Development of a stereoselective and scalable process for the preparation of a methylcyclobutanol-pyridyl ether

Article abstract of DOI:10.1016/j.bmc.2017.07.018

The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl ether 1 is described. Key aspects of this development including careful control of the stereochemistry, elimination of chromatography, and application to kilogram-scale

Full text of DOI:10.1016/j.bmc.2017.07.018

Accepted Manuscript
Development of a Stereoselective and Scalable Process for the Preparation of a
Methylcyclobutanol-Pyridyl Ether
Jeffrey T. Kuethe, Kallol Basu, Robert K. Orr, Eric Ashley, Marc Poirier, Lushi
Tan
PII:
S0968-0896(17)31027-1
DOI:
http://dx.doi.org/10.1016/j.bmc.2017.07.018
BMC 13855
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 May 2017
6 July 2017
10 July 2017
Please cite this article as: Kuethe, J.T., Basu, K., Orr, R.K., Ashley, E., Poirier, M., Tan, L., Development of a
Stereoselective and Scalable Process for the Preparation of a Methylcyclobutanol-Pyridyl Ether, Bioorganic &
Medicinal Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.07.018
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Development of a Stereoselective and Scalable Process
for the Preparation of a Methylcyclobutanol-Pyridyl
Ether
Jeffrey T. Kuethe,* Kallol Basu, Robert K. Orr, Eric Ashley, Marc Poirier, Lushi Tan
Department of Process Research and Development, Merck & Co., Inc., Kenilworth, New Jersey 07033,
USA
Jeffrey_Kuethe@merck.com
ABSTRACT : The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl
ether 1 is described. Key aspects of this development including careful control of the stereochemistry,
elimination of chromatography, and application to kilogram-scale synthesis are addressed.
Introduction
The ever-increasing speed with which drug candidates progress from late-stage discovery into early
development requires rapid development of suitable chemistry to meet aggressive delivery timelines.
Often multiple compounds varying significantly in structural design and complexity may be in
contention to enter early development. Pre-investment of process chemistry resources to solve
challenging synthetic chemistry issues prior to a compound entering development enables the rapid
progression of these candidates into high-dose pharmacokinetic (PK) studies and early toxicological
evaluation. While this only requires gram quantities for these studies, up to hundreds of grams may be
required to fully profile a candidate prior to entering development. In an effort to rapidly progress drug
candidates through each milestone on its way into development, the chemistry can evolve at an equally
1

rapid pace. In support of an accelerated drug discovery program, increasing quantities of compound 1
were required to advance a lead compound through the late stages of discovery and into development
(Figure 1). The existing route used to enable SAR involved a low yielding Mitsunobu reaction between
hydroxypyridine 2 and 3-hydroxymethylcyclobutanone 3 followed by addition of MeMgCl to give
compound 1 (Scheme 1). The addition of the Grignard reagent was moderately selective and produced
a mixture of cis/trans isomers, typically in 6:1 ratio which could only be separated by column
chromatography. The introduction of the Grignard reagent in the final step was well suited for the
development of structure-activity relationships (SAR) during discovery, because it provided access to an
array of compounds such as 5 in a single step. However, this approach was ill-suited for the preparation
of multi-gram quantities of compound 1 due to the difficulty in separating the isomers formed. In this
manuscript we describe the evolution of a scalable process leading the stereoselective synthesis of
multi-kilogram quantities of compound 1.
Figure 1. Target Compound of Interest.
Scheme 1. SAR Synthesis and Retrosynthetic Analysis
2

Results and Discussion
Our retrosynthetic approach to compound 1 is shown in Scheme 1 and was centered on an SNAr
displacement of readily available fluoropyridine 7 with diol 6. In order to avoid the use of
chromatographic separation of stereoisomers, it was deemed critical to control the stereoselectivity of
compound 1. While the synthesis of diol 6 had previously been reported,1 it was not stereoselective and
suffered from low yielding steps requiring the development of a new stereoselective synthesis of this
intermediate. Several routes were investigated in parallel in order to advance the lead compound with
an accelerated timeline.
Our initial investigations briefly focused on the one-pot in-situ generation of metalated diol 8 and its
subsequent addition to fluoropyridine 7 (Scheme 2). For example, treatment of ketone 3 with 2
3

