Development of a new synthesis for the large-scale preparation of triple reuptake inhibitor (-)-GSK1360707

Article abstract of DOI:10.1021/op100139f

The triple reuptake inhibitor, GSK1360707, was synthesized via an efficient, scalable route, which features a vinyl triflate Suzuki coupling followed by a single-step, double alkylative cyclopropanation with a dihalomethane. Also, a mechanistic understand

Full text of DOI:10.1021/op100139f

Organic Process Research & Development 2010, 14, 912–917
Development of a New Synthesis for the Large-Scale Preparation of Triple Reuptake
Inhibitor (-)-GSK1360707
Vassil I. Elitzin, Kimberly A. Harvey, Hyunjung Kim, Matthew Salmons, Matthew J. Sharp,* Elie A. Tabet, and
Matthew A. Toczko
Chemical DeVelopment, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, U.S.A.
Abstract:
migration of the olefin out of conjugation with the ester, likely
due to substrate deprotonation at the γ position rather than
conjugate addition.
The triple reuptake inhibitor, GSK1360707, was synthesized via
an efficient, scalable route, which features a vinyl triflate Suzuki
coupling followed by a single-step, double alkylative cyclopropa-
nation with a dihalomethane. Also, a mechanistic understanding
of the Suzuki reaction (as it relates to the control of a polychlo-
rinated biphenyl impurity) is discussed.
Next, we reduced ester 4a and attempted cyclopropanation
of the corresponding allylic alcohol (4b) and methyl ether (4c)
under Simmons-Smith conditions.9 We found that the Boc
protecting group was incompatible with the strongly Lewis
acidic conditions and caused substrate decomposition. A dichlo-
rocyclopropane was successfully installed in ∼50% yield by
reacting 4c with CHCl3/NaOH.10 However, several attempted
reaction conditions11 to selectively remove the cyclopropyl
chlorine atoms failed due to substrate decomposition.
Undeterred, we turned our attention to a different cyclopro-
panation strategy involving the alkylation of a dihydropyridone
ring with diiodomethane12 followed by a second, intramolecular
alkylation (Scheme 3). The desired cyclopropanation substrate
8 was prepared in two steps by the Mannich reaction of
commercially available 3,4-dichloroacetophenone 6 and ben-
zylamine followed by condensation with ethyl malonyl chlo-
ride.13 In line with our observations for the reactivity of enoate
4a, the product from this intramolecular condensation was
isolated as the thermodynamically more stable olefin isomer in
which the olefin is not conjugated with the carbonyl (the
corresponding conjugated isomer is presumably destabilized due
to A1,3 strain). Gratifyingly, treatment of 8 with NaH in THF
followed by diiodomethane afforded the product of alkylation
R to the ester (compound 9). This iodide could be isolated by
column chromatography in ∼75-80% yield, or preferentially
treated with a second equivalent of base to afford the desired
cyclopropane 10 in excellent overall yield. Presumably, this
second deprotonation occurs R to the nitrogen, and the resulting
allylic anion is intramolecularly alkylated with exclusive regi-
Introduction
Major depressive disorder (MDD) is the most common form
of depression.1 According to statistics, approximately 10 million
U.S. adults are classified as severely depressed.2 GSK1360707
is a potent serotonin, noradrenaline, and dopamine reuptake
(triple reuptake) inhibitor under development at GlaxoSmith-
Kline for the treatment of MDD. In order to fully evaluate the
clinical potential of GSK1360707, an efficient, safe, and scalable
synthetic route to the desired single enantiomer was required.
The original synthesis of GSK13607073 was deemed not
suitable for scale-up because of the high energy of decomposi-
tion of the diazomalonate intermediate, the throughput of the
synthesis (13 total steps, 11 longest linear, 5% overall yield),
and a laborious, low-yielding resolution4 of racemic GSK1360707
at the final step (Scheme 1).
Results and Discussion
Our first attempts at an alternate route to GSK1360707 are
shown in Scheme 2. Suzuki coupling5 of the conjugated vinyl
triflate (1, Vide infra)6 derived from the commercially available
ꢀ-ketoester 2 and 3,4-dichlorophenylboronic acid 3 afforded
R,ꢀ-unsaturated ester 4a (see Scheme 4 for details). Unfortu-
nately, all efforts to convert 4a to the corresponding cyclopro-
pane 5a by reaction with a variety of sulfur ylides7 or with basic
nitromethane8 failed. The major outcome in these reactions was
* Author to whom correspondence may be addressed. E-mail: matthew.j.sharp@
gsk.com.
(9) (a) Simmons, H.; Smith, R. J. Am. Chem. Soc. 1958, 80, 5323. (b)
Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. Chem. ReV. 2003,
103, 977.
(1) Chen, Z.; Skolnick, P. Expert Opin. InVestig. Drugs 2007, 16, 1365.
(2) Nemeroff, C. B. J. Psychiatry Res. 2007, 41, 189.
(3) Bertani, B.; Di Fabio, R.; Micheli, F.; Tedesco, G.; Terreni, S. PCT
Int. Appl. WO/2008/031772, 2008.
