification.10 Recrystallization studies with pure
isolated 2 indicated that polar solvent mixtures provided an
amorphous solid that was viscid and not amendable to
scale up (Table 1, entry 3); whereas cold n-hexane provided
>98% purity of an off white crystalline solid (Table 1, entry
4), The low recovery at –20 °C could be improved by con-
ducting the recrystallization at –40 °C (Table 1, entry 4). Ex-
ecution of the full process using crude petroleum ether ex-
tract followed by n-hexane isolation was successfully exe-
cuted three times on 1 kg scale to provide highly
reproducible yield and purity (Table 1, entries 6–8).11 The
isolated yield of the process on kilogram scale was lower
than the recrystallization of pure 2 (Table 1, entry 5) which
(+)-3-carene
Entry
Scale
Isolation solvent
Yield (%) GCAP (%)b
1
10 g
50 g
5 g
chromatography
PE
47
76
n/d
30
70
55
56
54
78
89
n/d
98
96
97
94
94
2
3c
4d
5d
6
recryst. MeOH/H2O
recryst. n-hexane/–20 °C
recryst. n-hexane/–40 °C
n-hexane/–40 °C
n-hexane/–40 °C
n-hexane/–40 °C
5 g
50 g
1.0 kg
1.0 kg
1.0 kg
7
8
a Unless otherwise noted: 1 equiv (+)-3-carene, 1,4-dioxane/water (2:1 v/v,
10 V), CaCO3 (1.3 equiv), NBS (1.3 equiv); V = mL solvent/g solute.
b Area percent purity of isolated product measured by GC; GCAP = gas
chromatography area percent.
c Run at 25 °C, material isolated as a viscid solid.
d The yield given is the recovery after recrystallization of pure isolated 2.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
S. M. Mennen et al.
Letter
Synlett
Table 2 Step 2: Experimental Resultsa
O
O
Me
O
Me
Me
Me
m-CPBA (1.3 equiv)
Me
Me
OH
Me
CH2Cl2 (10V)
14 h, 27 °C
Me
O
Me
Me
Me
Me
AgX
3
4
conditions
Br
1.24 kg
98% yield
97% purity
2
3
Scheme 2 Baeyer–Villiger rearrangement of 3
Entry
Scale
10 g
Base
AgX (equiv)
Conv. (%)b GCAP (%)c
1
n/a
n/a
Ag2O (2.0)
Ag2O (1.5)
AgNO3(2.0)
AgNO3(2.0)
AgNO3(1.5)
AgNO3(1.5)
AgNO3(1.5)
AgNO3(1.5)
quant.
70%
91
n/a
61
80
86
83
96
91
Acetate 4 is further processed to the alcohol by saponifi-
cation using LiOH. To improve the volumetric efficiency we
executed the process in 10 V of EtOH and six equivalents of
4 N LiOH to afford quantitative conversion into 5 (Table 3,
entry 1). Lowering the amount of base to four equivalents
of LiOH resulted in only 88% conversion to 5, which could
be driven to 99% conversion with the charge of an addition-
al two equivalents of LiOH (Table 3, entry 2). The low con-
version with four equivalents of LiOH is hypothesized to be
a result of residual 3-chlorobenzoic acid carried through
2
10 g
5 g
3
Na2CO3
quant.
quant.
quant.
quant.
>99
4
5 g
NaHCO3
NaHCO3
Et3N
5
5 g
6
25 g
7d
8d
250 g
2.2 kg
Et3N
Et3N
>99
a Unless otherwise noted, reactions were run at 25 °C.
b In-process conversion test for remaining 2 as measured by GC.
c Area percent purity of isolated product measured by GC; GCAP = gas chro-
matography area percent.
1
from step 3 which is observed in the crude H NMR spec-
trum.
d Reaction temperature –5 °C to 0 °C.
Table 3 Step 4: Experimental Resultsa
α-chloroketone in alcoholic solution mediated by AgNO3.13,14
We hypothesized that we could extend this investigation
and replace Ag2O with AgNO3 if an appropriate base was
added to the reaction which avoided base-mediated epoxi-
dation of the bromohydrin.7c Throughout the investigation
a general observation that stronger bases lead to increased
levels of impurities (Table 2).15 Triethylamine was found to
be best in terms of yield and purity of the product, with an
optimal reaction temperature between –5 °C and 0 °C (Ta-
ble 2, entry 6 vs. entry 7). Triethylamine was preferred over
the insoluble base NaHCO3 since AgBr precipitates through-
out the reaction and could negatively impact mass transfer
with an insoluble base. This new process was executed on
2.2 kg scale with only 1.5 equivalents of AgNO3 and afford-
ed results that were consistent with the smaller scale pro-
cess (Table 2, entry 8).