equivalents of MeMgBr at temperatures below -50 °C in 2-MeTHF followed by addition of
fluoropyridine 7 did not afford any detectable desired addition product 1. Instead, the fluoropyridine
starting material was recovered unchanged. After the addition of MeMgBr, a thick slurry of the
corresponding magnesium dialkoxide 8 formed. The insolubility of dialkoxide 8 may have accounted
for the lack of reactivity, but the general low nucleophilicity of magnesium alkoxides may have
contributed to the lack of reactivity.2 The reaction was repeated by forming the magnesium dialkoxide
at -50 °C and allowing it to warm to room temperature prior to the addition of fluoropyridine 7;
however, this also resulted in no detectable reaction to the desired product 1. Heating the reaction to
near reflux also did not afford any reaction. Since the magnesium dialkoxide of 8 proved unreactive it
was reasoned that the lithium alkoxide may offer increased solubility. To this end, reaction of ketone 3
with 2 equivalents of MeLi at -50 °C in 2-MeTHF was followed by warming the reaction slurry to room
temperature and the addition of fluoropyridine 7. Stirring the reaction mixture overnight at room
temperature afforded a 35% HPLC assay yield3 of compound 1 as a disappointing 4.3:1 mixture of
cis/trans isomers. The mass balance of the reaction could not be accounted for as apparent
decomposition of the starting material 7 was observed. If the lithium dialkoxide was formed at higher
temperatures than the initial -50 °C, further erosion in the selectivity was observed. With these results,
this approach was abandoned and efforts focused on a stereoselective synthesis of diol 6.
Scheme 2. Attempted One-Pot Conversion of Hydroxyketone 3 to Compound 1
Since the addition of MeLi to ketone 3 at low temperatures did not afford a high degree of
diastereoselectivity, it was reasoned that protection of the primary hydroxyl group with a bulky
4

protecting group may offer the opportunity for increased stereoselectivity (Scheme 3). Reaction of
alcohol 3 with TBDMS-Cl in the presence of Hünig’s base (DIPEA) afforded intermediate 9 in 95%
yield.4 Reaction of 9 with MeMgBr at -75 °C for 30 minutes followed by warming the reaction to -20
°C gave a ~5.3:1 mixture of cis- 10 and trans- 11 isomers as determined by analysis of the crude
1
reaction mixture by H NMR spectroscopy. While this result was encouraging, higher levels of
stereoselectivity were still required. Preparation of both the triisopropyl silyl (TIPS) and tert-
butyldiphenylsilyl (TBDPS) alcohols was accomplished by reaction of alcohol 3 with TIPS-Cl and
TBDPS-Cl respectively in the presence of imidazole and gave good, to excellent yields, of TIPS-
protected alcohol 12 (93%) and TBDPS-protected alcohol 135 (80%). Compound 13 proved to be a
highly crystalline solid and chromatography used in the preparation of compounds 9 and 12 was
completely avoided in the isolation of intermediate 13. The isolation of TBDPS-alcohol 13 simply
involved slurring the crude reaction mixture in heptane, filtration, and drying which produced
analytically pure compound 13. Reaction of TIPS-alcohol 12 with MeMgBr at -75 °C for 30 minutes
followed by warming the reaction to -20 °C afforded the same ~5.5:1 mixture of isomers 14 and 15 and
did not offer any advantage. However, reaction of TBDPS-alcohol 13 under the identical reaction
conditions gave a >20:1 mixture of isomers 16 and 17 in near quantitative yield. The increased steric
bulk of the TBDPS protecting group of compound 13 gave the necessary level of stereoselectivity
required for downstream processing and the chemistry was rapidly scaled to provide > 900 g of
compound 16 to support the aggressive timelines for the preparation of multi-hundred gram quantities
of intermediate 1.
Scheme 3. Grignard Addition to Protected Hydroxy Ketones
5

With an efficient synthesis of compound 16 in hand, attention turned to its conversion to
intermediate 1 (Scheme 4). Initial experiments probed the possible direct conversion of compound 16 to
intermediate 1 by reaction with fluoropyridine 7 in the presence of TBAF. Treatment of compound 16
with TBAF in the presence of fluoropyridine 7 in THF did not afford any detectable formation of
intermediate 1. Evidently, the initially formed tetrabutylammonium alkoxide was not able to displace
the fluorine atom on pyridine 7. Repeating the reaction in NMP and heating at 70 °C did result in the
formation of compound 1 but the reaction did not go to completion and was complicated by the
formation of other unidentified by-products. Based on these experiments, it was decided to remove the
TBDPS protecting group prior to reaction with fluoropyridine 7. Removal of the TBDPS-protecting
group with TBAF occurred cleanly in THF at 50 °C. The reaction was easily monitored for the
disappearance of the starting material and formation of TBDPS-F. Unfortunately, all attempts to work
up the reaction by quenching into any aqueous systems led to low recovery of diol 6 due to its high
water solubility. Thus an aqueous workup needed to be avoided. In order to circumvent this issue, the
crude reaction mixture was applied directly to a plug of silica gel and was eluted with a 3:1 mixture of
ethyl acetate (EtOAc) and hexane which yielded an 82% yield of diol 6.
6