(10) Sattar, A.; Arbale, A.; Kulkarni, G. Synth. Comm. 1990, 20, 2217.
(11) (a) Corsaro, A.; Chiacchio, U.; Adamo, R.; Pistara, V.; Rescifina, A.;
Romeo, R.; Catelani, G.; D’Andrea, F.; Mariani, M.; Attolino, E.
Tetrahedron 2004, 60, 3787. (b) Ashby, E.; Deshpande, A. J. Org.
Chem. 1994, 59, 3798. (c) Hutchins, R.; Kandasamy, D.; Dux, F., III;
Maryanoff, C.; Rotstein, D.; Goldsmith, B.; Burgoyne, W.; Cistone,
F.; Dalessandro, J.; Puglis, J. J. Org. Chem. 1978, 43, 2259.
(12) (a) Yoshizumi, T.; Miyazoe, H.; Sugimoto, Y.; Takahashi, H.;
Okamoto, O. Synthesis 2005, 10, 1593. (b) Dowd, P.; Choi, S.-C.
J. Am. Chem. Soc. 1987, 109, 3493.
(4) Resolution via the L-tartrate salt was unsuccessful. Resolution was
accomplished in low efficiency using L-dibenzoyltartrate.
(5) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(6) Ujjainwalla, F.; Warner, D.; Snedden, C.; Grisson, R.; Walsh, T.;
Wyvratt, M.; Kalyani, R.; MacNeil, T.; Tang, R.; Weinberg, D.; Van
der Ploeg, L.; Goulet, M. Bioorg. Med. Chem. Lett. 2005, 15, 4023.
(7) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(b) Trost, B. M.; Melvin, L. S. Sulfur Ylides; Academic Press: New
York, NY, 1975. (c) Cativiela, C.; Diaz-de-Villegas, M. D.; Jimenez,
A. I. Tetrahedron 1994, 50, 9157.
(13) Foguet, R.; Ramentol, J.; Petschen, I.; Sallares, J.; Camps, F.; Raga,
M.; Castello, J.; Armengol, M.; Fernandez-Cano, D. PCT Int. Appl.
WO/2002/053537, 2002.
(8) Melot, J.; Texier-Boullet, F.; Foucaud, A. Synthesis 1987, 4, 364.
912
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Vol. 14, No. 4, 2010 / Organic Process Research & Development
10.1021/op100139f  2010 American Chemical Society
Published on Web 06/22/2010

Scheme 1. Original synthesis of GSK13607073
Scheme 3. Cyclopropanation of dihydropyridone 8
lithium tert-butoxide and 3 equiv of chloroiodomethane at 0
°C afforded the desired cyclopropane 12 in 84% yield in a single
step. These alternative cyclopropanation conditions were deemed
more scalable than the ones described in Scheme 3.15,16 As
expected, compound 12 was found to be much more stable than
the corresponding benzyl protected lactam 10, which allowed
subsequent modifications en route to GSK1360707. Thus,
treatment of 12 with LiBH4 and MeOH17 cleanly reduced the
ester to the primary alcohol which was in turn methylated18 to
give the corresponding racemic methyl ether 13 in 97% yield.
At this stage we evaluated various chiral resolution options in
order to obtain the final product as a single enantiomer. We
determined that the penultimate intermediate 13 was an excellent
candidate for preparative chiral chromatography. An efficient
and practical separation was developed using ChiralPak AD
and heptane/IPA mobile phase that afforded the desired enan-
tiomer in 46% recovery and 99% ee with a throughput rate of
7.2 kg of racemic 13/day. Lastly, we found that rapid enamine
reduction and subsequent deprotection of the Boc-enamine
moiety could be accomplished in 96% yield in a single step by
treatment with triethylsilane and 8 equiv of TFA in toluene at
room temperature.19 After a basic aqueous workup, the final
product could then be isolated as a crystalline salt by treatment
of the free base with either phosphoric or L-(+)-tartaric acid.20
The absolute stereochemical configuration was confirmed by
single-crystal X-ray (Figure 1). This represented a synthesis of
enantiomerically pure GSK1360707 from commercially avail-
able materials in five steps and 21% overall yield.
Scheme 2. Unsuccessful cyclopropanation reactions
oselectivity.14 It is noteworthy that the second deprotonation/
alkylation sequence was unsuccessful in the absence of the
olefin.
Although we had successfully incorporated the cyclopropane
ring in the desired position, lactam 10 proved to be a nonviable
intermediate for the synthesis of GSK1360707. We found that
10 was unstable, particularly in the presence of even mild acids
such as aqueous NH4Cl, or under standard hydrogenation
conditions (1 atm H2, Pd/C). Thus, all attempts to convert 10
into GSK1360707 by reduction of the ester, lactam, and/or
olefin functional groups resulted in decomposition, presumably
Via cleavage of the cyclopropane ring.
On the basis of these results we turned our attention back to
the Suzuki coupling product 4a. We postulated that this substrate
could also undergo the double alkylation sequence with a
dihalomethane electrophile and would afford a more stable
cyclopropane that could then be converted to GSK1360707.