Steps 3 and 4: Conversion of 3 into 5 was conducted in a
two-step two-isolation sequence of a Baeyer–Villiger rear-
rangement followed by saponification of the resulting ace-
tate. Baeyer–Villiger rearrangement performed as expected
to afford 4 in 96–98% yield with 88–98% purity by GC. Ex-
traction of the 3-chlorobenzoic acid byproduct and excess
reagent after the reaction was changed from NaOH to NaH-
CO3 to avoid unplanned saponification of the acetate.
Purification of crude 4 was investigated by distillation
and was capable of improving the purity of 4 from 97% to
99%.16 When both crude and distilled 4 were investigated in
the downstream process, we found that both produced the
same quality final product and therefore purification after
step 3 was not justified. The Baeyer–Villiger process was ex-
ecuted on 1.24 kg scale affording 98% yield and 97% purity
(Scheme 2).
O
Me
Me
Me
4N LiOH (6.0 equiv)
Me
Me
O
OH
EtOH (10V)
2 h, 25 °C
4
5
Entry
Scale
Conv. (%)b
Yield (%)c
GCAP (%)d
1
2
3
4f
16 g
10 g
34 g
quant.
86
84
86
52
88
99
98
99
95 (quant.)e
quant.
1.31 kg
quant.
a Unless otherwise noted, reactions conditions were: 10 V of EtOH, 6.0
equiv 4 N LiOH, 25 °C for 2 h; V = mL solvent/g solute.
b In-process conversion test measured by GC.
c Unless purification conditions are noted, isolated yield based on crude
weight.
d Area percent purity of isolated product measured by GC; GCAP = gas
chromatography area percent.
e Reaction initially performed with 4.0 equiv LiOH, number in parenthesis
are after additional LiOH (2.0 equiv) was added.
f Crude (850 g) was purified by silica gel chromatography.
The scale-up batch was executed in a similar fashion as
the development batches, however, given the time pressure
on the project we were unable to fully evaluate if crude ma-
terial could be carried through to step 5. Chromatographic
purification was performed on a kilogramm-scale batch to
afford 4 with 99% purity and 60% yield for the purification
and the overall yield of 52% (Table 3, entry 4). Purification
of crude 5 by fractional distillation successfully removed
the residual 3-chlorobenzoic acid, however, the purification
did not significantly improve the product quality compared
to the crude material.17 Following the completion of the
campaign, we successfully demonstrated that crude materi-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
S. M. Mennen et al.
Letter
Synlett
al from step 4 could be fully telescoped through step 5, thus
avoiding the requirement for chromatography in step 4 for
future deliveries.
tion was safely scaled to 500 g scale to afford 6 in >96% pu-
rity by GC; however, the assay was only 78% w/w and sedi-
mentation occurred upon standing.
Step 5: Oxidation of alcohol 5 has previously been exe-
cuted with more than six equivalents of CrO3 in >60 V of
CH2Cl2 to prepare ketone 6 (Table 4, entry 1). The deploy-
ment of a chromium-based oxidation is undesirable due to
the carcinogenicity of chromium which requires careful
control of residual chromium in pharmaceutical products
and intermediates down to ppm levels.18 Additionally, the
use of chromium would result in an arduous cleaning pro-
cess to ensure there is no residual chromium in a multiuse
reactor that could carry over to other processes.
To improve the %w/w of isolated 6 we sought to focus
our efforts on a final isolation that could be used to purify
the reaction stream from the previous steps. We first at-
tempted to form a crystalline bisulfite adduct,21 however,
were unable to successfully form the adduct which we hy-
pothesized was due to steric interactions with the trans-an-
nular
gem-dimethyl.
Since
the
6,6-dimethylbicy-
clo[3.1.0]hexan-3-one (6) is a liquid we felt that the process
is suited for a final distillation. We found that distillation at
1.5 mmHg between 70 to 80 °C afforded 80% yield of 6 with
>99% w/w purity and was demonstrated on 0.25 kg scale.
Table 4 Step 5: Experimental Results
Me
Me
EtOH (10V)
Me
Me
OAc
OH
Me
Me
Me
Me
conditions
4N LiOH (6 equiv)
no chromatography
OH
O
4
5
5
6
Dess–Martin (1.2 equiv)
CH2Cl2 (2V)
Me
Me
O
Entry
Scale
5 g
Oxidant (equiv)
Yield (%)a
Purity (%)b
distillation of telescoped
40% yield over 2 steps
6
1
CrO3(6.25)
(COCl)2 (1.5)
MnO2 (1.2)
KMnO4 (1.0)
DMP (1.2)
DMP (1.2)
DMP (1.2)
81
75
0
86
56
n/a
n/a
97
96
97
99% w/w
2
5 g
2 g
Scheme 3 Telescoped process without chromatography
3
4
2 g
0
5c
6c
7c,d
12 g
500 g
10 g
85
99
95
Purification of the final step was a requirement to en-
sure consistent and high quality 6 for use in downstream
processing. We hypothesized that steps 4 and 5 could be
telescoped and final purification by distillation of 6 could
be successful. A batch of step 4 was executed on 100 g scale,
and the crude stream was processed through step 5
(Scheme 3). A portion of the of the final crude material was
distilled using conditions described above and afforded 6 in
comparable purity as when step 4 was isolated by chroma-
tography. The final two steps of the telescoped process
were isolated in a combined 38% yield compared to 41%
yield when chromatography was used at step 4. The tele-
scoped process was executed on small scale, and the recov-
ery at the final distillation would be expected to improve as
scale is increased. As such, the telescoped process will be
implemented in lieu of chromatography after step 4 for fu-
ture manufacturing.