Reaction of diol 6 and fluoropyridine 7 was quickly screened in the presence of a number of
bases (Scheme 4). For example, reaction in the presence of 1 equivalent of NaH in DMF at room
temperature afforded 50% conversion to compound 1 after 18 h. Addition of more NaH did not result in
further conversion. While the safe use of NaH on scale has been demonstrated,6 the low conversion and
the desire to avoid the possible safety issues associated with NaH necessitated examining alternative
bases (Table 1). Reaction in the presence of 1 equivalent of Cs2CO3 at room temperature in DMF did
not result in any conversion to compound 1. On the other hand, warming the mixture to 70 °C for 6 h
led to the formation of desired compound 1 but only at 50% conversion. Stirring an additional 48 h at
this temperature only led to 65% conversion. Additional base did not increase the conversion to
compound 1. Furthermore, it was discovered that stirring the reaction mixture with an overhead
mechanical stirrer resulted in a dramatic drop in the conversion (Table 1, entry 3). This suggested that
the grinding effect of a stir bar was providing increased surface area of the base to achieve higher
conversions.7 This grinding effect would not be possible on larger scale and efforts quickly turned to
alternative bases. Reaction of diol 6 and fluoropyridine 7 in the presence of 1 equivalent of NaOt-Bu in
DMF at 0 °C followed by warming to room temperature lead to 60% conversion to compound 1.
However, accompanying this was the formation of bis-alkylated by-product 18 in up to 16%.8 Slow
addition of one equivalent of KOt-Bu to a mixture of diol 6 and fluoropyridine 7 appeared to be the
cleanest reaction giving > 90% conversion to compound 1 in < 2 h at 0-5 °C and only resulted in the
formation over-alkylated by-product 18 in 3% yield (Table 1, entry 5). Interestingly, when all the
reagents were added together at the same time, the formation of by-product 18 reached up to 40% in the
presence of KOt-Bu. These results were further optimized in terms of solvent, temperature, and charge
of base. The optimal conditions involved slow addition of a solution of 1.15 equivalents of KOt-Bu in
THF to a solution of diol 6 (1.1 equivalents) and fluoropyridine 7 (1 equivalent) in a 1.7:1 ratio of DMF
and THF at 0-5 °C over several hours. Under these conditions the formation of by-product 18 was
minimized to <2% at near full conversion to compound 1 (Table 1, entry 6). Complete conversion to
compound 1 was not observed and there still remained up to 4-5% remaining starting material 7. The
7

isolation of compound 1 at this stage of development involved conversion of the free base of compound
1 to the HCl salt since a crystalline form of the free base had not been identified. Formation of the HCl
salt not only provided a crystalline intermediate, but also resulted in complete removal of any trace of
by-product 18, any possible undesired trans-isomer about the cyclobutanol ring, and remaining starting
material 7. Compound 1a was isolated as the HCl salt in 60-63% isolated yield. From initial proof-of-
concept of the chemistry described in Schemes 3-4 to execution on multi-hundred gram quantities of
compound 1a took under 2 months and greatly accelerated the lead compound to move from late stage
discovery to early development.
Scheme 4. Reaciton of Diol 6 with Fluoropyridine 7
Table 1. Effect of Base
Entry
Base (equiv)
Conversion
Percent 18
1
2
3
4
5
6
NaH (1)
Cs CO (1)
Cs CO (1)
NaOt-Bu (1)
KOt-Bu (1)
KOt-Bu (1)
50%
65%
35%a
60%
90%b
94%c
ND
3%
3%
16%
3%
< 2%
2
3
2
3
a. With mechanical stirring. b. Screening conditions. c. optimized conditions
8

Redesigned Protecting Group Free Approach
The chemistry outlined for the first generation approach to compound 1 was executed under tight
timelines and enabled the lead compound to progress rapidly into development; however, the
implementation of this route on larger scale required further development. Key issues that needed to be
addressed included further optimization of the cis/trans ratio of diol 6, elimination of chromatography
of compound 6, removal the use of a protecting group (TBDPS), and further optimization of the SNAr
displacement of fluoropyridine 7 with diol 6.
It was recognized that further improvement in the stereoselectivity for the chemistry described in
Scheme 3 would be a challenge and we elected to investigate alternative approaches to diol 6. Efforts
centered on the use of readily available ketoacid 19 as this was the precursor to hydroxymethyl ketone 3
(Scheme 5).9 Initial experiments involved exploring the addition of MeMgCl to a solution of ketoacid
19 in THF at -70 °C. Upon complete addition of the Grignard reagent, a thick gelatinous slurry formed
that was difficult to stir without the aid of a mechanical stirrer. Warming the reaction mixture at this
point to room temperature resulted in slurry that was easier to stir. Quenching the mixture with 1 M
H3PO4 and analysis of the crude NMR revealed the formation of ~7:1 ratio of desired cis-isomer 20 to
undesired trans-isomer 21. Although this result appeared to be discouraging at first, a serendipitous
discovery was made that allowed for the further exploration of this chemistry. It was found that
recrystallization of this initially formed mixture of isomers from methyl tert-butylether (MTBE)
provided >99:1 stereoselectivity for the cis-isomer 20 with minimal loss to the mother liquors. The
reaction was then fully optimized in terms of organometallic reagent, temperature, and reaction volume.
For example, reaction with MeLi under the conditions described above led to the expected formation of
a 7:1 mixture of isomers 20 and 21; however, there were also a number of unidentified by-products
observed and gas chromatography (GC) analysis of the crude reaction mixture only showed ~ 41% was
the desired product.10 Evaluation of MeMgBr also gave a 7:1 mixture of stereoisomers and GC showed
~70% of the crude material was the desired product. Reexamination of MeMgCl gave a GC profile that
9