The successful application of this strategy is shown in Scheme
4. As previously alluded to, the commercially available Boc-
protected ꢀ-keto ester 2 was treated with triflic anhydride in
the presence of Hu¨nig’s base to prepare the vinyl triflate 1.
Without isolation, 1 was subjected to the Suzuki coupling
conditions with 3,4-dichlorophenylboronic acid 3 to afford the
desired coupled product 4a. Treatment of 4a with 2.4 equiv of
(15) CH2ClI gave a cleaner process than CH2I2, presumably due to improved
stability of the intermediate primary chloride 11.
(16) Sodium hydride is generally not preferred on scale. For an excellent
discussion, see: Fluegeman, C.; Hilton, T.; Moder, K.; Stankovich,
R. Process Saf. Prog. 2005, 24 (2), 86.
(17) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000.
(18) Johnstone, R.; Rose, M. Tetrahedron 1979, 35, 2169.
(19) To the best of our knowledge, this tandem process has not been
described previously. For examples of Et3SiH/TFA reductions of
N-acyl enamines, see: (a) Lucarini, S.; Bedini, A.; Spadoni, G.;
Piersanti, G. Org. Biomol. Chem. 2008, 6, 147. (b) Taylor, M.;
Tokunaga, N.; Jacobsen, E. Angew. Chem., Int. Ed. 2005, 44, 6700.
(c) Wendeborn, S.; Lamberth, C.; Nebel, K.; Crowley, P. PCT Int.
Appl. WO/2006/100038, 2006.
(14) The same selectivity has been observed in intermolecular alkylations
of similar substrates: (a) Werner, J. A.; Cerbone, L R.; Frank, S. A.;
Ward, J. A.; Labib, P.; Tharp-Taylor, R. W.; Ryan, C. W. J. Org.
Chem. 1996, 61, 587. (b) Beak, P.; Lee, B. J. Org. Chem. 1989, 54,
458. (c) Sugg, E. E.; Portoghese, P. S. J. Med. Chem. 1986, 29, 2028.
(20) The L-tartrate salt was prepared in analogous fashion by treatment of
(-)-GSK1360707 free base with L-(+)-tartaric acid in EtOHssee the
Experimental Section. The L-tartrate salt was initially selected for
development; however, the phosphate salt was subsequently selected
on the basis of its superior solid-state properties.
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Scheme 5. Improved Suzuki coupling conditions
material was found to contain between 1 and 5% of the PCB
impurity by HPLC analysis. We needed to significantly lower
the amount of PCB formed in the coupling reaction before
scaling up the process and be confident that we could eliminate
this impurity from the final product, GSK1360707.
Palladium(II) catalysis has previously been implicated in the
dimerization of arylboronic acids.21 Therefore, we felt that it
was important to ensure the complete conversion of Pd(OAc)2
to the desired active Pd(0) catalyst for the Suzuki coupling
reaction,22 ideally in the absence of boronic acid. We further
speculated that using a slight excess of vinyl triflate in the
reaction should ensure that no free boronic acid would remain
and be available for homocoupling at the end of the reaction.
On the basis of the above rationale, we modified the conditions
by combining 1 equiv of vinyl triflate 1, 2.5 mol % Pd(OAc)2,
7.5 mol % PPh3, Hu¨nig’s base, and water in toluene at room
temperature, heating the mixture to 70 °C to preform the active
Pd(0) catalyst, and then adding 0.95 equiv of the boronic acid
as DMF/toluene solution over 1 h (Scheme 5). Using these
conditions lowered the level of PCB in intermediate 12 to <30
ppm. We also found that recrystallizing this intermediate from
heptane further lowered the PCB levels to <10 ppm.
Figure 1. X-ray structure of GSK1360707 L-tartrate.
Scheme 4. Synthesis of GSK1360707
Conclusion
We have developed a practical synthesis of the promising
antidepressant GSK1360707. This new route was facilitated by
our in-depth understanding of the Suzuki coupling mechanism
and its effect on PCB byproduct formation. Other noteworthy
transformations include the novel double alkylation-based
cyclopropanation method, the efficient enantiomeric separation,
and the final single-step reduction-deprotection. The final route
as depicted in Scheme 4 was recently scaled in our 200-gal
pilot plant to afford over 10 kg of (-)-GSK1360707 as the
phosphate salt.
Before further scaling up this new route we needed to
understand and control the formation of a potential polychlo-
rinated biphenyl (3,3′,4,4′-tetrachloro-1,1′-biphenyl, PCB-77)
impurity (a highly regulated class of compounds) that could be
produced in the Suzuki coupling reaction by dimerization of
the 3,4-dichlorophenyl boronic acid. For ease of analysis, we
chose to determine the PCB levels in intermediate 12 after the
cyclopropanation reaction since this intermediate is readily
isolated as a stable crystalline solid. The initial conditions for
the Suzuki coupling involved combining the reagents (1:1 vinyl
triflate/boronic acid, 2.5 mol % Pd(OAc)2, 7.5 mol % PPh3,
Hu¨nig’s base, water) in toluene at room temperature and heating
the mixture to 70 °C. This resulted in good yields of the product.