In conclusion we have demonstrated a refined process
for the synthesis of 6,6-dimethylbicyclo[3.1.0]hexan-3-one
(6) for readily available ≥90% (+)-3-carene. The process
avoids chromatography at step 1 with a simple cooling
crystallization. We have developed and demonstrated a
semi-Pinacol rearrangement that avoids a large excess of
silver oxide and instead uses only 1.5 equivalents of silver
nitrate buffered with a tertiary amine base. The cost impact
of changing the semi-Pinacol process resulted in significant
savings in the cost of materials and delivers a process that
no longer requires a complicated cleaning protocol. The
process has been demonstrated as being capable of through
a Isolated yield based on crude weight.
b Purity of isolated product measured by GC.
c Reaction conditions: Dess–Martin reagent (1.2 equiv)/CH2Cl2 (22 V), 0–20
°C, 3 h; V = mL solvent/g solute.
d Crude material from step 4 used.
Alternative oxidants which are readily available and
amendable to kilogram scale were investigated in an effort
to avoid CrO3. Swern oxidation provided 6 in 75% yield (Ta-
ble 4, entry 2), however, foul smell of the dimethylsulfide
byproduct is not desired and the cryogenic reactor available
to our team is made of stainless steel and is not compatible
with oxalyl chloride. Both MnO2 and KMnO4 were shown to
be incompetent oxidants for the desired transformations
(Table 4, entries 3 and 4). Dess–Martin periodane (DMP)
proved to be an excellent oxidant for the desired oxidation
providing a crude yield of 6 in >85% yield (Table 4, entries 5
and 6).19 DMP and IBX have been reported in the literature
to have potential shock hazards.20 All operations were exe-
cuted with a minimum 100 °C temperature window be-
tween the >130 °C decomposition temperature to ensure a
safe operating window. Additionally, we employed semi-
batch addition of DMP, and the reaction was quenched with
sodium thiosulfate prior to further manipulation. The reac-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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S. M. Mennen et al.
Letter
Synlett
processing from step 2 to step 5 by incorporation of a final
distillation to purify the desired bicyclic ketone 6. Lastly, we
have identified Dess–Martin periodinane as an alternative
to using the carcinogenic CrO3 as the final oxidant.
mixture was then diluted with water (20,000 mL, 20 V) and
extracted twice with PE (12,000 mL, 12 V). The combined
organic extracts were washed twice with 5% w/w Na2S2O3 solu-
tion (10,000 L, 10 V), dried over anhydrous Na2CO4, and concen-
trated under vacuum at 35 °C to get the crude product.
The crude product was dissolved in hexane (4,000 mL, 4 V),
cooled to –40 °C, and stirred for 30 min. The solid was filtered,
washed with chilled hexane (1,000 mL, 1 V), and dried at 25 °C
for 5 h to get 850 g of (1S,3R,4R,6R)-4-bromo-3,7,7-trimethylbi-
cyclo[4.1.0]heptan-3-ol as off-white solid as main crop with
95% GC purity. The mother liquor was cooled to –40 °C, stirred
for 30 min, filtered, dried, and isolated another 100 g as off-
white solid (second crop) with 94% purity by GC. Both the crops
material were mixed and taken forward into the next step. TLC:
PE/EtOAc (8:2); Stain solution: PMA (10% EtOH), yield 950 g
(56%). 1HNMR of first crop (300 MHz, CDCl3): δ = 0.69 (t, J = 7.26
Hz, 1 H), 0.80–0.88 (m, 1 H), 0.99 and 1.02 (s, 6 H), 1.30 (s, 3 H),
1.41 (d, J = 4.92 Hz, 1 H), 2.20 (dd, J = 14.63 and 9.72 Hz, 1 H),
2.34–2.49 (m, 2 H), 4.06 (dd, J = 10.79 and 7.95 Hz, 1 H).