was ~ 80% of the desired product so this reagent was selected for scale-up. The effect of temperature
was next examined. As noted above, at lower temperatures the reaction mixture tended to form
gelatinous slurries that could be difficult to stir. Running the reaction at 0 °C saw a decrease in the
stereoselectivity to ~ 4:1 and at -20 °C only increased the stereoselectity slightly to 6.3:1. While these
reactions stirred well, the decrease in selectivity was unacceptable. When the reaction was performed at
-50 °C, the desired 7:1 ratio was observed while maintaining good performance from a mixing
perspective. Given these results this temperature was selected. The reaction volume also proved crucial
to scale up. At higher dilution mixing was not problematic, but the more concentrated the reaction
volume was the more difficulties were encountered. The optimal volume selected was 30 L of THF per
kilogram of ketoacid 19. The reaction was scaled to multiple kilogram scale and provided acid 20 in
61% isolated yield after recrystallization from MTBE.
The reduction of acid 20 to give diol 6 was next examined (Scheme 5). Probe experiments
demonstrated that borane-THF in conjunction with a MeOH workup provided diol 6 effectively;
however, the use of commercial borane on scale was not desirable due to its inherent instability.11 While
generation of borane in-situ from NaBH4 and BF3-etherate was considered, this process is generally
exothermic and alternative reductions were investigated.12 Reduction of acid 20 with LiAlH4 was
examined and employed in the scale up of diol 6. Treatment of acid 6 with 2 equivalents of LiAlH4 at 0
°C did not result in full conversion to diol 6; however, if the reaction mixture was warmed to 55-60 °C
full conversion to diol 6 was observed. Work up and isolation of diol 6 was next examined. Due to the
fact that diol 6 was highly water soluble and extraction from water was challenging, an aqueous workup
needed to be avoided. Although a Fieser work up13 could be employed effectively, the exothermic
release of hydrogen resulting from the quenching of unreacted LiAlH4 at the end of the reaction needed
to be controlled.14 Therefore, at the end of the reaction of acid 20 with 2 equivalents of LiAlH4, the
reaction was cooled to 0 °C and the excess LiAlH4 was quenched with an excess of acetone. Following
a Fieser work up to remove aluminum salts, filtration and concentration gave a crude solution of diol 6
10

in THF that was sufficiently pure for use as a solution in the next step without further purification. The
overall yield of diol 6 was 94% for the reduction.
Finally, reexamination of the SNAr reaction between diol 6 and fluoropyridine 7 resulted in
further refinement of the chemistry and increased efficiency. For example, increasing the amount of
diol 6 to 1.5 equivalents and stirring at 0-5 °C for 24 h gave an increased yield of 80% by HPLC assay
with complete consumption of fluoropyridine 7. While examining the solubility of compound 1, it was
discovered that n-heptane was an excellent solvent for crystallization. In addition, the solvent also was
found to be effective at removing the by-product 18 which was formed in ~ 2.3%. The free base of
compound 1 was obtained in 75% yield for the SNAr reaction in >99.8% purity. The chemistry
described in Scheme 5 was ultimately executed on multi-kilogram scale to provide 7.3 kg of
intermediate 1
Scheme 5
Conclusion
In summary, the evolution of a robust process for the preparation of key intermediate 1 has been
described. While the first generation approach was able to provide sufficient quantities of compound 1
11