However, after conversion to cyclopropane 12, the isolated
Experimental Section
Mass spectra were obtained using a ThermoScientific LTQ
Orbitrap Discovery mass spectrometer using positive electro-
spray ionization (ESI). HPLC purity was determined on a
Hewlett-Packard series 1100 system using Agilent Eclipse XDB
C18 columns (150 mm × 4.6 mm, 3.5 µm), and a mixture of
water and acetonitrile as mobile phase (gradient at a flow rate
(21) (a) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. J. Am.
Chem. Soc. 2006, 128, 6829. (b) Yamamoto, Y.; Suzuki, R.; Hattori,
K.; Nishiyama, H. Synlett 2006, 1027. (c) Moreno-Manas, M.; Perez,
M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346.
(22) (a) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (b)
Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M.; Meyer, G. Orga-
nometallics 1995, 14, 5605. (c) Amatore, C.; Carre, E.; Jutand, A.;
M’Barki, M. Organometallics 1995, 14, 1818.
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1
of 1.0 mL/min and UV detector at 220 nm). Preparative Chiral
HPLC was conducted on a Chiralpak AD, 20 µm, 20 cm × 25
cm column at ambient temperature. Processing parameters:
Flow: 92 L/h; Detection: 225 and 280 nm; Feed stock: 80 g/L.
PCB-77 content was determined by a gradient, reversed-phase
HPLC using a polar embedded C14 column. The mobile phase
was (A) water with 0.05% v/v TFA and (B) acetonitrile with
0.05% v/v TFA. The gradient runs from 80 to 95% B over 5
min. The detection wavelength was 262 nm. The content of 1
in solution was determined by a gradient, reversed-phase HPLC
using a C18 column. The mobile phase is (A) water with 0.05%
v/v TFA and (B) acetonitrile with 0.05% v/v TFA. The gradient
runs from 0 to 95% B over 8 min. The detection wavelength is
255 nm. The content of 13 in solution was determined by a
gradient, reversed-phase HPLC using a C18 column. The
mobile phase is (A) water with 0.05% v/v TFA and (B)
acetonitrile with 0.05% v/v TFA. The gradient runs from 0 to
95% B over 8 min. The detection wavelength is 220 nm.
1-(1,1-Dimethylethyl) 3-ethyl 4-{[(trifluoromethyl)sulfo-
nyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (1). 1-(1,1-
Dimethylethyl)-3-ethyl 4-oxo-1,3-piperidinedicarboxylate (41.1
kg, 151.4 mol) dissolved in toluene (320 kg, 3473 mol) was
cooled to -5 °C and then treated with N,N-diisopropylethyl-
amine (29.4 kg, 1.5 equiv, 227 mol) at <5 °C. After 5 min,
trifluoromethanesulfonic anhydride (46.9 kg, 1.1 equiv, 167
mol) was added at <5 °C. The reaction mixture was warmed
to ∼0 °C. Upon disappearance of starting material 2 as
determined by HPLC, the reaction mixture was warmed to ∼20
°C and filtered. The solids were rinsed with toluene (35.6 kg,
387 mol), and the resultant toluene solution of 1 (chemically
unstable) was used directly in the next stage. Analytical data
obtained on a concentrated sample: 1H NMR (400 MHz, CDCl3)
δ 4.32-4.27 (m, 4H), 3.61 (t, J ) 5.7 Hz, 2H), 2.51-2.49 (m,
2H), 1.47 (s, 9H), 1.33 (t, J ) 7.1 Hz, 3H).
1-(1,1-Dimethylethyl)-3-ethyl 4-(3,4-dichlorophenyl)-5,6-
dihydro-1,3(2H)-pyridinedicarboxylate (4a). To the 1-(1,1-
dimethylethyl) 3-ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-
dihydro-1,3(2H)-pyridinedicarboxylate (1) solution in toluene
(51.4 kg, 127 mol, from previous reaction) was added N,N-
diisopropylethylamine (26.3 kg, 203.1 mol, 1.6 equiv), water
(34.25 kg, 1901 mol), triphenylphosphine (2.5 kg, 9.52 mol,
0.075 equiv), and palladium(II) acetate trimer (709 g, 1.1 mol,
0.0083 equiv). The reaction was heated to ∼70 °C. To the
reaction mixture was added over 1 h a solution of 3,4-
dichlorophenylboronic acid (23.3 kg, 122 mol, 0.96 equiv) in
N,N-dimethylformamide (21.3 kg, 291 mol) and toluene (115
kg, 1251 mol). After the complete consumption of 3 as
determined by HPLC, the reaction was cooled to ∼0 °C
followed by the addition of 1 N sodium hydroxide (308 L, 320
kg) at 0-15 °C. The reaction mixture was warmed to about 20
°C and stirred for ∼1 h. The reaction mixture was filtered, and
the aqueous layer was discarded. Next, 20% w/w aqueous
sodium bisulfite (401 kg) was added while maintaining the
temperature at 15-28 °C. The mixture was heated to ∼60 °C
and stirred for ∼1 h. The mixture was cooled to ∼22 °C and
filtered, and the aqueous layer was discarded. The organic layer
was washed with water (343 L, 343 kg) and used directly in
the next stage. Analytical data obtained on a concentrated
sample: H NMR (500 MHz, CDCl3) δ 7.39 (d, J ) 8.2 Hz,
1H), 7.23 (d, J ) 1.8 Hz, 1H), 6.96 (dd, J ) 2.0, 8.24 Hz, 1H),
4.24 (s, 2H), 3.99 (dd, J ) 7.1, 14.3 Hz, 2H), 3.59 (t, J ) 5.7
Hz, 2H), 2.44 (br s, 2H), 1.49 (s, 9H), 1.00 (br s, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 166.0 (br), 154.5, 144.2, 142.1,
132.2, 131.5, 130.2, 129.1, 126.6, 126.3, 80.3, 60.7, 44 (br),
40.5-39.4 (br), 32.8, 28.5, 13.8; IR (ATR) 2978 (w), 1693 (s),
1468 (m), 1418 (m), 1366 (m), 1294 (w), 1236 (s), 1163 (m),
1135 (m), 1114 (m), 1052 (m), 1030 (m), 996 (w), 899
(w), 820 (w), 764 (w); HRMS m/z 400.1077 [(M+); calcd for
C19H24Cl2NO4: 400.1077].