(12) Current costs from sigmaaldrich.com of 99% purity silver salt:
AgNO3(S6506-500G at $1,071.20/0.5kg) costs $546/mol 3 using
1.5 equiv AgNO3 and Ag2O (item: 221163-1KG at $2,195.00/kg)
costs $1,017/mol 3 using 2.0 equiv Ag2O.
(13) (a) Harding, K. E.; Trotter, J. W. J. Org. Chem. 1977, 42, 4157.
(b) Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem.
1988, 53, 4877.
(14) For examples of AgNO3-mediated ring expansion, see:
(a) Pauvert, M.; Dupont, V.; Guingant, A. Synlett 2002, 1350.
(b) Morimoto, T.; Yamazaki, A.; Achiwa, K. Chem. Pharm. Bull.
2004, 52, 1367.
(15) Throughout the investigation, an unidentified impurity was
present at 0.95 RRT. The impurity had the same nominal mass
by low resolution GC–MS as the desired product 3. The impurity
was present in varying amounts and is hypothesized to be the
result of either elimination of HBr or epoxidation.
(16) Distillation conditions: Batch temperature 54–56 °C, pressure
5–2 mbar, isolated yield 85% on 10 g scale. Equipment: Short
path distillation head with a combined cold-coil and Liebig con-
denser and affixed with a three-port distribution adapter.
(17) Distillation conditions: batch temperature 85–105 °C, pressure
10–1 mbar, isolated yield 88% on 7 g scale. Equipment: Short
path distillation head with a combined cold-coil and Liebig con-
denser and affixed with a three-port distribution adapter.
(18) International Conference on Harmonization (2014). M7(R4):
Assessment and Control of DNA Reactive (Mutagenic) Impuri-
ties in Pharmaceuticals to Limit Potential Carcinogenic Risk.
(19) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Dess,
D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(c) Boeckman, R. K.; Shao, S.; Mullins, J. J. Org. Synth. 2000, 77,
141.
Acknowledgment
We thank Karunanidhi S. and Balaji D. for analytical method develop-
ment and Dr. Jason Tedrow, Amgen Inc.; Andreas Reichelt, Amgen Inc.,
and Dr. Jegadeesh T, Syngene Intl. Ltd for their constant support
throughout this collaboration.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588484.
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(3) Charette, A.; Wilb, N. Synlett 2002, 176.
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(b) Blaszykowski, C.; Harrak, H.; Brancour, C.; Nakama, K.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Synthesis 2007,
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(5) Rigby, J. H.; Bellemin, A. Synthesis 1988, 188.
(6) Bolli, M.; Lehmann, D.; Mathys, B.; Mueller, C.; Nayler, O.;
Velker, J.; Weller, T. WO 2006100635A2, 2006.
(7) (a) Kuczyński, H.; Walkowicz, M.; Walkowicz, C.; Nowak, K.;
Siemion, I. Z. Rocz. Chem. 1964, 38, 1625. (b) Walkowicz, M.;
Kuczyński, H.; Walkowicz, C. Rocz. Chem. 1967, 41, 927. Bromo-
hydrin synthesis: (c) Crocker, W.; Grayson, D. H. Tetrahedron
Lett. 1969, 51, 4451. Synthesis of ketone from alcohol (post pin-
acol): (d) Lochyński, S.; Jarosz, B.; Walkowicz, M.; Piatkowski, K.
J. Prakt. Chemie. 1988, 284.
(8) Current costs from sigmaaldrich.com (Item: 94415-1ML at
$54.10; Item: W382108-1KG at $97).
(9) See Supporting Information for GC method details.
(10) Unidentified impurity was present at a relative retention time
(RRT) of 0.87 min by gas chromatography.
(11) (1S,3R,4R,6R)-4-Bromo-3,7,7-trimethylbicyclo[4.1.0]heptan-
3-ol (2)
To a clean and dry 45 L glass reactor was charged 1,4-dioxane
(8,000 mL, 8.0 V), water (4,000 mL, 4.0 V), (+)-3-carene (1,000 g,
7.3 mol), and CaCO3 (977 g, 9.8 mol), and the suspension was
cooled to 10 °C. NBS (1,698 g, 9.5 mol) was added in portions
over 1 h while maintaining the internal temperature. At the end
of addition, the resulting mixture was warmed to 20 °C and
maintained for 3 h, and the progress of the reaction was moni-
tored by GC until (+)-3-carene was not detected. The reaction
(20) (a) Plumb, J. B.; Harper, D. J. Chem. Eng. News. 1990 July 16, 3.
(b) Uyanik, M.; Ishihara, K. Aldrichimica Acta 2010, 43, 83.
(c) Boeckman, R. K.; Shao, S. Mullins J. 2000, 77, 141.
(21) Bercot, E. A.; Bio, M.; Chan, J.; Colyer, J.; Fang, Y.; Mennen, S.;
Milburn, R. R.; Tedrow, J.; Riahi, B. WO 2013173672, 2013.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E