under aggressive timelines for initial pharmacokinetic and toxicologlical studies, the need to provide
kilogram quantities to further progress development into the clinic necessitated the investigation of an
alternative approach. Features of the synthesis included the Grignard addition to ketoacid 19 followed
by the upgrade in stereoselectivity of acid 20 by crystallization, LAH reduction of 20, followed by an
improved yield of compound 1. The final process involved three synthetic transformations and
proceeded in 43% overall yield from ketoacid 19.
Experimental
All solvents and reagents were used as received from commercial sources. Analytical samples
were obtained by chromatography on silica gel using an ethyl acetate-hexane mixture as the eluent
unless specified otherwise. Water content (KF) was determined by Karl Fisher titration on a Metrohm
1
737 KF coulometer. H NMR and 13C NMR spectra were recorded on a Bruker 500 spectrometer at 500
and 125 MHz, respectively, with chemical shifts give in ppm relative to TMS at δ = 0.0. Reaction
mixtures and products were analyzed by reverse phase HPLC on a Agilent Technologies 1290
instrument using a 4.6 x 250 Symmetry Shield RP18 column. Solvent compositions consisted of 0.1%
H3PO4 and acetonitrile with a flow rate of 1.5 mL/min. GC analysis was performed on a Shimadzu GC-
200 using a DB-FFAP (30.0 X 0.32 µm I.D. X 1.00 µm) column from 20-240 °C.
Preparation of 3-(((Tert-butyldimethylsilyl)oxy)methylcyclobutan-1-one (9). To a stirred
solution of 1.00 g (10 mmol) of 3-(hydroxymethyl)cyclobutan-1-one 3 in 10 mL of THF was
added 1.91 mL (11.00 mmol) of Hünigs base followed by 1.58 g (10.50 mmol) of tert-
butyldimethylsilyl chloride. The resutling solution was stirred at room temperature of 18 h,
concentrated under reduced pressure, and purified by silica gel eluting 0-10% EtOAc/hexane to
afford 2.03 g (95%) of 3-(((tert-butyldimethylsilyl)oxy)methylcyclobutan-1-one 9 as a colorless
1
liquid: H NMR (CDCl3, 500 MHz) δ 0.08 (s, 6H), 0.92 (s, 9H), 2.60 (m, 1H), 2.92 (m, 2H), 3.07
(m, 2H), 3.77 (d, 2H, J = 5.50 Hz); 13C NMR (CDCl3, 125 MHz) δ -5.4, 18.3, 25.6, 25.8, 49.0, 65.1.
12

Preparation of 3-(((Triisopropylsilyl)oxy)methyl)cyclobutan-1-one (12). To a stirred
solution of 1.00 g (10 mmol) of 3-(hydroxymethyl)cyclobutan-1-one 3 in 10 mL of DMF was
added 0.9 g (13.0 mmol) of imidazole followed by 2.54 mL (12.0 mmol) of TIPS-Cl. The resulting
mixture was stirred at room temperature for 20 h, diluted with 15 mL of a 10% aqueous solution of
LiCl, and extracted with 20 mL of MTBE. The organic extract was washed with 10 mL of a 10%
aqueous solution of LiCl, dried over MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel chromatography eluting 0-10% EtOAc/hexane to give 2.38 g (93%) of 3-
(((triisopropylsilyl)oxy)methyl)cyclobutan-1-one 12 as a colorless liquid: 1H NMR (CDCl3, 500
MHz) δ 1.06-1.16 (m, 21H), 2.62 (m, 1H), 2.97-3.11 (m, 4H), 3.88 (d, 2H, J = 5.4 Hz); 13C NMR
(CDCl3, 125 MHz) δ 12.0, 17.7, 18.0, 25.9, 49.9, 65.3.
Preparation of 3-(((Tert-butyldiphenylsilyl)oxy)methyl)cyclobutan-1-one (13). Into a 20 L 4-
necked round-bottom flask equipped with a mechanical stirrer, temperature thermocouple, and 5 L
addition funnel was placed 1.10 kg (11.0 mmol) of 3-(hydroxymethyl)cyclobutan-1-one 3 in 10 L of
dichloromethane (10000 mL). To this solution was added 897 g (13.2 mol) of imidazole and the
mixture cooled to 0oC. To the mixture was added drop wise via the addition funnel 3.30 kg (12.0 mol)
of tert-butyl(chloro)diphenylsilane over 30 min and the mixture was allowed to warm to room
temperature and stirred an additional 30 min. The resulting solution was diluted with 5.0 L of water and
the layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated
under reduced pressure to give 2.70 kg (73%) of 3-[[(tert-butyldiphenylsilyl)oxy]methyl]cyclobutan-1-
1
one 13 as a white solid: H NMR (CDCl3, 500 MHz) δ 1.09 (s, 9H), 2.62 (m, 1H), 2.97 (m, 2H), 3.09
(m, 2H), 3.82 (d, 1H, J = 5.6 Hz), 7.40-7.48 (m, 6H), 7.67 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 19.9,
23.8, 27.1, 38.6, 68.1, 73.3, 109.4, 112.9, 150.6, 151.2, 160.3. Anal. Calcd. For C21H26O2Si: C, 74.51;
H, 7.74. Found: C, 74.23; H, 7.90.
Preparation of 3-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-methylcyclobutan-1-ol (16). Into a
10 L 4-necked round-bottom flask equipped with a mechanical stirrer, temperature thermocouple,
13