(()-3-(1,1-Dimethylethyl)-1-ethyl 6-(3,4-dichlorophenyl)-
3-azabicyclo[4.1.0]hept-4-ene-1,3-dicarboxylate (12). Lithium
t-butoxide (23.4 kg, 292 mol, 2.4 equiv) and 1-methyl-2-
pyrrolidinone (240 kg, 234 L) were stirred for ∼1 h at ∼25
°C. The resulting suspension was transferred to a pressure
vessel. The reactor was rinsed with 1-methyl-2-pyrrolidinone
(4.90 L, 5 kg) into the pressure vessel.
The 1-(1,1-dimethylethyl)-3-ethyl 4-(3,4-dichlorophenyl)-
5,6-dihydro-1,3(2H)-pyridinedicarboxylate (49 kg, 122 mol, 1
equiv. based on 100% yield in Suzuki and 3,4-dichlorophenyl-
boronic acid as limiting reagent) solution in toluene was distilled
under reduced pressure to remove the toluene. 1-Methyl-2-
pyrrolidinone (244 L, 250 kg) was added, and the resulting
solution was cooled to 20 °C. Chloroiodomethane (64.4 kg,
366 mol, 3 equiv) was charged into the reactor, and the resulting
slurry was cooled to ∼0 °C. The lithium tert-butoxide suspen-
sion prepared above was added at <10 °C. The resulting solution
was warmed to ∼20 °C and stirred until the starting material
was consumed by HPLC. Acetic acid (11 kg, 183 mol, 1.5
equiv) was added all at once, followed by water (342 kg, 342
L) over ∼30 min. The resulting slurry was cooled to 15 °C
and stirred for ∼30 min. The solids were collected by filtration.
Water (63.4 kg, 63.4 L) and methanol (147 kg, 186 L) were
charged into the reactor to rinse it, and the resulting aqueous
methanol solution was used to wash the product cake. The
resulting yellow solids were dried to a constant weight in a 55
°C vacuum oven to provide 42.1 kg of (()-3-(1,1-dimethyl-
ethyl)-1-ethyl 6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-
4-ene-1,3-dicarboxylate (12) (83.7% crude yield).
Recrystallization of (()-3-(1,1-Dimethylethyl)-1-ethyl
6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-4-ene-1,3-di-
carboxylate. (()-3-(1,1-Dimethylethyl)-1-ethyl 6-(3,4-dichlo-
rophenyl)-3-azabicyclo[4.1.0]hept-4-ene-1,3-dicarboxylate (41.8
kg, 101.5 mol) was suspended in heptane (209 L, 143 kg). The
resulting slurry was heated to ∼80 °C and filtered into a clean
reactor. The filter and lines were rinsed with heptane (41.8 L,
28.6 kg) preheated to ∼70 °C, and the rinse was combined with
the filtrate. The solution was heated to 80 °C and then cooled
to 43-47 °C over 60 min. Seed crystals of (()-3-(1,1-di-
methylethyl) 1-ethyl 6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]-
hept-4-ene-1,3-dicarboxylate (21 g, 0.0005 equiv) were added.
The slurry was cooled to 22 °C over 60 min. The solids were
collected by filtration, the reactor was rinsed with heptane (41.8
L, 28.6 kg), and the rinse was used to wash the filter cake. The
solids were dried to a constant weight in a 50-60 °C vacuum
oven to provide 31 kg of (()-3-(1,1-dimethylethyl)-1-ethyl
6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-4-ene-1,3-dicar-
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boxylate (74.2% yield) as an off-white solid. 1H NMR (CDCl3,
400 MHz) δ 7.35 (m, 2H), 7.11 (m, 1H), 6.65 (br m, 1H), 5.16
(br m, 1H), 4.27 (br m, 1H), 3.79 (br m, 3H), 2.32 (m, 1H),
1.59 (m, 1H), 1.52 (s, 9H), 0.94 (br m, 3H); 13C NMR (125.7
MHz, CDCl3) δ 169.1-168.9 (br), 152.6 (br), 140.6, 132, 131.1,
131, 129.9, 128.5, 124.3, 81.5, 60.9, 40.8-39.5 (br), 40.1, 31.6,
28.2, 23.2, 13.8; IR (ATR) 2976 (w), 1699 (s), 1640 (m), 1469
(w), 1356 (s), 1307 (m), 1245 (m), 1238 (m), 1161 (m), 1136
(s), 1045 (w), 946 (w), 873 (m), 771 (w), 737 (w), 678 (w);
HRMS m/z 412.1079 [(M+); calcd for C20H24Cl2NO4: 412.1077];
mp ) 111-113 °C.
(()-3-(1,1-dimethylethyl)-1-ethyl 6-(3,4-dichlorophenyl)-3-
azabicyclo[4.1.0]hept-4-ene-1,3-dicarboxylate (12) may be re-
worked if necessary to reduce amount of PCB No. 77 by
slurrying in heptane (3.42 wt) at 50 °C for 1 h. Cooling to room
temperature, filtering, and drying affords (()-3-(1,1-dimethyl-
ethyl)-1-ethyl 6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-
4-ene-1,3-dicarboxylate as a white solid.
(28.8 kg, 2 equiv, 203 mol) was added over 15 min, and the
reaction was stirred for 2 h at 20 °C until the remaining starting
material was <2% as determined by HPLC. Water (150 kg)
was added over 30 min, followed by heptane (257 kg), and the
mixture stirred for 1 h. The phases were separated, and the top
(organic) layer was washed with water (150 kg) and partially
concentrated under vacuum. The heptane solution of (()-1,1-
dimethylethyl 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-
3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate thus prepared was
used directly in preparative chiral chromatography next. (()-
1,1-Dimethylethyl-6-(3,4-dichlorophenyl)-1-[methyloxy)methyl]-
3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate ((()-13), 36.9 kg,
96 mol) was dissolved in 380 L (95/5 (v/v) heptane/IPA), and
the two enantiomers were separated by preparative chiral HPLC
on a Hipersep 200 Preparative HPLC system. The feed solution
was transferred to the Hipersep 200 feed vessel via a 1 µm
filter. Heptane was charged to solvent vessel A, and IPA was
charged to solvent vessel B. The Hipersep instrument was used
to mix the mobile phase, 95/5 heptane/IPA, by pumping 95%
from vessel A, and 5% from vessel B to elute the desired
enantiomer as the first eluting peak. A column containing
Chiralpak AD (20 µm particle size, 20 cm inner diameter ×25
cm length) was equilibrated by passing mobile phase through
the column at a flow rate of 100 L/h for 30 min. Chromatog-
raphy was run under the following conditions, and fractions
were collected until all of the feed had been processed.
Mobile phase: 95/5 heptane/IPA for 15 min, followed by
50/50 heptane/IPA for 7 min, and equilibration of the column
with 95/5 heptane/IPA for 4 min. Flow rates: 92 L/h. Detection:
290 nm. Temperature: 25 °C. Run time: 26 min. Column:
Chiralpak AD (20 µm), column dimensions: 20 cm ×25 cm.
Loading amount per injection: 100 g.
(()-1,1-Dimethylethyl-6-(3,4-dichlorophenyl)-1-(hydroxy-
methyl)-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate Reduc-
tion Product of 12 and Precursor to (()-13. (()-3-(1,
1-Dimethylethyl)-1-ethyl 6-(3,4-dichlorophenyl)-3-azabicyclo-
[4.1.0]hept-4-ene-1,3-dicarboxylate (41.8 kg, 101 mol) was
dissolved in THF (75 kg). A solution of 2 M LiBH4 in THF
(62 kg, 1.5 equiv, 155 mol) was added and the resulting
solution heated to 40 °C. Methanol (9.7 kg, 3 equiv, 304
mol) was added over ∼60 min (this reaction is exothermic
and releases hydrogen gas). The reaction was stirred for 40
min until consumption of starting material as determined by
HPLC, cooled to 20 °C and heptane (209 L) was added over
∼15 min. Water (84 L) was added over ∼10 min, and the
resulting slurry was stirred for 15-20 min (hydrogen gas is
released during this addition). Aqueous HCl (1 N, 167 L)