and 2 L addition funnel was added 900 g (2.66 mol) of 13 and 9.0 L of THF and the solution was
cooled to -75 oC. To the mixture was then added dropwise via the addition funnel 1.15 L (3.46 mol)
of a 3 M solution of CH3MgBr at such a rate that the internal temperature did not rise above -60 oC.
The mixture was stirred at this temperature for 30 minutes and then warmed to -20 oC and stirred for
an additional 30 minutes and then quenched with 3.0 L of a saturated aqueous solution of NH4Cl.
The mixture was extracted with EtOAc (2 X 5.0 L) and the combined organic extract was dried over
anhydrous sodium sulfate and concentrated under reduced pressure to afford 920 g (98%) of 3-
[[(tert-butyldiphenylsilyl)oxy]methyl]-1-methylcyclobutan-1-ol 16 as yellow oil that was sufficiently
pure for use in the next reaction without further purification. An analytical sample was prepared by
1
further purification on silica gel: H NMR (CDCl3, 500 MHz) δ 1.09 (s, 3H), 1.39 (s, 3H), 1.93 (m,
2H), 2.10-2.20 (m, 4H), 3.66 (d, 1H, J = 5.0 Hz), 7.39-7.47 (m, 6H), 7.68 (m, 4H); 13C NMR
(CDCl3, 125 MHz) δ 19.4, 26.9, 27.5, 40.3, 67.5, 69.7, 127.7, 129.7, 133.7, 135.8.
Preparation of 3-Hydroxy-3-methylcyclobutane-1-carboxylic acid (20). To the 1000 L reactor
was charged 10 kg (88.0 mol) of 3-oxocyclobutanecarboxylic acid 19 followed by 280 kg of THF.
The slurry was stirred at 25 ºC for 1h until all the solids dissolved. The solution was then cooled to -
55 ºC and 65.2 kg (193.0 mol) of a 3M solution of methylmagnesium chloride was added over 2 h.
Upon completion of the addition, the reaction mixtue was warmed to 22 ºC. After stirring for 7 h, the
reaction mixture was cooled to 5 ºC and quenched by the addition of 210 kg of a 1M aqueous
phosphoric acid solution over a period of 2.5 h. The temperature was increased to 22 ºC and the
mixture was stirred for 45 min. The layers were separated and the aqueous layer was extracted with
180 kg of 2-MeTHF. The organic extracts were combined, washed with 65 kg of a 25% aqueous
sodium chloride solution and concentrated under reduced pressure at 50 ºC. An azeotropic vacuum
distillation was then performed by the continuous distillation with MTBE (approximately 111 kg
MTBE used for the distillation) at 50 ºC until the water level reached < 1% by KF analysis. To the
resulting slurry was then added 22 kg of MTBE and the slurry was heated to 52 ºC for 4h. Upon
dissolving the crude solid, the mixture was then cooled to 22 ºC over the course of 5 h and held at the
14

same temperature for 7 h. The slurry was filtered, washed with 6.7 kg of MTBE and dried under
vacuum overnight at 40 °C to afford 7.1 kg (61%) of 3-hydroxy-3-methylcyclobutanecarboxylic acid
1
20. The trans-isomer was found to be < 1% by NMR analysis. H NMR (500 MHz, Methanol-d4)
2.68 (p, J = 8.9 Hz, 1H), 2.31 (td, J = 9.4, 2.4 Hz, 2H), 2.24 (td, J = 8.7, 2.5 Hz, 2H), 1.36 (s, 3H).
13C NMR (126 MHz, Methanol-d4) 177..43, 67..58, 400.40, 288.38, 225.54.
Preparation of 3-(Hydroxymethyl)-1-methylcyclobutan-1-ol (6).
Method A: In a 10 L round bottom flask containing 1.50 kg (4.23 mol) of alcohol 16 in 7 liters of
THF was added 4.65 L (4.65 mol) of a 1M solution of TBAF. The resulting solution was warmed to
50 °C and stirred at this temperature for 1 h. The resulting mixture was cooled to room temperature
and concentrated under reduced pressure. The residue was purified by silica gel chromatography to
1
afford 406 g (82%) of 3-(hydroxymethyl)-1-methylcyclobutan-1-ol 6 as a light yellow oil: H NMR
(CDCl3, 500 MHz) δ 1.41 (s, 3H), 1.79 (br m, 2H), 1.86 (m, 2H), 2.18 (m, 1H), 2.21 (m, 2H), 3.67 (d,
2H, J = 5.3 Hz); 13C NMR (CDCl3, 125 MHz) δ 27.0, 27.3, 38.7, 65.6, 69.2.
Method B: To a 500 L reactor was charged with 4.2 kg (110.7 mol) of LiAlH4 and 92 kg of THF
and the mixture was cooled to 0 °C. To the mixture was added 7.00 kg (53.8 mol) of hydroxy acid
19 in 106 kg of THF over the course of 3 h. After the addition was complete, the reaction mixture
was slowly warmed to 65 °C and stirred at this temperature of 8 h and then cooled to 0 °C. To the
mixture was added 12 kg of acetone over the course of 4 h to completely quench the remaining
LiAlH4. To the reaction mixture was then added sequentially 4.3 L of water over 1 h, 5.0 kg of a
15% aqueous solution of NaOH over 2h, and 8 L of water over 2 h. The slurry was stirred at 0 °C for
2 h, warmed to room temperature, and filtered. The filter cake was washed with 130 kg of THF and
the combined organic filtrate was dried over 32 kg of MgSO4, filtered, and concentrated under
reduced pressure by flushing with THF to a final volume of 15 L. This afforded 5.90 kg (94%) by
HPLC assay as a 22.8 wt% solution of diol 6 in THF. An analytical sample was identical to that
prepared by Method A.
15