was added over ∼15 min (hydrogen gas is released during
this addition), the mixture was stirred for 15 min, and the
layers were separated. The organic layer was washed with
water (209 L), and filtered. The resulting solution was used
directly in the next stage. Analytical data on a concentrated
Fractions of the desired enantiomer (containing <1% of the
undesired enantiomer by chiral HPLC) were concentrated under
vacuum to ∼40 L. Toluene (200 L) was added, and the volume
was reduced under vacuum to ∼40 L. This concentrated toluene
solution of (+)-1,1-dimethylethyl (1S,6R)-6-(3,4-dichlorophe-
nyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-4-ene-3-
carboxylate ((+)-13, 16.5 kg, 42.9 mol, 46% yield, 92%
recovery) was used directly in the next step. Analytical data
obtained on a concentrated sample: 1H NMR (400 MHz, CDCl3)
δ 7.40 (d, J ) 4 Hz, 1H), 7.37 (d, J ) 8 Hz, 1H), 7.15 (dd, J
) 8, 4 Hz, 1H), 6.55 (br m, 1H), 5.08 (br m, 1H), 4.19 (br m,
1H), 3.27 (br m, 1H), 3.10 (br s, 3H), 3.04 (br m, 1H), 2.96 (br
m, 1H), 1.49 (br s, 9H), 1.42 (d, J ) 4 Hz, 1H), 1.28 (br m,
1H); 13C NMR (100.6 MHz, CDCl3) δ 153.1 (br), 141.8, 132.3,
131.5, 130.8, 130.2, 129.1, 122.9 (br), 113.1 (br), 81.4, 75.3
(br), 59.0, 42.3-41.3, 35.6-35.0, 28.5, 28.3-27.8, 22.7; IR
(ATR) 2978 (w), 1700 (s), 1472 (m), 1367 (s), 1354 (s), 1239
(m), 1163 (s), 1102 (s), 1030 (m), 962 (w), 865 (w), 822 (w),
767 (m), 714 (w), 676 (w); HRMS m/z 384.1126 [(M+); calcd
1
sample: H NMR (400 MHz, CDCl3) δ 7.38 (br m, 2H),
7.15 (br m, 1H), 6.60 (br m, 1H), 5.12 (br m, 1H), 4.24 (br
m, 1H), 3.38 (br m, 2H), 3.29 (br m, 1H), 1.51 (br m, 10H),
1.30 (br m, 1H); 13C NMR (100.6 MHz, CDCl3) δ 153.2
(br), 141.7, 132.6, 131.2, 131.0, 130.5, 128.7, 123.1-122.8
(br), 113.1-112.6 (br), 81.5, 65.7, 42.0-41.0, 37.6-36.8,
32.1, 29.2-28.1, 22.9-22.2, 14.4; IR (ATR) 3430 (w), 2977
(w), 1702 (m), 1646 (m), 1471 (m), 1353 (s), 1237 (m), 1163
(s), 1127 (s), 1029 (m), 912 (w), 864 (w), 766 (m), 731 (m),
676 (w); HRMS m/z 370.0968 [(M+); calcd for
C18H22Cl2NO3: 370.0972].
(+)-1,1-Dimethylethyl-6-(3,4-dichlorophenyl)-1-[(methyl-
oxy)methyl]-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate: (+)-
13. (()-1,1-Dimethylethyl 6-(3,4-dichlorophenyl)-1-(hydroxy-
methyl)-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate (estimated
37.6 kg, 101 mol, amount based on 100% yield in reduction)
in heptane was dissolved in DMSO (290 kg, 263 L). After the
heptane was removed by distillation, the remaining solution was
cooled to ∼20 °C, treated with powdered potassium hydroxide
(22.8 kg, 4 equiv, 406 mol), and stirred for 15 min. Iodomethane
for C19H24Cl2NO3: 384.1128]; [R]25 ) +119.5 (c ) 1.90,
D
MeOH).
(-)-GSK1360707. 1,1-Dimethylethyl (1S,6R)-6-(3,4-dichlo-
rophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-4-ene-
3-carboxylate ((+)-13, 8.25 kg, 20.3 mol) was dissolved in
toluene (47.4 kg). The solution was treated with triethylsilane
(2.6 kg, 1.1 equiv, 22.5 mol), followed by the addition of
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trifluoroacetic acid (18.6 kg, 8 equiv, 163 mol) over 1 h at <30
°C (Caution: this reaction is exothermic and releases gas!).
The reaction was stirred at 20 °C for 3 h until the starting
material was consumed as determined by HPLC, then quenched
with 5 N sodium hydroxide (38.5 kg, 32.6 L, 8 equiv), heated
to 50 °C, and stirred for 30 min. The pH of the mixture was
approximately 13-14. The phases were separated, the toluene
layer was treated with 1 N sodium hydroxide (16.3 kg), and
the mixture was stirred for 10 min. The phases were separated,
the toluene layer was treated with water (15.7 kg), and the
mixture was cooled to 20 °C. The aqueous layer was removed
and the toluene layer was concentrated to ∼15 L. The solution
was used directly in the next stage. Analytical data on a
concentrated sample: 1H NMR (400 MHz, CDCl3) δ 7.43 (d,
J ) 4 Hz, 1H), 7.36 (d, J ) 8 Hz, 1H), 7.18 (dd, J ) 8, 4 Hz,
1H), 3.31 (d, J ) 12 Hz, 1H), 3.13 (s, 3H), 3.09 (d, J ) 12 Hz,
1H), 2.95 (d, J ) 8 Hz, 1H), 2.83 (d, J ) 8 Hz, 1H), 2.76
(m, 1H), 2.68 (m, 1H), 1.95 (m, 1H), 1.82 (m, 1H), 1.03 (d, J
(s), 1071 (s), 959 (s), 831 (m), 678 (m); [R]25D ) -25.8 (c )
0.970, H2O); HRMS m/z 286.0754 [(M+); calcd for
C14H18Cl2NO: 286.0760]; mp )210 °C.
GSK1360707 L-tartrate. (1S,6R)-6-(3,4-Dichlorophenyl)-
1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane (3.7 g, 12.9
mmol) was dissolved in 2-propanol (60 mL), to the solution
was added L-(+)-tartaric acid (2.7 g, 18.1 mmol, 1.4 equiv)
and the solution was heated to 80 °C. Water (12 mL) was added
and the solution stirred for 10 min. The resulting solution was
cooled to 0 °C at a rate of 0.2 °C/min, and then held at 0 °C
for 7 h. The resulting slurry was filtered and washed with
2-propanol (2 × 10 mL). The solid then dried under vacuum
for 5 h at 50 °C to give GSK1360707 L-tartrate of an off-white
1
solid (3.7 g, 65% yield). H NMR (400 MHz, DMSO-d6) δ
7.68 (d, J ) 2.01 Hz, 1 H), 7.60-7.56 (m, 1 H), 7.39-7.33
(m, 1 H), 3.85 (s, 2 H), 3.43 (d, J ) 13.55 Hz, 1 H), 3.11 (d,
J ) 13.19 Hz, 1 H), 3.04 (s, 4 H), 2.90-2.83 (m, 1 H),
2.79-2.67 (m, 2 H), 2.03 (t, J ) 5.26 Hz, 2 H), 1.22 (s, 2 H);
13C NMR (125.7 MHz, DMSO-d6) δ 174.7, 143.7, 131.3, 130.7,
130.3, 129.6, 129.2, 76.2, 71.8, 57.9, 43.7, 38.4, 29, 27.1, 22.4,
18.9; IR (ATR) 3434 (m), 3338 (m), 3034 (m), 2977 (m), 2876
(m), 2671 (w), 1657 (s), 1606 (s), 1563 (w), 1471 (s), 1394
(s), 1133 (s), 823 (m), 679 (s) cm-1; mp ) 193 °C.
) 8 Hz, 1H), 1.00 (d, J ) 8 Hz, 1H); [R]25 ) -5.7 (c )
D
0.07, CCl4).
(-)-GSK1360707 Phosphate. (1S,6R)-6-(3,4-Dichlorophe-
nyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane (5.81
kg, 20.3 mol, based on 100% yield in the previous step) was
dissolved in 1-propanol (31.5 kg), and the solution was heated
to 70 °C. Phosphoric acid (∼85.5 wt %, 2.33 kg, 1 equivalent,
20.3 mol) was added over ∼20 min. The resulting slurry was
cooled to 20 °C over 60 min and stirred for 30 min. The slurry
was cooled to 0 °C over 20 min, stirred for ∼60 min, filtered,
and washed with 1-propanol (6.3 kg). The solid was dried at
50 °C under vacuum for 18 h to give 6.4 kg of (-)-
GSK1360707 phosphate as a white solid (82% yield). 1H NMR
(500.0 MHz, D2O) δ 7.43 (d, J ) 2 Hz, 1H), 7.36 (d, J ) 8.3
Hz, 1H), 7.18 (dd, J ) 8.4, 2.2 Hz, 1H), 3.58 (d, J ) 13.7 Hz,
1H), 3.20 (d, J ) 13.9 Hz, 1H), 3.22-3.16 (m, 1H), 3.01 (s,
3H), 3.01 (d, J ) 9.7 Hz, 1H), 2.82-2.76 (m, 1H), 2.72 (d, J
) 10.4 Hz, 1H), 2.13-2.11 (m, 2H), 1.27 (d, J ) 6.4 Hz, 1H),
1.13 (d, J ) 6.2 Hz, 1H); 13C NMR (125.7 MHz, D2O) δ 142,
131.6, 131.1, 130.41, 130.37, 129, 76.4, 58.1, 44.7, 39.2, 28.4,
27.7, 21.9, 19.4; IR (ATR) 3059 (w), 2977 (m), 2942 (m), 2890
(m), 2649 (b), 1634 (m), 1591 (w), 1555 (w), 1456 (m), 1095
Acknowledgment
We thank D. Andreotti, S. Spada, and F. Micheli for useful
discussions regarding the initial synthetic route to GSK1360707.
We are also grateful to J. Grimes, D. Black, and M. Saulter for
analytical support, and to W. Clegg and L. Russo for the X-ray
structure of GSK1360707 L-tartrate.
Supporting Information Available
1H- and 13C NMR spectra for compounds 4a, 12, and (-)-
GSK1360707 phosphate; X-ray crystal structure of GSK1360707
L-tartrate.This material is available free of charge via the Internet
at http://pubs.acs.org.
Received for review May 19, 2010.
OP100139F
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