Preparation of 3-(((5-Bromo-6-methylpyridin-2-yl)oxy)methyl)-1-methylcyclobutan-1-ol (1).
Method A: To a dry ice/isopropanol bath chilled solution of 3.29 g (32.9 mmol) of 3-
(hydroxymethyl)cyclobutanone 3 in 75 mL of THF and 25 ml of dimethylimidazolone was added
dropwise over 15 minutes 41.1 mL (65.8 mmol) of a 1.6 M solution of MeLi while maintaining the
internal temperature below -50 °C. The mixture was then warmed to 30 °C, and approximately 50 mL
of THF was removed by vacuum distillation. After the distillation, 3.09 mL (26.3 mmol) of 3-bromo-6-
fluoro-2-methylpyridine 7 was added. The mixture was stirred at 30 ˚C for 18 h, then allowed to cool to
room temperature. The reaction was quenched with 26.3 mL (13.2 mmol) of a 0.5 M aqueous citric acid
solution and then diluted with 150 mL of ethyl acetate. The mixture was washed with 100 mL of water
followed by 50 mL of brine, dried over MgSO4, filtered, concentrated, and purified by silica gel
chromatography (10:90 to 60:40 EtOAc:Hexanes) to provide 2.65 g (4.3:1 cis/trans, 35%) of 3-(((5-
bromo-6-methylpyridin-2-yl)oxy)methyl)-1-methylcyclobutanol 1 as a clear oil that solidified upon
standing.
Method B : In a 20 L 4 necked round bottom flask equipped with a mechanical stirrer and 5 L
addition funnel was placed 594.8 g (3.13 mol) of 3-bromo-6-fluoro-2-methylpyridine 7, 4.0 L of DMF,
2.4 L of THF, and 400 g (3.44 mmol) of 3-(hydroxymethyl)-1-methylcyclobutan-1-ol 6. The mixture
was cooled to an internal temperature of 0 °C at which point 3.63 L (3.63 mol) of a 1M solution of Kot-
Bu was added at such a rate that the internal temperature did not exceed 5 °C. The resulting mixture was
stirred at 0-5 °C for 2 h, quenched by the addition of 5.0 L of saturated solution of NH4Cl, and extracted
with EtOAc (3 X 2.0 L). The resulting organic extract was washed with a 10 wt% aqueous solution of
LiCl (2 X 1.0 L) and dried over anhydrous sodium sulfate. The crude reaction mixture was filtered and
concentrated under reduced pressure. The residue was dissolved in 5.0 L of EtOAc and a solution of
782.5 mL of a 4 M solution of HCl in dioxane was added dropwise and the resulting slurry was stirred
at room temperature for 2 h. The slurry was filtered and the wet cake was washed with EtOAc and
dried under vacuum/N2sweep to provide 610.0 g (60%) of compound 1a as an analytically pure solid :
16

1H NMR (CDCl3, 500 MHz) δ 1.38 (s, 3H), 2.21 (m, 2H), 2.38 (m, 1H), 2.52 (m, 2H), 2.98 (s, 3H), 4.35
13
(d, 2H, J = 2.4 Hz), 7.06 (m, 1H), 8.31 (d, 1H, J = 8.9 Hz); C NMR (CDCl3, 125 MHz) δ 19.9, 23.8,
27.1, 39.6, 68.1, 73.3, 109.4, 112.9, 150.7, 151.2, 160.3. Anal. Calcd. For C12H16BrNO2: C, 50.37; H,
5.64; N, 4.89. Found: C, 50.65; H, 5.37; N, 4.93.
Method C: In a 500 L reactor was added 6.40 kg (33.7 mol) of fluoropyridine 7 , 5.90 kg (51.6
mol) of diol 6 and 51.0 kg of THF. The resulting mixture was cooled to 0 °C and 5.9 kg (52.7 mol) of
KOtBu in 54 kg of THF was added over the course of 4 h. The resulting mixture was stirred at 0 °C for
20 h and quenched with 19 kg of a saturated solution of NH4Cl. The layers were separated and the
aqueous layer was washed with 72 kg of heptane. The combined organic extracts were washed with 70
L of water (2X) and then concentrated under reduced pressure while solvent switching to heptane and a
final volume of ~ 20 L. The resulting slurry was then warmed to 55 °C to give a homogeneous solution
that was seeded with 10 grams of pure product 1. The slurry was stirred at 55 °C for 1.5 h and then
slowly cooled to 5 °C, stirred for 1 h, and then filtered. The crystalline solid was dried under
vacuum/N2 sweep at50 °C for 20 h to afford 7.27 kg (75.4%) of compound 1 as a colorless solid and the
1
free base: H NMR (CDCl3, 500 MHz) δ 1.40 (s, 3H), 1.82 (br s, 1H), 1.94 (m, 2H), 2.16-2.33 (m, 3H),
13
2.52 (s, 3H), 4.24 (d, 2H, J = 5.8 Hz), 6.45 (d, 1H, J = 8.6 Hz), 7.60 (d, 1H, J = 8.6 Hz); C NMR
(CDCl3, 125 MHz) δ 23.4, 24.5, 27.3, 40.6, 69.2, 70.0, 109.2, 111.5, 141.8, 154.1, 162.0. Anal. Calcd.
For C12H17BrClNO2: C, 44.67; H, 5.31; N, 4.34. Found: C, 44.60; H, 5.32; N, 4.27.
Acknowledgements
The Authors thank Dr. Peter G. Dormer and Melissa Lin of Merck & Co., Inc., Kenilworth, NJ
USA, for valuable NMR assistance. The Authors also thank Jin She, formely of Merck & Co., Inc,
Kenilworth, NJ USA, for helpful discussions during the execution of this work and Rongxin Huang of
WuXi AppTec for experimental assistance.
17

A. Supplementary data.
Supplementary data associated with this article can be found in the online version at:
These data include 1H NMR and 13C NMR spectra for all new compounds.
18

1 Du X, Hinklin RJ, Xiong Y, Dransfield P, Park J, Kohn TJ, Pattaropong V, Lai S, Fu Z, Jiao X, Chow
D, Jin L, Davda J, Veniant MM, Anderson DA, Baer BR, Bencsik JR, Boyd SA, Chicarelli MJ, Mohr
PJ, Wang B, Condroski KR, DeWolf WE, Conn M, Tran T, Yang J, Aicher TD, Medina JC, Coward P,
Houze JB. C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.
ACS Med. Chem. Lett. 2014; 5: 1284-1289.
2
House HO, Latham RA, Whitesides GM. The chemistry of Carbanions. XIII. The Nuclear Magnetic
Reasonance Spectra of Various Methylmagnesium Derivatives and Related Substances. 1967; 32: 2481-
2496.
3 HPLC assay yield refers to quantitative HPLC analysis using an analytically pure standard.
4
Mladenova G, Lee-Ruff E. Cyclobutanone Photoaducts of HCN and Malonitrile: Useful
Intermediates for the Synthesis of C-nucleosides. Tet. Lett. 2007; 48: 2787-2789.
5
Liotta DC, Mao S, Hager M. Preparation of Cyclobutyl Nucleosides for use in the treatment of
infections including Retroviridae, Hepadnaviridae, or Flaviviridae in Animals and Humans.
WO2006063281 A2.
McCabe Dunn JM, Duran-Capece A, Meehan M, Ulis J, Iwama T, Gloor G, Wong G, Bekos E. The
6
Safe use of Sodium Hydride on Scale: The Process Development of a Chloropyrimidine Displacement.
Org. Process Res. Dev. 2011; 15: 1442-1446 and references cited therein.
For leading references on the effect of partical size and reaction rate increases, see: (a) Meyers C,
7
Maes BUW, Loones KTJ, Bal G, Lemière GLF, Dommisse RA. J. Org. Chem. 2004; 69: 6010-6017.
(b) Wilk BK, Mwisiya N, Helom JL. Org. Process Res. Dev. 2008; 12: 785-786. (c) Qafisheh N,
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3023.
8
The structure of by-product 18 was determined by LCMS and NMR analysis of the crude reaction
mixture. By-product 18 was not isolated.
9 Both ketoalcohol 3 and ketoacid 19 are commercially available, for the reduction of 19 to 3, see: Liotta
DC, Mao S, Hager M. Preparation of Cyclobutyl Nucleosides for use in the treatment of infections
including Retroviridae, Hepadnaviridae, or Flaviviridae in Animals and Humans. WO2006063281 A2.
10 No attempts were made to determine the sturctures of the by-products that were formed.
11
Potyen M, Josyula KVB, Schuck M, Lu S, Gao P, Hewitt C. Borane-THF: New Solutions with
Improved Thermal Properties and Stability. Org. Process Res. Dev. 2007; 11: 210-214 and references
cited therein.
12 Zweifel G, Brown HC. Hyrdration of Olefins, Dienes, and Acetylenes via Hydroboration. Org. React.;
1963; 13: 1-54.
13
Typical workup: sequentially quench 1X gram of LAH with 1X mL of water, 1X mL of 15%
aqueous NaOH, 3X mL of water, see reference 9.
14 Fieser LF, Fieser M. Reagents for Organic Synthesis. 1967: 581-595.
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